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He-Xi Du,1–3 Xian-Guo Chen,1–3 Li Zhang,1–3 Yi Liu,1–3 Chang-Sheng Zhan,1–3 Jing Chen,1–3 Yong Zhang,1–3 Zi-Qiang Yu,1–3 Jin Zhang,4,5 Hong-Yi Yang,4,5 Kai Zhong,4,5 Chao-Zhao Liang1–31Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei 230022, People’s Republic of China; 2Institute of Urology, Anhui Medical University, Hefei 230022, People’s Republic of China; 3Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, People’s Republic of China; 4High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, People’s Republic of China; 5Key Laboratory of Anhui Province for High Magnetic Resonance Imaging, Hefei 230031, People’s Republic of ChinaBackground: Patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) frequently show depressive symptoms clinically and increasing evidence indicates a correlation between CP/CPPS and depression. However, the underlying mechanisms of CP/CPPS-related depression remain poorly understood. Here, we sought to determine the role of hippocampal microglial activation and neurobiological changes in a mouse model of experimental autoimmune prostatitis (EAP)-induced depression and the treatment efficacy of Chinese herb extract baicalein.Methods: EAP was induced through intradermal injection of prostate antigen and adjuvant twice. Then, mice were assessed for affective behaviors in the open field test, elevated plus maze, forced swim test, and tail suspension test. The morphology and function of microglia and astrocytes were detected by immunofluorescence, Western blotting, and transmission electron microscopy. Proinflammatory mediators along with serotonin transporter (SLC6A4/SERT) and indoleamine 2,3-dioxygenase (IDO) were quantified with reverse transcription-polymerase chain reaction (RT‑PCR), and serum serotonin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Proton magnetic resonance spectroscopy (1H-MRS) was performed to measure hippocampal glutamate levels. In addition, baicalein was used in a subset of EAP mice to test its anti-depressant action.Results: EAP was successfully established and induced depressive- and anxiety-like behavior in mice. Increasing levels of co-expressed ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) and ultrastructural observations suggested microglial activation and reactive astrocytosis in the hippocampus. These activated microglia resulted in increased expressions of multiple proinflammatory cytokines. Simultaneously, EAP mice showed higher gene expressions of SLC6A4 and IDO and lower concentrations of serotonin. 1H-MRS indicated a decrease in the glutamate + glutamine (Glx)/total creatine (tCr) ratio in EAP mice. Furthermore, baicalein treatment alleviated the depressive-like behavior and neuroinflammation by suppressing the nuclear factor-kappa B (NF-κB) pathway.Conclusion: Our data indicate that EAP-induced depressive-like behavior is linked to microglia activation and subsequent neurotransmitter metabolism. Moreover, baicalein attenuates behavioral changes by inhibiting neuroinflammation via downregulation of the NF-κB pathway.Keywords: EAP, microglial activation, serotonin, neurochemical changes, baicalein

Qing-ya Cui,1 Hong-shi Shen,1 Tian-qin Wu,1 Hai-fei Chen,1 Zi-qiang Yu,2 Zhao-yue Wang2 1Department of Hematology, PLA 100th Hospital, 2Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China Abstract: We report the case of a 59-year-old Chinese man who showed an asymptomatic coagulation factor V deficiency pattern after second intravenous treatment with ceftazidime. Normal pooled plasma failed to correct the abnormalities in a mixing test, and the presence of factor V inhibitor was confirmed by the Bethesda method. The coagulopathy was not corrected by transfusion of fresh frozen plasma and prothrombin complex concentrate, but rather by treatment with prednisone and withdrawal of dubious drugs. The findings reported here should prompt clinicians to watch for drug-induced coagulation factor deficiency. Keywords: acquired factor V deficiency, coagulopathy, prednisone

Bisphenols (BPs) and parabens (PBs) are of great concern for environmental pollution and human health because of their endocrine-disrupting effects and potential health hazards. Urinary biomonitoring of BPs and PBs can provide basic data for human internal exposure evaluation, which is a prerequisite for accurately assessing their health risks. In this study, we developed a new pretreatment procedure based on solid supported liquid-liquid extraction (SLE) for the simultaneous separation of ten BPs and five PBs in human urine, followed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. In the instrumental analysis, the HPLC conditions and MS/MS parameters were comprehensively optimized. Accurate qualitative and quantitative determination of ten BPs and five PBs was achieved by introducing a ternary gradient elution system of water, methanol, and acetonitrile for LC separation. During sample pretreatment, the extraction solvent and elution volume were optimized. Specifically, urine samples were held at room temperature and centrifuged at 3000 r/min for 10 min. The supernatant (2 mL) was then transferred to a glass tube, and the pH was adjusted to 5.0 using HCl (0.5 mL; 0.1 mol/L) and NaAc-HAc buffer (1.5 mL). Thereafter, β -glucuronidase-arylsulfatase (20 μL) and surrogate standard solutions (10 ng; 13 C 12 -BPS, 13 C 12 -BPAF, 13 C 6 -MeP, and 13 C 6 -BuP) were added, and the mixture was incubated in a shaker bath in the dark at 37 ℃ for 16 h. After incubation, the hydrolyzed sample (4 mL) was loaded onto an SLE cartridge and equilibrated for a minimum of 5 min to ensure the solution was completely absorbed by the packing material. Subsequently, the target chemicals were eluted with a mixed ethyl acetate/ n -hexane solution (3∶7, v/v; 15 mL). Separation of the targets was performed on a ZORBAX SB-C18 reversed-phase column (250 mm×4.6 mm, 5 μm) using an acetonitrile-methanol-water system as the mobile phase. The method was verified by spiking mixed urine samples at three levels (1, 5, and 50 μg/L), with the recoveries ranging from 84.3% to 119.8%. Except for bisphenols (BPS), whose matrix effect was calculated as -21.8%, the matrix effects of other analytes were lower than 20%, indicating low matrix interference. The linear ranges of the analytes varied from 0.1-500 μg/L to 1-500 μg/L, with correlation coefficients higher than 0.995. The method limits of quantification for target chemicals ranged from 0.03 to 0.30 μg/L, and the relative standard deviations of intra- and inter-day experiments were 1.4%-8.4% and 5.7%-14.6%, respectively, suggesting high stability and reproducibility. The method was successfully applied to the determination of ten BPs and five PBs in 10 urine samples from a general population. The concentrations of target chemicals in the human urine samples varied. Methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and bisphenol A (BPA) were detected in all samples, with median mass concentrations of 1.10, 0.60, 0.21, and 0.55 μg/L, respectively. The detection rates of the other chemicals were less than 50%, which may be related to the production and use of specific chemicals, their bioavailability, and biological metabolism in humans.

The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69. We focused on understanding the functional consequence of PSMC5 insufficiency and the P320R mutation in cells and found that both impair proteasome function and activate apoptosis. Interestingly, the P320R mutation impairs proteasome function by weakening the association between the 19S regulatory particle and the 20S core particle. Our study supports that proteasome dysfunction is the pathogenic cause of neurodevelopmental disorders in individuals carrying PSMC5 variants., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Traumatic brain injury (TBI) is an important health concern in the society. Previous studies have suggested that necroptosis occurs following TBI. However, the underlying mechanisms and roles of necroptosis are not well understood. In this study, we aimed to assess the role of receptor-interacting serine/threonine-protein kinase 3 (RIP3)-mediated necroptosis after TBI both in vitro and in vivo., Methods: We established a cell-stretching injury and mouse TBI model by applying a cell injury controller and controlled cortical impactor to evaluate the relationships among necroptosis, apotosis, inflammation, and TBI both in vitro and in vivo., Results: The results revealed that necroptosis mediated by RIP1, RIP3, and mixed lineage kinase domain-like protein was involved in secondary TBI. Additionally, protein kinase B (Akt), phosphorylated Akt, mammalian target of rapamycin (mTOR), and phosphorylated mTOR potentially contribute to necroptosis. The inhibition of RIP3 by GSK'872 (a specific inhibitor) blocked necroptosis and reduced the activity of Akt/mTOR, leading to the alleviation of inflammation by reducing the levels of NOD-, LRR- and pyrin domain-containing protein 3. Moreover, the inhibition of RIP3 by GSK'872 promoted the activity of cysteinyl aspartate specific proteinase-8, an enzyme involved in apoptosis and inflammation., Conclusions: These data demonstrate that RIP3 inhibition could improve the prognosis of TBI, based on the attenuation of inflammation by switching RIP3-dependent necroptosis to cysteinyl aspartate specific proteinase-8-dependent apoptosis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Precision measurements by the Alpha Magnetic Spectrometer (AMS) on the International Space Station of the deuteron (D) flux are presented. The measurements are based on 21×10^{6} D nuclei in the rigidity range from 1.9 to 21 GV collected from May 2011 to April 2021. We observe that over the entire rigidity range the D flux exhibits nearly identical time variations with the p, ^{3}He, and ^{4}He fluxes. Above 4.5 GV, the D/^{4}He flux ratio is time independent and its rigidity dependence is well described by a single power law ∝R^{Δ} with Δ_{D/^{4}He}=-0.108±0.005. This is in contrast with the ^{3}He/^{4}He flux ratio for which we find Δ_{^{3}He/^{4}He}=-0.289±0.003. Above ∼13  GV we find a nearly identical rigidity dependence of the D and p fluxes with a D/p flux ratio of 0.027±0.001. These unexpected observations indicate that cosmic deuterons have a sizable primarylike component. With a method independent of cosmic ray propagation, we obtain the primary component of the D flux equal to 9.4±0.5% of the ^{4}He flux and the secondary component of the D flux equal to 58±5% of the ^{3}He flux.

A palladium-catalyzed ring-opening cyclization of ( E ) & ( Z )-ene-vinylidenecyclopropanes has been developed via an intramolecular [3 + 2] cycloaddition process in the presence of a sterically bulky biaryl phosphine ligand, stereoselectively affording fused cis - & trans -bicyclo[4.3.0] skeletal products in good yields with a broad substrate scope and good functional tolerance. A plausible reaction mechanism was proposed on the basis of previous work and the DFT calculations.

There are >350 species of the Ophiobolus genus, which is not yet very well-known and lacks research reports on secondary metabolites. Three new 3,4-benzofuran polyketides 1-3, a new 3,4-benzofuran polyketide racemate 4, two new pairs of polyketide enantiomers (±)-5 and (±)-7, two new acetophenone derivatives 6 and 8, and three novel 1,4-dioxane aromatic polyketides 9-11, were isolated from a fungus Ophiobolus cirsii LZU-1509 derived from an important medicinal and economic crop Anaphalis lactea. The isolation was guided by LC-MS/MS-based GNPS molecular networking analysis. The planar structures and relative configurations were mainly elucidated by NMR and HR-ESI-MS data. Their absolute configurations were determined by using X-ray diffraction analysis and via comparing computational and experimental ECD, NMR, and specific optical rotation data. 9 possesses an unreported 5/6/6/6/5 five-ring framework with a 1,4-dioxane, and 10 and 11 feature unprecedented 6/6/6/5 and 6/6/5/6 four-ring frames containing a 1,4-dioxane. The biosynthetic pathways of 9-11 were proposed. 1-11 were nontoxic in HT-1080 and HepG2 tumor cells at a concentration of 20 μM, whereas 3 and 5 exerted higher antioxidant properties in the hydrogen peroxide-stimulated model in the neuron-like PC12 cells. They could be potential antioxidant agents for neuroprotection., Competing Interests: Declaration of Competing Interest The authors declare that there is no competing interest to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Enzymes play important roles not only in normal physiological processes but in the development of many diseases. In situ imaging of enzymes with high-resolution in living systems would helpful for clinical diagnosis and treatment. However, many molecular fluorescent probes suffer from the drawback of diffusing away from the reaction site of enzymes even out of the cells, losing the in situ information and resulting in poor imaging resolution. Quinone methide (QM) based self-immobilizing probes allow the fluorescent signal to be immobilized near the target for an extended period without deactivating the target enzymes, ensuring that it will provide amplified signals and in situ information of the target with high resolution. In this review, we summarized the recent progress of QM-based self-immobilizing probes including their design strategies, working mechanisms, classifications and applications in in situ enzyme imaging. This review calls for the development of more activatable QM-based probe with the advantages of high stability in the absence of the target but very high labeling efficiency after activation., (© 2024 Wiley-VCH GmbH.)

Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68 Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability in vitro and in vivo , and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of 68 Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, 68 Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

There is interest in developing sustainable materials displaying circularly polarized room-temperature phosphorescence, which have been scarcely reported. Here, we introduce biobased thin films exhibiting circularly polarized luminescence with simultaneous room-temperature phosphorescence. For this purpose, phosphorescence-active lignosulfonate biomolecules are co-assembled with cellulose nanocrystals in a chiral construct. The lignosulfonate is shown to capture the chirality generated by cellulose nanocrystals within the films, emitting circularly polarized phosphorescence with a 0.21 dissymmetry factor and 103 ms phosphorescence lifetime. By contrast with most organic phosphorescence materials, this chiral-phosphorescent system possesses phosphorescence stability, with no significant recession under extreme chemical environments. Meanwhile, the luminescent films resist water and humid environments but are fully biodegradable (16 days) in soil conditions. The introduced bio-based, environmentally-friendly circularly polarized phosphorescence system is expected to open many opportunities, as demonstrated here for information processing and anti-counterfeiting., (© 2024. The Author(s).)

We present the precision measurements of 11 years of daily cosmic positron fluxes in the rigidity range from 1.00 to 41.9 GV based on 3.4×10^{6} positrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The positron fluxes show distinctly different time variations from the electron fluxes at short and long timescales. A hysteresis between the electron fluxes and the positron fluxes is observed with a significance greater than 5σ at rigidities below 8.5 GV. On the contrary, the positron fluxes and the proton fluxes show similar time variation. Remarkably, we found that positron fluxes are modulated more than proton fluxes with a significance greater than 5σ for rigidities below 7 GV. These continuous daily positron fluxes, together with AMS daily electron, proton, and helium fluxes over an 11-year solar cycle, provide unique input to the understanding of both the charge-sign and mass dependencies of cosmic rays in the heliosphere.

Objective: To investigate the clinical phenotype and gene mutation characteristics of MYH9-related disorder (MYH9-RD). Methods: The clinical data of 66 patients with MYH9-RD in the First Affiliated Hospital of Soochow University from January 2010 to December 2022 were retrospectively analyzed. According to the bleeding symptom, the patients were divided into bleeding and non-bleeding group, and according to the mutation sites, the patients were divided into non-muscle myosin heavy chain ⅡA head region (MD) and tail region (TD) mutation group. Statistical analysis was made to explore the clinical features in different groups such as platelet counts, bleeding, renal function, cataracts and hearing as well as MYH9 gene mutations. Results: A total of 66 MYH9-RD patients were included, with 28 males and 38 females, diagnosis age of 1-63(26±2) years. And 41% (27/66) of the patients had no family history. All patients presented with macrothrombocytopenia and normal platelet aggregation(10/10), 92% (54/59) of the patients had visible blue inclusion bodies in neutrophils, 30% (20/66) had bleeding symptoms, 45% (22/49) had proteinuria or glomerulonephropathy, 20% (8/41) had bilateral hearing impairment, and 10% (4/42) had bilateral cataracts. 18 mutation sites were identified in total, including 15 missense, 1 splicing and 2 termination mutations. Among them, p.Asp1424Asn, p.Arg1933* and p.Arg702His/Cys mutations were identified in 56% (29/52) of the patients, and p.Ser96Leu, Arg1165Cys and p.Glu1841Lys mutations were recurrent mutations, while p.Ala44Thr, p.Asp1447Ala and c.3838-2A>G mutations were novel mutations. The average platelet count of patients in bleeding group was (19±3)×10 9 /L, which was significantly less than (36±3)×10 9 /L in non-bleeding group ( P <0.001). Compared with TD mutation group, patients of MD mutation group were presented with lower platelet count and higher risk of bleeding, as well as more severe clinical presentations including renal and hearing impairment and cataracts (all P <0.05). Conclusion: Mutations of p.Asp1424Asn, p.Arg1933* and p.Arg702His/Cys in MYH9 gene are hotspot mutations for MYH9-RD patients, Compared with TD mutation group, patients of MD mutation group were presented with lower platelet count and higher risk of bleeding, as well as more severe clinical presentations including renal and hearing impairment and cataracts.

The application of exogenous growth-regulating substances is an effective technique to enhance plant stress tolerance. Here, a hydroponic experiment was conducted to investigate the effects of exogenous basal application of 0.1 mmol·L -1 spermidine (Spd) on both the physiology and molecular biology of ryegrass root systems under varying degrees (0, 5, and 10 mg·L -1 ) of cadmium (Cd) stress using ryegrass as the test plants. The results of physiological studies revealed that Cd stress significantly reduced the physiological functions of the ryegrass root system, whereas the addition of Spd effectively alleviated the negative effects caused by Cd. The most significant effect was on the root soluble protein content, which increased by 90.91% and 158.35% compared with 5 mg·L -1 and 10 mg·L -1 Cd alone. Spd also inhibited the accumulation of oxidative stress products malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2 ) by increasing the ascorbic acid (ASA) and glutathione (GSH) content and peroxidase (POD) activity, whereas the effects on root activity and superoxide dismutase (SOD) activity were not significant. The results of molecular biology studies demonstrated that 10 mg·L -1 Cd stress caused differential expression of a large number of genes in ryegrass roots, and the number of differentially expressed genes, differential significance, and differential multiplicity were significantly reduced after the application of exogenous Spd. The most significant part of the GO enrichment analysis shifted from responding to organic cyclic compounds and aldehyde/ketone group transferase activity to responding to trivalent iron ions and 2'-deoxymugineic-acid 2'-dioxygenase activity. Single gene expression heat map analysis revealed that exogenous Spd upregulated the expression of genes encoding zinc-iron transporter protein and 2'-deoxymugineic-acid 2'-dioxygenase, which improved the uptake and utilization of iron by the root system. In conclusion, the application of certain concentrations of Spd could effectively regulate the response of ryegrass roots to Cd stress, enhance its tolerance physiology, and mitigate the toxic effects of Cd.

Parasitoid wasps are a diverse group of hymenopteran insects that serve as invaluable resources for pest biocontrol. To ensure successful parasitism, parasitoid wasps inject venom into their hosts to suppress their hosts' immunity, modulate hosts' development, metabolism, and even behavior. With over 600,000 estimated species, the diversity of parasitoid wasps surpasses that of other venomous animals, such as snakes, cone snails, and spiders. Parasitoid wasp venom is an underexplored source of bioactive molecules with potential applications in pest control and medicine. However, collecting parasitoid venom is challenging due to the inability to use direct or electrical stimulation and the difficulty in dissection because of their small size. Trichogramma is a genus of tiny (~0.5 mm) egg parasitoid wasps that are widely used for the biological control of lepidopteran pests in both agriculture and forests. Here, we report a method for extracting venom from T. dendrolimi using artificial hosts. These artificial hosts are created with polyethylene film and amino acid solutions and then inoculated with Trichogramma wasps for parasitism. The venom was subsequently collected and concentrated. This method enables the extraction of large amounts of Trichogramma venom while avoiding contamination from other tissues caused by dissection, a common issue in venom reservoir dissection protocols. This innovative approach facilitates the study of Trichogramma venom, paving the way for new research and potential applications.

Advanced drinking water treatment process using nanofiltration (NF) membranes has gained attention recently because it removes many challenging constituents in contaminated surface waters, such as dissolved organics and heavy metals. However, much literature has reported high variations and uncertainties of NF membranes for removing nitrogen compounds in the contaminated water-ammonium (NH 4 + ), nitrates (NO 3 - ), and nitrites (NO 2 - ). This study aimed to identify the ability of commercial NF membranes to remove NH 4 + , NO 2 - , and NO 3 - and clarify the mechanisms underlying their transport through NF membranes. This was examined by evaluating their rejection by three commercial NF membranes using artificial and actual river waters under various conditions (variable permeate flux, temperature, pH, and ionic strength). Ammonium commonly showed the highest removal among the three nitrogen compounds, followed by nitrites and nitrates. Interestingly, ammonium removal varied considerably from 6% to 86%, depending on the membrane type and operating conditions. The results indicated that the selected nitrogen compounds (NH 4 + , NO 2 - , and NO 3 - ) could be highly rejected depending on the clearance between their hydrated radius and the membrane's pore walls. Further, the rejection of the lowest molecular-weight nitrogen compound (NH 4 + ) could be higher than NO 2 - and NO 3 - due to its highest energy barrier and larger hydrated radius. This study suggests that compliance with the drinking water regulations of NH 4 + , NO 2 - , and NO 3 - can be reliably achieved by selecting appropriate membrane types and predicting the range of their removal under various feed water quality and operating conditions., 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 © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Autoimmune pancreatitis (AIP) is a rare and enigmatic immune-mediated inflammatory disease. We aimed to investigate the prevalence, characteristics, and associated factors of AIP-inflammatory bowel disease (IBD) in China., Methods: A retrospective bidirectional case-control study was performed. The diagnoses of IBD and AIP were made based on the European Crohn's and Colitis Organization guidelines and the International Consensus Diagnostic Criteria. IBD controls were matched by age, sex, and IBD type at a ratio of 1:4, while AIP controls were matched by AIP types., Results: The age-standardized prevalence of AIP-IBD patients in the IBD and AIP population were 292.0 and 8151.93 per 100 000 population, respectively. IBD patients had a higher risk of AIP compared to non-IBD patients (odds ratio 8.4, 95% confidence interval 4.7-14.9, P < 0.0001), and AIP patients had a higher risk of developing IBD compared to the general population in China. The mean age at diagnosis of IBD and AIP was 34.83 years and 40.42 years. IBD was diagnosed before AIP in seven cases. The median total IBD and AIP duration was 43.5 months and 13.5 months. Use of mesalamine and tuberculosis were associated with AIP in IBD patients (P = 0.031). And fecal occult blood test was associated with IBD in AIP patients (P = 0.008)., Conclusions: Most AIP-IBD patients had ulcerative colitis and type 2 AIP. IBD patients are more likely to develop AIP compared to the general population, and vice versa. Use of mesalamine and tuberculosis infection were associated with AIP, and fecal occult blood test was associated with IBD., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Circularly polarized luminescence (CPL) is attracting much interest because it can carry extensive optical information. CPL shows left- or right-handedness and can be regarded as part of high-level visual perception to supply an extra dimension of information with regard to regular light. A key to meeting the needs for practical applications is to develop the emerging field of ultra-dissymmetric CPL. Chiral liquid crystal (LC) assemblies─otherwise referred to as cholesteric liquid crystals (CLCs)─are essentially organized helical superstructures with a highly ordered one-dimensional orientation, and distinctly superior to regular helical supramolecules. CLCs can achieve a perfect equilibrium of molecular short-range interaction and long-range orientational order, enabling molecule-scale chirality on a helical pitch and observable scale. LC assembly could be an ideal strategy for amplifying chirality, making it accessible to ultra-dissymmetric CPL. Herein, we focused on some basic but important issues regarding CPL: (i) How can CPL be created from chiral dyes? (ii) Is the chirality of luminescent dyes an essential factor for the generation of CPL? That is, can all chiral dyes emit CPL and vice versa? (iii) How can CPL be transferred within intermolecular systems, and what principles of CPL transmission should be followed? Given these queries and our work, in this Perspective we discuss the generation, transmission, and modulation of CPL with chiral LC assembly, aiming to design and build up novel chiroptical materials. Recent applications of CPL-active LC microstructures in three-dimensional displays, circularly polarized lasers, and asymmetric catalysis are also discussed.

Introduction: The associations between the clinical characteristics of non-small cell lung cancer (NSCLC) and mutations in telomerase reverse transcriptase ( TERT ) gene remain unclear. In this study, we used next-generation sequencing (NGS) to investigate the incidence rate and clinical correlates of TERT mutations in patients with NSCLC., Methods: In total, 283 tumor samples from patients with NSCLC were tested using an NGS panel from September 2017 to May 2020. The genetic testing results and clinical data of all patients were collected., Results: TERT mutations were found in 30 patients, which were significantly associated with age, smoking history, sex, and metastasis ( P  < 0.05). Survival analyses showed that patients who carried TERT mutations had a poorer prognosis. Of the 30 TERT -mutation carriers, 17 harbored epidermal growth factor receptor ( EGFR ) mutations, which were significantly associated with sex, histopathology type, and metastasis ( P  < 0.05; overall survival [OS], 21 months; 95% confidence interval [CI], 8.153-33.847 months). Three TERT mutation patients harbored Kirsten rat sarcoma virus ( KRAS ) mutations, which were significantly associated with metastasis risk ( P  < 0.05), KRAS mutations carriers had a worse prognosis, with an OS of 10 months (95% CI, 8.153-33.847 months). Multivariate Cox regression analyses showed that age, cancer stage, and TERT mutation carrier status were independent risk factors for NSCLC, and the TERT mutation was 2.731 times higher than that without TERT mutation (95% CI, 1.689-4.418, P  < 0.001)., Conclusions: TERT mutations were present in 11% of patients with NSCLC. TERT mutations were associated with age, smoking history, sex, and distant metastasis. Co-mutations in TERT and EGFR/KRAS indicated a poor prognosis. The co-mutations of TERT and EGFR differed according to sex, histopathology type, and metastasis, whereas TERT and KRAS co-mutations were only associated with patient metastasis. Age, cancer stage, and TERT mutation carrier status were independent risk factors for poor prognosis in patients with NSCLC., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Objective: As China's population aging process accelerates, the expenditure of China's basic medical insurance fund for employees may increase significantly, which may threaten the sustainability of China's basic medical insurance fund for employees. This paper aims to forecast the future development of China's basic medical insurance fund for employees in the context of the increasingly severe aging of the population., Methods: This paper taking an empirical study from Shanghai as an example, constructs an actuarial model to analyze the impact of changes in the growth rate of per capita medical expenses due to non-demographic factors and in the population structure on the sustainability of the basic medical insurance fund for employees., Results: Shanghai basic medical insurance fund for employees can achieve the goal of sustainable operation in 2021-2035, with a cumulative balance of 402.150-817.751 billion yuan in 2035. The lower the growth rate of per capita medical expenses brought about by non-demographic factors, the better the sustainable operation of the fund., Conclusion: Shanghai basic medical insurance fund for employees can operate sustainably in the next 15 years, which can further reduce the contribution burden of enterprises, which lays the foundation for improving the basic medical insurance treatment for employees., 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 Yu, Chen, Qu, Wu and Zeng.)

We report the properties of primary cosmic-ray sulfur (S) in the rigidity range 2.15 GV to 3.0 TV based on 0.38×10^{6} sulfur nuclei collected by the Alpha Magnetic Spectrometer experiment (AMS). We observed that above 90 GV the rigidity dependence of the S flux is identical to the rigidity dependence of Ne-Mg-Si fluxes, which is different from the rigidity dependence of the He-C-O-Fe fluxes. We found that, similar to N, Na, and Al cosmic rays, over the entire rigidity range, the traditional primary cosmic rays S, Ne, Mg, and C all have sizeable secondary components, and the S, Ne, and Mg fluxes are well described by the weighted sum of the primary silicon flux and the secondary fluorine flux, and the C flux is well described by the weighted sum of the primary oxygen flux and the secondary boron flux. The primary and secondary contributions of the traditional primary cosmic-ray fluxes of C, Ne, Mg, and S (even Z elements) are distinctly different from the primary and secondary contributions of the N, Na, and Al (odd Z elements) fluxes. The abundance ratio at the source for S/Si is 0.167±0.006, for Ne/Si is 0.833±0.025, for Mg/Si is 0.994±0.029, and for C/O is 0.836±0.025. These values are determined independent of cosmic-ray propagation.

Objective: To observe the efficacy and adverse reactions of a combination therapy regimen based on bortezomib and glucocorticoids in recurrent/refractory immune thrombocytopenic purpura (iTTP) . Methods: Six patients with recurrent/refractory TTP were included and treated with a glucocorticoid and two courses of bortezomib-based regimen. The clinical remission status of patients, changes in ADAMTS13 activity/ADAMTS13 inhibitor, and the occurrence of treatment-related adverse reactions were observed. Results: Of the 6 patients, 2 were males and 4 were females, with a median age of 21.5 (18-68) years. Refractory TTP was found in 1 case and recurrent TTP in 5 cases. Glucocorticoids were administered with reference to prednisone at 1 mg·kg(-1)·d(-1), and gradually reduced in dosage after achieving clinical remission. Bortezomib is subcutaneously administered at 1.3 mg/m(2) on days 1, 4, 8, and 11 with a 28-day treatment course consisting of 2 courses. Six patients achieved clinical remission after receiving bortezomib as the main treatment. ADMATS13 activity returned to normal in all patients with TTP after treatment, and the ADAMTS13 inhibitor turned negative. Thrombocytopenia is the most common adverse reaction after treatment, with other adverse reactions, including peripheral neuritis and abdominal pain, but ultimately all patients returned to normal. In a median follow-up of 26 (9-41) months, 5 patients maintained sustained remission, and 1 patient relapsed after 16 months of bortezomib treatment. Conclusion: Combination therapy of bortezomib and glucocorticoids has a satisfactory therapeutic effect and controllable adverse reactions for recurrent/refractory iTTP.

Quantum liquid, in the form of a self-bound droplet, is stabilized by a subtle balance between the mean-field contribution and quantum fluctuations. While a liquid-gas transition is expected when such a balance is broken, it remains elusive whether liquid-gas critical points exist in the quantum regime. Here, we study the quantum criticality in a binary Bose mixture undergoing the liquid-gas transition. We show that, beyond a narrow stability window of the self-bound liquid, a liquid-gas coexistence persists, which eventually transits into a homogeneous mixture. Importantly, we identify two distinct critical points where the liquid-gas coexistence terminates. These critical points are characterized by rich critical behaviors in their vicinity, including divergent susceptibility, unique phonon-mode softening, and enhanced density correlations. The liquid-gas transition and the critical points can be readily explored in ultracold atoms confined to a box potential. Our work highlights the thermodynamic approach as a powerful tool in revealing the quantum liquid-gas criticality, and paves the way for further studies of critical phenomena in quantum liquids.

Objective: To explore the utility of stool-based DNA test of methylated SDC2 (m SDC2 ) for colorectal cancer (CRC) screening in residents of Shipai Town, Dongguan City. Methods: This was a cross-sectional study. Using a cluster sampling method, residents of 18 villages in Shipai Town, Dongguan City were screened for CRC from May 2021 to February 2022. In this study, m SDC2 testing was employed as a preliminary screening method. Colonoscopy examination was recommended for individuals identified as high-risk based on the positive m SDC2 tests. The final screening results, including the rate of positive m SDC2 tests, the rate of colonoscopy compliance, the rate of lesions detection, and the cost-effectiveness of screening, were analyzed to explore the benefits of this screening strategy. Results: A total of 10 708 residents were enrolled and completed m SDC2 testing, giving a participation rate of 54.99% (10 708/19 474) and a pass rate of 97.87% (10 708/10 941). These individuals included 4 713 men (44.01%) and 5 995 women (55.99%) with a mean age of (54.52±9.64) years. The participants were allocated to four age groups (40-49, 50-59, 60-69, and 70-74 years), comprising 35.21%(3770/10 708), 36.25% (3882/10 708), 18.84% (2017/10 708), and 9.70% (1039/10 708) of all participants, respectively. m SDC2 testing was positive in 821/10 708 (7.67%) participants, 521 of whom underwent colonoscopy, resulting in a compliance rate of 63.46% (521/821). After eliminating of 8 individuals without pathology results, data from 513 individuals were finally analyzed. Colonoscopy detection rate differed significantly between age groups (χ 2 =23.155, P <0.001),ranging from a low of 60.74% in the 40-49 year age group to a high of 86.11% in the 70-74 year age group. Colonoscopies resulted in the diagnosis of 25 (4.87%) CRCs, 192 (37.43%) advanced adenomas, 67 (13.06%) early adenomas, 15 (2.92%) serrated polyps, and 86 (16.76%) non- adenomatous polyps. The 25 CRCs were Stage 0 in 14 (56.0%) individuals, stage I in 4 (16.0%), and Stage II in 7(28.0%). Thus, 18 of the detected CRCs were at an early stage. The early detection rate of CRCs and advanced adenomas was 96.77% (210/217). The rate of m SDC2 testing for all intestinal lesions was 75.05% (385/513). In particular, the financial benefit of this screening was 32.64 million yuan, and the benefit-cost ratio was 6.0. Conclusion: Screening for CRCs using stool-based m SDC2 testing combined with colonoscopy has a high lesion detection rate and a high cost-effectiveness ratio. This is a CRC screening strategy that deserves to be promoted in China.

We present the precision measurements of 11 years of daily cosmic electron fluxes in the rigidity interval from 1.00 to 41.9 GV based on 2.0×10^{8} electrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The electron fluxes exhibit variations on multiple timescales. Recurrent electron flux variations with periods of 27 days, 13.5 days, and 9 days are observed. We find that the electron fluxes show distinctly different time variations from the proton fluxes. Remarkably, a hysteresis between the electron flux and the proton flux is observed with a significance of greater than 6σ at rigidities below 8.5 GV. Furthermore, significant structures in the electron-proton hysteresis are observed corresponding to sharp structures in both fluxes. This continuous daily electron data provide unique input to the understanding of the charge sign dependence of cosmic rays over an 11-year solar cycle.

We aimed to identify the immune and Toll-like receptor (TLR) signaling pathway related feature lncRNAs to construct the diagnostic nomograms for acute ischemic stroke (AIS). Two AIS-associated expression profiles GSE16561 and GSE22255 were downloaded from NCBI Gene Expression Omnibus, the former was the training set and the latter was the validation set. The differential expression genes (DEGs) and lncRNAs (DElncRNAs) related to TLR signaling pathway were identified between AIS and control groups. The single sample gene set enrichment analysis (ssGSEA) was applied to evaluate the immune infiltration. The immune and TLR signaling pathway related DElncRNAs were determined. Three optimization algorithms were utilized to select the immune and TLR signaling pathway related feature lncRNAs to construct the diagnostic nomograms of AIS. Based on the lncRNA signature, a ceRNA network was constructed. 37 DEGs and 28 DElncRNAs related to TLR signaling pathway were identified in GSE16561. 16 immune cell types exhibited significant differences in distribution between AIS and control groups. 28 immune and TLR signaling pathway related DElncRNAs were determined. 8 immune and TLR signaling pathway related feature lncRNAs were selected. The diagnostic nomograms of AIS performed well in both datasets. A ceRNA network was constructed consisting of 7 immune and TLR signaling pathway related feature lncRNAs as well as 19 AIS related miRNAs and 21 TLR signaling pathway related genes. LINC00173, LINC01089, LINC02210, MIR600HG, SNHG14, TP73-AS1, LINC00680 and CASC2 may be the potential biomarkers of AIS diagnosis, and TLR signaling pathway may be a promising immune related therapeutic target for AIS., (© 2023. The Author(s).)

Charge redistribution on surface of Ru nanoparticle can significantly affect electrocatalytic HER activity. Herein, a double atomic-tuned RuBi SAA/Bi@OG nanostructure that features RuBi single-atom alloy nanoparticle supported by Bi-O single-site-doped graphene was successfully developed by one-step pyrolysis method. The alloyed Bi single atom and adjacent Bi-O single site in RuBi SAA/Bi@OG can synergistically manipulate electron transfer on Ru surface leading to optimum charge redistribution. Thus, the resulting RuBi SAA/Bi@OG exhibits superior alkaline HER activity. Its mass activity is up to 65000 mA mg -1 at an overpotential of 150 mV, which is 72.2 times as much as that of commercial Pt/C. DFT calculations reveal that the RuBi SAA/Bi@OG possesses the optimum charge redistribution, which is most beneficial to strengthen adsorption of water and weaken hydrogen-adsorption free energy in HER process. This double atomic-tuned strategy on surface charge redistribution of Ru nanoparticle opens a new way to develop highly efficient electrocatalysts., (© 2023 Wiley-VCH GmbH.)

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function. However, a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells. To be excited, the development of ionizable drug delivery systems (IDDSs) has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019 (COVID-19) in 2021. Compared with conventional cationic gene vectors, IDDSs can decrease the toxicity of carriers to cell membranes, and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures. Despite the progress, there remain necessary requirements for designing more efficient IDDSs for precise gene therapy. Herein, we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms. The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of pDNA and four kinds of RNA. In particular, organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity. We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future, and indicate ideas for developing next generation gene vectors., (© 2023. The Author(s).)

Coordination environment and site density have great impacts on the catalytic performance for single atoms (SAs). Herein, the site density of Mo-SAs on red polymeric carbon nitrides (RPCN) is modulated via a local carbonization strategy to controllably catch adventitious O atoms from open environment. The addition of melamine derivants with hydrocarbyl chains induces local carbonization during RPCN pyrolysis. These local carbonization regions bring abundant graphitic N 3C to anchor Mo-SAs, and most of Mo-SAs catch the O atoms in air, forming the O 2 -covered Mo-N 3 coordination. The dopants of carbon source with different structures and amounts can modulate the site density of Mo-SAs, therefore controlling the amounts of coordinated O atoms. Furthermore, coordinated O atoms around Mo-SAs construct the catalytic environment with Lewis base and gather photo-generated electrons under light. Such O-covered Mo-SAs endow RPCN materials (Mo-RPCN) with a strong ability for hydrogen abstraction, leading to the 99.51% ratio (28.8 mmol min -1  g -1 ) rate for thioanisole conversion with H 2 O 2 assisted advance oxidation technology. This work brings a new sight on the coordinated atoms dominant oxidation process., (© 2022 Wiley-VCH GmbH.)

Sixteen new polyketides, ophicirsins A-P ( 1-16 ), including four novel carbon skeletons ( 5-9 , 14 , 15 , and 16 ), were isolated from the extract of an endophytic fungus Ophiobolus cirsii LZU-1509. The unique frameworks of ophicirsin N ( 14 ) and O ( 15 ) feature a different cyclic ether connected with an aromatic ring system. Ophicirsin P ( 16 ) is characterized by the unprecedented heterozygote of a polyketide and an alkaloid. The absolute stereochemistries of those polyketides were characterized via single-crystal X-ray diffraction analysis and the experimental and computational electric circular dichroism spectra comparison. Theoretical reaction pathways in the fermentation to generate different novel skeletons starting from acetyl CoA and malonyl CoA helped to assign their structures. Compounds 1-16 appear almost nontoxic in HepG2 and HT-1080 tumor cells. Their antioxidant effects were further evaluated, and 15 exhibits an excellent protection activity in hydrogen peroxide-stimulated oxidative damage in neuron-like PC12 cells via screening all compounds. Moreover, 15 displays a greater ability to scavenge the 2,2-diphenyl-1-picrylhydrazyl free radicals than resveratrol. Taken together, these findings suggest that the novel polyketides could serve as potential antioxidant agents for neuroprotection.

Objective: To report the clinical manifestations and laboratory features of five patients with congenital thrombotic thrombocytopenic purpura (cTTP) and explore its standardized clinical diagnosis and treatment along with a review of literature. Methods: Clinical data of patients, such as age of onset, disease manifestation, personal history, family history, and misdiagnosed disease, were collected. Treatment outcomes, therapeutic effects of plasma infusion, and organ function evaluation were observed. The relationship among the clinical manifestations, treatment outcomes, and ADAMTS13 gene mutation of patients with cTTP was analyzed. Additionally, detection of ADAMTS13 activity and analysis of ADAMTS13 gene mutation were explored. Results: The age of onset of cTTP was either in childhood or adulthood except in one case, which was at the age of 1. The primary manifestations were obvious thrombocytopenia, anemia, and different degrees of nervous system involvement. Most of the patients were initially suspected of having immune thrombocytopenia. Acute cTTP was induced by pregnancy and infection in two and one case, respectively. ADAMTS13 gene mutation was detected in all cases, and there was an inherent relationship between the mutation site, clinical manifestations, and degree of organ injury. Therapeutic or prophylactic plasma transfusion was effective for treating cTTP. Conclusions: The clinical manifestations of cTTP vary among individuals, resulting in frequent misdiagnosis that delays treatment. ADAMTS13 activity detection in plasma and ADAMTS13 gene mutation analysis are important bases to diagnose cTTP. Prophylactic plasma transfusion is vital to prevent the onset of the disease.

To investigate the possible effect of FoxO on coxsackievirus B3 (CVB3) -induced cardiomyocyte inflammation and apoptosis via modulation of the TLR4/NF-κB signaling pathway.Viral myocarditis (VMC) models were establied via CVB3 infection both in vivo and in vitro. Western blotting was adopted to detect FoxO1 and TLR4 expressions in myocardial tissues and cells. Cardiomyocytes of suckling mouse were divided into the control, CVB3, CVB3 + pcDNA, CVB3 + pcDNA-FoxO1, CVB3 + TLR4 siRNA, and CVB3 + pcDNA-FoxO1 + TLR4 siRNA groups. Flow cytometry was employed to evaluate cell apoptosis. The expressions of inflammatory factors including TNF-α, IL-1β, and IL-6 were detected via quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Then, TLR4/NF-κB pathway-related proteins were determined via Western blotting.VMC mice had increased FoxO1 and TLR4 expressions in myocardial tissues. Cardiomyocytes with CVB3 infection also had upregulated protein expressions of p-FoxO1/FoxO1 and TLR4. Compared with those in the control group, the cardiomyocytes in the CVB3 group were increased in LDH and CK-MB levels, cell apoptosis rate and inflammatory factors (TNF-α, IL-1β and IL-6), as well as protein expressions of TLR4 and p-p65/p65. Compared with those in the CVB3 group, the cardiomyocytes in the CVB3 + pcDNA-FoxO1 group were further upregulated whereas those in the CVB3 +TLR4 siRNA group were downregulated in the aforementioned indicators. Furthermore, TLR4 siRNA can reverse the effect of pcDNA-FoxO1 on the aggravation of cardiomyocyte injury induced by CVB3 infection.FoxO1 can upregulate the TLR4/NF-κB signaling pathway to promote cardiomyocyte apoptosis and inflammatory injury in CVB3-induced VMC.

Objective: To apply Bionano Saphyr visual full-length DNA optical mapping technology to the precise genetic diagnosis of hemophilia A carriers., Methods: For 2 suspected F8 gene deficiency female carriers who could not be diagnosed by conventional next-generation sequencing technology, the full-length DNA optical mapping technology was used to detect and scan the sample X chromosome full-length visual haplotype characteristic map, which was compared with the normal haplotype. The gene structure variation information of the samples was obtained by compare with DNA atlas library., Results: The average fluorescent marker length of the X chromosome DNA molecular where the F8 gene was located in the two samples was greater than 2.5 Mbp, and the average copy number was greater than 20×. After comparative analysis, one of the samples was a proximal inversion of intron 22 of the F8 gene, and another was an inversion of intron 22 accompanied by multiple deletions of large fragments., Conclusions: Bionano technology has a good detection rate for gene defects with large length and complex variation. In the absence of a proband or accurate genetic diagnosis results of the proband, the application of this technology to detect the heterozygous complex variant of the F8 gene is of great significance for the prenatal diagnosis and pre-pregnancy diagnosis of hemophilia carriers.

Objective: This cross-sectional study aimed to investigate the current attention and intervention of oncologists on oxaliplatin (OXA)-induced adverse reactions (ADRs)., Methods: In 31 provinces or administrative regions across China, 401 oncologists were surveyed through a self-designed questionnaire. The survey queried the basic information of respondents, clinical use of OXA, OXA-induced ADRs, and relative interventions. Chi-square tests and multiple logistic regression were used to explore the sociodemographic factors influencing the safety perception of OXA and the relevant interventions., Results: The survey showed that the age of respondents was mainly distributed between 30 and 40 years and the working period for most oncologists was no more than 5 years. Oncologists with long working years were more willing to conduct patient education and inquire about ADRs than those with short working years. The rate of ADRs reported by oncologists with intermediate professional titles was significantly higher than that reported by oncologists with junior and senior professional titles., Conclusion: Our findings indicate that oncologists in mainland China are concerned about OXA-induced ADRs, but the reporting of ADRs still needs to be strengthened. Therefore, training and educational programs are urgently needed to improve the risk management of OXA-induced ADRs among oncologists., (© 2022. Huazhong University of Science and Technology.)

Glioma is one of the most prevalent cancers diseases in the worldwide. Kinesin superfamily protein 4 (KIF4), a KIF member classified in Kinesin 4 has been indicated as a mediator acted in tumorigenesis of human cancer. However, the mechanism of KIF4A on glioma is yet to be investigated. This study aimed to explore the potential function and mechanism of KIF4A in gliomas. We analyzed the KIF4A expression and the prognosis in gliomas patients using The Cancer Genome Atlas (TCGA) databases. KIF4A level in normal human astrocyte cell (NHA) and glioma cell lines were examined by Western blot. We studied the function of KIF4A on proliferation, migration, invasion, cell cycle in glioma cell lines using a series of in vitro and in vivo experiments. Chromatin Immunoprecipitation (ChIP) analysis was applied to searching potential KIF4A related downstream in glioma. We identified the significant up-regulated expression of KIF4A both in glioma tissues and cell. Glioma patients with elevated KIF4A expression have shorter survival. Down-regulation of KIF4A exerted inhibitory effect on cell proliferation, invasion and migration. We crucially identified that KIF4A drives gliomas growth by transcriptional repression of Rac1/Cdc42 to induce cytoskeletal remodeling in glioma cells. Knockdown of KIF4A decreased RohA, Rac1, Cdc42, Pak1 and Pak2 expression level. Our study provided a prospect that KIF4A functions as an oncogene in glioma., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To investigate whether co-transfection of wild-type VWFpp with VWF mutant in D1 region is able to correct VWF defects in biosynthesis and secretion., Methods: Four VWF mutant plasmids were single transfected into HEK 293 cells, or co-transfected into HEK 293 cells with the wild type VWFpp plasmids. The VWF in supernatant and lysate of transfected cells were analyzed by ELISA, vertical VWF multimer electrophoresis. The retention of VWF in endoplasmic reticulum of transfected cells were detected by immunofluorescence confocal microscope., Results: In the vertical VWF multimer analysis, with co-expressing VWF mutant and VWFpp, the VWF multimer bands disappeared, and the VWF antigen in both supernatant and lysate of cells decreased, compared with the single expression of VWF mutant. Although the intracellular levels of VWF antigens decreased after co-expression, the retention rate of VWF mutant decreased in endoplasmic reticulum., Conclusion: VWFpp can reduce the retention of VWF in endoplasmic reticulum, assists the transport of VWF between subcellular organelles. However, VWFpp inhibits the biosynthesis and secretion of VWF about the mutant in D1 domain.

Background and Objective: Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS., Methods: First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes., Results: Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets., Conclusions: ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS., (© 2022. The Author(s).)

When diffusion coefficients of different components in a mixture are similar, NMR spectra of pure individual components are difficult to be obtained via a diffusion-ordered spectroscopy (DOSY) experiment. Two-dimensional correlation spectroscopy (2D-COS) is used to analyze the data from the DOSY experiment. Through the properties of the systematic absence of cross-peak (SACP) in the 2D asynchronous spectra, spectra of pure components can be obtained even if their diffusion coefficients are similar. However, fluctuations in peak-position and peak-width are often unavoidable in NMR spectra, which makes SACPs unrecognizable. To address the problem, a 2D quotient spectrum is used to identify the masked SACPs. However, undesirable interference peaks due to the fluctuations in peak-position and peak-width are still present when we extract a spectrum of a component by slicing the 2D asynchronous spectrum across the SACP. A genetic algorithm (GA) is used to select a suitable subset of spectra where the diversities of peak-position and peak-width are significantly reduced. Then, we used the selected spectra to construct a refined 2D asynchronous spectrum so that the spectra of pure components with significant attenuated interference can be obtained. The above approach has been proven to be effective on a model system and a real-world example, demonstrating that 2D-COS possesses a bright perspective in the analysis of the bilinear data from DOSY experiments.

ROS1 is a proto-oncogene encoding a receptor tyrosine protein kinase (RTK), homologous to the v - Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, whose ligands are still being investigated. ROS1 fusion genes have been identified in various types of tumours. As an oncoprotein, it promotes cell proliferation, activation and cell cycle progression by activating downstream signalling pathways, accelerating the development and progression of non-small cell lung cancer (NSCLC). Studies have demonstrated that ROS1 inhibitors are effective in patients with ROS1-positive NSCLC and are used for first-line clinical treatment. These small molecule inhibitors provide a rational therapeutic option for the treatment of ROS1-positive patients. Inevitably, ROS1 inhibitor resistance mutations occur, leading to tumours recurrence or progression. Here, we comprehensively review the identified biological properties and Differential subcellular localisation of ROS1 fusion oncoprotein promotes tumours progression. We summarise recently completed and ongoing clinical trials of the classic and new ROS1 inhibitors. More importantly, we classify the complex evolving tumours cell resistance mechanisms. This review contributes to our understanding of the biological properties of ROS1 and current therapeutic advances and resistant tumours cells, and the future directions to develop ROS1 inhibitors with durable effects.