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Yixuan Zeng,1,2,* Wenyuan Guo,1,* Guangqing Xu,3 Qinmei Wang,4 Luyang Feng,1,2 Simei Long,1 Fengyin Liang,1 Yi Huang,1 Xilin Lu,1 Shichang Li,5 Jiebin Zhou,5 Jean-Marc Burgunder,6 Jiyan Pang,5 Zhong Pei1,2 1Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, 2Guangzhou Center, Chinese Huntington’s Disease Network, 3Department of Rehabilitation, The First Affiliated Hospital, 4Key laboratory on Assisted Circulation, Ministry of Health, Department of Cardiovascular Medicine of the First Affiliated Hospital, 5School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 6Swiss Huntington’s Disease Center, Department of Neurology, University of Bern, Bern, Switzerland *These authors contributed equally to this work Abstract: Huntington’s disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington’s disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson’s and Alzheimer’s diseases. To identify potential neuroprotective molecules for Huntington’s disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington’s disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington’s disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results. Keywords: Huntington’s disease, mutant Huntingtin, xyloketal derivatives, Caenorhabditis elegans, protein misfolding, molecular target

Reverse intersystem crossing (RISC) has become possible by minimizing the energy gap between the first excited singlet (S 1 ) and triplet state (T 1 ), which facilitates the thermally activated delayed fluorescence (TADF). Due to the small singlet-triplet energy gap, the S 1 and T 1 states exhibit comparable redox reactivity, leading organic TADF compounds to be potent photocatalysts. Here, we report such TADF compounds with multiple donor units designed as an efficient photocatalyst for the direct C(sp 3 )-H carbamoylation of saturated aza-heterocycles. The results obtained by photophysical investigations and chemical calculations confirm that both the S 1 and T 1 states are involved in the photocatalysis cycle, with the fast spin-flip from the S 1 to triplet states being a crucial factor in the enhancement of catalytic performance. The findings will be beneficial for the design of novel, efficient organic photocatalysis with TADF characteristics and aid in the development of organic photocatalysis.

Industrial biosynthesis of β-nicotinamide mononucleotide (β-NMN) lacks a highly active nicotinamide riboside kinase for the phosphorylation process. Cumbersome preprocessing steps and excessive ATP addition contribute to its increased cost. To tackle these challenges, a docking combination simulation (DCS) semirational mutagenesis strategy was designed in this study, combining various modification strategies to obtain a mutant NRK-TRA with 2.9-fold higher enzyme activity. Molecular dynamics simulations and structural analysis demonstrate the enhancement of its structural stability. High-density fermentation was achieved through a 5 L fermentation tank, with a titer reaching 208.3 U/mL, the highest in the current report. An ATP-cycling whole-cell catalytic system was employed and optimized by introducing a polyphosphate kinase 2 (PPK2) recombinant strain, and 15.16 g/L β-NMN was obtained through a series of batch transformation experiments. This study provides a new strategy for the efficient screening of highly active enzyme variants and offers a green and promising biotransformation system for NMN production.

Objective: To investigate the effect and safety of transradial stent angioplasty using double guide wires for severe stenosis of vertebral artery ostium at a lower location., Methods: Patients with severe stenosis of the vertebral artery ostium at a lower location treated with transradial stent angioplasty were retrospectively enrolled. All the clinical and endovascular treatment data were analyzed., Results: Thirty-nine patients were enrolled. A low location of the vertebral artery ostium was present in 33 (84.6%) patients and an ultra-low location in 6 (15.4%). Transradial stent angioplasty was performed in all patients. In one patient who had a tortuous radial artery, the transradial access was failed. In the other 38 (97.4%) patients, transradial stent angioplasty was all successful. The sharp angle formed between the vertebral artery and the subclavian artery was significantly (P < 0.0001) increased from 15° to 65° (36° ± 11°) before to 70-125° (90° ± 17°) after insertion of a support guide wire. No damage was found in all support guide wires. Thirty-nine stents were deployed, and the preoperative stenosis rate of 70%-98% (85% ± 13%) was significantly (P < 0.0001) decreased to 0-25% (16%) immediately after stenting. Six-12 months after surgery, 29 (74.4% or 29/39) patients were followed up with imaging, and 9 (31.0%) patients experienced in-stent restenosis, with endovascular retreatment being performed in 3 (33.3%) patients., Conclusions: Transradial stent angioplasty using double guide wires is safe and effective for the treatment of severe stenosis of the vertebral artery ostium at a lower location even though more studies are necessary to confirm this., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To investigate the effect and safety of recanalization of stenosed or occluded venous sinuses for dural arteriovenous fistulas (DAVFs) and possible mechanism of DAVF formation, patients with DAVF accompanied by venous sinus stenosis or occlusion treated with balloon angioplasty and/or stenting were retrospectively enrolled. The clinical data, treatment outcomes and complications were analyzed. In 7 patients enrolled, the DAVF was Cognard IIa grade in 3 (42.9% or 3/7) and IIa + b in 4 (57.1% or 4/7) patients, including complex DAVFs in 2 (28.6% or 2/7). The angioplasty procedure was successful in all (100%) patients, including complete cure in 3 (42.9% or 3/7) patients with the initial Cognard grade IIa, transformation from Cognard grade IIa + b to I in 2 (28.6% or 2/7) patients, and unchanged Cognard grade IIa + b in 2 (28.6% or 2/7) patients. The symptoms were all improved. At 3-month angiographic follow-up, 5 (71.4% or 5/7) cases were cured, whereas 2 cases still had grade I fistulas but no clinical symptoms. Staged embolization in 2 patients resulted in significant symptom improvement. At the last follow-up of a median 4 years, no clinical symptoms were present in 5 (71.4% or 5/7) patients, intermittent headache in 1 (14.3% or 1/7), and death from trauma in 1 (14.3% or 1/7). In conclusion, endovascular recanalization of occluded or stenosed venous sinuses using balloon angioplasty and stenting is able to induce occlusion of DAVFs and is a safe and efficient treatment approach for DAVFs which are possibly caused by significant pressure increase., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N 6 -methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Pathogenic bacterial membrane proteins (MPs) are a class of vaccine and antibiotic development targets with widespread clinical application. However, the inherent hydrophobicity of MPs poses a challenge to fold correctly in living cells. Herein, we present a comprehensive method to improve the soluble form of MP antigen by rationally designing multi-epitope chimeric antigen (ChA) and screening two classes of protein-assisting folding element. The study uses a homologous protein antigen as a functional scaffold to generate a ChA possessing four epitopes from transferrin-binding protein A of Glaesserella parasuis. Our engineered strain, which co-expresses P17 tagged-ChA and endogenous chaperones groEL-ES, yields a 0.346 g/L highly soluble ChA with the property of HPS-positive serum reaction. Moreover, the protein titer of ChA reaches 4.27 g/L with >90% soluble proportion in 5-L bioreactor, which is the highest titer reported so far. The results highlight a timely approach to design and improve the soluble expression of MP antigen in industrially viable applications., (© 2024 Wiley Periodicals LLC.)

Background: Development of distant metastasis (DM) is a major concern during treatment of nasopharyngeal carcinoma (NPC). However, studies have demonstrated improved distant control and survival in patients with advanced NPC with the addition of chemotherapy to concomitant chemoradiotherapy. Therefore, precise prediction of metastasis in patients with NPC is crucial., Aim: To develop a predictive model for metastasis in NPC using detailed magnetic resonance imaging (MRI) reports., Methods: This retrospective study included 792 patients with non-distant metastatic NPC. A total of 469 imaging variables were obtained from detailed MRI reports. Data were stratified and randomly split into training (50%) and testing sets. Gradient boosting tree (GBT) models were built and used to select variables for predicting DM. A full model comprising all variables and a reduced model with the top-five variables were built. Model performance was assessed by area under the curve (AUC)., Results: Among the 792 patients, 94 developed DM during follow-up. The number of metastatic cervical nodes (30.9%), tumor invasion in the posterior half of the nasal cavity (9.7%), two sides of the pharyngeal recess (6.2%), tubal torus (3.3%), and single side of the parapharyngeal space (2.7%) were the top-five contributors for predicting DM, based on their relative importance in GBT models. The testing AUC of the full model was 0.75 (95% confidence interval [CI]: 0.69-0.82). The testing AUC of the reduced model was 0.75 (95%CI: 0.68-0.82). For the whole dataset, the full (AUC = 0.76, 95%CI: 0.72-0.82) and reduced models (AUC = 0.76, 95%CI: 0.71-0.81) outperformed the tumor node-staging system (AUC = 0.67, 95%CI: 0.61-0.73)., Conclusion: The GBT model outperformed the tumor node-staging system in predicting metastasis in NPC. The number of metastatic cervical nodes was identified as the principal contributing variable., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Colonoscopy is the most frequently used diagnostic and therapeutic tool for the treatment of colorectal diseases. Although the complication rate is low, it can be potentially serious. Intussusception is a rare and severe complication often associated with polypectomy. Only a handful of post-colonoscopy intussusception cases have been reported, making this study a valuable addition to the medical literature., Case Summary: Case 1: A 61-year-old man underwent colonoscopy with polypectomy for chronic abdominal pain. The patient experienced abdominal pain 11 hours later but was still discharged after pain management. He was readmitted due to recurring pain. Computed tomography (CT) showed colo-colonic intussusception. Initial conservative management and attempts at endoscopic reduction failed; therefore, laparoscopic right hemicolectomy was performed. Histopathological examination revealed tubular adenomas in the polyps and inflammation in the resected specimens. Case 2: A 59-year-old woman underwent colonoscopy with polypectomy for a polyp in the transverse colon. She experienced upper abdominal pain, fever, nausea, and vomiting 9 hours after the procedure. Emergency CT and blood tests revealed a colo-colonic intussusception near the hepatic flexure and an elevated white blood cell count. Initial attempts at endoscopic reduction failed and conservative treatment showed no improvement. She underwent successful laparoscopic reduction and recovered uneventfully. Histopathological examination of the resected polyp revealed hyperplasia., Conclusion: Post-colonoscopy intussusception in adults is rare, and polypectomy may contribute to its occurrence. Early diagnosis is crucial, with prompt CT examination serving as key. After excluding malignancies, conservative management and reduction of intussusception should be considered before surgical bowel resection., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

To investigate the effect and safety of percutaneous endovascular angioplasty (PEA) with optional stenting for the treatment of severe stenosis or occlusion of subclavian artery, patients with severe stenosis ≥ 70% or occlusion of subclavian artery treated with PEA were retrospectively enrolled. The clinical data were analyzed. A total of 222 patients were retrospectively enrolled, including 151 males (68.0%) and 71 females (32.0%) aged 48-86 (mean 63.9 ± 9.0) years. Forty-seven (21.2%) patients had comorbidities. Subclavian artery stenosis ≥ 70% was present in 201 (90.5%) patients and complete subclavian occlusion in 21 (9.5%) cases. Angioplasty was successfully performed in all (100%) patients. Balloon-expandable stents were used in 190 (85.6%) cases, and self-expandable stents in 20 (9.0%) cases. Only 12 (5.4%) cases were treated with balloon dilation only. Among 210 patients treated with stent angioplasty, 71 (33.8% or 71/210) cases underwent balloon pre-dilation, 139 (66.2% or 139/210) had direct deployment of balloon-expandable stents, and 2 (1.0% or 2/210) experienced balloon post-dilation. Distal embolization protection devices were used in 5 (2.3% or 5/222) cases. Periprocedural complications occurred in 3 (1.4%) patients, including aortic dissection in 2 (0.9%) cases and right middle cerebral artery embolism in 1 (0.5%). No hemorrhage occurred. Among 182 (82.0%) patients with 6-month follow-up, restenosis > 70% occurred in 1 (0.5%) patient, and among 68 (30.6%) patients with 12-month follow-up, restenosis > 70% took place in 11 (16.2%) patients. Percutaneous endovascular angioplasty can be safely and efficiently performed for the treatment of severe stenosis ≥ 70% or occlusion of subclavian artery., (© 2024. The Author(s).)

Meningeal lymphatic vessels (MLVs) have crucial roles in removing metabolic waste and toxic proteins from the brain and transporting them to the periphery. Aged mice show impaired meningeal lymphatic function. Nevertheless, as the disease progresses, and significant pathological changes manifest in the brain, treating the condition becomes increasingly challenging. Therefore, investigating the alterations in the structure and function of MLVs in the early stages of aging is critical for preventing age-related central nervous system degenerative diseases. We detected the structure and function of MLVs in young, middle-aged, and aged mice. Middle-aged mice, compared with young and aged mice, showed enhanced meningeal lymphatic function along with MLV expansion and performed better in the Y maze test. Moreover, age-related changes in meningeal lymphatic function were closely associated with vascular endothelial growth factor-C (VEGF-C) expression in the brain cortex. Our data suggested that the cerebral cortex may serve as a target for VEGF-C supplementation to ameliorate meningeal lymphatic dysfunction, thus providing a new strategy for preventing age-related central nervous system diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dual tasks (DTs) combining walking with a cognitive task can cause various levels of cognitive-motor interference, depending on which brain resources are recruited in each case. However, the brain activation and functional connectivity underlying cognitive-motor interferences remain to be elucidated. Therefore, this study investigated the neural correlation during different DT conditions in 40 healthy young adults (mean age: 27.53 years, 28 women). The DTs included walking during subtraction or N-Back tasks. Cognitive-motor interference was calculated, and brain activation and functional connectivity were analysed. Portable functional near-infrared spectroscopy was utilized to monitor haemodynamics in the prefrontal cortex (PFC), motor cortex and parietal cortex during each task. Walking interference (decrease in walking speed during DT) was greater than cognitive interference (decrease in cognitive performance during DT), regardless of the type of task. Brain activation in the bilateral PFC and parietal cortex was greater for walking during subtraction than for standing subtraction. Furthermore, brain activation was higher in the bilateral motor and parietal and PFCs for walking during subtraction than for walking alone, but only increased in the PFC for walking during N-Back. Coherence between the bilateral lateral PFC and between the left lateral PFC and left motor cortex was significantly greater for walking during 2-Back than for walking. The PFC, a critical brain region for organizing cognitive and motor functions, played a crucial role in integrating information coming from multiple brain networks required for completing DTs. Therefore, the PFC could be a potential target for the modulation and improvement of cognitive-motor functions during neurorehabilitation., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The electrochemical performance of pristine metal-organic xerogels as anodes in lithium-ion batteries is reported for the first time. We propose a novel synthesis approach for the in situ generation of highly dispersed, ultrafine cobalt sulfide nanoparticles on humic acid gels (CoSHA). The CoS nanoparticles in CoSHA have an average diameter of approximately 3 nm. CoSHA electrodes demonstrate enhanced lithium storage capacity, delivering a capacity of 662 mAh g -1 at 0.1 A g -1 . They also show stable long-term cycling performance, with no capacity decay after 900 cycles at 1.0 A g -1 . Furthermore, our experiments indicate that the improved lithium-ion adsorption results from the oxygen-containing functional groups in humic acid and the ultrafine CoS active sites. This study offers a practical methodology for synthesizing ultrafine metal sulfides and new insights into using pristine gel-based electrodes for energy storage and conversion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To investigate the significance of atherosclerotic plaque location in hybrid surgery comprising both endovascular recanalization approaches and carotid endarterectomy for symptomatic atherosclerotic non-acute long-segment occlusion of the internal carotid artery (ICA), 162 patients were enrolled, including 120 (74.1%) patients in the proximal plaque group and 42 (25.9%) in the distal plaque group. Surgical recanalization was performed in all patients, with successful recanalization in 119 (99.2%) patients in the proximal and 39 (92.9%) in the distal plaque group. The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162). Periprocedural complications occurred in 5 (4.2% or 5/120) patients in the proximal plaque group, including neck infection in two (1.7%), recurrent nerve injury in 1 (0.8%), and laryngeal edema in 2 (1.7%), and 2 (4.8%) in the distal plaque group, including femoral puncture infection in 2 (4.8%). No severe complications occurred in either group. Univariate analysis showed plaque location was a significant (P = 0.018) risk factor for successful recanalization, and multivariate analysis indicated that the plaque location remained a significant independent risk factor for recanalization success (P = 0.017). In follow-up 6-48 months after the recanalization surgery, reocclusion occurred in two (2.8%) patients in the proximal plaque group and 4 (13.3%) in the distal plaque group. In conclusion, although hybrid surgery achieves similar outcomes in patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques, plaque location may be a significant risk factor for successful recanalization of symptomatic non-acute long-segment ICA occlusion., (© 2024. The Author(s).)

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered., Methods: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo., Results: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice., Conclusion: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Owing to its diverse activation processes including single-electron transfer (SET) and hydrogen-atom transfer (HAT), visible-light photocatalysis has emerged as a sustainable and efficient platform for organic synthesis. These processes provide a powerful avenue for the direct functionalization of C(sp 3 )-H bonds under mild conditions. Over the past decade, there have been remarkable advances in the enantioselective functionalization of the C(sp 3 )-H bond via photocatalysis combined with conventional asymmetric catalysis. Herein, we summarize the advances in asymmetric C(sp 3 )-H functionalization involving visible-light photocatalysis and discuss two main pathways in this emerging field: (a) SET-driven carbocation intermediates are followed by stereospecific nucleophile attacks; and (b) photodriven alkyl radical intermediates are further enantioselectively captured by (i) chiral π-SOMOphile reagents, (ii) stereoselective transition-metal complexes, and (iii) another distinct stereoscopic radical species. We aim to summarize key advances in reaction design, catalyst development, and mechanistic understanding, to provide new insights into this rapidly evolving area of research.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>10 4 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Organic dyads with intramolecular charge-transfer (ICT) character are emerging as viable and more sustainable photocatalysts than metal-based complexes. Herein, a carbazole- and naphthalimide-based organic dyad ( Cz-NI ) was designed as an efficient organic photocatalyst for the direct C(sp 3 )-H carbamoylation of saturated aza-heterocycles. Aiming at understanding the effect of environment, especially the solvent polarity on photocatalysis performance, the excited-state dynamics of Cz-NI in different polar solvents were studied by femtosecond (fs) and nanosecond (ns) time-resolved transient absorption (TA) spectroscopy. Fs-TA measurements indicate that the formation of an intramolecular charge separation (ICS) state with twisted structural feature in polar solvents is driven and stabilized by solvation dynamics. Combined with chemical calculations, we found that orbital decoupling, poor conjugation between Cz and NI groups due to intramolecular torsional motion and transition moments associated with ICT emission, limits excited-state deactivation through radiation and nonradiation transition to the ground state. In addition, the orthogonal π-system of the ICS state enables the efficient spin-orbit, charge-transfer intersystem crossing to a triplet state, which is localized on the NI group. Spectroscopic and computational results reveal the formation of an ICS state at an appropriate energy that enables the population of the triplet state with high quantum yield, and the localized triplet state has long lifetime and high reduction potential for subsequent reactions. Therefore, solvent-solute interaction, especially the solvation-coupled excited-state structural relaxation, is the main factor that the photocatalysis efficiency of Cz-NI has a significant polarity correlation.

Herein we present a novel protocol to access α-functionalized saturated aza-heterocycles, and a variety of nucleophilic groups, such as indole, naphthol, phenol, pyrrole, furyl, nitromethyl, and cyano, could be easily installed into saturated aza-heterocycles. Furthermore, a range of biologically valuable 3,3'-diindolylmethane derivatives could also be readily accessed under mild photocatalytic conditions.

Purpose: This study aims to investigate the effect and feasibility of intra-aortic catheter looping via transradial access in angioplasty for symptomatic intracranial severe (>70%) atherosclerotic stenosis or occlusion of large arteries (SISOLAs)., Materials and Methods: Patients with SISOLAs who underwent transradial endovascular angioplasty using the catheter looping technique in the ascending aorta were retrospectively enrolled. The clinical data and treatment outcomes were analyzed., Results: Fifteen patients aged 48-71 years were enrolled in this study. Left vertebrobasilar artery occlusion was present in 1 (6.7%) patient, severe left middle cerebral artery stenosis in 7 (46.7%) patients, severe left internal carotid artery (ICA) stenosis of the ophthalmic segment in 4 (26.7%) patients, severe left ICA stenosis of the cavernous segment in 2 (13.3%) patients, and severe right middle cerebral artery stenosis in 2 (13.3%) patients. The arterial stenosis ranged from 70 to 92% (mean 86%) before stenting. The looping of a guiding catheter in the ascending aorta via transradial access for angioplasty was successful in all patients (100%). The vertebral artery intracranial segment occlusion was successfully recanalized, while severe stenosis in the remaining 14 patients was successfully eliminated. After endovascular recanalization, the residual stenosis was reduced by 12-26% (median 18%). No puncture-related complications or surgical-related neurological complications occurred in these patients. In the follow-up angiography conducted on 10 (66.7%) patients after 6-25 months, no in-stent restenosis was detected., Conclusion: Intra-aortic guiding catheter looping via transradial access for endovascular angioplasty of SISOLAs is technically safe, feasible, and effective, especially when the transfemoral artery approach is difficult or impossible to undertake., 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 Xu, Xia, Cai, Yang, Zhao, Xue, Wang, Li and Gao.)

The cell cycle regulator cyclin D3 (CCND3) is highly expressed in multiple myeloma (MM) and it promotes MM cell proliferation. After a certain phase of cell cycle, CCND3 is rapidly degraded, which is essential for the strict control of MM cell cycle progress and proliferation. In the present study, we investigated the molecular mechanisms regulating CCND3 degradation in MM cells. By utilizing affinity purification-coupled tandem mass spectrometry, we identified the deubiquitinase USP10 interacting with CCND3 in human MM OPM2 and KMS11 cell lines. Furthermore, USP10 specifically prevented CCND3 from K48-linked polyubiquitination and proteasomal degradation, therefore enhancing its activity. We demonstrated that the N-terminal domain (aa. 1-205) of USP10 was dispensable for binding to and deubiquitinating CCND3. Although Thr283 was important for CCND3 activity, it was dispensable for CCND3 ubiquitination and stability modulated by USP10. By stabilizing CCND3, USP10 activated the CCND3/CDK4/6 signaling pathway, phosphorylated Rb, and upregulated CDK4, CDK6 and E2F-1 in OPM2 and KMS11 cells. Consistent with these findings, inhibition of USP10 by Spautin-1 resulted in accumulation of CCND3 with K48-linked polyubiquitination and degradation that synergized with Palbociclib, a CDK4/6 inhibitor, to induce MM cell apoptosis. In nude mice bearing myeloma xenografts with OPM2 and KMS11 cells, combined administration of Spautin-l and Palbociclib almost suppressed tumor growth within 30 days. This study thus identifies USP10 as the first deubiquitinase of CCND3 and also finds that targeting the USP10/CCND3/CDK4/6 axis may be a novel modality for the treatment of myeloma., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin-4 (AQP4) expressed on the perivascular astrocytic end-feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ-aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABA A R) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation-continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4-dependent manner by activating the GABA A R. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition-related diseases., (© 2023 International Society for Neurochemistry.)

This paper aimed to investigate the role and potential mechanism of p53 on primordial follicle activation. Firstly, the p53 mRNA expression in the ovary of neonatal mice at 3, 5, 7 and 9 days post-partum (dpp) and the subcellular localization of p53 were detected to confirm the expression pattern of p53. Secondly, 2 dpp and 3 dpp ovaries were cultured with p53 inhibitor Pifithrin-μ (PFT-μ, 5 μmol/L) or equal volume of dimethyl sulfoxide for 3 days. The function of p53 in primordial follicle activation was determined by hematoxylin staining and whole ovary follicle counting. The proliferation of cell was detected by immunohistochemistry. The relative mRNA levels and protein levels of the key molecules involved in the classical pathways associated with the growing follicles were examined by immunofluorescence staining, Western blot and real-time PCR, respectively. Finally, rapamycin (RAP) was used to intervene the mTOR signaling pathway, and ovaries were divided into four groups: Control, RAP (1 μmol/L), PFT-μ (5 μmol/L), PFT-μ (5 μmol/L) + RAP (1 μmol/L) groups. The number of follicles in each group was determined by hematoxylin staining and whole ovary follicle counting. The results showed that the expression of p53 mRNA was decreased with the activation of primordial follicles in physiological condition. p53 was expressed in granulosa cells and oocyte cytoplasm of the primordial follicles and growing follicles, and the expression of p53 in the primordial follicles was higher than that in the growing follicles. Inhibition of p53 promoted follicle activation and reduced the primordial follicle reserve. Inhibition of p53 promoted the proliferation of the granulosa cells and oocytes. The mRNA and protein expression levels of key molecules in the PI3K/AKT signaling pathway including AKT, PTEN, and FOXO3a were not significantly changed after PFT-μ treatment, while the expression of RPS6/p-RPS6, the downstream effectors of the mTOR signaling pathway, was upregulated. Inhibition of both p53 and mTOR blocked p53 inhibition-induced primordial follicle activation. Collectively, these findings suggest that p53 may inhibit primordial follicle activation through the mTOR signaling pathway to maintain the primordial follicle reserve.

The underlying mechanisms of Cinnamomum kanehirae -stimulated growth and metabolism of Antrodia camphorata remain unknown. Herein, we first observed that the methanol extract of C. kanehirae trunk (MECK) (2 g/L) showed a potent stimulatory effect on A. camphorata triterpenoids production (115.6 mg/L). Second, MECK treatment considerably increased the category and abundance of many secondary metabolites in the mycelia. We identified 93 terpenoids (8 newly formed and 49 upregulated) in the MECK-treated mycelia, wherein 21 terpenoids were the same as those in the fruiting bodies. Third, 42 out of the 93 terpenoids were annotated in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, mainly involving monoterpenoids and diterpenoids syntheses. Finally, 27 monoterpenes and 16 sesquiterpenes were detected in the MECK, and the two terpenoids with the highest abundance (linalool and α-pinene) were selected for verification and found to considerably increase the terpenoids production of A. camphorata and demonstrate the regulation of mRNA expression levels of nine key genes in the mevalonate pathway via RT-qPCR. This study is beneficial for elucidating the terpenoids synthesis mechanism in A. camphorata .

Purpose: The study aimed to investigate the feasibility and effect of transradial access with intra-aortic catheter looping for the treatment of intracranial aneurysms., Materials and Methods: This retrospective one-center study was performed on patients with intracranial aneurysms which were embolized through transradial access with intra-aortic catheter looping because of the difficulty of transfemoral access or transradial access without intra-aortic catheter looping. The imaging and clinical data were analyzed., Results: A total of 11 patients were enrolled, including seven (63.6%) male patients. Most patients were associated with one or two risk factors of atherosclerosis. There were nine aneurysms in the left internal carotid artery system and two aneurysms in the right internal carotid artery system. All 11 patients had complications with different anatomic variations or vascular diseases, which made endovascular operation via the transfemoral artery difficult or a failure. The right transradial artery approach was adopted in all patients, and the success rate of intra-aortic catheter looping was 100%. Embolization of intracranial aneurysms was successfully completed in all patients. No instability of the guide catheter was encountered. No puncture site complications or surgical-related neurological complications occurred., Conclusion: Transradial access with intra-aortic catheter looping for embolization of intracranial aneurysms is technically feasible, safe, and efficient as an important supplementary approach to the routine transfemoral access or transradial access without intra-aortic catheter looping., 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 Xu, Ba, Cai, Yang, Zhao, Xue, Li and Gao.)

Chronic liver disease or repeated damage to hepatocytes can give rise to hepatic fibrosis. Hepatic fibrosis (HF) is a pathological process of excessive sedimentation of extracellular matrix (ECM) proteins such as collagens, glycoproteins, and proteoglycans (PGs) in the hepatic parenchyma. Changes in the composition of the ECM lead to the stiffness of the matrix that destroys its inherent mechanical homeostasis, and a mechanical homeostasis imbalance activates hepatic stellate cells (HSCs) into myofibroblasts, which can overproliferate and secrete large amounts of ECM proteins. Excessive ECM proteins are gradually deposited in the Disse gap, and matrix regeneration fails, which further leads to changes in ECM components and an increase in stiffness, forming a vicious cycle. These processes promote the occurrence and development of hepatic fibrosis. In this review, the dynamic process of ECM remodeling of HF and the activation of HSCs into mechanotransduction signaling pathways for myofibroblasts to participate in HF are discussed. These mechanotransduction signaling pathways may have potential therapeutic targets for repairing or reversing fibrosis., 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 Zhao, Deng, Xu, Lin, Lu and Chen.)

Introduction: NADH pyrophosphatase, a hydrolase catalyzing the phosphate bond of NADH to reduced nicotinamide mononucleotide, has potential applications in the food, cosmetic and pharmaceutical industry. Methods: Here, we investigated the effects of vector screening, promoter and RBS strategies on NADH pyrophosphatase expression and protein engineering on its enzymatic activity and thermal stability. Results: In this study, we describe a NADH pyrophosphatase derived from Escherichia coli ( EcNudc ). Strategies focusing on expression regulation including screening vectors, optimizing promoters and ribosome binding sites were utilized to enhance the productivity of EcNudc (1.8 U/mL). Moreover, protein engineering was adopted to further improve the catalytic properties of EcNudc , achieving 3.3-fold higher activity and 3.6-fold greater thermostability at 50°C. Furthermore, fermentation for the combined mutant R148A-H149E ( EcNudc-M ) production in a 7 L fermenter was implemented and the enzyme activity of EcNudc-M reached 33.0 U/mL. Finally, the EcNudc-M was applied in the catalysis of NADH with the highest NMNH yield of 16.65 g/L. Discussion: In conclusion, we constructed a commercially available genetically engineered strain with high activity and thermal stability of NADH pyrophosphatase, laying a broad foundation for the biocatalytic industrial production of NMNH and expand its application range., Competing Interests: Authors YL, GM, MH, J-SS, and Z-HX are employed by Yixing Institute of Food and Biotechnology Co., Ltd. and Seragon Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Gong, Marshall, Su, Hall, Li, Xu, Shi and Xu.)

Purpose: To explore the effectiveness of the model based on non-negative matrix factorization (NMF), analyze the tumor microenvironment and immune microenvironment for evaluating the prognosis of lung adenocarcinoma, establish a risk model, and screen independent prognostic factors., Methods: Downloading the transcription data files and clinical information files of lung adenocarcinoma from TCGA database and GO database, the R software was used to establish the NMF cluster model, and then the survival analysis between groups, tumor microenvironment analysis, and immune microenvironment analysis was performed according to the NMF cluster result. R software was used to construct prognostic models and calculate risk scores. Survival analysis was used to compare survival differences between different risk score groups., Results: Two ICD subgroups were established according to the NMF model. The survival of the ICD low-expression subgroup was better than that of the ICD high-expression subgroup. Univariate COX analysis screened out HSP90AA1, IL1, and NT5E as prognostic genes, and the prognostic model established on this basis has clinical guiding significance., Conclusion: The model based on NMF has the prognostic ability for lung adenocarcinoma, and the prognostic model of ICD-related genes has a certain guiding significance for survival., Competing Interests: The authors declare no competing interests., (©2023TheAuthors.PublishedbyElsevierLtd.)

A mild metal-free C-N bond activation strategy for the direct conversion of inert tertiary amines with acyl chlorides into tertiary amides via organic photoredox catalysis is presented. In this protocol, a novel organic photocatalyst (Cz-NI-Ph) that showed excellent catalytic performance during C-N bond cleavage is developed. Moreover, this reaction features green and mild conditions, broad substrate scope, and readily available raw materials.

Hederacoside C (HSC) has attracted much attention as a novel modulator of inflammation, but its anti-inflammatory mechanism remains elusive. In the present study, we investigated how HSC attenuated intestinal inflammation in vivo and in vitro. HSC injection significantly alleviated TNBS-induced colitis by inhibiting pro-inflammatory cytokine production and colonic epithelial cell apoptosis, and partially restored colonic epithelial cell proliferation. The therapeutic effect of HSC injection was comparable to that of oral administration of mesalazine (200 mg·kg -1 ·d -1 , i.g.). In LPS-stimulated human intestinal epithelial Caco-2 cells, pretreatment with HSC (0.1, 1, 10 μM) significantly inhibited activation of MAPK/NF-κB and its downstream signaling pathways. Pretreatment with HSC prevented LPS-induced TLR4 dimerization and MyD88 recruitment in vitro. Quantitative proteomic analysis revealed that HSC injection regulated 18 proteins in the colon samples, mainly clustered in neutrophil degranulation. Among them, S100A9 involved in the degranulation of neutrophils was one of the most significantly down-regulated proteins. HSC suppressed the expression of S100A9 and its downstream genes including TLR4, MAPK, and NF-κB axes in colon. In Caco-2 cells, recombinant S100A9 protein activated the MAPK/NF-κB signaling pathway and induced inflammation, which were ameliorated by pretreatment with HSC. Notably, HSC attenuated neutrophil recruitment and degranulation as well as S100A9 release in vitro and in vivo. In addition, HSC promoted the expression of tight junction proteins and repaired the epithelial barrier via inhibiting S100A9. Our results verify that HSC ameliorates colitis via restoring impaired intestinal barrier through moderating S100A9/MAPK and neutrophil recruitment inactivation, suggesting that HSC is a promising therapeutic candidate for colitis., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

In recent year, widespread declines of Populus bolleana Lauche trees (P. bolleana, which dieback from the top down) and Haloxylon ammodendron shrubs (H. ammodendron, which dieback starting from their outer canopy) have occurred. To investigate how both intra-canopy hydraulic changes and plasticity in hydraulic properties create differences in vulnerability between these two species, we conducted a drought simulation field experiment. We analyzed branch hydraulic vulnerability, leaf water potential (Ψ), photosynthesis (A), stomatal conductance (gs), non-structural carbohydrate (NSCs) contents and morphological traits of the plants as the plants underwent a partial canopy dieback. Our results showed that: (1) the hydraulic architecture was very different between the two life forms; (2) H. ammodendron exhibited a drought tolerance response with weak stomatal control, and thus a sharp decline in Ψ while P. bolleana showed a drought avoidance response with tighter stomatal control that maintained a relatively stable Ψ; (3) the Ψ of H. ammodendron showed relative consistent symptoms of drought stress with increasing plant stature, but the Ψ of P. bolleana showed greater drought stress in higher portions of the crown; (4) prolonged drought caused P. bolleana to consume and H. ammodendron to accumulate NSCs in the branches of their upper canopy. Thus, the prolonged drought caused the shoots of the upper canopy of P. bolleana to experience greater vulnerability leading to dieback of the upper branches first, while all the twigs of the outer canopy of H. ammodendron experienced nearly identical degrees of vulnerability, and thus dieback occurred uniformly. Our results indicate that intra-canopy hydraulic change and their plasticity under drought was the main cause of the observed canopy dieback patterns in both species. However, more work is needed to further establish that hydraulic limitation as a function of plant stature was the sole mechanism for causing the divergent canopy dieback patterns., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Published by Elsevier B.V.)

Background and Purpose: Extracranial artery stenosis (ECAS) is associated with the presence of individual markers of cerebral small vessel disease (CSVD). Here, we investigated the relationship between severe extracranial artery stenosis or occlusion and CSVD in patients with large artery atherosclerotic (LAA) cerebral infarction., Methods: A total of 128 patients with LAA cerebral infarction who met our specific inclusion criteria were selected, including 92 males and 36 females. These patients were divided into three groups based on whether they had severe symptomatic extracranial arterial stenosis or occlusion, severe asymptomatic extracranial artery stenosis or occlusion, or severe extracranial artery stenosis or occlusion (both symptomatic and asymptomatic). Intra-group comparisons were then performed to examine whether there were any differences in the total CSVD scores and Fazekas scores., Results: Patients with severe extracranial arterial stenosis or occlusion and those with severe asymptomatic extracranial arterial stenosis or occlusion had a significantly higher total CSVD score ( P < 0.05), but there were no significant differences between the groups in terms of Fazekas scores. Furthermore, there were no significant difference in the total CSVD scores and Fazekas scores when compared between patients with or without severe symptomatic extracranial arterial stenosis or occlusion., Conclusion: Severe stenosis or occlusion of the contralateral extracranial artery may increase the incidence of CSVD in patients with LAA cerebral infarction. Active and effective clinical intervention following comprehensive evaluation should be undertaken for unilateral cerebral infarction patients with severe stenosis or occlusion of the contralateral extracranial arterial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dai, Yu, Wang, Liu and Xu.)

The optoelectronic properties of two-dimensional (2D) transition metal dichalcogenide (TMDC) monolayers such as WS 2 are largely dominated by excitons due to strong Coulomb interactions in these 2D confined monolayers, which lead to formation of Rydberg-like excitonic states below the free quasiparticle band gap. The precise knowledge of high order Rydberg excitonic states is of great importance for both fundamental understanding such as many-electron effects and device applications such as optical switching and quantum process information. Bright excitonic states could be probed by linear optical spectroscopy, while probing dark excitonic states generally requires nonlinear optical (NLO) spectroscopy. Conventional optical methods for probing high-order Rydberg excitonic states were generally performed at cryogenic temperatures to ensure enough signal-to-noise ratio (SNR) and narrow line width. Here we have designed a hybrid nanostructure of monolayer WS 2 integrated with a plasmonic cavity and investigated their NLO properties at the single particle level. Giant enhancement in NLO responses, stronger excitonic resonance effects, and narrowed line widths of NLO excitation spectra were observed when monolayer WS 2 was placed in our carefully designed plasmonic cavity. Optimum enhancement of 1000-, 3000-, and 3800-fold were achieved for two-photon photoluminescence (2PPL), second harmonic generation (SHG), and third-harmonic generation (THG), respectively, in the optimized cavity structure. The line width of SHG excitation spectra was reduced from 43 down to 15 meV. Plasmon enhanced NLO responses brought improved SNR and spectral resolution, which allowed us to distinguish discrete excitonic states with small energy differences at room temperature. By using three complementary NLO techniques in combination with linear optical spectroscopy, energies of Rydberg excitonic states of A (1s, 2s, 2p, 3s, 3p, 4s), B (1s), and C and D excitons of monolayer WS 2 have been accurately determined, which allow us to determine exciton binding energy and quasiparticle bandgap. It was interesting to find that the 2p lies 30 meV below 2s, which lends strong support to the theoretical prediction of nonlocal dielectric screening effects based on a non-hydrogenic model. Our results show that plasmon enhanced NLO spectroscopy could serve as a general method for probing high order Rydberg excitonic states of 2D materials.

Double perovskites with bright emission, low toxicity, and excellent stability have drawn considerable attention. Herein, we report the hydrothermal synthesis of Mn 2+ -doped Cs 2 Na 1- x Ag x BiCl 6 double perovskites that exhibit dual emission modes. Introducing Ag + ions to Cs 2 NaBiCl 6 samples enables a bright self-trapped exciton (STE) emission in orange-red color, whereas Mn 2+ dopants induce a yellow-orange emission. Importantly, Mn 2+ doping into Cs 2 Na 1- x Ag x BiCl 6 double perovskites with an indirect bandgap enables a high photoluminescence quantum yield of 49.52 ± 2%. Density functional theory calculations reveal that bringing Ag + ions into Cs 2 NaBiCl 6 can localize wave function to the [AgCl 6 ] 5- octahedron and convert dark transitions to bright STE transitions. Moreover, the 3d orbitals of Mn 2+ dopants hybridize with Bi-6p and Cl-3p orbitals at the conduction band minimum, resulting in direct electron transfer from the host to Mn 2+ and a significant increase in photoluminescence efficiency. These results shed light on the optical physical process of Mn 2+ -doped systems, providing useful information for further improvement of the photoluminescence efficiency of double perovskites.

Leaf drought tolerance traits influence plant survival in water deficit conditions, and these traits are influenced by both the plant's evolutionary history and the environment in which the plant is currently growing. However, due to the substantial phenotypic plasticity in leaf traits, we still do not know to what degree variation in leaf traits is governed by species' phylogenetic history or by their environment. To explore this question, we re-examined a drought tolerance dataset from 37 native Australian shrub species with varying climate origins growing in a common garden located in Melbourne, Australia. We previously measured seven leaf morphophysiological traits, and here, we estimated how phylogenetically conserved these traits are. We quantified phylogeny and the strength of correlation between the morphological traits and physiological traits before and after accounting for shared phylogenetic history. We also evaluated the relationship between species' leaf traits and the climate of their native ranges. We present three main findings: (a) most leaf drought tolerance traits had weak phylogenetic signals, which is consistent with the convergent evolution of these traits. (b) There is weak but consistent coordination between distinct leaf drought tolerance traits, which can be masked due to species' phylogenetic histories. (c) Leaf drought tolerance traits show strong correlations with the climate of species' origins, and this relationship is only weakly impacted by phylogenetic signals. Therefore, the role of phylogeny on the coordination among leaf functional traits and their links to climate were limited. A better understanding of trait-environment relationships might be more pivotal than understanding the evolution of these traits for improving the predictions of species' response to climate change-type drought, especially for shrub species that span substantial aridity gradients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Kandlikar and Vaz.)

Background: The current integrated pest management (IPM) curative strategy for soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), relies on responsive spraying foliar insecticides during the R1-R5 soybean stage when aphid abundance reaches the economic threshold (ET) of 250 aphids plant -1 (traditional IPM). By analyzing the relationship between aphid abundance and yield loss before the R1 stage, we developed an early-stage ET. We propose to spray foliar insecticides on plants colonized with aphids using the early-stage ET as a trigger (improved IPM), together with seed treatment to manage A. glycines and delay them exceeding the ET of 250 aphids plant -1 in the late stage for whole-field spraying (traditional IPM). Finally, we compared the cost-benefit probabilities of the three management approaches., Results: The early-stage ET over all potential yields, market prices, and control costs was 64 aphids plant -1 , providing growers 7 days of preparation time to spray foliar insecticides before the economic injury level of 187 aphids plant -1 was reached. Improved IPM achieved the highest cost-benefit probabilities followed by traditional IPM, and the seed treatment achieved the lowest. However, in fields where the pressure from white grubs was high, the probability of achieving a positive net return with seed treatment was higher than that in other locations., Conclusion: Improved IPM based on early-stage ET of 64 aphids plant -1 was the most cost-effective of all the three approaches. Neonicotinoid seed treatment can be applied as an insurance strategy to supplement A. glycines IPM in Liaoning, China. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Purpose: To investigate the effect and safety of flow diverters in the treatment of unruptured dissecting intracranial aneurysms of the vertebral artery in comparison with stent-assisted coiling or stenting alone., Materials and Methods: Patients with unruptured dissecting intracranial aneurysms of the vertebral artery treated with the flow diverter, stent-assisted coiling, or stenting alone were retrospectively enrolled. The clinical data were analyzed and compared., Results: Twenty-five patients were enrolled in the flow diversion group and 42 patients in the stenting group. Twenty-six flow diverters were deployed in the flow diversion group. Immediate angiography revealed contrast agent retention within the aneurysm cavity in all patients. In the stenting group, 48 stents were deployed, and immediate angiographic outcome showed O'Kelly-Marotta (OKM) grade D in 18 (42.9%) aneurysms, grade C in 16 (38.1%), and grade B in 8 (19.0%). Periprocedural ischemic complications of thrombosis occurred in two (4.8%) patients and were treated with thrombolysis. In the flow diversion group, 19 (76%) patients underwent angiographic follow-up 3-46 (median 24) months after the procedure, with the OKM grade D in 11 (57.9%) patients, C in two (10.5%), and B in six (31.6%). The aneurysm recurrence rate was zero, and all diverters remained patent. Asymptomatic instent stenosis occurred in two (10.5%) patients. In seven of the ten patients with mild or moderate parent artery stenosis before the procedure who experienced angiographic follow-up, the stenosis was improved in five (71.4%) patients. In the stenting group, angiographic follow-up was carried out in 33 (78.6%) patients 6-58 months (median 34) after the procedure, with OKM grade D in 22 (66.7%) patients, grade C in five (15.2%), grade B in three (9.1%), and aneurysm recurrence (grade B, with increased contrast agent into the aneurysm cavity) in three (9.1%). Five (16.7%) patients experienced asymptomatic instent stenosis, and six of the 12 patients (50%) with parent artery stenosis were improved., Conclusion: Flow diverters with or without selective adjunctive coiling for the treatment of unruptured dissecting intracranial aneurysms of the vertebral artery may be safe and effective with good occlusion effects not inferior to those of stent-assisted coiling and stenting alone even though the long-term effect still warrants confirmation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Xu, Gao, Gao, Zhang, Wang and Li.)

Amyloid- β (A β ) deposition plays a crucial role in the occurrence and development of Alzheimer's disease (AD), and impaired A β clearance is the leading cause of A β deposition. Recently, studies have found that the glymphatic system performs similar functions to the peripheral lymphatic system. Glymphatic fluid transport mainly consists of cerebrospinal fluid (CSF) entering the brain from the paravascular space (PVS) by penetrating arteries and CSF and interstitial fluid exchanging mediated by aquaporin-4 (AQP4). This system promotes the drainage of interstitial fluid (ISF) in the parenchyma and removes metabolic waste, including A β , in the brain. Glymphatic system dysfunction plays an essential role in the occurrence and progression of AD. Regulation of glymphatic fluid transport may be a critical target for AD therapy. This study explored the regulatory effects of continuous theta-burst stimulation (CTBS) on the glymphatic system in APPswe/PS1dE9 (APP/PS1) mice with two-photon imaging. The results demonstrated that CTBS could increase glymphatic fluid transport, especially CSF and ISF exchange, mediated by improved AQP4 polarization. In addition, the accelerated glymphatic pathway reduced A β deposition and enhanced spatial memory cognition. It provided new insight into the clinical prevention and treatment of A β deposition-related diseases., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Cheng Wu et al.)

Objective: The pathogenesis of chronic pancreatitis (CP) is not completely clear. With further studies, smoking is toxic to the pancreas. This study classified smoking-related CP as a new etiology of CP and defined the cutoff of smoking., Design: Patients with CP admitted from January 2000 to December 2013 were included in the study. The characteristics were compared between smoking patients, drinking patients, and a group of patients who never smoke or drink (control group). The cumulative rates of steatorrhea, diabetes mellitus (DM), pancreatic pseudocyst (PPC), pancreatic stone, and biliary stricture after the onset of CP were calculated, respectively., Results: A total of 1,324 patients were included. Among them, 55 were smoking patients, 80 were drinking patients, and 1,189 were controls. The characteristics of smokers are different from the other two groups, especially in age at the onset and diagnosis of CP, initial manifestation, and type of pain. The development of DM ( P = 0.011) and PPC ( P = 0.033) was significantly more common and earlier in the smokers than in the other two groups. Steatorrhea also developed significantly more in the smokers than in the controls ( P = 0.029). Smokers tend to delay the formation of pancreatic stones and steatorrhea., Conclusion: The clinical characteristics of smoking-related CP is different from CP of other etiologies. A new type of CP, smoking-related CP, was put forward. Smoking-related CP should be separated from idiopathic CP and defined as a new independent subtype of CP different from alcoholic CP or idiopathic CP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hao, Liu, Dong, Yi, Wang, Xin, Guo, He, Bi, Ji, Wang, Du, Lin, Zhang, Zeng, Zou, Chen, Pan, Liao, Xu, Li and Hu.)

Objective: To evaluate the success rate of His-Purkinje system pacing (HPSP) in patients with various sites of atrioventricular block (AVB) and provide clinical evidence for the selection of HPSP in patients with AVB. Methods: This is a retrospective case analysis. 637 patients with AVB who underwent permanent cardiac pacemaker implantation and requiring high proportion of ventricular pacing from March 2016 to September 2021 in the Department of Cardiology, General Hospital of Northern Theater Command were enrolled. The site of AVB was determined by electrophysiological examination. His bundle pacing (HBP) was performed in the first 130 patients (20.4%) who were classified as the HBP group and HPSP included HBP and/or left bundle branch pacing (LBBP) was performed in later 507 patients (79.6%) and these patients were classified as the HPSP group. The basic clinical information such as age and sex of the two groups was compared, and the success rates of HBP or HPSP in patients with different sites of AVB and QRS intervals were analyzed. Results: The age of HBP group was (66.4±15.9) years with 75 males (57.7%). The age of HPSP group was (66.8±13.6) years with 288 (56.8%) males. Among 637 patients, 63.0% (401/637) had atrioventricular node block; 22.9% (146/637) had intra-His block; 14.1% (90/637) had distal or inferior His bundle block. Totally, the success rate of HPSP was higher than that of HBP [93.9% (476/507) vs. 86.9% (113/130), P <0.05]. In each group of patients with various AVB sites, the success rate of HPSP was higher than that of HBP respectively and both success rates of HBP and HPSP showed a declining trend with the distant AVB site. The success rate of HBP in patients with atrioventricular node block and intra-His block was higher than that in patients with distal or inferior His bundle block [95.2% (79/83) vs. 47.1% (8/17), P <0.001; 86.7% (26/30) vs. 47.1% (8/17), P =0.010]. The success rate of HPSP was higher than that of HBP in patients with distal or inferior His bundle block [87.7% (64/73) vs 47.1% (8/17), P =0.001]. In patients with QRS<120 ms, 94.9% (520/548) of AVB sites were in atrioventricular node or intra-His, and HBP had a similar high success rate with HPSP [95.6% (109/114) vs. 96.3% (418/434), P =0.943] in these patients. In patients with QRS ≥ 120 ms, 69.7% (62/89) of AVB sites were at distal or inferior His bundle, and the success rate of HBP was only 25.0% (4/16), while the success rate of HPSP was as high as 79.5% (58/73), P <0.001. Conclusions: In patients with QRS<120 ms and atrioventricular node block or intra-His block, success rates of HBP and HPSP are similarly high and HBP might be considered as the first choice. In patients with QRS ≥ 120 ms and AVB site at distal or inferior His bundle, the success rate of HPSP is higher than that of HBP, suggesting LBBP should be considered as the first-line treatment option.

Angiotensin-converting enzyme 2 (ACE2) or exercise training (ExT) is beneficial to hypertension, but their combined effects remain unknown. In this study, lentivirus containing enhanced green fluorescent protein (eGFP) and ACE2 were microinjected into the paraventricular nucleus (PVN) of young male spontaneous hypertensive rats (SHRs), and SHRs were assigned into five groups: sedentary (SHR), SHR-ExT, SHR-eGFP, ACE2 gene (SHR-ACE2), and ACE2 gene combined with ExT (SHR-ACE2-ExT). Wistar-Kyoto (WKY) rats were used as a control. ACE2 gene or ExT significantly delayed the elevation of blood pressure, and the combined effect prevented the development and progression of prehypertension. Either ACE2 overexpression or ExT improved arterial baroreflex sensitivity (BRS), whereas the combined effect normalized BRS in SHR. Compared with SHR, SHR-ACE2 and SHR-ExT displayed a significantly higher level of ACE2 protein but had lower plasma norepinephrine (NE) and angiotensin II (AngII) as well as angiotensin II type 1 receptor (AT1) protein expression in the PVN. SHR-ACE2-ExT showed the largest decrease in AngII and AT1 protein expression. Reactive oxygen species (ROS) level and NADPH oxidase (NOX2 and NOX4) protein expression in PVN were also decreased in SHR-ACE2-ExT group than in SHR-ACE2 and SHR-ExT groups. It was concluded that the combined effect has effectively prevented prehypertension progression and baroreflex dysfunction in SHR, which is associated with the reduction in AngII/AT1 axis function and oxidative stress in the PVN. NEW & NOTEWORTHY Angiotensin-converting enzyme 2 ( ACE2 ) gene in combination with exercise training (ExT) delayed the progression of hypertension via normalizing the blunted baroreflex sensitivity (BRS) and inhibiting sympathetic nerve activity (SNA). Its underlying mechanism may be related to the inhibition of AngII/AT1 axis function and central oxidative stress in the paraventricular nucleus (PVN) of prehypertensive rats.

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a predominant role in cancer immunotherapy which catalyzes the initial and rate limiting steps of the kynurenine pathway as a key enzyme. To explore novel IDO1 inhibitors, five derivatives of erlotinib-linked 1,2,3-triazole compounds were designed by using a structure-based drug design strategy. Drug-target interactions (DTI) were predicted by DeePurpose, an easy-to-use deep learning library that contains more than 50 algorithms. The DTI prediction results suggested that the designed molecules have potential inhibitory activities for IDO1. Chemical syntheses and bioassays showed that the compounds exhibited remarkable inhibitory activities against IDO1, among them, compound e was the most potent with an IC 50 value of 0.32 ± 0.07 μM in the Hela cell assay. The docking model and ADME analysis exhibited that the effective interactions of these compounds with heme iron and better drug-likeness ensured the IDO1 inhibitory activities. The studies suggested that compound e was a novel and interesting IDO1 inhibitor for further development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Gong, Zhu, Yao, Peng, Sun, Yang and Mao.)

It is a long-standing goal to fabricate conductive molecular nanowires (NWs) on semiconductor surfaces. Anchoring molecules to pre-patterned surface nanostructures is a practical approach to construct molecular NWs on semiconductor surfaces. Previously, well-ordered inorganic Ge NWs were deduced to spontaneously grow onto Pt/Ge(001) surfaces after annealing at an elevated temperature. In this work, we further demonstrate that organic 7,7,8,8-tetracyanoquinodimethane (TCNQ) molecular NWs can self-assemble onto the atomic NWs on Pt/Ge(001) surfaces. The outer nitrogen atoms in TCNQ molecules hybridize with under-coordinated Ge atoms in Ge NWs with an energy release of ∼1.14 eV per molecule, and electrons transfer from Ge NWs to the frontier orbitals of anchored TCNQs resulting in a negatively charged state. This largely tailors the electronic configurations of TCNQs and Pt/Ge(001) surfaces, enhancing the electron transport along the dimer row direction. The TCNQ molecular NWs coupled with the Ge NWs represent an exemplary showcase for the fabrication of molecular NWs on semiconductor surfaces., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)