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Introduction: Combination immunotherapy holds promise for improving survival in responsive glioblastoma (GBM) patients. Programmed death-ligand 1 (PD-L1) expression in immune microenvironment (IME) is the most important predictive biomarker for immunotherapy. Due to the heterogeneous distribution of PD-L1, post-operative histopathology fails to accurately capture its expression in residual tumors, making intra-operative diagnosis crucial for GBM treatment strategies. However, the current methods for evaluating the expression of PD-L1 are still time-consuming., Objective: To overcome the PD-L1 heterogeneity and enable rapid, accurate, and label-free imaging of PD-L1 expression level in GBM IME at the tissue level., Methods: We proposed a novel intra-operative diagnostic method, Machine Learning Cascade (MLC)-based Raman histopathology, which uses a coordinate localization system (CLS), hierarchical clustering analysis (HCA), support vector machine (SVM), and similarity analysis (SA). This method enables visualization of PD-L1 expression in glioma cells, CD8 + T cells, macrophages, and normal cells in addition to the tumor/normal boundary. The study quantified PD-L1 expression levels using the tumor proportion, combined positive, and cellular composition scores (TPS, CPS, and CCS, respectively) based on Raman data. Furthermore, the association between Raman spectral features and biomolecules was examined biochemically., Results: The entire process from signal collection to visualization could be completed within 30 min. In an orthotopic glioma mouse model, the MLC-based Raman histopathology demonstrated a high average accuracy (0.990) for identifying different cells and exhibited strong concordance with multiplex immunofluorescence (84.31 %) and traditional pathologists' scoring (R 2  ≥ 0.9). Moreover, the peak intensities at 837 and 874 cm -1 showed a positive linear correlation with PD-L1 expression level., Conclusions: This study introduced a new and extendable diagnostic method to achieve rapid and accurate visualization of PD-L1 expression in GBM IMB at the tissular level, leading to great potential in GBM intraoperative diagnosis for guiding surgery and post-operative immunotherapy., 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. Production and hosting by Elsevier B.V.)

Precise identification of glioblastoma (GBM) microinfiltration, which is essential for achieving complete resection, remains an enormous challenge in clinical practice. Here, the study demonstrates that Raman spectroscopy effectively identifies GBM microinfiltration with cellular resolution in clinical specimens. The spectral differences between infiltrative lesions and normal brain tissues are attributed to phospholipids, nucleic acids, amino acids, and unsaturated fatty acids. These biochemical metabolites identified by Raman spectroscopy are further confirmed by spatial metabolomics. Based on differential spectra, Raman imaging resolves important morphological information relevant to GBM lesions in a label-free manner. The area under the receiver operating characteristic curve (AUC) for Raman spectroscopy combined with machine learning in detecting infiltrative lesions exceeds 95%. Most importantly, the cancer cell threshold identified by Raman spectroscopy is as low as 3 human GBM cells per 0.01 mm 2 . Raman spectroscopy enables the detection of previously undetectable diffusely infiltrative cancer cells, which holds potential value in guiding complete tumor resection in GBM patients., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Ethnopharmacological Relevance: Celosia Semen (CS) serves as a traditional Chinese medicine (TCM) for promoting liver health and enhancing vision, with extensive clinical applications. Triterpenoid saponins represent the primary active components of CS, with the highest concentration of Celosin I (CI) detected. The urgent need for effective NAFLD treatments motivated us assess the beneficial effects of total saponins from CS (TSCS) and CI., Aims of the Study: To investigate the therapeutic effects of TSCS and CI on NAFLD and its underlying molecular mechanisms., Materials and Methods: The impact of TSCS and CI on NAFLD was evaluated through in vitro and in vivo methodologies, utilizing high-fat diet (HFD) and palmitic acid/oleic acid modeling on C57BL/6J mice and AML12 cells, respectively. Biochemical analysis, H&E and Oil red O staining were used to characterize the lipid-lowering and hepatoprotective activities of TSCS and CI. Lipidomics discerned the impact of TSCS and CI interventions on liver lipid composition, distribution and alteration in NFALD mice. RT-qPCR and western blotting detected the influence of TSCS and CI on genes linked to de novo lipogenesis, fat calculation uptake, oxidation and esterification. The docking analysis anticipated the interaction of six major triterpenoid saponins within TSCS with SREBP1., Results: TSCS and CI markedly diminished lipid accumulation induced by high fat both in vivo and in vitro. TSCS and CI also mitigated hepatic steatosis and liver injury induced by HFD through the reduction of TC, TG, FAs, ALT, and AST, even at minimal dose of 25 mg/kg. Lipidomics indicated that TSCS and CI had the potential to modulate the lipid metabolism network, rectify lipid metabolic dysregulation induced by NAFLD, decrease the levels of harmful lipids, and elevate the levels of advantageous lipids. Furthermore, TSCS and CI exhibited a strong affinity to SREBP1, thereby might directly influence the expression of SREBP1 and a cascade of essential enzymes involved in de novo lipogenesis, and finally resulting in a diminished synthesis of novel lipids., Conclusion: TSCS and CI were confirmed firstly as key active components of CS in amending hepatic steatosis and mitigate liver damage in NAFLD, outlining the preliminary mechanism. They warrant further exploration as drug candidates for NAFLD treatment, especially in light of the current shortage of medications and limited therapeutic options., Competing Interests: Declaration of competing interest The authors declared no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Acute kidney injury (AKI) is a severe condition in hospitalized patients and carries high mortality. The influence of statin use on the outcomes of AKI patients remains inconsistent. We aimed to discover the association between statin use and in-hospital mortality., Methods: This retrospective study screened all adult admissions in Peking University First Hospital between 1 January 2018 and 31 December 2020, and patients with AKI during hospitalization were included. Exposure was defined as any statin prescription prior to AKI onset. Patients were followed up until death or discharge. The primary outcome was in-hospital all-cause mortality; secondary outcomes included cardiovascular- and sepsis-related mortality, elevated transaminases, rhabdomyolysis and kidney nonrecovery at discharge., Results: A total of 2034 AKI patients were included. 551 (27%) patients were statin users. During a median of 10 days of follow-up, we documented 283 (14%) in-hospital deaths. Compared with statin nonusers, statin users experienced a significantly lower risk in in-hospital all-cause mortality (adjust hazard ratio [aHR], 0.54; 95% CI, 0.35-0.84) and cardiovascular-related mortality (aHR, 0.48; 95% CI, 0.24-0.97) after covariate adjustment. The survival benefit of statin use was consistent across subgroups, that is, age, sex, initial AKI stage and major surgery (all P for heterogeneity >.05). For sepsis-related mortality, elevated transaminases, rhabdomyolysis and kidney nonrecovery, the association was no longer significant in the fully adjusted model. For any type of statins, a statistically significant association was only observed in atorvastatin (aHR, 0.49; 95% CI, 0.30-0.81)., Conclusions: Statin use may improve survival, and atorvastatin may be preferred in patients with AKI., (© 2024 Asian Pacific Society of Nephrology.)

Background: Toxic components frequently exhibit unique characteristics and activities, offering ample opportunities for the advancement of anti-cancer medications. As the main hepatotoxic component of Dioscorea bulbifera L. (DB), Diosbulbin B (DIOB) has been widely studied for its anti-tumor activity at nontoxic doses. However, the effectiveness and mechanism of DIOB against non-small cell lung cancer (NSCLC) remains unclear., Purpose: To evaluate the anti-NSCLC activity of DIOB and to elucidate the specific mechanism of action., Method: The effect of DIOB on NSCLCL in vitro was evaluated through CCK8, colony formation, and flow cytometry. The in vivo efficacy and safety of DIOB in treating NSCLC were assessed using various techniques, including HE staining, tunel staining, immunohistochemistry, and biochemical index detection. To understand the underlying mechanism, cell transfection, western blotting, molecular docking, cellular thermal shift assay (CESTA), and surface plasmon resonance (SPR) were employed for investigation., Results: DIOB effectively hindered the progression of NSCLC both in vitro and in vivo settings at a no-observed-adverse-effect concentration (NOAEC) and a safe dosage. Specifically, DIOB induced significant G0/G1 phase arrest and apoptosis in A549, PC-9, and H1299 cells, while also notably inhibiting the growth of subcutaneous tumors in nude mice. Mechanistically, DIOB could directly interact with oncogene Yin Yang 1 (YY1) and inhibit its expression. The reduction in YY1 resulted in the triggering of the tumor suppressor P53, which induced cell cycle arrest and apoptosis in NSCLC cells by inhibiting the expression of Cyclin A2, B2, CDK1, CDK2, CDK4, BCL-2, and inducing the expression of BAX. In NSCLC cells, the induction of G0/G1 phase arrest and apoptosis by DIOB was effectively reversed when YY1 was overexpressed or P53 was knocked down. Importantly, we observed that DIOB exerted the same effect by directly influencing the expression of YY1-regulated c-Myc and BIM, particularly in the absence of P53., Conclusion: For the inaugural investigation, this research unveiled the anti-NSCLC impact of DIOB, alongside its fundamental mechanism. DIOB has demonstrated potential as a treatment agent for NSCLC due to its impressive efficacy in countering NSCLC., Competing Interests: Declaration of competing interest The authors declared no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Visible light-induced, transition metal-free oxidative dehydroxylation and C-H amidation of α-hydroxy ketones involving Ritter-type amidation has been developed, leading to the selective synthesis of α,α-diamido- and α-monoamido ketones with tunable selectivity as well as broad substrate tolerance.

Background: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism., Purpose: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH)., Methods: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling., Results: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation., Conclusion: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The radical 1,4-functionalizations of 1,3-enynes have emerged as a powerful strategy for the synthesis of multisubstituted allenes. However, the phosphorus-centered radical-initiated transformations remain largely elusive. Herein, visible-light photoredox catalytic regioselective radical hydrophosphinylation of 1,3-enynes with diaryl phosphine oxides as phosphinoyl radical precursors has been realized. This protocol features mild conditions, a wide substrate scope, and good functional group tolerance, producing a diverse range of phosphinoyl-substituted allenes in moderate to good yields with high atom economy. Detailed mechanistic experiments revealed a radical-polar crossover process in the reaction.

The saponin-enriched extract from Celosiae Semen is a promising resource owing to its lipid-lowering activity. However, triterpenoid saponins are difficult to extract owing to their high molecular weight and strong water solubility. The aim of this paper was to explore an eco-friendly and effective technology of extraction and enrichment of total triterpenoid saponins to obtain high lipid-lowering fractions. Initially, Box-Behnken design experiments were employed to optimize the heat reflux extraction process on the basic of mono-factor experiments. Afterwards, the crude extract was further purified using D-101 resin, and the purification parameters were investigated based on adsorption/desorption experiments and biological activity assay. Under optimal conditions, the purity of the finally obtained total triterpenoid saponins was increased by 7.28-fold. The lipid-lowering activities of the six main triterpenoid saponins were evaluated in HepG2 cells induced by palmitic acid. The results of Oil Red O staining showed that the compounds all exhibited potential lipid-lowering activity. The structure-activity relationship analysis suggested that the oligosaccharide chain at C-28 played an essential role in their lipid-lowering activity and the substituent group at C-23 site also showed important effects. The optimal extraction and purification methods may facilitate the utilization of Celosiae Semen for the industrial production as a functional food and drug., (© 2024 John Wiley & Sons Ltd.)

Objectives: To investigate the risk factors for the failure of ibuprofen treatment in preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA)., Methods: A retrospective collection of clinical data was conducted on preterm infants with a gestational age of <34 weeks who were diagnosed with hsPDA and treated at the Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, from January 2018 to June 2023. The subjects were divided into two groups based on the treatment approach: the ibuprofen group (95 cases) and the ibuprofen plus surgery group (44 cases). The risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA were identified by binary logistic regression analysis., Results: The binary logistic regression analysis revealed that an increased diameter of the ductus arteriosus, a resistance index (RI) value of the middle cerebral artery ≥0.80, and prolonged total invasive mechanical ventilation time were risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA ( P <0.05). Receiver operating characteristic curve analysis showed that a ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days had significant predictive value for the failure of ibuprofen treatment in preterm infants with hsPDA ( P <0.05). The combined predictive value of these three factors was the highest, with an area under the curve of 0.843, a sensitivity of 86.5%, and a specificity of 75.0% ( P <0.05)., Conclusions: A ductus arteriosus diameter >2.85 mm, a middle cerebral artery RI value ≥0.80, and a total invasive mechanical ventilation time >16 days are risk factors for the failure of ibuprofen treatment in preterm infants with hsPDA, and they are of significant predictive value for the necessity of surgical treatment following the failure of ibuprofen treatment.

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2 + lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed "Nanoengineered RBCs," for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Cascade reactions represent an efficient and economical synthetic approach, enabling the rapid synthesis of a wide array of structurally complex organic compounds. These compounds, previously inaccessible, can now be synthesized in a remarkably limited number of steps. Concurrently, the photochemical reactions of organic molecules have gained prominence as a potent strategy for accessing a diverse range of radical species and intermediates. This is achieved in a controlled manner under mild conditions. Owing to the relentless endeavors of chemists, significant strides have been made in the realm of photochemical cascade reactions. These advancements have facilitated the synthesis of novel molecular structures with high complexity, structures that are typically challenging to generate under thermal conditions. In this review, we comprehensively summarize and underscore the recent pivotal advancements in visible-light-induced cascade reactions. Our focus is on the elucidation of multiple photochemical catalytic cycles, emphasizing the catalytic activation modes and the types of reactions involved.

Objectives: This study was performed to explore the preventive and therapeutic effects of Lactobacillus plantarum ZFM4 on H. pylori infections of the stomach tissue in C57BL/6 mice., Methods: In this study, 40 specific-pathogen-free female C57BL/6 mice were randomly divided into five groups, namely, the control, ZFM4 pretreatment) ZFM4 pretreatment before H. pylori infected), model ( H. pylori infected), triple therapy ( H. pylori infected and treated with triple therapy), and ZFM4 treatment groups ( H. pylori infected and treated with ZFM4). The preventive and therapeutic effects of Lactobacillus plantarum ZFM4 were evaluated in H. pylori- infected C57BL/6 mice by assessing gastric tissue morphology, inflammatory cytokine levels, microbial composition, and microbial diversity., Results: Lactobacillus plantarum ZFM4 was able to survive in low gastric pH and play a role in preventing H. pylori infection. This was evident from a reduction in both, the gastric inflammatory response and expression of inflammatory factors caused by H. pylori infection. Lactobacillus plantarum ZFM4 could also inhibit the growth of H. pylori via its beneficial impact on the gastric microbiota., Conclusion: Our findings suggest that Lactobacillus plantarum ZFM4 offers superior preventive effects against H. pylori infections when used alone. However, the therapeutic effect on established infections is weaker. Further clinical trials are needed to confirm the specific dosage, duration, and other aspects of administration., 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 Yu, Wu, Sun, Gu and Zhou.)

Electroencephalography (EEG) is a non-invasive measurement method for brain activity. Due to its safety, high resolution, and hypersensitivity to dynamic changes in brain neural signals, EEG has aroused much interest in scientific research and medical fields. This article reviews the types of EEG signals, multiple EEG signal analysis methods, and the application of relevant methods in the neuroscience field and for diagnosing neurological diseases. First, three types of EEG signals, including time-invariant EEG, accurate event-related EEG, and random event-related EEG, are introduced. Second, five main directions for the methods of EEG analysis, including power spectrum analysis, time-frequency analysis, connectivity analysis, source localization methods, and machine learning methods, are described in the main section, along with different sub-methods and effect evaluations for solving the same problem. Finally, the application scenarios of different EEG analysis methods are emphasized, and the advantages and disadvantages of similar methods are distinguished. This article is expected to assist researchers in selecting suitable EEG analysis methods based on their research objectives, provide references for subsequent research, and summarize current issues and prospects for the future., (© 2023. The Author(s).)

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC 50  = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma., 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 Masson SAS. All rights reserved.)

We present numerical results for three-dimensional (3D) solitons with symmetries of the semi-vortex (SV) and mixed-mode (MM) types, which can be created in spinor Bose-Einstein condensates of Rydberg atoms under the action of the spin-orbit coupling (SOC). By means of systematic numerical computations, we demonstrate that the interplay of SOC and long-range spherically symmetric Rydberg interactions stabilize the 3D solitons, improving their resistance to collapse. We find how the stability range depends on the strengths of the SOC and Rydberg interactions and the soft-core atomic radius., (© 2023. Springer Nature Limited.)

Ormosia hosiei Hemsl. et Wils (Fabaceae family) is an arbor species endemic to China. The seeds of O. hosiei have been used as traditional Chinese medicine to treat hernia, abdominal pain, blood stasis and amenorrhea. Cytisine-like and angustifoline type alkaloids were main components identified from this plant. In our research on the bioactive alkaloids from the promising Chinese medicinal plants, four new angustifoline type alkaloids (1-4) and a new cytisine-like alkaloid (5), named hosimosine A-E, together with 13 known analogues (6-18) were isolated from the seeds of O. hosiei. Their structures were elucidated by the extensive spectroscopic methods, especially the interpretation of NMR spectra and specific rotations, along with the methods of NMR and ECD calculation. Compounds 1-4 were identified as two pairs of epimers, whose relative configurations were deduced from density functional theory (DFT) calculations of NMR chemical shifts and DP4+ analysis, and absolute configurations were determined by comparison of their experimental and theoretical ECD spectra. Compound 5 displayed two sets of NMR data caused by the existence of tautomeric forms. Compounds 14, 17 and 18 were determined to be enantiomers of literature compounds. Some of the isolates exhibited moderate cytotoxic effects against HepG2, A2780 and MCF-7 cells., 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 B.V. All rights reserved.)

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

Cerium element with a unique electric structure can be used to modify semiconductor photocatalysts to enhance their photocatalytic performances. In this work, Ce-doped TiO 2 (Ce/TiO 2 ) was successfully achieved using the sol-gel method. The structural characterization methods confirm that Ce was doped in the lattice of anatase TiO 2 , which led to a smaller grain size. The performance test results show that the Ce doped in anatase TiO 2 significantly enhances the charge transport efficiency and broadens the light absorption range, resulting in higher photocatalytic performance. The Ce/TiO 2 exhibited a photocurrent density of 10.9 μA/cm 2 at 1.0 V vs. Ag/AgCl, 2.5 times higher than that of pure TiO 2 (4.3 μA/cm 2 ) under AM 1.5 G light. The hydrogen (H 2 ) production rate of the Ce/TiO 2 was approximately 0.33 μmol/h/g, which is more than twice as much as that of the pure anatase TiO 2 (0.12 μmol/h/g). This work demonstrates the effect of Ce doping in the lattice of TiO 2 for enhanced photocatalytic hydrogen production.

The development and application of traditional drugs represented by small molecule chemical drugs and biological agents, especially inhibitors, have become the mainstream drug development. In recent years, targeted protein degradation (TPD) technology has become one of the most promising methods to remove specific disease-related proteins using cell self-destruction mechanisms. Many different TPD strategies are emerging based on the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), including but not limited to proteolysis-targeting chimeras (PROTAC), molecular glues (MG), lysosome targeting chimeras (LYTAC), chaperone-mediated autophagy (CMA)-targeting chimeras, autophagy-targeting chimera (AUTAC), autophagosome-tethering compound (ATTEC), and autophagy-targeting chimera (AUTOTAC). The advent of targeted degradation technology can change most protein targets in human cells from undruggable to druggable, greatly expanding the therapeutic prospect of refractory diseases such as metabolic syndrome. Here, we summarize the latest progress of major TPD technologies, especially in metabolic syndrome and look forward to providing new insights for drug discovery., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by oxidative stress that triggers motor neurons loss in the brain and spinal cord. However, the mechanisms underlying the exact role of oxidative stress in ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides are known to have extensive physiological and pathological consequences to tissues. Here, we discovered that the deficiency of glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led to the accumulation of phospholipid peroxides and resulted in a loss of motor neurons in spinal cords of ALS mice. Mutant human SOD1 G93A transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or phospholipid peroxidation inhibitor, ferrostatin-1. The results showed that impaired motor performance and neural loss induced by SOD1 G93A toxicity in the lumbar spine were substantially alleviated by ferrostatin-1 treatment and AAV-mediated GPX4 delivery. In addition, the denervation of neuron-muscle junction and spinal atrophy in ALS mice were rescued by neural GPX4 overexpression, suggesting that GPX4 is essential for the motor neural maintenance and function. In comparison, conditional knockdown of Gpx4 in the spinal cords of Gpx4 fl/fl mice triggered an obvious increase of phospholipid peroxides and the occurrence of ALS-like motor phenotype. Altogether, our findings underscore the importance of GPX4 in maintaining phospholipid redox homeostasis in the spinal cord and presents GPX4 as an attractive therapeutic target for ALS treatment., 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 © 2022. Production and hosting by Elsevier B.V.)

In this work, a simple one-step hydrothermal method was employed to prepare the Ce-doped Fe 2 O 3 ordered nanorod arrays (CFT). The Ce doping successfully narrowed the band gap of Fe 2 O 3 , which improved the visible light absorption performance. In addition, with the help of Ce doping, the recombination of electron/hole pairs was significantly inhibited. The external voltage will make the performance of the Ce-doped sample better. Therefore, the Ce-doped Fe 2 O 3 has reached superior photoelectrochemical (PEC) performance with a high photocurrent density of 1.47 mA/cm 2 at 1.6 V vs. RHE (Reversible Hydrogen Electrode), which is 7.3 times higher than that of pristine Fe 2 O 3 nanorod arrays (FT). The Hydrogen (H 2 ) production from PEC water splitting of Fe 2 O 3 was highly improved by Ce doping to achieve an evolution rate of 21 μmol/cm 2 /h.

Obesity has become one of the most serious public health problems worldwide, and an increasing number of studies indicate that the gut microbiota can affect host metabolism. Therefore, the present study was conducted to evaluate whether long-term use of probiotics can alleviate host obesity and metabolism by altering gut microbiota. The high-fat diet (HFD) starting from weaned period led to higher levels of visceral fat and a significantly heavier liver in male mice. Moreover, HFD resulted in disorders of glucose and lipid metabolism, changes in insulin-resistance indices (IR), and an increase in serum insulin and leptin in mice. Of note, 15 weeks use of Lacticaseibacillus paracasei N1115 decreased visceral fat, liver weight, serum levels of insulin and leptin, and IR and alleviated lipid dysmetabolism. HFD resulted in a significant increase in the relative abundance of Bilophila , Lachnoclostridium , and Blautia and may decrease the faecal short-chain fatty acid (SCFA) levels in mice; in turn, treatment with the potential probiotic strain L. paracasei N1115 protected mice from these negative effects. HFD significant impaired the physiology of the host especially in male mice and dramatically changed the composition of host gut microbiota. However, the use of potential probiotic strain, such as L. paracasei N1115, may prevent these impairments due to HFD via effecting the host gut microbiota and SCFA.

Background and Purpose: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese., Methods: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed., Results: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction., Conclusions: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD., (© 2022 European Academy of Neurology.)

Objective: To explore and study the clinical usefulness of continuous dynamic recording of left cardiac function changes forevaluation the improvement in patients with chronic disease after 3 months of intensive control of individualized precision exercise overall manage program. Methods: From 2018 to 2021, 21 patients with chronic cardiovascular and cerebrovascular metabolic diseases mainly controlled by our team were selected to complete the cardiopulmonary exercise test (CPET) and Non-invasive synchronous cardiac function detector (N-ISCFD), electrocardiogram, radial pulse wave, jugular pulse wave and cardiogram data were continuously recorded for 50s.According to the titration results under CPET and continuous functional parameters monitoring, a holistic plan with individualized moderate exercise intensity as the core was developed for 3 months of intensive management, and then N-ISCFD data collection was repeatedafter signing the informed consent. All N-ISCFD data were analyzed in the 50s according to the optimal report mode of Fuwai Hospital and 52 cardiac functional indexes were calculated. The data before and after the enhanced control were compared and the paired T-test was used to statistically analyze the changes of groups. Results: Twenty-one patients with chronic diseases (16 male and 5 female) were (54.05±12.77,29~75) years, BMI (25.53±4.04,16.62~31.7) kg/m 2 .Comparison with baseline,the whole group analysis: ①The body weight, BMI, systolic blood pressure and diastolic blood pressure of patients were significantly decreased( P ＜0.01).②CPET Peak VO 2 was (64.93±24.22, 26.96~103.48) %Pred before enhanced control, and (85.22±30.31, 43.95~140.48) %Pred after enhanced control, and increased (35.09±27.87, 0.12~129.35) % after enhanced control compared with before enhanced control. The AT, Peak VO 2 /HR, Peak Work Rate, OUEP, FVC, FEV 1 , FEV3/FVC% and MVV were significantly increased ( P ＜0.01) and the Lowest VE/VCO 2 and VE/VCO 2 Slope were significantly decreased( P ＜0.01).③Core indicators of left heart function:Ejection fraction was significantly increased from (0.60±0.12,0.40~0.88) to(0.66±0.09, 0.53~0.87)( P ＜ 0.01), by (12.39±14.90,-12.32~41.11)%. The total peripheral resistance was significantly decreased from (1579.52±425.45,779.46~2409.61) G/(cm 4 ·s),to(1340.44±261.49,756.05~1827.01) G/(cm 4 ·s)( P ＜0.01), by (12.00±17.27,37.79~28.61) %.The left stroke index, cardiac total power, ejective pressure and left ventricular end diastolic volumewere significantly improved ( P ＜0.05).The change analysis of each indicator for each patient is shown in the individualized analysis section of this study. Conclusion: Use CPET and continuous functional monitoring we can safely and effectively develop the overall program of individualized exercise in patients with chronic diseases. Long-term intensive management and control can safely and effectively significantly improve the cardiovascular function of patients. Continuous dynamic recording of changes in left and right cardiac functional parameters can be a simple way to supplement CPET to evaluate cardiovascular function.

Background: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers., Methods: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72 . Forty-one ALS-associated genes were analysed., Findings: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72 , FUS , NEK1 , TARDBP and TBK1 . By burden analysis, rare variants in SOD1 , FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition., Conclusions: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Phospholipid peroxidation of polyunsaturated fatty acids at the bis-allylic position drives ferroptosis. Here we identify a novel role for phospholipid peroxidation in the inhibition of autophagy. Using in vitro and in vivo models, we report that phospholipid peroxidation induced by glutathione peroxidase-4 inhibition and arachidonate 15-lipoxygenase overexpression leads to overload of peroxidized phospholipids and culminate in inhibition of autophagy. Functional and lipidomics analysis further demonstrated that inhibition of autophagy was associated with an increase of peroxidized phosphatidylethanolamine (PE) conjugated LC3. We further demonstrate that autophagy inhibition occurred due to preferential cleavage of peroxidized LC3-PE by ATG4B to yield delipidated LC3. Mouse models of phospholipid peroxidation and autophagy additionally supported a role for peroxidized PE in autophagy inhibition. Our results agree with the recognized role of endoplasmic reticulum as the primary source for autophagosomal membranes. In summary, our studies demonstrated that phospholipid peroxidation inhibited autophagy via stimulating the ATG4B-mediated delipidation of peroxidized LC3-PE., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Deer antler is a globally widely used precious natural medicine and the material of deer horn gelatin. However, identification of deer antler species based on traditional approaches are problematic because of their similarity in appearance and physical-chemical properties. In this study, we performed a comprehensive antler peptidome analysis using a label-free approach: nano LC-Orbitrap MS was applied to discover peptide biomarkers in deer adult beta-globin (HBB A ), and HPLC-Triple Quadrupole MS was used to verify their specificity. Nineteen peptide biomarkers were found, on which foundation a strategy for antlers and a strategy for antler mixtures such as flakes or powder are provided to identify seven species of deer antler including Eurasian elk ( Alces alces ), reindeer ( Rangifer tarandus ), white-tailed deer ( Odocoileus viginianus ), white-lipped deer ( Przewalskium albirostris ), fallow deer ( Dama dama ), sika deer ( Cervus nippon ), and red deer ( Cervus elaphus ) simultaneously. It is worth noting that our search found that the HBB A gene of sika deer, red deer, and North American wapiti ( Cervus canadensis ) in China may have undergone severe genetic drifts.

Silica gel, octadecyl-silica(ODS), Sephadex LH-20, and semi-preparative high performance liquid chromatography(HPLC) was performed to isolate nine cephalotaxine-type alkaloids from Cephalotaxus sinensis: 8-oxodeoxyharringtonine(1), 8-oxonordeoxyharringtonine(2), cephafortunine A(3), 8-oxocephalotaxine(4), deoxyharringtonine(5), acetylcephalotaxine(6), cephalotaxine(7), epicephalotaxine(8), and cephalotaxinone(9). Compounds 1 and 2 were identified for the first time and their structures were determined by high-resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), nuclear magnetic resonance(NMR), and electronic circular dichroism(ECD). Compounds 1-3 and 5 significantly inhibited the transcription of nuclear factor kappa B(NF-κB), with the half-maximal inhibitory concentration(IC&#95;(50)) of(3.91±0.70),(2.99±0.45),(7.84±0.51), and(1.46±0.17) μmol·L~(-1), respectively.

Objective: To compare the reproducibility and performance of quantitative metrics between ZOOMit and conventional intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in the diagnosis of early- and mid-stage Sjögren's syndrome (SS)., Materials and Methods: Twenty-two patients (mean age ± standard deviation, 52.0 ± 10.8 years; male:female, 2:20) with early- or mid-stage SS and 20 healthy controls (46.9 ± 14.6 years; male:female, 7:13) were prospectively enrolled in our study. ZOOMit IVIM and conventional IVIM MRI were performed simultaneously in all individuals using a 3T scanner. Quantitative IVIM parameters - including tissue diffusivity (D), pseudodiffusion coefficient (D * ), and perfusion fraction (f) - inter- and intra-observer reproducibility in measuring these parameters, and their ability to distinguish patients with SS from healthy individuals were assessed and compared between ZOOMit IVIM and conventional IVIM methods, appropriately. MR gland nodular grade (MRG) was also examined., Results: Inter- and intra-observer reproducibility was better with ZOOMit imaging than with conventional IVIM imaging (ZOOMit vs. conventional, intraclass correlation coefficient of 0.897-0.941 vs. 0.667-0.782 for inter-observer reproducibility and 0.891-0.968 vs. 0.814-0.853 for intra-observer reproducibility). Significant differences in ZOOMit f, ZOOMit D * , conventional D * , and MRG between patients with SS and healthy individuals (all p < 0.05) were observed. ZOOMit D * outperformed conventional D * in diagnosing early- and mid-stage SS (area under receiver operating curve, 0.867 and 0.658, respectively; p = 0.002). The combination of ZOOMit D * , MRG, and ZOOMit f as a new diagnostic index for SS, increased diagnostic area under the curve to 0.961, which was higher than that of any single parameter (all p < 0.01)., Conclusion: Considering its better reproducibility and performance, ZOOMit IVIM may be preferred over conventional IVIM MRI, and may subsequently improve the ability to diagnose early- and mid-stage SS., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 The Korean Society of Radiology.)

The globally dominant N 2 -fixing cyanobacteria Trichodesmium and Crocosphaera provide vital nitrogen supplies to subtropical and tropical oceans, but little is known about how they will be affected by long-term ocean warming. We tested their thermal responses using experimental evolution methods during 2 years of selection at optimal (28°C), supra-optimal (32°C) and suboptimal (22°C) temperatures. After several hundred generations under thermal selection, changes in growth parameters, as well as N and C fixation rates, suggested that Trichodesmium did not adapt to the three selection temperature regimes during the 2-year evolution experiment, but could instead rapidly and reversibly acclimate to temperature shifts from 20°C to 34°C. In contrast, over the same timeframe apparent thermal adaptation was observed in Crocosphaera, as evidenced by irreversible phenotypic changes as well as whole-genome sequencing and variant analysis. Especially under stressful warming conditions (34°C), 32°C-selected Crocosphaera cells had an advantage in survival and nitrogen fixation over cell lines selected at 22°C and 28°C. The distinct strategies of phenotypic plasticity versus irreversible adaptation in these two sympatric diazotrophs are both viable ways to maintain fitness despite long-term temperature changes, and so could help to stabilize key ocean nitrogen cycle functions under future warming scenarios., (© 2022 Society for Applied Microbiology and John Wiley & Sons Ltd.)

The highly desirable synthesis of the widely-used primary amides directly from alcohols and ammonia via acceptorless dehydrogenative coupling represents a clean, atom-economical, sustainable process. Nevertheless, such a reaction has not been previously reported, and the existing catalytic systems instead generate other N-containing products, e.g. , amines, imines and nitriles. Herein, we demonstrate an efficient and selective ruthenium-catalyzed synthesis of primary amides from alcohols and ammonia gas, accompanied by H 2 liberation. Various aliphatic and aromatic primary amides were synthesized in high yields, with no observable N-containing byproducts. The selectivity of this system toward primary amide formation is rationalized through density functional theory (DFT) calculations, which show that dehydrogenation of the hemiaminal intermediate into primary amide is energetically favored over its dehydration into imine., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: The present study combined resting-state functional connectivity (FC) and Granger causality analysis (GCA) to explore frontostriatal network dysfunction in unilateral acute tinnitus (AT) patients with hearing loss., Methods: The participants included 42 AT patients and 43 healthy control (HC) subjects who underwent resting-state functional magnetic resonance imaging (fMRI) scans. Based on the seed regions in the frontostriatal network, FC and GCA were conducted between the AT patients and HC subjects. Correlation analyses were used to examine correlations among altered FC values, GCA values, and clinical features in AT patients., Results: Compared with HCs, AT patients showed a general reduction in FC between the seed regions in the frontostriatal network and nonauditory areas, including the frontal cortices, midcingulate cortex (MCC), supramarginal gyrus, and postcentral gyrus (PoCG). Using the GCA algorithm, we detected abnormal effective connectivity (EC) in the inferior occipital gyrus, MCC, Cerebelum&#95;Crus1, and PoCG. Furthermore, correlations between disrupted FC/EC and clinical characteristics, especially tinnitus distress-related characteristics, were found in AT patients., Conclusions: Our work demonstrated abnormal FC and EC between the frontostriatal network and several nonauditory regions in AT patients with hearing loss, suggesting that multiple large-scale network dysfunctions and interactions are involved in the perception of tinnitus. These findings not only enhance the current understanding of the frontostriatal network in tinnitus but also serve as a reminder of the importance of focusing on tinnitus at an early stage., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study aimed to investigate the value and feasibility of combining fractional anisotropy (FA) values from diffusion tensor imaging (DTI) and total kidney volume (TKV) for the assessment of kidney function in chronic kidney disease (CKD)., Materials and Methods: Fifty-one patients were included in this study. All MRI examinations were performed with a 3.0 T scanner. DTI was used to measure FA values, and TKV was obtained from DTI and T2-weighted imaging (T2WI). Patients were divided into three groups (mild, moderate, severe) according to eGFR, which was calculated with serum creatinine. Differences in the FA values of the cortex and medulla were analysed among the three groups, and the relationships of FA values, TKV, and the product of the FA values and TKV with eGFR were analysed. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic efficiency of the FA values, TKV, and the product of the FA values and TKV for kidney function in different CKD stages., Results: Medullary FA values (m-FA), TKV, and the product of the m-FA values and TKV (m-FA-TKV) were significantly correlated with eGFR (r = 0.653, 0.685, and 0.797, respectively; all P < 0.001). ROC curve analysis showed that m-FA-TKV exhibited better diagnostic performance than m-FA values (P = 0.022)., Conclusion: m-FA-TKV obtained by DTI significantly improves the accuracy of kidney function assessment in CKD patients., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Furfural and 5-hydroxymethyl furfural (HMF) are abundantly available biomass-derived renewable chemical feedstocks, and their oxidation to furoic acid and furan-2,5-dicarboxylic acid (FDCA), respectively, is a research area with huge prospective applications in food, cosmetics, optics, and renewable polymer industries. Water-based oxidation of furfural/HMF is a lucrative approach for simultaneous generation of H 2 and furoic acid/FDCA. However, this process is currently limited to (photo)electrochemical methods that can be challenging to control, improve, and scale up. Herein, we report well-defined ruthenium pincer catalysts for direct homogeneous oxidation of furfural/HMF to furoic acid/FDCA, using alkaline water as the formal oxidant while producing pure H 2 as the reaction byproduct. Mechanistic studies indicate that the ruthenium complex not only catalyzes the aqueous oxidation but also actively suppresses background decomposition by facilitating initial Tishchenko coupling of substrates, which is crucial for reaction selectivity. With further improvement, this process can be used in scaled-up facilities for a simultaneous renewable building block and fuel production.

Two unprecedented ent-18,19-dinoricetexane diterpenoid glycosides, named abieshanesides A (1) and B (2), together with seven known compounds, have been isolated from the dead trunks and branches of Abies beshanzuensis M.H. Wu. To our knowledge, abieshanesides A and B represent the first ent-18,19-dinoricetexane diterpenoid glycosides found in natural sources. Their structures and absolute configurations were elucidated by using a combination of spectroscopic techniques and comparison of experimental and calculated electronic circular dichroism (ECD) data. The MTT experiments showed that (E)-resveratrol (7) could inhibit viability of MH7A cells with the IC 50 value of 12.5 μM. Compound 7 was able to block MH7A cell proliferation and was associated with G 0 /G 1 -phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 7 significantly induced the proliferation of MH7A cells in a dose-dependent manner., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To develop a convolutional neural network (CNN) model for the detection, precise anatomical localization (right 1-12th and left 1-12th) and classification (fresh, healing and old fractures) of rib fractures automatically, and to compare the performance with the experienced radiologists., Materials and Methods: A total of 640 rib fracture patients with 340,501 annotations were retrospectively collected from three hospitals. They consisted of a classification training dataset (n = 482), a localization training dataset (n = 30), an internal testing dataset (n = 90) and an external testing dataset (n = 38). RetinaNet with rib localization postprocessing and the result merging technique were employed to structure the CNN model. ROC curve, free-response ROC curve, AUC, precision, recall, and F1-score were calculated to choose the better option between model I (training classification and localization data together) and model II (adding an additional classification model to model I)., Results: The detection and classification performance of rib fractures was better in model II than in model I. The sensitivity of localization reached 97.11% and 94.87% on the right and left ribs, respectively. In the external dataset with different CT scanner and slice thickness, model II showed better diagnostic performance. Moreover, the CNN model was superior in diagnosing fresh and healing fractures to 5 radiologists and consumed shorter diagnosis time., Conclusions: Our CNN model was capable of detection, precise anatomical localization, and classification of rib fractures automatically., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To explore the distribution characteristics of pathogens in adult patients with community-acquired pneumonia (CAP) and to provide basis for the diagnosis, treatment, prevention of CAP. Methods: 1 446 inpatients with CAP were prospectively enrolled in a third-class hospital in Beijing in recent 5 years (from January 2015 to December 2019). Respiratory tract samples were collected for smear, culture, nucleic acid, antigen and antibody detection to identify the pathogen of CAP. Mann-Whitney U test was used for continuous variables and χ 2 test or Fisher's exact test was used for categorical data for statistical analysis. Results: Among the 1 446 patients, 822 (56.85%) patients were infected with a single pathogen, 231 (15.98%) patients were infected with multiple pathogens, and 393 (27.18%) patients were not clear about the pathogen. Influenza virus is the first pathogen of CAP (20.95%, 303/1 446), mainly H1N1 (8.51%, 123/1 446), followed by mycoplasma pneumoniae (7.19%, 104/1 446), Mycobacterium tuberculosis (5.33%, 77/1 446) and Streptococcus pneumoniae (5.05%, 73/1 446). The outbreak of H1N1 occurred from December 2018 to February 2019, and the epidemic of mycoplasma pneumoniae pneumonia was monitored from August to November 2019. Patients under 65 years old had high detection rates of Mycoplasma pneumoniae (14.41% vs. 2.41%, χ²=74.712, P <0.001), Streptococcus pneumoniae (8.16% vs. 2.99%, χ²=18.156, P< 0.001), rhinovirus (6.08% vs. 3.56%, χ²=5.025, P< 0.025), Chlamydia pneumoniae (5.90% vs. 1.15%, χ²=26.542, P< 0.001) and adenovirus (3.13% vs. 0.92%, χ²=9.547, P =0.002). The severe disease rate of CAP was 14.66% (212/1 446), and the average mortality rate was 3.66% (53/1 446). The severe illness rate and mortality rate of bacterial-viral co-infection were 28.97% (31/107) and 19.63% (21/107), respectively. Conclusions: Influenza virus is the primary pathogen of adult CAP. Outbreaks of Mycoplasma pneumoniae and H1N1 were detected in 2018 and 2019, respectively. The remission rate and mortality rate of virus-bacteria co-infection were significantly higher than those of single pathogen infection. Accurate etiological basis not only plays a role in clinical diagnosis and treatment, but also provides important data support for prevention and early warning.

A cooperative Rh(II)/Pd(0) dual-catalysis strategy that promotes a cyclization/allylic alkylation cascade of stable α-diazo-δ-keto-esters has been developed. Highly substituted 3(2 H )-furanones with a C2-quaternary center can be obtained efficiently under mild conditions via one-pot synthesis. Remarkably, this binary catalytic system shows high chemo-, regio-, and stereoselectivity and excellent tolerance to various functionalities.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, P meta  = 8.36 × 10 -8 , OR = 1.29; rs7259428, 19q12, ZNF536, P meta  = 7.58 × 10 -8 , OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, P meta  = 1.95 × 10 -8 ; rs2414487, 15q21.3, LOC145783, P meta  = 4.53 × 10 -9 ; rs2106525, 7q31.1, MDFIC, P meta  = 6.24 × 10 -9 ). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice., (© 2021. The Author(s).)

A LC-Q-Orbitrap HRMS analytical method for both qualitative screening and quantitative determination of 90 synthetic dyes including ten groups of isomers in foods has been established. An in-house synthetic dyes database and characteristic ions were also developed. Based on Q-Orbitrap HRMS, mass spectrum and fragmentation patterns of synthetic dyes were studied, which indicated that double charged ions were usually the main precursor ions. Matrix effects were successfully eliminated by the C 18 d-SPE clean-up coupled with dilute and shoot approach with methanol-water (1:4, v/v) in 100-fold. For most of the compounds, mean recoveries were satisfactory between 70% and 120% with RSD < 20% at three spiked level in the range of 0.025-1.0 mg/kg. The screening detection limits ranged from 0.025 - 1.0 mg/kg. Method validation showed that the established method was efficient, rapid and high-throughput, which has been successfully applied to the monitoring of these water-soluble synthetic dyes in foods., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An investigation on the extract from the plant Trichilia sinensis Bentv. led to the isolation of 13 new limonoids (1-13), in which two were of khayalactone skeleton and 11 were phragmalin-type limonoids, and eight known phragmalin-type limonoids (14-21). Their structures were elucidated by using spectroscopic techniques and HRESIMS experiment. Compounds 6 and 17 displayed potent protein tyrosine phosphatase 1B inhibitory activity with IC 50 values of 1.2 ± 0.1 and 8.1 ± 0.5 μM, respectively., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present study aimed to explore associations between brain activity in the auditory cortex and clinical and psychiatric characteristics in patients with migraine without aura (MwoA) during interictal periods. Resting-state data were acquired from patients with episodic MwoA (n = 34) and healthy controls (n = 30). Independent component analysis was used to extract and calculate the resting-state auditory network. Subsequently, we analyzed the correlations between spontaneous activity in the auditory cortex and clinical and psychiatric features in interictal MwoA. Compared with healthy controls, patients with MwoA showed increased activity in the left superior temporal gyrus (STG), postcentral gyrus (PoCG) and insula. Brain activity in the left STG was positively correlated with anxiety scores, and activity in the left PoCG was negatively correlated with anxiety and depression scores. No significant differences were found in intracranial volume between the two groups. This study indicated that functional impairment and altered integration linked to the auditory cortex existed in patients with MwoA in the interictal period, suggesting that auditory-associated cortex disruption as a biomarker may be implemented for the early diagnosis and prediction of neuropsychiatric impairment in interictal MwoA patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Objective: To segment images through an unsupervised method as an alternative to manual labeling., Methods: A total of 100 whole slide image (WSI) data of HE stained and Pap stained slides were selected as the research and test objects, including 70 breast slides, 20 lung slides and 10 thyroid slides. In order to ensure the diversity of data, the breast slides included those of normal tissue, inflammation and tumor, the lung slides were mainly neoplasms in the lower lobe, including those of inflammation and tumor, and the thyroid slides were of cells, all benign, obtained through fine needle aspiration. The maximum total magnification (original magnification) of each image was 400 times, and the file format was NDPI. Each WSI was manually labeled, and the labeled area of each WSI was more than 10 fields of vision. The labeled information was to be used for validity verification. An unsupervised image segmentation technique based on superpixel and fully convolution neural network algorithms was constructed and used to segment any region of interest (ROI) of unlabeled WSI. In comparison with the region adjacency graph merging method, the segmentation effect of the two methods was assessed with the under segmentation error, the boundary recall and the mean Intersection-over-Union, and the efficiency of the two methods was also compared. In the comparison of execution efficiency, the test process included the preprocessing time of superpixel, and excluded the time of loading the deep learning engine., Results: Unsupervised automatic segmentation was implemented for any ROI region of WSI according to the texture and color. The results of the breast slides, lung slides and thyroid slides showed slight differences, and multiple tests yielded stable results. However, the performance of this method in differentiating inflammation and tumor was average. The under-segmentation error, the boundary recall and the mean Intersection-over-Union were 19.10%, 82.06% and 45.06%, respectively. The under segmentation error, the boundary recall and the mean Intersection-over-Union for the region adjacency graph merging method were 21.52%, 78.39% and 44.81%, respectively. The average time consumption of the whole process was 0.27 s in GPU mode and 1.30 s in CPU mode. The average time consumption of the region adjacency graph merging method was 10.5 s in CPU mode because the method of region adjacency graph merging was not realized in the GPU mode., Conclusion: This method produced ideal pixel level labeling results through simple human-computer interaction, which could effectively reduce the cost of digital pathology slide data labeling. Compared with the region adjacency graph merging method, this method had better performance in processing image texture and had faster processing speed., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

A simple and efficient system for the hydration and α-deuteration of nitriles to form amides, α-deuterated nitriles, and α-deuterated amides catalyzed by a single pincer complex of the earth-abundant manganese capable of metal-ligand cooperation is reported. The reaction is selective and tolerates a wide range of functional groups, giving the corresponding amides in moderate to good yields. Changing the solvent from tert -butanol to toluene and using D 2 O results in formation of α-deuterated nitriles in high selectivity. Moreover, α-deuterated amides can be obtained in one step directly from nitriles and D 2 O in THF. Preliminary mechanistic studies suggest the transformations contributing toward activation of the nitriles via a metal-ligand cooperative pathway, generating the manganese ketimido and enamido pincer complexes as the key intermediates for further transformations., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Objective: To study the different methods of artificial intelligence (AI)-assisted Ki-67 scoring of clinical invasive ductal carcinoma (IDC) of the breast and to compare the results., Methods: A total of 100 diagnosed IDC cases were collected, including slides of HE staining and immunohistochemical Ki-67 staining and diagnosis results. The slides were scanned and turned into whole slide image (WSI), which were then scored with AI. There were two AI scoring methods. One was fully automatic counting by AI, which used the scoring system of Ki-67 automatic diagnosis to do counting with the whole image of WSI. The second method was semi-automatic AI counting, which required manual selection of areas for counting, and then relied on an intelligent microscope to conduct automatic counting. The diagnostic results of pathologists were taken as the results of pure manual counting. Then the Ki-67 scores obtained by manual counting, semi-automatic AI counting and automatic AI counting were pairwise compared. The Ki-67 scores obtained from the manual counting (pathological diagnosis results), semi-automatic AI and automatic AI counts were pair-wise compared and classified according to three levels of difference: difference ≤10%, difference of >10%-<30% and difference ≥30%. Intra-class correlation coefficient ( ICC ) was used to evaluate the correlation., Results: The automatic AI counting of Ki-67 takes 5-8 minutes per case, the semi-automatic AI counting takes 2-3 minutes per case, and the manual counting takes 1-3 minutes per case. When results of the two AI counting methods were compared, the difference in Ki-67 scores was all within 10% (100% of the total), and the ICC index being 0.992. The difference between manual counting and semi-automatic AI was less than 10% in 60 cases (60% of the total), between 10% and 30% in 37 cases (37% of the total), and more than 30% in only 3 cases (3% of the total), ICC index being 0.724. When comparing automatic AI with manual counting, 78 cases (78% of the total) had a difference of ≤10%, 17 cases (17% of the total) had a difference of between 10% and 30%, and 5 cases (5%) had a difference of ≥30%, the ICC index being 0.720. The ICC values showed that there was little difference between the results of the two AI counting methods, indicating good repeatability, but the repeatability between AI counting and manual counting was not particularly ideal., Conclusion: AI automatic counting has the advantage of requiring less manpower, for the pathologist is involved only for the verification of the diagnosis results at the end. However, the semi-automatic method is better suited to the diagnostic habits of pathologists and has a shorter turn-over time compared with that of the fully automatic AI counting method. Furthermore, in spite of its higher repeatability, AI counting, cannot serve as a full substitute for pathologists, but should instead be viewed as a powerful auxiliary tool., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

The current existing methods for the amide bond synthesis via acceptorless dehydrogenative coupling of amines and alcohols all require high reaction temperatures for effective catalysis, typically involving reflux in toluene, limiting their potential practical applications. Herein, we report a system for this reaction that proceeds under mild conditions (reflux in diethyl ether, boiling point 34.6 °C) using ruthenium PNNH complexes. The low-temperature activity stems from the ability of Ru-PNNH complexes to activate alcohol and hemiaminals at near-ambient temperatures through the assistance of the terminal N-H proton. Mechanistic studies reveal the presence of an unexpected aldehyde-bound ruthenium species during the reaction, which is also the catalytic resting state. We further utilize the low-temperature activity to synthesize several simple amide bond-containing commercially available pharmaceutical drugs from the corresponding amines and alcohols via the dehydrogenative coupling method., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Objective: To develop a convolutional neural network (CNN) model for the automatic detection and classification of rib fractures in actual clinical practice based on cross-modal data (clinical information and CT images)., Materials: In this retrospective study, CT images and clinical information (age, sex and medical history) from 1020 participants were collected and divided into a single-centre training set (n = 760; age: 55.8 ± 13.4 years; men: 500), a single-centre testing set (n = 134; age: 53.1 ± 14.3 years; men: 90), and two independent multicentre testing sets from two different hospitals (n = 62, age: 57.97 ± 11.88, men: 41; n = 64, age: 57.40 ± 13.36, men: 35). A Faster Region-based CNN (Faster R-CNN) model was applied to integrate CT images and clinical information. Then, a result merging technique was used to convert 2D inferences into 3D lesion results. The diagnostic performance was assessed on the basis of the receiver operating characteristic (ROC) curve, free-response ROC (fROC) curve, precision, recall (sensitivity), F1-score, and diagnosis time. The classification performance was evaluated in terms of the area under the ROC curve (AUC), sensitivity, and specificity., Results: The CNN model showed improved performance on fresh, healing, and old fractures and yielded good classification performance for all three categories when both clinical information and CT images were used compared to the use of CT images alone. Compared with experienced radiologists, the CNN model achieved higher sensitivity (mean sensitivity: 0.95 > 0.77, 0.89 > 0.61 and 0.80 > 0.55), comparable precision (mean precision: 0.91 > 0.87, 0.84 > 0.77, and 0.95 > 0.70), and a shorter diagnosis time (average reduction of 126.15 s)., Conclusions: A CNN model combining CT images and clinical information can automatically detect and classify rib fractures with good performance and feasibility in actual clinical practice., Key Points: • The developed convolutional neural network (CNN) performed better in fresh, healing, and old fractures and yielded a good classification performance in three categories, if both (clinical information and CT images) were used compared to CT images alone. • The CNN model had a higher sensitivity and matched precision in three categories than experienced radiologists with a shorter diagnosis time in actual clinical practice.