自古只有蛇咬人,而南非的这位57岁的Lucas Sibanda却演绎了一场“人咬蛇”的“活剧”,他的利嘴钢牙竟然让一条巨蟒逃之夭夭,从而拾回自己一条老命。文章虽然很短,却写得文采斐然。标题出现了Python(巨蟒),而在文章里,作者却分别换用mons...自古只有蛇咬人,而南非的这位57岁的Lucas Sibanda却演绎了一场“人咬蛇”的“活剧”,他的利嘴钢牙竟然让一条巨蟒逃之夭夭,从而拾回自己一条老命。文章虽然很短,却写得文采斐然。标题出现了Python(巨蟒),而在文章里,作者却分别换用monster和reptile的表达,以求遣词之新,这在英语中称为Elegant Variation(求雅换词),以下三句中的动词你是否觉得用得也很精彩:1/A South African man bit his way to freedom. 2/I froze for almost 10 seconds. 3/Sibanda sank his teeth into…】展开更多
Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limite...Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.展开更多
The escape and establishment of Iberian wild goats,Capra pyrenaica,from an enclosure in the 1990s marked the beginning of the recovery of the species in the Pyrenees.This population has occupied part of the Prepyrenee...The escape and establishment of Iberian wild goats,Capra pyrenaica,from an enclosure in the 1990s marked the beginning of the recovery of the species in the Pyrenees.This population has occupied part of the Prepyrenees and has contacted another population reintroduced in France since 2014.It coexists with other wild ungulates,including the feral and domestic goats Capra hircus that has been living free since the 1960s.Today it’s the largest Iberian wild goat Pyrenean population.Between 2006 and 2022 we monitored the population and its expansion based on vantage points,itineraries and testimonies.The results indicate:(i)a population,of uncertain genetic origin,in numerical(15%average annual growth)and areal expansion,with the capacity to connect with other populations;(ii)an estimate of at least 500 individuals;(iii)in the process of expansion in contact with Iberian wild goats from France;(iv)sympatry with feral and domestic goat population in its main nucleus whose estimate exceeds 2000 specimens and(v)hybridization with feral and domestic goats.In 2022 sustainable hunt started with a hunting quota of 20 individuals.Genetic characterization and the establishment of an international coordinated monitoring are two of the current priorities.展开更多
Small interfering RNAs(siRNA)provide a novel and highly specific therapy due to their ability to effectively silence target genes,to date six siRNA therapeutics are approved for clinical use.Even so,some critical chal...Small interfering RNAs(siRNA)provide a novel and highly specific therapy due to their ability to effectively silence target genes,to date six siRNA therapeutics are approved for clinical use.Even so,some critical challenges remain to overcome in the therapeutic application of siRNAs,with delivery issues at the forefront.Among them,endo/lysosomal barrier is one of the important but often-neglected limitations hindering the delivery of siRNA therapeutics.In this review,we summarize the promising strategies that facilitate siRNAs overcoming endo/lysosomal barriers based on the cellular uptake and intracellular transport pathways,including promoting escape once endocytosis into the endo/lysosomes and bypassing lysosomes via endosome-Golgi-endoplasmic reticulum(ER)pathway or nonendocytosis pathway,and discuss the principal considerations and the future directions of promoting endo/lysosomal escape in the development of therapeutic siRNAs.展开更多
Functional constraints between different types of antipredator behavior should be common,especially if they are on the opposite sides of the behavioral spectrum such as flight and post-capture immobility.We examined a...Functional constraints between different types of antipredator behavior should be common,especially if they are on the opposite sides of the behavioral spectrum such as flight and post-capture immobility.We examined a potential compromise between post-capture immobility displays and sprint speed in dice snakes(Natrix tessellata),using a field-based approach.We sampled snakes(N=238)from two populations:from a dense island population free of mammal predators,and from a less dense mainland population,preyed upon by both bird and mammal predators.We explored the effects of sexual maturity,temperature,body size,presence of palpable food in the gut,and injuries on the occurrence and duration of post-capture immobility as well as sprint speed.Our results confirm the existence of functional constraints between locomotor performance and post-capture immobility in dice snakes.Faster dice snakes start escaping promptly after release,while slower individuals utilize more passive antipredator behaviors such as death feigning.Local adaptations seem to have great influence on behavioral compromise,since the mammal-free island population exhibited a higher incidence of post-capture immobility and a significantly lower sprint speed,compared to the less dense mainland population.Additionally,immature individuals tended to avoid death feigning and their post-capture immobility lasted shorter compared to adult individuals.It remains to be seen how individuals adjust their behavior to accomodate locomotor constraints,and in which specific phases of the predator-prey interaction these adjustments occur.展开更多
Urbanization has significantly altered the habitat structure and behavioral patterns of animals.In urban environments with frequent human disturbances,animals may undergo adaptive adjustments in their escape behaviors...Urbanization has significantly altered the habitat structure and behavioral patterns of animals.In urban environments with frequent human disturbances,animals may undergo adaptive adjustments in their escape behaviors.This study focuses on Eurasian Tree Sparrows(Passer montanus)from five cities across different latitudes in China,comparing their flight initiation distance(FID)in urban and rural areas to assess the impact of urbanization on their escape behavior and the trend of ecological homogenization.The results confirm the established pattern at the geographic level:a reduction of FID in urban habitats and a decrease in FID with increasing latitude.That is,northern populations of the Eurasian Tree Sparrow in China are bolder than the southern populations.In addition,FID is positively correlated with flock size,with rural flocks exhibiting more pronounced group behavior(observed flocking frequency for urban and rural is 28.74%vs.40.7%,flock size variance is 26.90 vs.55.63).Despite the differences between northern and southern latitudes,the variability of FID in urban individuals consistently remains lower than that in rural areas,supporting the trend of reduced variability in escape behavior among birds in urban environments.Driven by urbanization,the escape behavior of Eurasian Tree Sparrows tends toward ecological homogenization,meaning that behavioral differences between urban areas in different cities are diminishing.This trend may obscure the behavioral variability brought about by latitude gradients,indicating that urbanization not only shapes the behavioral adaptations of birds but also potentially weakens their behavioral diversity.展开更多
Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolv...Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolves,the emergence of acquired resistance leads to treatment failure.Many researches have shown that non-coding RNAs(ncRNAs)not only influence lung cancer progression but also act as potential mediators of immunotherapy and chemotherapy resistance in lung cancer,mediating drug resistance by regulating multiple targets and pathways.In addition,the regulation of immune response by ncRNAs is dualistic,forming a microenvironment for inhibits/promotes immune escape through changes in the expression of immune checkpoints.The aim of this review is to understand the effects of ncRNAs on the occurrence and development of lung cancer,focusing on the role of ncRNAs in regulating drug resistance of lung cancer.展开更多
Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is no...Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is not fully understood.This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC.Methods:Tissue immunohistochemistry,TCGA,and GEO databases were used to analyze the expression of YBX1 in ICC.The expression of YBX1 was silenced and overexpressed in cell lines.Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses.Actinomycin D,RNA immunoprecipitation,and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes.Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC.Results:The research findings indicated that ICC exhibited high levels of YBX1 expression,which was strongly associated with unfavorable outcomes.YBX1 promoted tumor progression by suppressing antitumor T-cell responses.YBX1 enhanced signal transducer and activator of transcription 1(STAT1)translation by serving as a 5-methylated cytosine(m5C)reader and activating the STAT1/PD-L1 pathway.Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1,STAT1,and PD-L1 expression.Conclusions:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.展开更多
The diffusion trajectory of a Brownian particle passing over the saddle point of a two-dimensional quadratic potential energy surface is tracked in detail according to the deep learning strategies.Generative adversari...The diffusion trajectory of a Brownian particle passing over the saddle point of a two-dimensional quadratic potential energy surface is tracked in detail according to the deep learning strategies.Generative adversarial networks(GANs)emanating in the category of machine learning(ML)frameworks are used to generate and assess the rationality of the data.While their optimization is based on the long short-term memory(LSTM)strategies.In addition to drawing a heat map,the optimal path of two-dimensional(2D)diffusion is simultaneously demonstrated in a stereoscopic space.The results of our simulation are completely consistent with the previous theoretical predictions.展开更多
Zebrafish larvae are useful for identifying chemicals against lateral line(LL)hair cell(HC)damage and this type of chemical screen mainly focuses on searching for protectors against cell death.To expand the candidate ...Zebrafish larvae are useful for identifying chemicals against lateral line(LL)hair cell(HC)damage and this type of chemical screen mainly focuses on searching for protectors against cell death.To expand the candidate pool of HC protectors,a self-built acoustic escape response(AER)-detecting system was developed to apply both low-frequency near-field sound transmission and AER image acquisition/processing modules.The device quickly confirmed the changed LL HC functions caused by most known ototoxins,protectors,and neural transmission modifiers,or knockdown of LL HC-expressing genes.With ten devices wired in tandem,five‘hit’chemicals were identified from 124 cyclin-dependent kinase inhibitors to partially restore cisplatin-damaged AER in less than a day.AS2863619,ribociclib,and SU9516 among the hits,protected the HCs in the mouse cochlea.Therefore,using free-swimming larval zebrafish,the self-made AER-detecting device can efficiently identify compounds that are protective against HC damage,including cell death and loss-of-function.展开更多
Atmospheric escape plays a critical role in shaping the long-term climate evolution of Mars.Among the various escape mechanisms,energetic neutral atoms(ENAs)generated through charge exchange between solar wind ions an...Atmospheric escape plays a critical role in shaping the long-term climate evolution of Mars.Among the various escape mechanisms,energetic neutral atoms(ENAs)generated through charge exchange between solar wind ions and exospheric neutrals serve as an important diagnostic for ion-neutral interactions and upper atmospheric loss.This study presents direct observations of hydrogen ENAs(H-ENAs)on the dayside of Mars by using the Mars Ion and Neutral Particle Analyzer(MINPA)onboard China’s Tianwen-1 orbiter.By analyzing H-ENA data during a coronal mass ejection and a stream interaction region from December 29,2021,to January 1,2022,and comparing these data with MAVEN/SWIA(Mars Atmosphere and Volatile EvolutioN/Solar Wind Ion Analyzer)solar wind measurements,we examine the temporal evolution of H-ENA flux and the associated sputtered escape of atmospheric constituents.The observed H-ENA velocity is consistent with upstream solar wind ions,and the H-ENA-to-ion intensity ratio is used to infer variations in exospheric density,revealing a delayed response to enhanced solar wind activity.Penetrating H-ENA intensities reach up to 5.3×10^(6)s^(−1) cm^(−2),with energy fluxes on the order of(0.5-8.1)×10^(−3) mW/m^(2).The estimated oxygen sputtered escape rate driven by penetrating H-ENAs ranges from 5.5×10^(23)s^(−1) to 5.2×10^(24)s^(−1),comparable to or exceeding previous estimates based on penetrating ions.The findings highlight the need for low-altitude H-ENA observations to better quantify their atmospheric interactions and refine our understanding of nonthermal escape processes at Mars.展开更多
Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the target...Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes;however,the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability,cytosolic delivery and subsequent therapeutic efficacy.In this case,the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo/lysosomal escape,which relies on the development of safe and efficient nanodelivery systems.A deeper mechanistic understanding in the endo/lysosomal escape will guide the development of more efficient nano-delivery systems.In this review,we summarize various mechanisms by which nanoparticles escape from the endo/lysosome,and showcase the recent progress in dissecting the endo/lysosomal approaches based on nano-delivery systems.Emphasis will lie on the properties of nanoparticles that govern the endo/lysosomal escape pathway as well as the latest promising applications in vaccine delivery and genetic engineering field.展开更多
Non-small cell lung cancer(NSCLC)is a leading cause of cancer-related mortality worldwide1-3.While radioimmuno-therapy shows promise in boosting antitumor immunity,the clinical outcomes have been inconsistent4 and are...Non-small cell lung cancer(NSCLC)is a leading cause of cancer-related mortality worldwide1-3.While radioimmuno-therapy shows promise in boosting antitumor immunity,the clinical outcomes have been inconsistent4 and are often lim-ited by the immunosuppressive tumor microenvironment(TME).Cyclooxygenase(COX)-2 and the COX-2 downstream product,prostaglandin E2(PGE2),are increasingly implicated in immune escape5,6 but the impact on radioimmunother-apy efficacy has not been explored.TCF1-expressing CD8+T cells demonstrate defining functional properties of progeni-tor-exhausted T cells,including clonal expansion through self-renewal capacity and multipotent differentiation toward terminal effector phenotypes,while maintaining long-term persistence critical for sustaining antitumor immunity7-9.Given the central role in anti-tumor immune maintenance,TCF1+CD8+T cells are likely critical to radioimmunotherapy efficacy10.The role of COX-2 inhibition in enhancing the effi-cacy of radioimmunotherapy efficacy in NSCLC was investi-gated in the current study.展开更多
Conventional nutritional supplements frequently demonstrate limited clinical effectiveness due to the harsh milieu of the gastrointestinal tract,inefficient transepithelial transport,and rapid systemic clearance.Nanol...Conventional nutritional supplements frequently demonstrate limited clinical effectiveness due to the harsh milieu of the gastrointestinal tract,inefficient transepithelial transport,and rapid systemic clearance.Nanoliposomal delivery platforms-lipid bilayer vesicles on the nanometer scale-have attracted attention as an adaptive strategy to shield sensitive nutrients,navigate biological barriers,and deliver payloads directly to target tissues or even sub-cellular organelles.Despite a growing body of literature,a consolidated appraisal of design principles,targeting modalities,and translational hurdles is still needed to guide future nutraceutical innovation.We aim to:(1)Summarize the physicochemical foundations of nanoliposomal nutrient carriers;(2)Delineate state-of-the-art approaches for organ-specific and organelle-specific targeting,with particular emphasis on renal and mitochondrial delivery;(3)Evaluate current evidence supporting therapeutic benefits in cardiometabolic,neuroprotective,and renal-repair contexts;and(4)Map unresolved challenges-including manufacturing scale-up,cost,and regulatory oversight-to inform a roadmap for clinical translation.A systematic literature search was performed across PubMed,Web of Science,and Scopus through May 2025 using Boolean combinations of“nanoliposome”,“nutrient”,“targeted delivery”,“bioavailability”,and organ-specific terms(e.g.,“kidney”,“mitochondria”).Primary research articles,systematic reviews,and relevant meta-analyses written in English were included.Data were extracted on liposomal composition,particle size,surface modifications(e.g.,polyethylene glycol,ligand conjugation),in vitro and in vivo bio-distribution,efficacy outcomes,and safety profiles.Key design variables were mapped against reported biological performance to identify convergent principles.Sixty-four original studies and twenty-one reviews met inclusion criteria.Encapsulation within phosphatidylcholine-rich bilayers consistently enhanced nutrient stability in simulated gastric fluid and improved Caco-2 trans-epithelial transport two-fold to ten-fold compared with free compound controls.Ligand-mediated strategies-such as folate,lactoferrin,or peptide conjugation-achieved organ-specific accumulation,with kidney-directed liposomes demonstrating up to a four-fold increase in renal cortex uptake.Mitochondrial targeting using amphipathic peptides(e.g.,SS-31)or triphenylphosphonium moieties delivered antioxidant nutrients to the organelle,restoring mitochondrial membrane potential and reducing reactive oxygen species(ROS)in preclinical cardiomyopathy and neurodegeneration models.Endosomal escape was most effectively triggered by fusogenic lipids(e.g.,dioleoylphosphatidylethanolamine)or pH-responsive polymers.PEGylation prolonged circulation half-life by 3-6 hours but elicited anti-polyethylene glycol antibodies in approximately one-quarter of recipients;emerging natural sterol-mimetic or collagen-mimetic coatings showed comparable stealth behavior with superior biodegradability.Scalability remains limited:Only three studies reported pilot-scale(>10 L)batches with Good Manufacturing Practice-compliant reproducibility.Targeted nanoliposomal systems substantially improve nutrient stability,absorption,and tissue specificity,offering a credible route to transform supplement efficacy for cardiometabolic,renal,and neuroprotective indications.Optimization of lipid composition,escape mechanisms,and biocompatible surface chemistries can further enhance therapeutic indices.Nonetheless,industrial-scale manufacturing,cost containment,and immunogenicity mitigation remain critical obstacles.Addressing these gaps through standardized characterization protocols,head-to-head clinical trials,and biomaterial innovation will be essential to unlock the full potential of nanoliposomal nutraceuticals in routine healthcare practice.展开更多
This editorial focuses on the recent article by Yang et al in the World Journal of Gastrointestinal Oncology,which highlights the role of interlukin-17A in promoting hepatocellular carcinoma(HCC)progression by up-regu...This editorial focuses on the recent article by Yang et al in the World Journal of Gastrointestinal Oncology,which highlights the role of interlukin-17A in promoting hepatocellular carcinoma(HCC)progression by up-regulated programmed cell death protein-1(PD-1)/programmed cell death protein ligand-1(PD-L1)expression.Previous,the high PD-1/PD-L1 level was due to hepatitis virus infection leading to systemic innate immune tolerance and cluster of differen-tiation 8+T cells exhaustion,ultimately leading to HCC.Recently,interesting studies have found that the malignant progression of metabolic dysfunction-associated steatotic/fatty liver disease(MASLD/MAFLD),that is former nonalcoholic fatty liver disease,was achieved by up-regulated PD-L1 level that was activated the cGAS-STING pathway under lipid accumulation with mito-chondrial DNA overflow and up-regulated PD-1/PD-L1 to promote MASLD malignant transformation via immune escape.These data suggested that PD-1 or PD-L1 should be a promising target for preventing or delaying non-viral liver disease malignant progression except of antiviral therapy for HCC.展开更多
文摘自古只有蛇咬人,而南非的这位57岁的Lucas Sibanda却演绎了一场“人咬蛇”的“活剧”,他的利嘴钢牙竟然让一条巨蟒逃之夭夭,从而拾回自己一条老命。文章虽然很短,却写得文采斐然。标题出现了Python(巨蟒),而在文章里,作者却分别换用monster和reptile的表达,以求遣词之新,这在英语中称为Elegant Variation(求雅换词),以下三句中的动词你是否觉得用得也很精彩:1/A South African man bit his way to freedom. 2/I froze for almost 10 seconds. 3/Sibanda sank his teeth into…】
基金supported by grants from the Dongguan Science and Technology of Social Development Program(No.20231800940192)the Talent Development Foundation of the First Dongguan Affiliated Hospital of Guangdong Medical University(No.PU2023002).
文摘Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.
基金funded by the Government of Aragon through several consultancy projects from 2006 to 2022
文摘The escape and establishment of Iberian wild goats,Capra pyrenaica,from an enclosure in the 1990s marked the beginning of the recovery of the species in the Pyrenees.This population has occupied part of the Prepyrenees and has contacted another population reintroduced in France since 2014.It coexists with other wild ungulates,including the feral and domestic goats Capra hircus that has been living free since the 1960s.Today it’s the largest Iberian wild goat Pyrenean population.Between 2006 and 2022 we monitored the population and its expansion based on vantage points,itineraries and testimonies.The results indicate:(i)a population,of uncertain genetic origin,in numerical(15%average annual growth)and areal expansion,with the capacity to connect with other populations;(ii)an estimate of at least 500 individuals;(iii)in the process of expansion in contact with Iberian wild goats from France;(iv)sympatry with feral and domestic goat population in its main nucleus whose estimate exceeds 2000 specimens and(v)hybridization with feral and domestic goats.In 2022 sustainable hunt started with a hunting quota of 20 individuals.Genetic characterization and the establishment of an international coordinated monitoring are two of the current priorities.
基金supported by National Natural Science Foundation of China(No.82173769)the National Key R&D Program of China(No.2021YFE0106900)+1 种基金Applied Basic Research Multiinvestment Foundation of Tianjin(No.21JCYBJC01540)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(No.2023ZD019)。
文摘Small interfering RNAs(siRNA)provide a novel and highly specific therapy due to their ability to effectively silence target genes,to date six siRNA therapeutics are approved for clinical use.Even so,some critical challenges remain to overcome in the therapeutic application of siRNAs,with delivery issues at the forefront.Among them,endo/lysosomal barrier is one of the important but often-neglected limitations hindering the delivery of siRNA therapeutics.In this review,we summarize the promising strategies that facilitate siRNAs overcoming endo/lysosomal barriers based on the cellular uptake and intracellular transport pathways,including promoting escape once endocytosis into the endo/lysosomes and bypassing lysosomes via endosome-Golgi-endoplasmic reticulum(ER)pathway or nonendocytosis pathway,and discuss the principal considerations and the future directions of promoting endo/lysosomal escape in the development of therapeutic siRNAs.
基金supported by the Prespa-Ohrid Nature Trust and the Aage V.Jensen Foundation via PrespaNet's"Prespa Project(2021-2024)"the Rufford Foundation(grant number 30090-1)the Ministry of Science,Technological Development and Innovation of the Republic of Serbia(grant numbers451-03-0133012020-14/2627,451-03-47/2023-01/200178,451-03-47/2023-01/200007).
文摘Functional constraints between different types of antipredator behavior should be common,especially if they are on the opposite sides of the behavioral spectrum such as flight and post-capture immobility.We examined a potential compromise between post-capture immobility displays and sprint speed in dice snakes(Natrix tessellata),using a field-based approach.We sampled snakes(N=238)from two populations:from a dense island population free of mammal predators,and from a less dense mainland population,preyed upon by both bird and mammal predators.We explored the effects of sexual maturity,temperature,body size,presence of palpable food in the gut,and injuries on the occurrence and duration of post-capture immobility as well as sprint speed.Our results confirm the existence of functional constraints between locomotor performance and post-capture immobility in dice snakes.Faster dice snakes start escaping promptly after release,while slower individuals utilize more passive antipredator behaviors such as death feigning.Local adaptations seem to have great influence on behavioral compromise,since the mammal-free island population exhibited a higher incidence of post-capture immobility and a significantly lower sprint speed,compared to the less dense mainland population.Additionally,immature individuals tended to avoid death feigning and their post-capture immobility lasted shorter compared to adult individuals.It remains to be seen how individuals adjust their behavior to accomodate locomotor constraints,and in which specific phases of the predator-prey interaction these adjustments occur.
基金supported by the National Key R&D Program of China(2023YFF1304600)。
文摘Urbanization has significantly altered the habitat structure and behavioral patterns of animals.In urban environments with frequent human disturbances,animals may undergo adaptive adjustments in their escape behaviors.This study focuses on Eurasian Tree Sparrows(Passer montanus)from five cities across different latitudes in China,comparing their flight initiation distance(FID)in urban and rural areas to assess the impact of urbanization on their escape behavior and the trend of ecological homogenization.The results confirm the established pattern at the geographic level:a reduction of FID in urban habitats and a decrease in FID with increasing latitude.That is,northern populations of the Eurasian Tree Sparrow in China are bolder than the southern populations.In addition,FID is positively correlated with flock size,with rural flocks exhibiting more pronounced group behavior(observed flocking frequency for urban and rural is 28.74%vs.40.7%,flock size variance is 26.90 vs.55.63).Despite the differences between northern and southern latitudes,the variability of FID in urban individuals consistently remains lower than that in rural areas,supporting the trend of reduced variability in escape behavior among birds in urban environments.Driven by urbanization,the escape behavior of Eurasian Tree Sparrows tends toward ecological homogenization,meaning that behavioral differences between urban areas in different cities are diminishing.This trend may obscure the behavioral variability brought about by latitude gradients,indicating that urbanization not only shapes the behavioral adaptations of birds but also potentially weakens their behavioral diversity.
文摘Lung cancer is a common cause of cancer-related death globally.The majority of lung cancer patients initially benefit from chemotherapy and immunotherapy.However,as the treatment cycle progresses and the disease evolves,the emergence of acquired resistance leads to treatment failure.Many researches have shown that non-coding RNAs(ncRNAs)not only influence lung cancer progression but also act as potential mediators of immunotherapy and chemotherapy resistance in lung cancer,mediating drug resistance by regulating multiple targets and pathways.In addition,the regulation of immune response by ncRNAs is dualistic,forming a microenvironment for inhibits/promotes immune escape through changes in the expression of immune checkpoints.The aim of this review is to understand the effects of ncRNAs on the occurrence and development of lung cancer,focusing on the role of ncRNAs in regulating drug resistance of lung cancer.
基金supported by a grant from the National Natural Science Foundation of China(No.82070643)。
文摘Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is not fully understood.This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC.Methods:Tissue immunohistochemistry,TCGA,and GEO databases were used to analyze the expression of YBX1 in ICC.The expression of YBX1 was silenced and overexpressed in cell lines.Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses.Actinomycin D,RNA immunoprecipitation,and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes.Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC.Results:The research findings indicated that ICC exhibited high levels of YBX1 expression,which was strongly associated with unfavorable outcomes.YBX1 promoted tumor progression by suppressing antitumor T-cell responses.YBX1 enhanced signal transducer and activator of transcription 1(STAT1)translation by serving as a 5-methylated cytosine(m5C)reader and activating the STAT1/PD-L1 pathway.Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1,STAT1,and PD-L1 expression.Conclusions:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.
基金supported by the Natural Science Foundation of Shandong Province(Grant No.ZR2020MA092)the Innovation Project for Graduate Students of Ludong University(Grant No.IPGS2024-048).
文摘The diffusion trajectory of a Brownian particle passing over the saddle point of a two-dimensional quadratic potential energy surface is tracked in detail according to the deep learning strategies.Generative adversarial networks(GANs)emanating in the category of machine learning(ML)frameworks are used to generate and assess the rationality of the data.While their optimization is based on the long short-term memory(LSTM)strategies.In addition to drawing a heat map,the optimal path of two-dimensional(2D)diffusion is simultaneously demonstrated in a stereoscopic space.The results of our simulation are completely consistent with the previous theoretical predictions.
基金supported by grants from Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(2023SHIBS0002)the National Key Research and Development Program of China(2023YFF1203505)+5 种基金the National Key R&D Program of China(2024YFC2417900)Shenzhen Municipal Science and Technology Innovation Council(202110293000007)Shenzhen Science and Technology Program(KJZD20230923114909019)the National Key R&D Program of China(2018YFA0801006)the National Natural Science Foundation of China(31771618)Guangdong Natural Science Foundation(2022A1515011878).
文摘Zebrafish larvae are useful for identifying chemicals against lateral line(LL)hair cell(HC)damage and this type of chemical screen mainly focuses on searching for protectors against cell death.To expand the candidate pool of HC protectors,a self-built acoustic escape response(AER)-detecting system was developed to apply both low-frequency near-field sound transmission and AER image acquisition/processing modules.The device quickly confirmed the changed LL HC functions caused by most known ototoxins,protectors,and neural transmission modifiers,or knockdown of LL HC-expressing genes.With ten devices wired in tandem,five‘hit’chemicals were identified from 124 cyclin-dependent kinase inhibitors to partially restore cisplatin-damaged AER in less than a day.AS2863619,ribociclib,and SU9516 among the hits,protected the HCs in the mouse cochlea.Therefore,using free-swimming larval zebrafish,the self-made AER-detecting device can efficiently identify compounds that are protective against HC damage,including cell death and loss-of-function.
基金supported by the National Natural Science Foundation of China (Grant Nos. 42188101, 42274211, 41974170, 42374184, 42122032, and 41974196)the Chinese Academy of Sciences (Grant Nos. QYZDJSSW-JSC028, XDA15052500, XDA17010301, and XDB41000000)+3 种基金the CNSA (Grant No. D050103)the Specialized Research Fund for State Key Laboratories of Chinathe Specialized Research Fund for Laboratory of Geospace Environment of the University of Science and Technology of Chinasupported by the International Space Science Institute (ISSI) in Bern and Beijing through the ISSI/ISSI-BJ International Team Project titled “Understanding the Mars Space Environment Through Multi-Spacecraft Measurements” (ISSI Team Project No. 23-582 and ISSI-BJ Team Project No. 58)
文摘Atmospheric escape plays a critical role in shaping the long-term climate evolution of Mars.Among the various escape mechanisms,energetic neutral atoms(ENAs)generated through charge exchange between solar wind ions and exospheric neutrals serve as an important diagnostic for ion-neutral interactions and upper atmospheric loss.This study presents direct observations of hydrogen ENAs(H-ENAs)on the dayside of Mars by using the Mars Ion and Neutral Particle Analyzer(MINPA)onboard China’s Tianwen-1 orbiter.By analyzing H-ENA data during a coronal mass ejection and a stream interaction region from December 29,2021,to January 1,2022,and comparing these data with MAVEN/SWIA(Mars Atmosphere and Volatile EvolutioN/Solar Wind Ion Analyzer)solar wind measurements,we examine the temporal evolution of H-ENA flux and the associated sputtered escape of atmospheric constituents.The observed H-ENA velocity is consistent with upstream solar wind ions,and the H-ENA-to-ion intensity ratio is used to infer variations in exospheric density,revealing a delayed response to enhanced solar wind activity.Penetrating H-ENA intensities reach up to 5.3×10^(6)s^(−1) cm^(−2),with energy fluxes on the order of(0.5-8.1)×10^(−3) mW/m^(2).The estimated oxygen sputtered escape rate driven by penetrating H-ENAs ranges from 5.5×10^(23)s^(−1) to 5.2×10^(24)s^(−1),comparable to or exceeding previous estimates based on penetrating ions.The findings highlight the need for low-altitude H-ENA observations to better quantify their atmospheric interactions and refine our understanding of nonthermal escape processes at Mars.
基金support from the Postdoctoral Fellowship Scheme of The Chinese University of Hong Kong,the Postdoctoral Fellowship Program of CPSF(GZC20241828)The China Postdoctoral Science Foundation(2024M763416).
文摘Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes;however,the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability,cytosolic delivery and subsequent therapeutic efficacy.In this case,the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo/lysosomal escape,which relies on the development of safe and efficient nanodelivery systems.A deeper mechanistic understanding in the endo/lysosomal escape will guide the development of more efficient nano-delivery systems.In this review,we summarize various mechanisms by which nanoparticles escape from the endo/lysosome,and showcase the recent progress in dissecting the endo/lysosomal approaches based on nano-delivery systems.Emphasis will lie on the properties of nanoparticles that govern the endo/lysosomal escape pathway as well as the latest promising applications in vaccine delivery and genetic engineering field.
基金funded by the National Natural Science Foundation of China(Grant Nos.82030082 and 82272845)the Natural Science Foundation of Shandong Province(Grant No.ZR2023LZL001).
文摘Non-small cell lung cancer(NSCLC)is a leading cause of cancer-related mortality worldwide1-3.While radioimmuno-therapy shows promise in boosting antitumor immunity,the clinical outcomes have been inconsistent4 and are often lim-ited by the immunosuppressive tumor microenvironment(TME).Cyclooxygenase(COX)-2 and the COX-2 downstream product,prostaglandin E2(PGE2),are increasingly implicated in immune escape5,6 but the impact on radioimmunother-apy efficacy has not been explored.TCF1-expressing CD8+T cells demonstrate defining functional properties of progeni-tor-exhausted T cells,including clonal expansion through self-renewal capacity and multipotent differentiation toward terminal effector phenotypes,while maintaining long-term persistence critical for sustaining antitumor immunity7-9.Given the central role in anti-tumor immune maintenance,TCF1+CD8+T cells are likely critical to radioimmunotherapy efficacy10.The role of COX-2 inhibition in enhancing the effi-cacy of radioimmunotherapy efficacy in NSCLC was investi-gated in the current study.
文摘Conventional nutritional supplements frequently demonstrate limited clinical effectiveness due to the harsh milieu of the gastrointestinal tract,inefficient transepithelial transport,and rapid systemic clearance.Nanoliposomal delivery platforms-lipid bilayer vesicles on the nanometer scale-have attracted attention as an adaptive strategy to shield sensitive nutrients,navigate biological barriers,and deliver payloads directly to target tissues or even sub-cellular organelles.Despite a growing body of literature,a consolidated appraisal of design principles,targeting modalities,and translational hurdles is still needed to guide future nutraceutical innovation.We aim to:(1)Summarize the physicochemical foundations of nanoliposomal nutrient carriers;(2)Delineate state-of-the-art approaches for organ-specific and organelle-specific targeting,with particular emphasis on renal and mitochondrial delivery;(3)Evaluate current evidence supporting therapeutic benefits in cardiometabolic,neuroprotective,and renal-repair contexts;and(4)Map unresolved challenges-including manufacturing scale-up,cost,and regulatory oversight-to inform a roadmap for clinical translation.A systematic literature search was performed across PubMed,Web of Science,and Scopus through May 2025 using Boolean combinations of“nanoliposome”,“nutrient”,“targeted delivery”,“bioavailability”,and organ-specific terms(e.g.,“kidney”,“mitochondria”).Primary research articles,systematic reviews,and relevant meta-analyses written in English were included.Data were extracted on liposomal composition,particle size,surface modifications(e.g.,polyethylene glycol,ligand conjugation),in vitro and in vivo bio-distribution,efficacy outcomes,and safety profiles.Key design variables were mapped against reported biological performance to identify convergent principles.Sixty-four original studies and twenty-one reviews met inclusion criteria.Encapsulation within phosphatidylcholine-rich bilayers consistently enhanced nutrient stability in simulated gastric fluid and improved Caco-2 trans-epithelial transport two-fold to ten-fold compared with free compound controls.Ligand-mediated strategies-such as folate,lactoferrin,or peptide conjugation-achieved organ-specific accumulation,with kidney-directed liposomes demonstrating up to a four-fold increase in renal cortex uptake.Mitochondrial targeting using amphipathic peptides(e.g.,SS-31)or triphenylphosphonium moieties delivered antioxidant nutrients to the organelle,restoring mitochondrial membrane potential and reducing reactive oxygen species(ROS)in preclinical cardiomyopathy and neurodegeneration models.Endosomal escape was most effectively triggered by fusogenic lipids(e.g.,dioleoylphosphatidylethanolamine)or pH-responsive polymers.PEGylation prolonged circulation half-life by 3-6 hours but elicited anti-polyethylene glycol antibodies in approximately one-quarter of recipients;emerging natural sterol-mimetic or collagen-mimetic coatings showed comparable stealth behavior with superior biodegradability.Scalability remains limited:Only three studies reported pilot-scale(>10 L)batches with Good Manufacturing Practice-compliant reproducibility.Targeted nanoliposomal systems substantially improve nutrient stability,absorption,and tissue specificity,offering a credible route to transform supplement efficacy for cardiometabolic,renal,and neuroprotective indications.Optimization of lipid composition,escape mechanisms,and biocompatible surface chemistries can further enhance therapeutic indices.Nonetheless,industrial-scale manufacturing,cost containment,and immunogenicity mitigation remain critical obstacles.Addressing these gaps through standardized characterization protocols,head-to-head clinical trials,and biomaterial innovation will be essential to unlock the full potential of nanoliposomal nutraceuticals in routine healthcare practice.
基金Supported by National Natural Science Foundation of China,No.81673241 and No.32470985.
文摘This editorial focuses on the recent article by Yang et al in the World Journal of Gastrointestinal Oncology,which highlights the role of interlukin-17A in promoting hepatocellular carcinoma(HCC)progression by up-regulated programmed cell death protein-1(PD-1)/programmed cell death protein ligand-1(PD-L1)expression.Previous,the high PD-1/PD-L1 level was due to hepatitis virus infection leading to systemic innate immune tolerance and cluster of differen-tiation 8+T cells exhaustion,ultimately leading to HCC.Recently,interesting studies have found that the malignant progression of metabolic dysfunction-associated steatotic/fatty liver disease(MASLD/MAFLD),that is former nonalcoholic fatty liver disease,was achieved by up-regulated PD-L1 level that was activated the cGAS-STING pathway under lipid accumulation with mito-chondrial DNA overflow and up-regulated PD-1/PD-L1 to promote MASLD malignant transformation via immune escape.These data suggested that PD-1 or PD-L1 should be a promising target for preventing or delaying non-viral liver disease malignant progression except of antiviral therapy for HCC.
