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Cun Zhang,1,* Lei Jiang,2,3,* Ke Hu,2,* Liang Chen,2 Yi-Jia Zhang,2 Hao-Zhe Shi,2 Su-Mei He,4 Xiao Chen,5 Dong-Dong Wang2 1Department of Pharmacy, Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Department of Pharmacy, Taixing People’s Hospital, Taixing, Jiangsu, 225400, People’s Republic of China; 4Department of Pharmacy, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu, 215153, People’s Republic of China; 5School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Su-Mei He, Department of Pharmacy, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 1 Lijiang Road, Suzhou, Jiangsu, 215153, People’s Republic of China, Email hehe8204@163.com Dong-Dong Wang, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, Jiangsu, 221004, People’s Republic of China, Email 13852029591@163.comObjective: Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug–drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients.Methods: In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM).Results: Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40– 70, and 70– 100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40– 60, and 60– 100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40– 53, and 53– 100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40– 100 kg schizophrenia patients, respectively.Conclusion: Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients.Keywords: aripiprazole, olanzapine, population pharmacokinetics, initial dosage optimization, schizophrenia patients

Jin-Ping Li,1,2 Yin-Xue Yang,3 Qi-Lun Liu,1 Zhi-Wei Zhou,2,4 Shu-Ting Pan,2,5 Zhi-Xu He,4 Xueji Zhang,6 Tianxin Yang,7 Si-Yuan Pan,8 Wei Duan,9 Shu-Ming He,10 Xiao-Wu Chen,11 Jia-Xuan Qiu,5 Shu-Feng Zhou2,41Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 4Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China; 5Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 6Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China; 7Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA; 8Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 9School of Medicine, Deakin University, Waurn Ponds, VIC, Australia; 10Department of Obstetrics and Gynecology, Xiaolan People’s Hospital affiliated to Southern Medical University, Zhongshan, Guangdong, People’s Republic of China; 11Department of General Surgery, The First People’s Hospital of Shunde affiliated to Southern Medical University, Shunde, Foshan, Guangdong, People’s Republic of China Abstract: Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and ß-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy. Keywords: Danusertib, breast cancer, cell cycle, apoptosis, autophagy, EMT

Although the intervertebral discs are the most studied region of the spinal motion segment with respect to their degeneration and contributions to back pain, it is becoming increasingly evident that degeneration of adjacent structures including the facet joints, vertebral endplates and paraspinal muscles occurs concomitant with disc degeneration. However, crosstalk between these adjacent components of the motion segment remains understudied, particularly in preclinical large animal models. In this study, intervertebral disc degeneration was induced in goat cervical discs via intradiscal injection of 2U or 5U of chondroitinase ABC (ChABC). Disc degeneration and trans-endplate small molecule diffusion into the disc were assessed at 12 weeks using in vivo MRI T2 mapping and post-contrast enhanced T1 mapping. Animals were euthanized at 12 weeks post-ChABC injection for end-term structure-function analysis of the disc, vertebral endplate and facet tissues. Intradiscal injection of ChABC yielded a spectrum of disc degeneration independent of ChABC dosage. Increasing severity of disc degeneration correlated with increased vertebral endplate bone density. In levels that did not exhibit severe degeneration or endplate resorptions, we demonstrated a significant correlation between NP T2 values and disc diffusion properties. Early-stage osteoarthritis of the facet joints was observed concomitant with disc degeneration, characterized primarily by alterations in facet cartilage mechanical properties. This work established a large animal model of whole spinal motion segment degeneration, including correlations between trans-endplate diffusion and disc health, which can be utilized to increase the translational relevance of studies evaluating strategies for disc regeneration or repair.

Back and neck pain have become primary reasons for disability and healthcare spending globally. While the causes of back pain are multifactorial, intervertebral disc degeneration is frequently cited as a primary source of pain. The annulus fibrosus (AF) and nucleus pulposus (NP) subcomponents of the disc are common targets for regenerative therapeutics. However, disc degeneration is also associated with degenerative changes to adjacent spinal tissues, and successful regenerative therapies will likely need to consider and address the pathology of adjacent spinal structures beyond solely the disc subcomponents. This review summarises the current state of knowledge in the field regarding associations between back pain, disc degeneration, and degeneration of the cartilaginous and bony endplates, the AF-vertebral body interface, the facet joints and spinal muscles, in addition to a discussion of regenerative strategies for treating pain and degeneration from a whole motion segment perspective.

Purpose: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method., Methods: The E max model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with E max model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4-10 ng/ml., Results: In machine learning model, the E max from tacrolimus effecting proteinuria in IMN patients was -72.7%, the ET 50 was 0.43 months, and the time to achieving 25% E max , 50% E max , 75% E max , and 80% (plateau) E max of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively., Conclusion: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4-10 ng/ml for at least 1.72 months., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: Olanzapine is used for treating bipolar disorder (BPD); however, the optimal initial dosing regimen is unclear. The present study aimed to investigate the optimal olanzapine initial dosage in patients with BPD via model-informed precision dosing (MIPD) based on a real-world study., Methods: Thirty-nine patients with BPD from the real-world study were collected to construct the MIPD model., Results: Weight, combined used quetiapine influenced olanzapine clearances in patients with BPD, where the clearance rates were 0.152:1 in patients with or without quetiapine under the same weight. We simulated olanzapine doses once a day or twice a day, of which twice a day was optimal. Without quetiapine, for twice-a-day olanzapine doses, 0.80, 0.70, and 0.60 mg/kg/day were suitable for 40- to 56-kg BPD patients, 56- to 74-kg BPD patients, and 74- to 100-kg BPD patients, respectively. With quetiapine, for twice-a-day olanzapine doses, 0.05 mg/kg/day was suitable for 40- to 100-kg BPD patients., Conclusion: This study was the first to investigate the optimal olanzapine initial dosage in patients with BPD via MIPD based on a real-world study, providing clinical reference for the precision medication of olanzapine in BPD patients., 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 Chen, Hu, Shi, Chen, Zhang, He, Zhang and Wang.)

Objective: The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model., Methods: The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit., Results: For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively., Conclusion: The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

An ammonium ylide-based relay annulation was disclosed, which uses DABCO as the catalyst and oxindole-derived α,β-unsaturated ketimines and γ-bromo-crotonates as the starting materials. This method enables the rapid assembly of a series of structurally novel spiro-polycyclic oxindoles containing a bicyclo[4.1.0]heptane moiety through simultaneous generation of three new bonds and two rings in one step under mild reaction conditions.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics., Research Design and Methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects., Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg -1 day -1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg -1 day -1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg -1 day -1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg -1 day -1 were recommended for those weighing 40-60 and 60-120 kg, respectively., Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia., 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 Zhang, Jiang, Hu, Zhang, Han, Chen, Bulubu, Dong, Shi, He, Yu, Chen and Wang.)

Recently a dark matter-electron (DM-electron) paradigm has drawn much attention. Models beyond the standard halo model describing DM accelerated by high energy celestial bodies are under intense examination as well. In this Letter, a velocity components analysis (VCA) method dedicated to swift analysis of accelerated DM-electron interactions via semiconductor detectors is proposed and the first HPGe detector-based accelerated DM-electron analysis is realized. Utilizing the method, the first germanium based constraint on sub-GeV solar reflected DM-electron interaction is presented with the 205.4  kg·day dataset from the CDEX-10 experiment. In the heavy mediator scenario, our result excels in the mass range of 5-15  keV/c^{2}, achieving a 3 orders of magnitude improvement comparing with previous semiconductor experiments. In the light mediator scenario, the strongest laboratory constraint for DM lighter than 0.1  MeV/c^{2} is presented. The result proves the feasibility and demonstrates the vast potential of the VCA technique in future accelerated DM-electron analyses with semiconductor detectors.

The recent emergence of Janus 2D materials like SnSSe, derived from SnS 2 , reveals unique electrical and optical features, such as asymmetrical electronic structure, enhanced carrier mobility, and tunable bandgap. Previous theoretical studies have discuss the electronic properties of Janus SnSSe, but experimental evidence is limited. This study presents a two-step method for synthesizing Janus SnSSe, involving hydrogen plasma treatment and in situ selenization. Optimized conditions (38 W, 1.5 min, 250 °C) are determined using Raman spectroscopy and AFM analysis. XPS confirmed SnSSe's elemental composition, while KPFM reveals a significant reduction in the work function (from 5.26 down to 5.14 eV) for the first time, indicating asymmetrically induced n-type doping. Finally, field-effect transistors (FETs) derived from SnSSe exhibited significantly enhanced mobility and on-current, as well as n-type doping, compared to SnS 2 -based FETs. These findings lay a crucial foundation for developing high-performance 2D electronic and optoelectronic devices., (© 2024 Wiley‐VCH GmbH.)

The exploitation of new reactive species and novel transformation modes for their synthetic applications have significantly promoted the development of synthetic organic methodology, drug discovery, and advanced functional materials. α-Iminyl radical cations, a class of distonic ions, exhibit great synthetic potential for the synthesis of valuable molecules. For their generation, radical conjugate addition to α,β-unsaturated iminium ions represents a concise yet highly challenging route, because the in situ generated species are short-lived and highly reactive and they have a high tendency to cause radical elimination (β-scission) to regenerate the more stable iminium ions. Herein, we report a new transformation mode of the α-iminyl radical cation, that is to say, 1,5-hydrogen atom transfer (1,5-HAT). Such a strategy can generate a species bearing multiple reactive sites, which serves as a platform to realize (asymmetric) relay annulations. The present iron/secondary amine synergistic catalysis causes a modular assembly of a broad spectrum of new structurally fused pyridines including axially chiral heterobiaryls, and exhibits good functional group tolerance. A series of mechanistic experiments support the α-iminyl radical cation-induced 1,5-HAT, and the formation of several radical species in the relay annulations. Various synthetic transformations of the reaction products demonstrate the usefulness of this relay annulation protocol for the synthesis of significant molecules., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The inherent flammability of most polymeric materials poses a significant fire hazard, leading to substantial property damage and loss of life. A universal flame-retardant protective coating is considered as a promising strategy to mitigate such risks; however, simultaneously achieving high transparency of the coatings remains a great challenge. Here, inspired by the moth eye effect, we designed a nanoporous structure into a protective coating that leverages a hydrophilic-hydrophobic interactive assembly facilitated by phosphoric acid protonated amino siloxane. The coating demonstrates robust adhesion to a diverse range of substrates, including but not limited to fabrics, foams, paper, and wood. As expected, its moth-eye-inspired nanoporous structure conferred a high visible light transparency of >97% and water vapor transmittance of 96%. The synergistic effect among phosphorus (P), nitrogen (N), and silicon (Si) largely enhanced the char-forming ability and restricted the decomposition of the coated substrates, which successfully endowed the coating with high fire-fighting performance. More importantly, for both flexible and rigid substrates, the coated samples all possessed great mechanical properties. This work provides a new insight for the design of protective coatings, particularly focusing on achieving high transparency.

Main Conclusion: A stable genetic transformation system for Erigeron breviscapus was developed. We cloned the EbYUC2 gene and genetically transformed it into Arabidopsis thaliana and E. breviscapus. The leaf number, YUC2 gene expression, and the endogenous auxin content in transgenic plants were significantly increased. Erigeron breviscapus is a prescription drug for the clinical treatment of cardiovascular and cerebrovascular diseases. The rosette leaves have the highest content of the major active compound scutellarin and are an important component in the yield of E. breviscapus. However, little is known about the genes related to the leaf number and flowering time of E. breviscapus. In our previous study, we identified three candidate genes related to the leaf number and flowering of E. breviscapus by combining resequencing data and genome-wide association study (GWAS). However, their specific functions remain to be characterized. In this study, we cloned and transformed the previously identified full-length EbYUC2 gene into Arabidopsis thaliana, developed the first stable genetic transformation system for E. breviscapus, and obtained the transgenic plants overexpressing EbYUC2. Compared with wild-type plants, the transgenic plants showed a significant increase in the number of leaves, which was correlated with the increased expression of EbYUC2. Consistently, the endogenous auxin content, particularly indole-3-acetic acid, in transgenic plants was also significantly increased. These results suggest that EbYUC2 may control the leaf number by regulating auxin biosynthesis, thereby laying a foundation for revealing the molecular mechanism governing the leaf number and flowering time of E. breviscapus., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The dose-dependent pharmacological response to dapagliflozin in patients with type 2 diabetes mellitus (T2DM) with regard to weight loss remain unknown. The aim of the present study was to investigate the effects of dapagliflozin on weight loss in patients with T2DM. A total of 8,545 patients with T2DM from 24 randomized controlled trials reported in the literature were selected for inclusion in the study. Data from these trials were analyzed using maximal effect (E max ) models with nonlinear mixed effects modeling; the evaluation index was the body weight change rate from baseline values. Patients treated with 2.5 mg/day dapagliflozin exhibited an E max of -3.04%, and the time taken for therapy to reach half of the E max (ET 50 ) was estimated to be 30.8 weeks for patients treated with this dose. Patients treated with 5, 10 and 20 mg/day dapagliflozin exhibited E max values of -6.57, -4.12 and -3.23%, respectively, and their ET 50 values were estimated to be 27.3, 20.4 and 4.23 weeks, respectively. The data indicated ideal linear relationships between individual predictions and observations, suggesting the optimal fitting of the final models. The present study is the first systematic analysis of the effect of dapagliflozin on weight loss in patients with T2DM. The application of dapagliflozin at 5 mg/day exhibited a greater weight loss effect compared with the other doses used, and the weight loss onset time shortened as the dose of dapagliflozin increased., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Han et al.)

A metal-free three-component protocol that combines a hydroxylamine-Passerini reaction and hetero-Cope rearrangement was realized, which enables the modular assembly of a wide range of structurally new and interesting 2-aminoanilines bearing an α-hydroxyamide substructure.

Background: The treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1β/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB., Purpose: The aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus., Methods: Wistar rats were randomly divided normal control (NC) group, PTDM group, sirolimus intervention (SIR) group. Transcriptomic analysis was used to screen potential mechanism of PTDM. Biochemical index detections were used to test the indicators of pancreatic injury. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot were used to verify the underlying mechanism., Results: Compared with NC group, the level of insulin was significant reduction (P < 0.01), inversely the level of glucagon was significantly increase (P < 0.01) in PTDM group. Transcriptomic analysis indicated Syk/BLNK/NF-κB signaling was significantly up-regulated in PTDM group. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot verified Syk/BLNK/NF-κB and TNF-α/IL-1β were all significantly increased (P < 0.05 or P < 0.01), demonstrating the mechanism of tacrolimus-induced pancreatic injury via Syk/BLNK/NF-κB signaling. In addition, compared with PTDM group, the levels of weight, FPG, AMY, and GSP in SIR group were significant ameliorative (P < 0.05 or P < 0.01), and the expressions of p-NF-κB, TNF-α/IL-1β in SIR group were significantly reduction (P < 0.05 or P < 0.01), showing Syk/BLNK/NF-κB signaling promoted pancreatic injury induced by tacrolimus and potential protective effect from rapamycin reducing NF-κB., Conclusion: Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and rapamycin has a potentially protective effect by down-regulating NF-κB. Further validation and clinical studies are needed in the future., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The appropriate initial dosage of tacrolimus is undefined in Chinese pediatric lung transplant patients with normal hematocrit values. The purpose of this study is to optimize the initial dose of tacrolimus in Chinese children who are undergoing lung transplantation and have normal hematocrit levels., Methods: The present study is based on a published population pharmacokinetic model of tacrolimus in lung transplant patients and uses the Monte Carlo simulation to optimize the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels., Results: Within normal hematocrit levels, for children with lung transplantation who do not carry the CYP3A5*1 gene and have no coadministration with voriconazole, it is recommended to administer tacrolimus at a dosage of 0.02 mg/kg/day, divided into two doses, for children weighing 10-32 kg, and a dosage of 0.03 mg/kg/day, also divided into two doses, for children weighing 32-40 kg. For children with lung transplantation who carry the CYP3A5*1 gene and have no coadministration with voriconazole, tacrolimus dosages of 0.02, 0.03, and 0.04 mg/kg/day split into two doses are recommended for children weighing 10-15, 15-32, and 32-40 kg, respectively. For children with lung transplantation who do not carry the CYP3A5*1 gene and have coadministration with voriconazole, tacrolimus dosages of 0.01 and 0.02 mg/kg/day split into two doses are recommended for children weighing 10-17 and 17-40 kg, respectively. For children with lung transplantation who carry the CYP3A5*1 gene and have coadministration with voriconazole, a tacrolimus dosage of 0.02 mg/kg/day split into two doses is recommended for children weighing 10-40 kg., Conclusions: It is the first time to optimize the initial dosage of tacrolimus in Chinese children undergoing lung transplantation within normal hematocrit., 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., (© 2024 Hu, He, Zhang, Zhang, Gu, Shi and Wang.)

Main Conclusion: The oxidosqualene cyclases (OSCs) generating triterpenoid skeletons in Cyclocarya paliurus were identified for the first time, and two uridine diphosphate (UDP)-glycosyltransferases (UGTs) catalyzing the glycosylation of flavonoids were characterized. Cyclocarya paliurus, a native rare dicotyledonous plant in China, contains an abundance of triterpenoid saponins and flavonoid glycosides that exhibit valuable pharmaceutical effects in preventing hypertension, hyperlipidemia, and diabetes. However, the molecular mechanism explaining the biosynthesis of triterpenoid saponin and flavonoid glycoside in C. paliurus remains unclear. In this study, the triterpene content in different tissues and the expression pattern of genes encoding the key enzymes associated with triterpenoid saponin and flavonoid glycoside biosynthesis were studied using transcriptome and metabolome analysis. The eight upstream oxidosqualene cyclases (OSCs) involved in triterpenoid saponin biosynthesis were functionally characterized, among them CpalOSC6 catalyzed 2,3;22,23-dioxidosqualene to form 3-epicabraleadiol; CpalOSC8 cyclized 2,3-oxidosqualene to generate dammarenediol-II; CpalOSC2 and CpalOSC3 produced β-amyrin and CpalOSC4 produced cycloartenol, while CpalOSC2-CpalOSC5, CpalOSC7, and CpalOSC8 all produced lanosterol. However, no catalytic product was detected for CpalOSC1. Moreover, two downstream flavonoid uridine diphosphate (UDP)-glycosyltransferases (UGTs) (CpalUGT015 and CpalUGT100) that catalyze the last step of flavonoid glycoside biosynthesis were functionally elucidated. These results uncovered the key genes involved in the biosynthesis of triterpenoid saponins and flavonoid glycosides in C. paliurus that could be applied to produce flavonoid glycosides and key triterpenoid saponins in the future via a synthetic strategy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Clostridioides difficile is the leading cause of antibiotic-associated infectious diarrhea. The development of C.difficile infection is tied to perturbations of the bacterial community in the gastrointestinal tract, called the gastrointestinal microbiota. Repairing the gastrointestinal microbiota by introducing lab-designed bacterial communities, or defined microbial communities, has recently shown promise as therapeutics against C.difficile infection, however, the mechanisms of action of defined microbial communities remain unclear. Using an antibiotic- C.difficile mouse model, we report the ability of an 18-member community and a refined 4-member community to protect mice from two ribotypes of C.difficile (CD027, CD078; p < 0.05). Furthermore, bacteria-free supernatant delivered orally to mice from the 4-member community proteolyzed C.difficile toxins in vitro and protected mice from C.difficile infection in vivo (p < 0.05). This study demonstrates that bacteria-free supernatant is sufficient to protect mice from C.difficile; and could be further explored as a therapeutic strategy against C.difficile infection., (© 2024. The Author(s).)

Background: Delayed or missed dosages caused by poor medication compliance significantly affected the treatment of diseases in children., Aims: The present study aimed to investigate the influence of delayed or missed dosages on sirolimus pharmacokinetics (PK) in pediatric tuberous sclerosis complex (TSC) patients and to recommend remedial dosages for nonadherent patients., Methods: A published sirolimus population PK model in pediatric TSC patients was used to assess the influence of different nonadherence scenarios and recommend optimally remedial dosages based on Monte Carlo simulation. Thirteen nonadherent scenarios were simulated in this study, including delayed 2h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 23.5 h, and missed one dosage. Remedial dosing strategies contained 10-200% of scheduled dosages. The optimal remedial dosage was that with the maximum probability of returning the individual therapeutic range., Results: For delayed or missed sirolimus dosages in pediatric TSC patients, when the delayed time was 0-8 h, 8-10 h, 10-18 h, 18-22.7 h, 22.7-24 h, 70%, 60%, 40%, 30%, 20% scheduled dosages were recommended to take immediately. When one dosage was missed, 120% of scheduled dosages were recommended at the next dose., Conclusion: It was the first time to recommend remedial dosages for delayed or missed sirolimus therapy caused by poor medication compliance in pediatric TSC patients based on Monte Carlo simulation. Meanwhile, the present study provided a potential solution for delayed or missed dosages in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration., Methods: Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen., Results: In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively., Conclusion: The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Due to the narrow therapeutic window and large pharmacokinetic variation of valproic acid (VPA), it is difficult to make an optimal dosage regimen. The present study aims to optimize the initial dosage of VPA in patients with bipolar disorder., Methods: A total of 126 patients with bipolar disorder treated by VPA were included to construct the VPA population pharmacokinetic model retrospectively. Sex differences and combined use of clozapine were found to significantly affect VPA clearance in patients with bipolar disorder. The initial dosage of VPA was further optimized in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively., Results: The CL/F and V/F of VPA in patients with bipolar disorder were 11.3 L/h and 36.4 L, respectively. It was found that sex differences and combined use of clozapine significantly affected VPA clearance in patients with bipolar disorder. At the same weight, the VPA clearance rates were 1.134, 1, 1.276884, and 1.126 in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. This study further optimized the initial dosage of VPA in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively., Conclusion: This study is the first to investigate the initial dosage optimization of VPA in patients with bipolar disorder based on sex differences and the combined use of clozapine. Male patients had higher clearance, and the recommended initial dose decreased with increasing weight, providing a reference for the precision drug use of VPA in clinical patients with bipolar disorder., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Myocardial ischemia-reperfusion (MI/R) can exacerbate the initial cardiac damage in the myocardial functional changes, including dysfunction of left ventricular contractility. Oestrogen has been proven to protect the cardiovascular system. However, whether the oestrogen or its metabolites play the main role in attenuating dysfunction of left ventricular contractility is unknown., Methods and Results: This study used the LC-MS/MS to detect oestrogen and its metabolites in clinical serum samples (n = 62) with heart diseases. After correlation analysis with markers of myocardial injury including cTnI (P < 0.01), CK-MB (P < 0.05), and D-Dimer (P < 0.001), 16α-OHE1 was identified. The result from LC-MS/MS in female and ovariectomised (OVX) rat serum samples (n = 5) matched the findings in patients. In MI/R model of animal, the recovery of left ventricular developed pressure (LVDP), rate pressure product (RPP), dp/dt max and dp/dt min after MI/R in OVX or male group were worsened than those in female group. Also, the infarction area of OVX or male group was larger than that in females (n = 5, p < 0.01). Furthermore, LC3 II in the left ventricle of OVX and male group was lower than that in females (n = 5, p < 0.01) by immunofluorescence. In H9C2 cells, after the application of 16α-OHE1, the number of autophagosomes was further increased and other organelles improved in MI/R. Simultaneously, LC3 II, Beclin1, ATG5, and p-AMPK/AMPK were increased, and p-mTOR/mTOR was decreased (n = 3, p < 0.01) by Simple Western., Conclusion: 16α-OHE1 could attenuate left ventricle contractility dysfunction via autophagy regulation after MI/R, which also offered fresh perspectives on therapeutical treatment for attenuating MI/R injury., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest ., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The present study aimed to explore the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on liver functions in patients with nonalcoholic fatty liver disease (NAFLD)., Research Design and Methods: A total of 4771 patients with NAFLD were included for analysis by means of nonlinear mixed effect modeling, where the change rates of liver functions were taken as the evaluation indexes so as to eliminate the potential baseline effects., Results: For ALT and AST, the E max of SGLT-2 inhibitors was -17.8% and -13.9%, respectively, and the ET 50 was 6.86 weeks and 10 weeks, respectively. Furthermore, the duration time to achieve 25%, 50%, 75%, and 80% E max were 2.3 weeks, 6.86 weeks, 20.6 weeks, 27.5 weeks in ALT, 3.4 weeks, 10 weeks, 30 weeks, 40 weeks in AST, respectively. Thus, to realize the plateau period (80% of E max ) of SGLT-2 inhibitors on ALT and AST in patients with NAFLD, 100 mg/day canagliflozin (or 10 mg/day dapagliflozin or 10 mg/day empagliflozin) needs to be taken for 20.6 weeks and 30 weeks, respectively., Conclusions: The present study explored the quantitative effects of SGLT-2 inhibitors on liver functions and recommends a therapeutic regimen in patients with NAFLD.

There has been a long-standing debate about the mechanism of the unusual superconductivity in alkali-intercalated fullerides. In this Letter, using high-resolution angle-resolved photoemission spectroscopy, we systematically investigate the electronic structures of superconducting K&#95;{3}C&#95;{60} thin films. We observe a dispersive energy band crossing the Fermi level with the occupied bandwidth of about 130 meV. The measured band structure shows prominent quasiparticle kinks and a replica band involving the Jahn-Teller active phonon modes, which reflects strong electron-phonon coupling in the system. The electron-phonon coupling constant is estimated to be about 1.2, which dominates the quasiparticle mass renormalization. Moreover, we observe an isotropic nodeless superconducting gap beyond the mean-field estimation (2Δ/k&#95;{B}T&#95;{c}≈5). Both the large electron-phonon coupling constant and large reduced superconducting gap suggest a strong-coupling superconductivity in K&#95;{3}C&#95;{60}, while the electronic correlation effect is suggested by the observation of a waterfall-like band dispersion and the small bandwidth compared with the effective Coulomb interaction. Our results not only directly visualize the crucial band structure but also provide important insights into the mechanism of the unusual superconductivity of fulleride compounds.

Background: Facilitating the recurrence of spontaneous voiding is considered to be a way to prevent urinary retention after surgery, which is of great importance in cholecystectomy. This study aimed to assess the effect of transcutaneous electrical acupoint stimulation (TEAS) on spontaneous voiding recovery after laparoscopic cholecystectom., Methods: Participants who underwent elective laparoscopic cholecystectomy were randomly assigned to either the TEAS group or the sham group. Active TEAS or sham TEAS at specific acupuncture points was conducted intraoperatively and postoperatively. The primary outcome was the recovery speed of spontaneous voiding ability after surgery and secondary outcomes included postoperative urinary retention (POUR), voiding dysfunction, pain, anxiety and depression, and early recovery after surgery., Results: A total of 1,948 participants were recruited and randomized to TEAS (n = 975) or sham (n = 973) between August 2018 and June 2020. TEAS shortens the time delay of the first spontaneous voiding after laparoscopic cholecystectomy (5.6 h [IQR, 3.7-8.1 h] in the TEAS group vs 7.0 h [IQR, 4.7-9.7 h] in the sham group) (p < 0.001). The TEAS group experienced less POUR (p = 0.020), less voiding difficulty (p < 0.001), less anxiety and depression (p < 0.001), reduced pain (p = 0.007), and earlier ambulation (p = 0.01) than the sham group., Conclusions: Our results showed that TEAS is an effective approach to accelerate the recovery of spontaneous voiding and reduce POUR which facilitates recovery for patients after laparoscopic cholecystectomy., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Objective: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy., Methods: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3∼AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed., Results: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3∼AE displayed highly potent cytotoxicity to cancer cells with IC 50 at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3∼AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-β in athymic mice., Conclusion: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2022. Published by Elsevier B.V.)

Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AE max ) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AE max , the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AE max ) and -3.27% (52% AE max ), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices., 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 © 2023 Wang, Zhang, Hu, He, Zhu and Chen.)

Objectives: Cyclosporin is one of the therapeutic regimens for hemophagocytic lymphohistiocytosis (HLH); however, the optimal dosage of cyclosporine in children with HLH is unknown. It has been found that piperacillin-tazobactam affects the cyclosporine pharmacokinetic process in pediatric HLH patients. Thus, the purpose of the present study was to recommend cyclosporin dosage for pediatric HLH with and without piperacillin- tazobactam., Methods: A previously established cyclosporine population pharmacokinetic model for pediatric HLH patients has been used in this study to recommend optimal dosage based on Monte Carlo simulation. The pediatric HLH patients have been included in eight weight groups (5, 10, 20, 30, 40, 50, 60, 70 kg) for sixteen dosages (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 mg/kg), split into one dose or two doses., Results: The optimal cyclosporin dosages for children having HLH without piperacillin-tazobactam have been found to be 15, 13, 12, 11, 10, and 9 mg/kg, split into two doses for weights of 5-7, 7-10, 10-20, 20-28, 28-45, and 45-70 kg, respectively. For children with HLH, optimal cyclosporin dosages with piperacillin-tazobactam have been found to be 8 and 7 mg/kg, split into two doses for weights of 5-20 and 20-70 kg, respectively., Conclusion: It is the first time that the cyclosporin dosage regimens for HLH in children have been developed based on Monte Carlo simulation, and the initial dosage optimizations of cyclosporine in pediatric HLH patients have been recommended., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The aim of the present study is to investigate the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the quality of life in heart failure (HF) patients. A total of 14,674 HF patients from two dapagliflozin and three empagliflozin studies is included for analysis via the nonlinear mixed-effect modeling (NONMEM) software, among which the change rate of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score is used as the evaluation index. There is no significant difference in the pharmacodynamics influencing the quality of life in HF patients between the SGLT-2 inhibitors: 10 mg/day dapagliflozin and 10 mg/day empagliflozin. For the clinical summary score (CSS), total symptom score (TSS), and overall summary score (OSS), the E max of the SGLT-2 inhibitors on the quality of life in HF patients is 3.74%, 4.43%, and 4.84%, respectively, and ET 50 is 2.23, 4.37, and 7.15 weeks, respectively. In addition, the time duration of achieving 25%, 50%, 75%, and 80% E max is 0.75, 2.23, 6.69, and 8.92 weeks for the CSS; 1.46, 4.37, 13.11, and 17.48 weeks for the TSS; and 2.39, 7.15, 21.45, and 28.6 weeks for the OSS, respectively. Therefore, to reach the plateau period (80% of E max ) of SGLT-2 inhibitors on the CSS, TSS, and OSS, 10 mg/day dapagliflozin (or 10 mg/day empagliflozin) is required to be taken for 8.92 weeks, 17.48 weeks, and 28.6 weeks, respectively. This is the first time that the quantitative effects of SGLT-2 inhibitors on the quality of life in HF patients are being explored., 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 © 2022 Wang, Zhang, Zhu, He and Chen.)

In the presence of CuOAc, a series of unsymmetric ureas can be generated in moderate to good yields under mild reaction conditions (10 mol% of CuOAc, 2 equiv t -BuONa or PhONa, 30 °C), using aryl isocyanides and O -benzoyl hydroxylamines as the readily accessible starting materials. The reactions might undergo a cascade process involving isocyanide insertion into the N-O bond and Mumm-type rearrangement. This work represents a rare example of isocyanide insertion into N-O bonds, which would extend isocyanide insertion chemistry.

A search for exotic dark matter (DM) in the sub-GeV mass range has been conducted using 205 kg day data taken from a p-type point contact germanium detector of the CDEX-10 experiment at China's Jinping underground laboratory. New low-mass dark matter searching channels, neutral current fermionic DM absorption (χ+A→ν+A) and DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), have been analyzed with an energy threshold of 160 eVee. No significant signal was found; thus new limits on the DM-nucleon interaction cross section are set for both models at the sub-GeV DM mass region. A cross section limit for the fermionic DM absorption is set to be 2.5×10^{-46}  cm^{2} (90% C.L.) at DM mass of 10  MeV/c^{2}. For the DM-nucleus 3→2 scattering scenario, limits are extended to DM mass of 5 and 14  MeV/c^{2} for the massless dark photon and bound DM final state, respectively.

We present improved germanium-based constraints on sub-GeV dark matter via dark matter-electron (χ-e) scattering using the 205.4  kg·day dataset from the CDEX-10 experiment. Using a novel calculation technique, we attain predicted χ-e scattering spectra observable in high-purity germanium detectors. In the heavy mediator scenario, our results achieve 3 orders of magnitude of improvement for m&#95;{χ} larger than 80  MeV/c^{2} compared to previous germanium-based χ-e results. We also present the most stringent χ-e cross-section limit to date among experiments using solid-state detectors for m&#95;{χ} larger than 90  MeV/c^{2} with heavy mediators and m&#95;{χ} larger than 100  MeV/c^{2} with electric dipole coupling. The result proves the feasibility and demonstrates the vast potential of a new χ-e detection method with high-purity germanium detectors in ultralow radioactive background.

What Is Known and Objectives: The present study aimed to predict the effect of sirolimus on disease activity in patients with systemic lupus erythematosus (SLE) using machine learning and to recommend appropriate sirolimus dosage regimen for patients with SLE., Methods: The E max model was selected for machine learning, where the evaluation indicator was the change rate of systemic lupus erythematosus disease activity index from baseline value., Results: A total 103 patients with SLE were included for modelling, where the E max , ET 50 were -53.9%, 1.53 months in the final model respectively, and the evaluation of the final model was good. Further simulation found that the follow-up time to achieve 25%, 50%, 75% and 80% (plateau) E max of sirolimus effecting on disease activity in patients with SLE were 0.51, 1.53, 4.59 and 6.12 months, respectively. In addition, the sirolimus dosage was flexible and adjusted according to drug concentration, where the intersection of sirolimus concentration range included in this study was about 8-10 ng/ml., What Is New and Conclusions: This study was the first time to predict the effect of sirolimus on disease activity in patients with SLE and in order to achieve better therapeutic effect maintaining a concentration of 8-10 ng/ml sirolimus for at least 6.12 months was necessary., (© 2022 John Wiley & Sons Ltd.)

A variety of devices used in daily life and biomedical field will generate magnetic fields with different parameters, raising concern about their influences on people's physiological functions. Multiple experimental works have been devoted to the influences of magnetic fields on circadian rhythms, yet the findings were not always consistent due to the differences in magnetic field parameters and experimental organisms. Also, clear regulatory mechanisms have not been found. By systematizing the major achievements in research on magnetic and circadian rhythms based on magnetic flux density and analyzing the potential mechanisms of the magnetic fields affecting circadian rhythms, this review sheds light on the effects of magnetic fields on circadian rhythms and the potential applications in biomedicine.

What Is Known and Objectives: The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients., Methods: This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients., Results: Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10-16, 16-30, and 30-40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10-16, 16-25, 25-30, and 30-40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10-40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10-24 and 24-40 kg, respectively., What Is New and Conclusions: This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients., (© 2022 John Wiley & Sons Ltd.)

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in various effector cells and have been proved to play vital roles in smooth muscle contraction and digestive secretion. However, there are relatively few literatures revealing the roles of mAChRs in inflammatory processes, and its underlying regulatory mechanisms have not been elucidated. Taking the advantages of live imaging of zebrafish, we found that inhibition of mAChRs resulted in increased neutrophils recruitment and proinflammatory cytokines expression, whereas activation of mAChRs led to opposite outcome. Subsequently, we found that mAChRs regulated the expression of arginases (args), and pharmacological intervention of args level could reverse the effects of mAChRs on neutrophils migration and cytokines expression, suggesting that args are important downstream proteins of mAChRs that mediate the regulation of inflammatory response. In this study, we identified args as novel downstream proteins of mAChRs in inflammatory responses, providing additional evidence for system immune regulation of cholinergic receptors., Competing Interests: Declaration of conflicting interests 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 © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), increases the serotonin levels in the brain to treat depression. Antidepressants have been demonstrated to modulate circadian rhythm, but the underlying mechanisms by which antidepressants regulate circadian rhythm require more research. This study aimed to investigate the role of FLX on circadian rhythm by analyzing the movement behavior and internal circadian oscillations in zebrafish. The results showed that the expression of clock genes clock1a and bmal1b was significantly down-regulated, and the amplitude reduction and phase shift were observed after FLX treatment. Furthermore, FLX exposure inhibited the expression of aanat2, which led to a decrease in nocturnal melatonin secretion. aanat2 -/- larvae showed disrupted circadian rhythm. These findings may help reveal the effect of FLX exposure on the circadian rhythm and locomotor activity. It may provide theoretical data for the clinical application of FLX., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The present study aimed to explore the effect of carnitine supplementation on body weight in patients with polycystic ovary syndrome (PCOS) and predict an appropriate dosage schedule using a machine-learning approach. Data were obtained from literature mining and the rates of body weight change from the initial values were selected as the therapeutic index. The maximal effect (E max ) model was built up as the machine-learning model. A total of 242 patients with PCOS were included for analysis. In the machine-learning model, the E max of carnitine supplementation on body weight was -3.92%, the ET 50 was 3.6 weeks, and the treatment times to realize 25%, 50%, 75%, and 80% (plateau) E max of carnitine supplementation on body weight were 1.2, 3.6, 10.8, and 14.4 weeks, respectively. In addition, no significant relationship of dose-response was found in the dosage range of carnitine supplementation used in the present study, indicating the lower limit of carnitine supplementation dosage, 250 mg/day, could be used as a suitable dosage. The present study first explored the effect of carnitine supplementation on body weight in patients with PCOS, and in order to realize the optimal therapeutic effect, carnitine supplementation needs 250 mg/day for at least 14.4 weeks., 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 © 2022 Wang, Li, Mao, He, Zhu and Wei.)

Objectives: The purpose of this study was to explore the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on urine albumin to creatinine ratio (UACR) in type 2 diabetes mellitus (T2DM) patients and to recommend appropriate medication care scheme., Methods: 8371 T2DM patients from four dapagliflozin studies and two canagliflozin studies were collected for analyzing with nonlinear mixed effect model (NONMEM). The change rates of UACR from baseline were intended to be evaluation indicators., Results: In the present study, there was no significant difference in the effects on UACR using dapagliflozin or canagliflozin treatment in T2DM patients. The maximal effect ( E max ) and the treatment duration of reaching half of E max (ET 50 ) from SGLT-2 inhibitors on UACR in T2DM patients were -19.2% and 0.448 weeks, respectively. Further, the treatment duration to reach 25%, 50%, 75%, and 80% E max was 0.150 weeks, 0.448 weeks, 1.344 weeks, and 1.792 weeks, respectively. Namely, for achieving the plateau period (80% of E max ) of SGLT-2 inhibitors on UACR in T2DM patients, 10 mg/day dapagliflozin (or 100 mg/day canagliflozin) should be taken for at least 1.792 weeks., Conclusions: To our knowledge, the present study explored the effects of SGLT-2 inhibitors on UACR in T2DM patients, meanwhile, recommended appropriate medication care scheme for the first time., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Dong-Dong Wang et al.)

The present study aimed to explore the effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients. Aplastic anemia patients were used to establish a population pharmacokinetic model by the nonlinear mixed effect (NONMEM), and concentrations of ciclosporin were simulated by Monte Carlo method. With the same weight, the ciclosporin clearance rates were 0.387:1 in patients with or without cimetidine, respectively. In the measured ciclosporin concentrations, compared to aplastic anemia patients without cimetidine, ciclosporin concentrations were higher in patients with cimetidine (P < 0.01). Further research found that at the same body weight and same dose, ciclosporin concentrations in aplastic anemia patients with cimetidine were indeed higher than those in patients without cimetidine (P < 0.01). The initial recommended ciclosporin dose for patients without cimetidine were 7mg/kg splited into two doses for weight of 40-60kg, and 6mg/kg splited into two doses for weight of 60-100kg. The patients with cimetidine were recommended to take 3mg/kg ciclosporin splited into two doses for weight of 40-100kg. It was the first time to explore the effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients. Patients coadministration of cimetidine, may need low ciclosporin dose., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mitochondria need to interact with the nucleus under homeostasis and stress to maintain cellular demands and nuclear transcriptional programs. Disrupted mitonuclear interaction is involved in many disease processes. However, the role of mitonuclear signaling regulators in endotoxin-induced acute lung injury (ALI) remains unknown. Nicotinamide adenine dinucleotide (NAD + ) is closely related to mitonuclear interaction with its central role in mitochondrial metabolism. In the current study, C57BL/6J mice were administrated with lipopolysaccharide 15 mg/kg to induce endotoxin-induced ALI and investigated whether the NAD + precursor nicotinamide mononucleotide (NMN) could preserve mitonuclear interaction and alleviate ALI. After pretreatment with NMN for 7 days, NAD + levels in the mitochondrial, nucleus, and total intracellular were significantly increased in endotoxemia mice. Moreover, supplementation of NMN alleviated lung pathologic injury, reduced ROS levels, increased MnSOD activities, mitigated mitochondrial dysfunction, ameliorated the defects in the nucleus morphology, and these cytoprotective effects were accompanied by preserving mitonuclear interaction (including mitonuclear protein imbalance and the mitochondrial unfolded protein response, UPR mt ). Furthermore, NAD + -mediated mitonuclear protein imbalance and UPR mt are probably regulated by deacetylase Sirtuin1 (SIRT1). Taken together, our results indicated that NMN pretreatment ameliorated ALI by inducing mitonuclear protein imbalance and activating the UPR mt in an SIRT1-dependent manner.

Normal dissolved oxygen in water is essential for maintaining the physiological functions of fish, but environmental pollution, such as eutrophication can lead to a decrease in oxygen content in water. How this reduction of dissolved oxygen in water affects the immune functions of fish and the potential regulatory mechanisms have not been thoroughly elucidated. In this study, we made full use of the aquatic model animal zebrafish to explore this question. In a model of LPS-induced inflammation, we found that hypoxia induced by infusing nitrogen into water increased the expression of pro-inflammatory cytokines, such as il-1β, il-6, and il-8. In vivo imaging also showed that hypoxia significantly increased neutrophil migration to the site of caudal fin injury in the transgenic line. Subsequently, we found that the phosphorylation level of ERK protein was significantly activated upon hypoxia and proved the roles of ERK signaling in the expression of pro-inflammatory cytokines and neutrophil migration in zebrafish. This study indicated that reduced water oxygen significantly increases the inflammatory response of the zebrafish., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations., Methods: 20,019 patients with T2DM were enrolled. The maximal effect ( E max ) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM)., Results: For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max , and treatment duration to reach half of the maximal effects (ET 50 ) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight., Conclusions: This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Dong-Dong Wang et al.)

N-acetylcholine receptors (AChRs) are mainly distributed in the postsynaptic membrane and have been widely studied for their control of muscle contraction by regulating neural action potentials. However, the influences of AChRs on immune responses and potential mechanisms remain unclear. Here, we used the advantages of live imaging of zebrafish to explore the regulation process of AChRs on inflammatory responses. Pharmacologically activating of the receptor, we found that the expression of pro-inflammatory cytokines il-1β, il-6, tnf-α and il-8 was significantly up-regulated and neutrophil migration to injury sites was also significantly increased. However, these phenomena were reversed under antagonism of the receptor activity. Results showed that interfering with nAChRs functions did not significantly affect zebrafish motion behavior. Results also showed that activation and antagonism of nAChRs function could regulate the phosphorylation of ERK protein respectively. We further demonstrated that ERK participated in the regulation of AChRs in cytokines expression and neutrophils migration in zebrafish. This study preliminarily revealed the roles of AChRs in inflammatory processes and their potential mechanism, providing additional evidence of peripheral immune regulation by cholinergic receptors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To perform environmental sampling and molecular identification of Paragonimus in endemic regions, which may help in minimizing transmission among humans., Methods: Mountain crabs from the genus Potamiscus were collected and the encysted metacercariae were extracted and subjected to morphological identification, followed by animal inoculation in Sprague-Dawley (SD) rats. After 112 days of infection, animals were killed and adult worms were extracted from lungs and muscles. The morphology of adult worms was characterized by microscopy and molecular identification was done by polymerase chain reaction, followed by sequencing of cox1 and ITS2 genes. Phylogenetic analysis was done by maximum parsimony method., Results: A total of 447 crabs were captured from the streams of Tongchang Town, Jinping County, Yunnan Province, China. The infection rate was found to be 41% (186 out of 447 crabs). The metacercariae of Paragonimus skrjabini was identified by the characteristics round or spherical encysted form measuring 410 to 460 × 400 to 460 µm. After animal infection in SD rats, adults were presumptively confirmed to be P. skrjabini, which was also confirmed by gene amplification and sequence analysis of cox1 and ITS2 regions. Paragonimus skrjabini clustered with previously reported P. skrjabini from Yunnan and Vietnam. The confidence values of their branches were > 95%. Phylogenetic analysis of the ITS2 region revealed two distinct clusters with distinct geographical grouping. Phylogenetic analysis with the combined data sets reiterated the geographical grouping with P. skrjabini from Yunnan clustering with strains from Vietnam., Conclusion: Metacercariae of P. skrjabini was discovered in freshwater crabs in Yunnan province, China, and the strains were phylogenetically related to P. skrjabini from Vietnam., (© 2021. The Author(s).)

Graphene is known as an atomically thin, transparent, highly electrically and thermally conductive, light-weight, and the strongest 2D material. We investigate disruptive application of graphene as a target of laser-driven ion acceleration. We develop large-area suspended graphene (LSG) and by transferring graphene layer by layer we control the thickness with precision down to a single atomic layer. Direct irradiations of the LSG targets generate MeV protons and carbons from sub-relativistic to relativistic laser intensities from low contrast to high contrast conditions without plasma mirror, evidently showing the durability of graphene., (© 2022. The Author(s).)

What Is Known and Objectives: Dapagliflozin was the first oral treatment approved in type 1 diabetes mellitus (T1DM) patients, simultaneously improving body weight. However, the time course and dose effect of dapagliflozin on loss of weight in T1DM patients was still unknown. The present study aimed to investigate quantitative relationship between dapagliflozin and loss of weight in T1DM patients based on Model-based Meta-analysis., Methods: Five dapagliflozin dosage groups, two of them were 5 mg/day and three of them were 10 mg/day, 1612 T1DM patients were analysed with maximal effect (E max ) model, and evaluation index was change rate of body weight from baseline value., Results: In these T1DM patients, dosages were not incorporated into model, indicating no significant dose-response relationship between 5 and 10 mg/day affecting loss of weight. E max and the treatment duration to reach half of the maximal effects (ET 50 ) of dapagliflozin influencing loss of weight in T1DM patients were -4.9% and 10.4 weeks, and the duration to achieve 25%, 50%, 75%, and 80% (plateau) of E max were 3.5, 10.4, 31.2, and 41.6 weeks., What Is New and Conclusions: It was the first time to explore quantitative relationship between dapagliflozin and loss of weight in T1DM patients. To achieve the plateau period in loss of weight, 5 mg/day dapagliflozin was required for at least 41.6 weeks., (© 2021 John Wiley & Sons Ltd.)

Tandem mass spectrometry has been the principal method in shotgun proteomics for peptide and protein identification. However, incorrect identifications reported by proteome search engines are still unknown, and further validation methods are needed. We have proposed a validation method pValid before, but its scope of application is limited because two features used in pValid are related to open database search and sub-optimal peptide candidates for tandem mass spectra, and the performance on complex datasets still has room for improvement. In this study, we developed a more comprehensive validation method, pValid 2, to break these limitations by removing the two features and bringing in a new feature related to the retention time predicted by a deep learning-based method pPredRT. pValid 2 yielded an average false positive rate of 0.03% and an average false negative rate of 1.37% on three testing datasets, better than those of pValid, and flagged 8.47% to 11.31% more incorrect identifications than pValid on two complex datasets. Moreover, pValid 2 flagged almost all decoy identifications in validating the open-search datasets. In addition, the function of validating identifications given by MaxQuant and MS-GF+ was implemented in pValid 2, and the validation results showed that pValid 2 performed dramatically better than three metabolic labeling validation methods. Further considering its cost-effectiveness as a pure computational approach, pValid 2 has the potential to be a widely used validation tool for peptide identifications of any proteome search engines in shotgun proteomics. SIGNIFICANCE: Identification results given by shotgun proteomics are vital to life science research. The correctness of identifications deeply affects the precision of the subsequent studies about protein structures and functions, protein-protein interactions, pathogenic mechanism, and targeted drugs. Thus, validating the correctness of identifications is crucial and urgent. In 2019, we developed an identification credibility validation method named pValid, whose false positive rate (FPR) is 0.03% and false negative rate (FNR) is 1.79%, comparable to those of the gold standard, i.e., the Synthetic-peptide validation method. However, pValid can only be used for validating the results from pFind, and its validation performance on a few complex datasets still has room for improvement. So, in this submission, we proposed pValid 2, a more comprehensive computational validation method that can validate identifications from any proteome search engines with increased discriminating power., (Copyright © 2021 Elsevier B.V. All rights reserved.)