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Photo-induced crosslinked and anti-PD-l1 peptide incorporated liposomes to promote PD-l1 multivalent binding for effective immune checkpoint blockade therapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1428-1440页

作者： Youngjoo lee Sukyung Song Suah Yang Jinseong kim Yujeong Moon Nayeon Shim Hong Yeol Yoon Sehoon kim man kyu Shim kwangmeyung kim kU-kIST Graduate School of Converging Science and Technology Korea UniversitySeoul 02841Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea College of Pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul 03760Republic of Korea Department of Bioengineering Korea UniversitySeoul 02841Republic of Korea

Immune checkpoint blockade(ICB)therapy targeting PD-l1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory to ICB therapy owing to the PD-l1 recycling mechanism.Herein,we propose photo-induced crosslinked and anti-PD-l1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-lPs)to promote PD-l1 multivalent binding for inducing lysosomal degradation of PD-l1 in tumor cells.The ICB-lPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-l1peptide(D-form NYSkPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-l1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV irradiation.The 10 mol% antiPD-l1-DSPE-PEG_(2k)incorporated ICB-lPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum condition.Importantly,the ICB-lPs efficiently promote the multivalent binding with PD-l1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-l1 to the lysosomes,wherein the durable PD-l1 degradation is observed for72 h,in contrast to anti PD-l1 m Abs showing the rapid PD-l1 recycling within 9 h.The in vitro coculture experiments with CD8^(+)T cells show that ICB-lPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-l1/PD-1 axis.When ICB-lPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-l1 degradation.Collectively,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-l1 peptide incorporated liposome formulation that promotes PD-l1 multivalent binding for trafficking of PD-l1 toward the lysosomes instead of the recycling endosome

关键词： Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Crosslinked lipid nanoparticles Anti-PD-l1 peptide Tumor-targeting PD-l1 multivalent binding lysosomal PD-l1 degradation

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Cool white light and tunable multicolor emission from Tb^(3+)/Dy^(3+)co-activated glasses under different excitations for WlEDs

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Journal of Rare Earths 2024年第1期42卷 46-56,I0002页

作者： l.Vijayalakshmi k.Naveen kumar Jong Dae Baek Department of Automotive Engineering Yeungnam UniversityGyeongsanGyeongbuk38541Republic of Korea Department of Mechanical Engineering Yeungnam UniversityGyeongsan38541Republic of Korea

A set of co-doped(Tb^(3+)/Dy^(3+))lithium zinc borate(lZB)glasses were developed by melt quenching.The structural evaluation was performed for synthesized glassy matrices.The Dy^(3+)and Tb^(3+)individually doped glasses exhibit intense yellow and green luminescence bands at 575 nm(^(4)F_(9/2)→^(6)H_(13/2))and543 nm(^(5)D_(4)→^(7)F_(5)),respectively.The sensitization effect of Dy^(3+)on Tb^(3+)was analyzed by increasing the Tb^(3+)content with respect to the optimum Dy^(3+)content(0.5 mol%)in Dy^(3+)/Tb^(3+).The spectral overlay of Dy^(3+)luminescence and Tb^(3+)absorption profiles,Dy^(3+)/Tb^(3+)Pl spectra under different excitations 352,362,376,and 385 nm,shortening decay lifetimes of Dy^(3+)in Dy^(3+)/Tb^(3+)co-activated glasses,energy transfer(ET)parameters,chromaticity coordinates and their corresponding correlated temperatures all help to explain ET from Dy^(3+)to Tb^(3+).At 385 nm of Dy^(3+)excitation,the optimized co-activated(0.5Dy^(3+)+1.0Tb^(3+)):lZB glass displays cool white light emission.The non-radiative ET from Dy^(3+)to Tb^(3+)is dominated by electric dipole-dipole interaction and its ET efficiency was calculated to be 63%.At the same time,reverse ET from Tb^(3+)to Dy^(3+)was also analyzed.The shift in color coordinates from dominant yellow to greenish-yellow,green and white light emission suggests that Dy^(3+)/Tb^(3+)coactivated lZB glasses can be a potential candidate for UV converted multicolor and white light emitting devices.

关键词： Rare earths Photoluminescence Energy transfer Spectral overlap Decay lifetime Multicolor emitting lEDs

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Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations:a scoping review

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Neural Regeneration Research 2024年第8期19卷 1686-1695页

作者： Avery l.Miller Nathan k.Evanson J.Michael Taylor University of Cincinnati College of Medicine CincinnatiOHUSA Department of Pediatrics University of CincinnatiCincinnatiOHUSA Department of Neurology and Rehabilitation Medicine University of CincinnatiCincinnatiOHUSA Division of Pediatric Rehabilitation Medicine Cincinnati Children’s Hospital Medical CenterCincinnatiOHUSA Division of Neurology Cincinnati Children’s Hospital Medical CenterCincinnatiOHUSA

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients.Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury,but relatively less is known about the effect in pediatric populations.The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibito rs as a potential a djuvant treatment fo r neurocognitive decline in pediatric patients with traumatic brain injury.Investigators queried PubMed to identify literature published from database inception thro ugh June 2023 desc ribing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions.Based on preselected search criteria,340 unique papers we re selected for title and abstra ct screening.Thirty-two reco rds were reviewed in full after eliminating preclinical studies and pape rs outside the scope of the project.In adult traumatic brain injury,we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tole rated and shows both objective and patient-reported efficacy for reducing cognitive impairment.In children,3 pape rs report on 5 children recovering from traumatic brain injury,showing limited efficacy.An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group.Given its promise for efficacy in adults with traumatic brain injury and tole rability in pediatric patients,we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

关键词： acetylcholinesterase inhibitor adult cognition donepezil pediatrics traumatic brain injury

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SARS-CoV-2 and innate immunity:the good,the bad,and the"goldilocks"

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Cellular & Molecular Immunology 2024年第2期21卷 171-183页

作者： Benjamin l.Sievers Mark T.k.Cheng kata Csiba Bo Meng Ravindra k.Gupta Department of Medicine University of CambridgeCambridgeUK Cambridge Institute of Therapeutic Immunology&Infectious Disease(CITID) Department of MedicineUniversity of CambridgeCambridgeUk

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity.knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically.The humoral response to SARS-CoV-2 infection has been the focus of intense research,and the role of the innate immune system has received significantly less attention.Here,we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems.We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

关键词： SARS-CoV-2 Innate immune response Interferon Cytokines Inflammation Antiviral targets

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Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice

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Chinese Journal of Integrative Medicine 2024年第4期30卷 311-321页

作者： lea ling-Yu kan Ben Chung-lap Chan Grace Gar-lee Yue lI Pei-ting Sharon Sze-man Hon HUANG Dan-qi Miranda Sin-man Tsang Clara Bik-San lau Ping-Chung leung Chun-kwok Wong Institute of Chinese Medicine The Chinese University of Hong KongHong Kong SARChina State key laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Chemical Pathology The Chinese University of Hong KongHong Kong SARChina China-Australia International Research Centre for Chinese Medicine School of Health and Biomedical SciencesSTEM CollegeRMIT UniversityBundooraVictoriaAustralia li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine The Chinese University of Hong Kong SARHong KongChina

Objective To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula(4HF)and doxorubicin in triple-negative breast cancer(TNBC).Methods Murine-derived triple-negative mammary carcinoma cell line,4T1 cells,was cultured and inoculated into mouse mammary glands.Sixty-six mice were randomly assigned into 6 groups(n=11 in ench):naive,control,lD 4HF(low dose 4HF),HD 4HF(high dose 4HF),lD 4HF+D(low dose and doxorubicin),and D(doxorubicin).Apart from the naive group,each mouse received subcutaneous inoculation with 5×10^(5)4T1 cells resuspended in 100µl of normal saline in the mammary fat pads.Starting from the day of tumor cell inoculation,tumors were grown for 6 days.The lD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF,respectively.The lD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin(5 mg/kg).The D group received weekly intraperitoneal injections of doxorubicin(5 mg/kg).The treatment naive mice received daily oral gavage of 0.2 ml double distilled water and 0.1 ml normal saline via intraperitoneal injection once a week.The control group received daily oral gavage of 0.2 ml double-distilled water.The treatment period was 30 days.At the end of treatment,mice organs were harvested to analyze immunological activities via immunophenotyping,gene and multiplex analysis,histological staining,and gut microbiota analysis.Results Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens(Pltered the hypoxia and overall immune lymphocyte landscape,and manipulated gut microbiota to favor the anti-tumor immunological activities.Moreover,immunosuppressive genes,cytokines,and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated(P<0.05).4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response(P<

关键词： adjunctivetherapy breast cancer cytokines Chinese medicine tumor microenvironment

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Pancreatic surgery and tertiary pancreatitis services warrant provision for support from a specialist diabetes team

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World Journal of Diabetes 2024年第4期15卷 598-605页

作者： Vasileios k Mavroeidis Jennifer knapton Francesca Saffioti Daniel l Morganstein Department of HPB Surgery Bristol Royal InfirmaryUniversity Hospitals Bristol and Weston NHS Foundation TrustBristol BS28HWUnited Kingdom Department of Gastrointestinal Surgery Southmead HospitalNorth Bristol NHS TrustBristol BS105NBUnited Kingdom Department of Academic Surgery Royal Marsden NHS Foundation TrustLondon SW36JJUnited Kingdom Department of Gastroenterology and Hepatology Oxford University Hospitals NHS Foundation TrustOxford OX39DUUnited Kingdom UCl Institute for liver and Digestive Health University College LondonLondon NW32PFUnited Kingdom Department of Endocrinology Chelsea and Westminster Hospital NHS Foundation TrustLondon SW109NHUnited Kingdom Department of Gastrointestinal Unit Royal Marsden NHS Foundation TrustLondon SW36JJUnited Kingdom

Pancreatic surgery units undertake several complex operations,albeit with consi-derable morbidity and mortality,as is the case for the management of complicated acute pancreatitis or chronic pancreatitis.The centralisation of pancreatic surgery services,with the development of designated large-volume centres,has contribu-ted to significantly improved outcomes.In this editorial,we discuss the complex associations between diabetes mellitus(DM)and pancreatic/periampullary disease in the context of pancreatic surgery and overall management of complex pancreatitis,highlighting the consequential needs and the indispensable role of specialist diabetes teams in support of tertiary pancreatic services.Type 3c pan-creatogenic DM,refers to DM developing in the setting of exocrine pancreatic disease,and its identification and management can be challenging,while the glycaemic control of such patients may affect their course of treatment and outcome.Adequate preoperative diabetes assessment is warranted to aid identification of patients who are likely to need commencement or escalation of glucose lowering therapy in the postoperative period.The incidence of new onset diabetes after pancreatic resection is widely variable in the literature,and depends on the type and extent of pancreatic resection,as is the case with pancreatic parenchymal loss in the context of severe pancreatitis.Early involvement of a specialist diabetes team is essential to ensure a holistic management.In the current era,large volume pancreatic surgery services commonly abide by the principles of enhanced recovery after surgery,with inclusion of provisions for optimisation of the perioperative glycaemic control,to improve outcomes.While various guidelines are available to aid perioperative management of DM,auditing and quality improvement platforms have highlighted deficiencies in the perioperative management of diabetic patients and areas of required improvement.The need for perioperative support of diabetic patients by specialist diabetes teams is uniform

关键词： Pancreatectomy Pancreatoduodenectomy Whipple’s Pancreatitis Diabetes specialist Type 3c pancreatogenic diabetes mellitus

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Higher-dimensional Chen-lee-liu equation and asymmetric peakon soliton

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Chinese Physics B 2024年第4期33卷 224-229页

作者：韩巧红贾曼 School of Physical Science and Technology Ningbo UniversityNingbo 315211China

Integrable systems play a crucial role in physics and mathematics.In particular,the traditional(1+1)-dimensional and(2+1)-dimensional integrable systems have received significant attention due to the rarity of integrable systems in higher dimensions.Recent studies have shown that abundant higher-dimensional integrable systems can be constructed from(1+1)-dimensional integrable systems by using a deformation algorithm.Here we establish a new(2+1)-dimensional Chen-lee-liu(C-l-l)equation using the deformation algorithm from the(1+1)-dimensional C-l-l equation.The new system is integrable with its lax pair obtained by applying the deformation algorithm to that of the(1+1)-dimension.It is challenging to obtain the exact solutions for the new integrable system because the new system combines both the original C-l-l equation and its reciprocal transformation.The traveling wave solutions are derived in implicit function expression,and some asymmetry peakon solutions are found.

关键词： higher dimensional Chen-lee-liu equation lax integrable system deformation algorithm implicit traveling wave solutions

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Association of total bilirubin with depression risk in adults with diabetes:A cross-sectional study

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World Journal of Clinical Cases 2024年第18期12卷 3428-3437页

作者： man-li Ye Jie-ke Wang Department of laboratory Medicine The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina Department of Hand and Plastic Surgery The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina

BACkGROUND Individuals with diabetes mellitus are more likely to experience depression,although most patients remain undiagnosed.The relation between total bilirubin and depression has been increasingly discussed,but limited studies have examined the association of total bilirubin with depression risk in adults with diabetes,which warrants attention.AIM To investigate the association between total bilirubin levels and the risk of depression in adults with diabetes.METHODS The study included adults with diabetes from the National Health and Nutrition Examination Survey 2007-2018.Depression was determined using the Patient Health Questionnaire-9.Multivariable logistic regression,propensity scorematched analysis and restricted cubic spline models were utilized to investigate the association between total bilirubin levels and depression risk in adults with diabetes.RESUlTS The study included 4758 adults with diabetes,of whom 602(12.7%)were diagnosed with depression.After adjusting for covariates,we found that diabetic adults with lower total bilirubin levels had a higher risk of depression(OR=1.230,95%CI:1.006-1.503,P=0.043).This association was further confirmed after propensity score matching(OR=1.303,95%CI:1.034-1.641,P=0.025).Subgroup analyses showed no significant dependence of age,body mass index,sex,race or hypertension on this association.Restricted cubic spline models displayed an inverted U-shaped association of total bilirubin levels with depression risk within the lower range of total bilirubin levels.The depression risk heightened with the increasing levels of total bilirubin,reaching the highest risk at 6.81μmol/l and decreasing thereafter.CONClUSION In adults with diabetes,those with lower levels of total bilirubin were more likely to have depressive symptoms.Serum total bilirubin levels may be used as an additional indicator to assess depression risk in adults with diabetes.

关键词： Depression Total bilirubin Diabetes National health and nutrition examination survey Mental health Patient health questionnaire-9

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lactobacillus plantarum J26 alleviates alcohol-induced oxidative liver injury by regulating the Nrf2 signaling pathway

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Food Science and Human Wellness 2024年第4期13卷 2068-2078页

作者： Hongxuan li Shasha Cheng Yuhong Wang Yilin Sun Jiaxin Zhang Mingshuang Sun Chaoxin man Yu Zhang Yujun Jiang key laboratory of Dairy Science Ministry of EducationCollege of Food Science and EngineeringNortheast Agricultural UniversityHarbin 150030China

Oxidative stress is one of the main ways to cause alcohol-induced liver injury,and alcoholic liver disease(AlD)has been a common health problem worldwide.lactic acid bacteria(lAB)is also considered as a potential treatment to alleviate alcohol-induced liver injury.lactobacillus plantarum J26 is a lAB isolated from Chinese traditional fermented dairy products with excellent probiotic effects.This study aimed to establish a mice model of alcoholic liver injury through acute-on-chronic alcohol feeding and to study the alleviating effect of pre-intake of l.plantarum J26 on alcohol-induced oxidative liver injury and focus on its potential mechanism of alleviating effect.The results showed that pre-intake of l.plantarum J26 could improve liver pathological changes,reduce lipid accumulation,increase mitochondrial ATP and mitochondrial(mtDNA)levels,and alleviate liver injury.In addition,pre-intake l.plantarum J26 can improve the level of short-chain fatty acids(SCFAs)in the intestines in mice,short chain fatty acids can be used as a signaling molecule activation of nuclear factor E2-related factor 2(Nrf2)signaling pathway to alleviate liver oxidative stress,and maintain mitochondrial homeostasis by regulating the expression of genes related to mitochondrial dynamics and autophagy,thereby reducing cell apoptosis to alleviate alcohol-induced oxidative liver injury.

关键词： Alcoholic liver disease Probiotics Nuclear factor E2-related factor 2(Nrf2) Oxidative stress Short-chain fatty acids

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large-scale interplant exchange of macromolecules between soybean and dodder under nutrient stresses

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Plant Diversity 2024年第1期46卷 116-125页

作者： Jingxiong Zhang Shalan li Wenxing li Zerui Feng Shuhan Zhang Xijie Zheng Yuxing Xu Guojing Shen man Zhao Guoyan Cao Xuna Wu Jianqiang Wu Department of Economic Plants and Biotechnology Yunnan Key Laboratory for Wild Plant ResourcesKunming Institute of BotanyChinese Academy of SciencesKunming 650201China CAS Center for Excellence in Biotic Interactions University of Chinese Academy of SciencesBeijing 100049China State key laboratory of Conservation and Utilization of Bio-Resources in Yunnan and Center for life Science School of Life SciencesYunnan UniversityKunming 650500China

Parasitic plants and their hosts communicate through haustorial connections.Nutrient deficiency is a common stress for plants,yet little is known about whether and how host plants and parasites communicate during adaptation to such nutrient stresses.In this study,we used transcriptomics and proteomics to analyze how soybean(Glycine max)and its parasitizing dodder(Cuscuta australis)respond to nitrate and phosphate deficiency(-N and-P).After-N and-P treatment,the soybean and dodder plants exhibited substantial changes of transcriptome and proteome,although soybean plants showed very few transcriptional responses to-P and dodder did not show any transcriptional changes to either-N or-P.Importantly,large-scale interplant transport of mRNAs and proteins was detected.Although the mobile mRNAs only comprised at most 0.2%of the transcriptomes,the foreign mobile proteins could reach 6.8%of the total proteins,suggesting that proteins may be the major forms of interplant communications.Furthermore,the interplant mobility of macromolecules was specifically affected by the nutrient regimes and the transport of these macromolecules was very likely independently regulated.This study provides new insight into the communication between host plants and parasites under stress conditions.

关键词： Cuscuta Mobile molecules Nutrient deficiency Host plant-parasitic plant interaction Interplant transport Systemic signaling

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