This paper reviews recent developments and key advances in terahertz(THz)science,technology,and applications,focusing on 3 core areas:astronomy,telecommunications,and biophysics.In THz astronomy,it highlights major di...This paper reviews recent developments and key advances in terahertz(THz)science,technology,and applications,focusing on 3 core areas:astronomy,telecommunications,and biophysics.In THz astronomy,it highlights major discoveries and ongoing projects,emphasizing the role of advanced superconducting technologies,including superconductor–insulator–superconductor(SIS)mixers,hot electron boundedness spectroscopy(HEB),transition-edge sensors(TESs),and kinetic inductance detectors(KIDs),while exploring prospects in the field.For THz telecommunication,it discusses progress in solid-state sources,new communication technologies operating within the THz band,and diverse modulation methods that enhance transmission capabilities.In THz biophysics,the focus shifts to the physical modulation of THz waves and their impact across biological systems,from whole organisms to cellular and molecular levels,emphasizing nonthermal effects and fundamental mechanisms.This review concludes with an analysis of the challenges and perspectives shaping the future of THz technology.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients...BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients with advanced HCC.Different patterns of treatment responsiveness have been identified in differentiated hepatoblastoma HepG2 cells and metastatic HCC SNU449 cells.AIM To define the long non-codingRNA-microRNA-mRNA(lncRNA-miRNA-mRNA)predicted signatures related to selected hallmarks of cancer(apoptosis,autophagy,cell stress,cell dedifferentiation and invasiveness)in RNAseq studies using Sorafenib-treated HepG2 and SNU449 cells.Various available software analyses allowed us to establish the lncRNA-miRNA-mRNA regulatory axes following treatment in HepG2 and SNU449 cells.METHODS HepG2 and SNU449 cells were treated with Sorafenib(10μmol/L)for 24 hours.Total RNA,including small and long RNA,was extracted with a commercial miRNeasy kit.RNAseq was carried out for the identification of changes in lncRNA-miRNA-mRNA regulatory axes.RESULTS MALAT,THAP9-AS1 and SNGH17 appeared to coordinately regulate miR-374b-3p and miR-769-5p that led to upregulation of SMAD7,TIRARP,TFAP4 and FAXDC2 in HepG2 cells.SNHG12,EPB41 L4A-AS1,LINC01578,SNHG12 and GAS5 interacted with let-7b-3p,miR-195-5p and VEGFA in SNU449 cells.The axes MALAT1/hsamir-374b-3p/SMAD7 and MALAT1/hsa-mir-769-5p/TFAP4 were of high relevance for Sorafenib response in HepG2 cells,whereas PVT1/hsa-miR-195-5p/VEGFA was responsible for the differential response of SNU449 cells to Sorafenib treatment.CONCLUSION Critical lncRNAs acting as sponges of miRNA were identified that regulated mRNA expression,whose proteins mainly increased the antitumor effectiveness of the treatment(SMAD7,TIRARP,TFAP4,FAXDC2 and ADRB2).However,the broad regulatory axis leading to increased VEGFA expression may be related to the side effect of Sorafenib in SNU449 cells.展开更多
In this article,we explored the role of adipose tissue,especially mesenteric adipose tissue and creeping fat,and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease(CD).C...In this article,we explored the role of adipose tissue,especially mesenteric adipose tissue and creeping fat,and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease(CD).CD is a form of inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract,influenced by genetic predisposition,gut microbiota dysbiosis,and environmental factors.Gut microbiota plays a crucial role in modulating immune response and intestinal inflammation and is associated with the onset and progression of CD.Further,visceral adipose tissue,particularly creeping fat,a mesenteric adipose tissue characterized by hypertrophy and fibrosis,has been implicated in CD pathogenesis,inflammation,and fibrosis.The bacteria from the gut microbiota may translocate into mesenteric adipose tissue,contributing to the formation of creeping fat and influencing CD progression.Although creeping fat may be a protective barrier against bacterial invasion,its expansion can damage adjacent tissues,leading to complications.Modulating gut microbiota through interventions such as fecal microbiota transplantation,probiotics,and prebiotics has shown potential in managing CD.However,more research is needed to clarify the mechanisms linking gut dysbiosis,creeping fat,and CD progression and develop targeted therapies for microbiota modulation and fat-related complications in patients with CD.展开更多
An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease prog...An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.展开更多
Neonatal hypoxic-ischemic encephalopathy(HIE)is a significant cause of disability in children.Improving brain function and accelerating neurological recovery may require a combination of neuroprotective and pro-regene...Neonatal hypoxic-ischemic encephalopathy(HIE)is a significant cause of disability in children.Improving brain function and accelerating neurological recovery may require a combination of neuroprotective and pro-regenerative treatments at different stages of HIE.While the first hours after the neonatal insult are the most critical period for neuroprotection,the existence of secondary and tertiary mechanisms of brain injury offers the possibility of preventing delayed neurodegeneration in the subsequent days,weeks,or months(Levison et al.,2022).展开更多
Parkinson's disease(PD),a chronic and com-mon neurodegenerative disease,is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-...Parkinson's disease(PD),a chronic and com-mon neurodegenerative disease,is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein.Type 2 diabetes mellitus(T2DM)is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion.Extensive evidence has con-firmed shared pathogenic mechanisms underlying PD and T2DM,such as oxidative stress caused by insulin resistance,mitochondrial dysfunction,inflammation,and disorders of energy metabolism.Conventional drugs for treating T2DM,such as metformin and glucagon-like peptide-1 receptor ago-nists,affect nerve repair.Even drugs for treating PD,such as levodopa,can affect insulin secretion.This review sum-marizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.展开更多
Depressive disorder is a chronic,recurring,and potentially life-endangering neuropsychiatric disease.According to a report by the World Health Organization,the global population suffering from depression is experienci...Depressive disorder is a chronic,recurring,and potentially life-endangering neuropsychiatric disease.According to a report by the World Health Organization,the global population suffering from depression is experiencing a significant annual increase.Despite its prevalence and considerable impact on people,little is known about its pathogenesis.One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression.Furthermore,the neural circuit mechanism of depression induced by various factors is particularly complex.Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression,a comparison between the neural circuits of depression induced by various factors is essential for its treatment.In this review,we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression,aiming to provide a theoretical basis for depression prevention.展开更多
Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HN...Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.展开更多
Background:How AMP activated protein kinase(AMPK)signaling regulates mito-chondrial functions and mitophagy in human trophoblast cells remains unclear.This study was designed to investigate potential players mediating...Background:How AMP activated protein kinase(AMPK)signaling regulates mito-chondrial functions and mitophagy in human trophoblast cells remains unclear.This study was designed to investigate potential players mediating the regulation of AMPK on mitochondrial functions and mitophagy by next generation RNA-seq.Methods:We compared ATP production in protein kinase AMP-activated catalytic subunit alpha 1/2(PRKAA1/2)knockdown(AKD)and control BeWo cells using the Seahorse real-time ATP rate test,then analyzed gene expression profiling by RNA-seq.Differentially expressed genes(DEG)were examined by Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment.Then protein-protein interactions(PPI)among mitochondria related genes were fur-ther analyzed using Metascape and Ingenuity Pathway Analysis(IPA)software.Results:Both mitochondrial and glycolytic ATP production in AKD cells were lower than in the control BeWo cells(CT),with a greater reduction of mitochondrial ATP production.A total of 1092 DEGs were identified,with 405 upregulated and 687 downregulated.GO analysis identified 60 genes associated with the term‘mitochon-drion’in the cellular component domain.PPI analysis identified three clusters of mito-chondria related genes,including aldo-keto reductase family 1 member B10 and B15(AKR1B10,AKR1B15),alanyl-tRNA synthetase 1(AARS1),mitochondrial ribosomal protein S6(MRPS6),mitochondrial calcium uniporter dominant negative subunit beta(MCUB)and dihydrolipoamide branched chain transacylase E2(DBT).Conclusions:In summary,this study identified multiple mitochondria related genes regulated by AMPK in BeWo cells,and among them,three clusters of genes may po-tentially contribute to altered mitochondrial functions in response to reduced AMPK signaling.展开更多
Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration ...Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Iα-loop-helix Iβmotif which corresponds to helix I of other P 450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,theγ-domain.The structure reveals a homodimer in which theγ-domain of one molecule interacts with theβ-domain of another.The plane of heme group makes an angle of approximately 40°with the helix Iα-loop-helix Iβmotif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recognition.Phe-301,Ser-303 and Gly-305 from the helix Iα-loop-helix Iβmotif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.展开更多
The article written by Zhao et al,which was recently accepted for publication,introduces an innovative method that combines deep learning-based feature extraction with a radiomics nomogram to create a noninvasive proc...The article written by Zhao et al,which was recently accepted for publication,introduces an innovative method that combines deep learning-based feature extraction with a radiomics nomogram to create a noninvasive procedure for determining perineural invasion status in patients with rectal cancer.This method is an artificial intelligence application in which researchers segment their own datasets,derive features and analyze their weights.It was found that the support vector machine was the most effective model in the arterial and venous phases.A support vector machine is a machine learning algorithm based on a vector space that finds a decision boundary between the two classes furthest from any point in the training data.展开更多
Non-alcoholic fatty liver disease(NAFLD)is the fastest-growing global contributor to the disease burden associated with the consequences of chronic liver disease,including cirrhosis and liver cancer.It is projected th...Non-alcoholic fatty liver disease(NAFLD)is the fastest-growing global contributor to the disease burden associated with the consequences of chronic liver disease,including cirrhosis and liver cancer.It is projected that more than fifty percent of the adult population,including women,smokers,and individuals without metabolic syndrome,will have NAFLD by 2040.Various mechanisms linking the gut microbiome to NAFLD and the consequent fibrosis have been discerned,which suggest the dysbiosis-induced impairment of gut endothelial barrier function,leading to hepatic inflammation through the translocation of bacterial components.NAFLD is progressively associated with environmental variables,especially exposure to heavy metals that impair liver metabolism,produce oxidative stress,and exacerbate inflammation,hence accelerating its progression.These toxicants also modify the composition of gut microbiota,hence intensifying liver damage.Comprehending the processes by which heavy metals contribute to NAFLD is essential for formulating tailored therapies.This review examines strategies to alleviate liver toxicity caused by heavy metals,including chelation therapy,dietary modifications(antioxidants and hepatoprotective nutrients),gut microbiome modulation via probiotics and postbiotics like short-chain fatty acids to restore intestinal barrier function and use of essential minerals like selenium,with potent antioxidant characteristics.Employing these measures may offer an integrated approach for addressing NAFLD in individuals subjected to heavy metal poisoning.展开更多
Nucleosomes play a vital role in chromatin organization and gene regulation,acting as key hubs that inter-act with various chromatin-associated factors through diverse binding mechanisms.Recent research has highlighte...Nucleosomes play a vital role in chromatin organization and gene regulation,acting as key hubs that inter-act with various chromatin-associated factors through diverse binding mechanisms.Recent research has highlighted the prevalence of mutations in linker histones across different types of cancer,emphasizing their critical involvement in cancer progression.These cancer-associated mutations in linker histones have been shown to disrupt nucleosome stacking and the formation of higher-order chromatin structures,which in turn significantly affect epigenetic regulatory processes.In this review,we provide a comprehensive analysis of how cancer-associated linker histone mutations alter their physicochemical properties,influencing their binding to nucleosomes,and overall chromatin architecture.Additionally,we explore the significant impact of mutations near post-translational modification sites,which further modulate chromatin dynamics and regulatory functions,offering insights into their role in oncogenesis and potential therapeutic targets.展开更多
Biomedical scaffold fabrication has seen advancements in mimicking the native extracellular matrix through intricate three-dimensional(3D)structures conducive to tissue regeneration.Coiled fibrous scaffolds have emerg...Biomedical scaffold fabrication has seen advancements in mimicking the native extracellular matrix through intricate three-dimensional(3D)structures conducive to tissue regeneration.Coiled fibrous scaffolds have emerged as promising substrates owing to their ability to provide unique topographical cues.In this study,coiled poly(ε-caprolactone)(PCL)fibrous bundles were fabricated using an alginate-based composite system,and processed with 3D printing.The unique structure was obtained through the die-swell phenomenon related to the release of residual stresses from the printed strut,thereby transforming aligned PCL fibers into coiled structures.The effects of printing parameters,such as pneumatic pressure and nozzle moving speed,on fiber morphology were investigated to ensure a consistent formation of coiled PCL fibers.The resulting coiled PCL fibrous scaffold demonstrated higher activation of mechanotransduction signaling as well as upregulation of osteogenic-related genes in human adipose stem cells(hASCs),supporting its potential in bone tissue engineering.展开更多
In this paper, we investigate the effect of exceptional points(EPs) on the violation of Leggett–Garg inequality(LGI) and no-signaling-in-time(NSIT) conditions and compare the different effects between the Hamiltonian...In this paper, we investigate the effect of exceptional points(EPs) on the violation of Leggett–Garg inequality(LGI) and no-signaling-in-time(NSIT) conditions and compare the different effects between the Hamiltonian EP(HEP) and Liouvillian EP(LEP) on those violations. We consider an open system consisting of two coupled qubits and each qubit is contacted with a thermal bath at a different temperature. In the case of omitting quantum jumps, we find that the system exhibits a second-order HEP, which separates the parameter space into an overdamped regime and an underdamped regime. In this situation, the LGI and NSIT conditions can be violated in both regimes and not violated at the HEP. In the case of without omitting quantum jumps, we find that the system exhibits a third-order LEP, which also separates the parameter space into an overdamped regime and an underdamped regime. In this situation, the LGI can only be violated in the underdamped regime with large coupling strength between the qubits.Conversely, the NSIT conditions can be violated in both regimes, as well as at the LEP, except in the overdamped regime with small coupling strength between the qubits. Comparing the violations of the LGI and NSIT conditions with HEP and LEP, we find that the quantum jumps would reduce the generation of coherence, enhance the decoherence, and lead to narrower parameter regimes that the LGI and NSIT conditions can be violated. Furthermore, in both cases,the NSIT conditions can be violated in a wider parameter regime than the LGI.展开更多
With prolonged exposure in the human body,titanium alloy implants face challenges associated with bacterial attachment and proliferation,leading to implant failure and severe complications.Photothermal therapy(PTT)eme...With prolonged exposure in the human body,titanium alloy implants face challenges associated with bacterial attachment and proliferation,leading to implant failure and severe complications.Photothermal therapy(PTT)emerges as an efficient strategy for biofilm elimination.However,the local high temperature of PTT and incomplete bacteria ablation in low-temperature PTT pose risks of damage to normal tissues and biofilm recalcitrance,respectively.In this study,we synergistically combined photothermal therapy and chemotherapy to mildly disrupt biofilms of Staphylococcus aureus(S.aureus)to enhance the efficiency of biofilm ablation.The synergistic nanoplatform comprises near-infrared-light responsive con-jugated polymers,heat-sensitive liposomes,and the antibiotic daptomycin for biofilm elimination.The heat generated by conjugated polymers,stimulated with 808 nm light,alters biofilm permeability and releases antibiotics locally to eradicate biofilm.The nanoparticles exhibit biofilm dispersion activity and can effectively inhibit biofilm growth for up to 5 days.Consequently,this nanoplatform based on conjugated polymers offers a reliable method for ablating biofilms on titanium alloy implant and exhibits potential in drug-resistant clinical applications.展开更多
Congenital disorders of glycosylation(CDG)are a cluster of monogenic disorders resulting from defects in glycosylation.FCSK encodes fucokinase,an enzyme that catalyzes the phosphorylation of L-fucose to generate fucos...Congenital disorders of glycosylation(CDG)are a cluster of monogenic disorders resulting from defects in glycosylation.FCSK encodes fucokinase,an enzyme that catalyzes the phosphorylation of L-fucose to generate fucose-1-phosphate,an important step in fucosylation.Mutations in FCSK lead to CDG with an autosomal recessive inheritance pattern,primarily manifesting as developmental delay,hypotonia,and brain abnormalities.However,no fcsk mutant animal models have yet been established.This study constructed the first fcsk knockout(fcsk^(-/-))zebrafish model using CRISPR/Cas9 technology.Notably,fcsk^(-/-)zebrafish exhibited impaired growth,characterized by delayed epiboly and DNA accumulation during early embryonic development,as well as brain atrophy in adulthood.Larval-stage fcsk^(-/-)zebrafish displayed locomotor deficits and increased susceptibility to pentylenetetrazole-induced seizures.In adulthood,fcsk^(-/-)zebrafish showed neurodevelopmental abnormalities,including increased anxiety,decreased aggression,reduced social preference,and impaired memory.Additionally,total protein fucosylation was markedly reduced in fcsk^(-/-)zebrafish,accompanied by decreased expression of pofut2,which encodes protein Ofucosyltransferase 2,an enzyme involved in the fucosylation salvage pathway.Apoptotic activity was elevated in the midbrain-hindbrain boundary(MHB)of fcsk^(-/-)zebrafish.Supplementation with GDP-L-fucose or the human FCSK gene restored developmental defects and total protein fucosylation in fcsk^(-/-)zebrafish.RNA sequencing revealed dysregulated gene expression associated with glycosylation,apoptosis,and neurodegenerative diseases.These findings suggest that fcsk^(-/-)zebrafish exhibit neurodevelopmental disorders,providing the first fcsk gene knockout animal model and offering a platform for investigating the molecular underpinnings of the disease and facilitating drug screening efforts.展开更多
Objective:Activation of mitophagy is a promising option to overcome the mitochondrial malfunction that accompanies many diseases.Herein,we investigate the mechanisms underlying the ability of sodium lactate and pyruva...Objective:Activation of mitophagy is a promising option to overcome the mitochondrial malfunction that accompanies many diseases.Herein,we investigate the mechanisms underlying the ability of sodium lactate and pyruvate to initiate mitophagy,from the perspective of action on mitochondrial network and expression levels.Methods:Fluorescent and confocal microscopy was used to assess key cell parameters characterizing the state of the mitochondrial network and the level of mitophagy in human fibroblasts carrying mutations in genes encoding LRRK2 and PINK1 after the combined application of lactate and pyruvate and after direct acidification.qRT-PCR was used to study the expression levels of key mitophagy genes.Results:Cells with a mutation in the PINK1 gene showed a lower basal cytosolic pH.The application of sodium lactate and pyruvate to the cells with mutations associated with Parkinson’s disease caused intracellular acidification.Lowering extracellular pH to 6.0 led to a decrease in mitochondrial membrane potential,while the effect of lactate and pyruvate tended to increase this parameter.Extracellular acidification,as well as the effects of lactate and pyruvate,led to an increased level of mitophagy,and also affected such parameters of the mitochondrial network morphology as the ratio of individual to network mitochondria,branch length in mitochondrial network,number of mitochondrial junctions in the network,and also altered the expression of key mitophagy genes.Conclusion:Direct acidification and one induced by lactate and pyruvate do not differ in the efficiency of their effects on the mitochondrial network and mitophagy but change the cell fate differently.The mechanisms of acidification-induced activation of mitophagy differ in control and mutant fibroblasts.展开更多
In contrast to the conventional spermiogram, metabolomics approaches give insights into the molecular composition of semen and mayprovide more detailed information on the fertility status of the respective donor. Give...In contrast to the conventional spermiogram, metabolomics approaches give insights into the molecular composition of semen and mayprovide more detailed information on the fertility status of the respective donor. Given the intra-individual variability of spermiogramparameters between two donations, this study sought to elucidate the biological variability of the seminal plasma metabolome overan average period of 8 weeks. Two time-shifted semen samples from 15 healthy donors were compared by a targeted metabolomicsapproach utilizing the Biocrates AbsoluteIDQ p180 kit. Next to intraclass correlation coefficients (ICC), which represent a measureof reliability, coefficients of variation within individuals(CVW) and coefficients of variation between individuals (CVB) were calculatedfor each metabolite to demonstrate its stability. Furthermore, men were divided into two cohorts, a similar sperm concentration(SSC) and a differing sperm concentration (DSC) cohort, based on the observed variance in sperm concentration between the twosemen donations. The ICC was higher in the SSC compared to the DSC cohort. The levels of 18 metabolites, primarily acylcarnitines,varied between the initial and subsequent donations. After subdivision into subgroups, only ornithine and phosphatidylcholine 40:5exhibited differential levels between the two donations in the SSC group, compared to 14 metabolites in the DSCgroup.CVBwashigher than CVW but both differed between the metabolite subclasses. Biogenic amines were identified as the least reliable analytesover time, exhibiting the highest CVW,compared to sphingomyelins, which demonstrated the highest reliability with the lowestvariation.CVB was the highest for ether-bound glycerophosphatidylcholines and the lowest for amino acids.展开更多
Background:Glucocorticoids are used as anti-inflammatory drugs for the treatment of various diseases,however,their side effects on normal brain tissue remain underinvestigated.Objectives:The study aimed to investigate...Background:Glucocorticoids are used as anti-inflammatory drugs for the treatment of various diseases,however,their side effects on normal brain tissue remain underinvestigated.Objectives:The study aimed to investigate dexamethasone(DXM)effects on cell composition and myelin content in the mouse brain tissue.Methods:C57Bl/6 male mice(n 60)received single and ten multiple intraperitoneal DXM injections(2.5 mg/kg),and the studied=parameters were analysed at 1,3,7,10 days after a single DXM injection and 15,30,60,and 90 days after the multiple injections.Oligodendrocytes,microglia,and astrocytes were assayed by immunohistochemistry with specific antibodies(Olig2,CD68,and GFAP,respectively)in the corpus callosum of the normal brain tissue.The myelin content was estimated by staining with LuxolFastBlue.The presence of GFAP isoforms was determined by western blotting.Results:DXM administration did not affect oligodendrocytes in the mouse brain but temporarily significantly decreased myelin content(1.2-fold,p 0.0058;1.4-fold,p 0.0001)at 3–15 days time points.At the same time,DXM significantly=<decreased the number of microglial cells(1.5–3.5-fold,p 0.0001)and significantly increased astrocytes(1.8-fold,p<<0.0001).Prolonged administration of DXM resulted in the decrease of the main GFAPα-isoform(50 kDa)and the appearance of shorter GFAP isoforms(30 kDa,42 kDa,44 kDa)similar to that in some neurodegenerative animal models.Conclusion:DXM can modify the cell composition of the normal mouse brain tissue by decreasing microglial cells and increasing astrocytes.Long-term use of DXM results in the inhibition of myelin formation and the appearance of truncated GFAP isoforms,suggesting its ability to induce neurodegeneration-like changes in the normal mouse brain.展开更多
基金supported by the National Key R&D Program of China(grant number 2023YFA1608200)the National Science Foundation of China(grant numbers 1925304 and 12204547)the XPLORER PRIZE.
文摘This paper reviews recent developments and key advances in terahertz(THz)science,technology,and applications,focusing on 3 core areas:astronomy,telecommunications,and biophysics.In THz astronomy,it highlights major discoveries and ongoing projects,emphasizing the role of advanced superconducting technologies,including superconductor–insulator–superconductor(SIS)mixers,hot electron boundedness spectroscopy(HEB),transition-edge sensors(TESs),and kinetic inductance detectors(KIDs),while exploring prospects in the field.For THz telecommunication,it discusses progress in solid-state sources,new communication technologies operating within the THz band,and diverse modulation methods that enhance transmission capabilities.In THz biophysics,the focus shifts to the physical modulation of THz waves and their impact across biological systems,from whole organisms to cellular and molecular levels,emphasizing nonthermal effects and fundamental mechanisms.This review concludes with an analysis of the challenges and perspectives shaping the future of THz technology.
基金Supported by Instituto de Salud Carlos III(ISCiii),No.PI19/01266 and No.PI22/00857Consejería de Salud y Familias(Junta de Andalucía),No.PI-0216-2020 and No.PIP-0215-2020Biomedical Research Network Center for Liver and Digestive Diseases(CIBERehd)founded by the ISCIII and co-financed by European Regional Development Fund“A way to achieve Europe”ERDF.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients with advanced HCC.Different patterns of treatment responsiveness have been identified in differentiated hepatoblastoma HepG2 cells and metastatic HCC SNU449 cells.AIM To define the long non-codingRNA-microRNA-mRNA(lncRNA-miRNA-mRNA)predicted signatures related to selected hallmarks of cancer(apoptosis,autophagy,cell stress,cell dedifferentiation and invasiveness)in RNAseq studies using Sorafenib-treated HepG2 and SNU449 cells.Various available software analyses allowed us to establish the lncRNA-miRNA-mRNA regulatory axes following treatment in HepG2 and SNU449 cells.METHODS HepG2 and SNU449 cells were treated with Sorafenib(10μmol/L)for 24 hours.Total RNA,including small and long RNA,was extracted with a commercial miRNeasy kit.RNAseq was carried out for the identification of changes in lncRNA-miRNA-mRNA regulatory axes.RESULTS MALAT,THAP9-AS1 and SNGH17 appeared to coordinately regulate miR-374b-3p and miR-769-5p that led to upregulation of SMAD7,TIRARP,TFAP4 and FAXDC2 in HepG2 cells.SNHG12,EPB41 L4A-AS1,LINC01578,SNHG12 and GAS5 interacted with let-7b-3p,miR-195-5p and VEGFA in SNU449 cells.The axes MALAT1/hsamir-374b-3p/SMAD7 and MALAT1/hsa-mir-769-5p/TFAP4 were of high relevance for Sorafenib response in HepG2 cells,whereas PVT1/hsa-miR-195-5p/VEGFA was responsible for the differential response of SNU449 cells to Sorafenib treatment.CONCLUSION Critical lncRNAs acting as sponges of miRNA were identified that regulated mRNA expression,whose proteins mainly increased the antitumor effectiveness of the treatment(SMAD7,TIRARP,TFAP4,FAXDC2 and ADRB2).However,the broad regulatory axis leading to increased VEGFA expression may be related to the side effect of Sorafenib in SNU449 cells.
基金Supported by the Postdoctoral Scholarship Grant,No.5552/2024 PROPG/PROPE N°06/2024.
文摘In this article,we explored the role of adipose tissue,especially mesenteric adipose tissue and creeping fat,and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease(CD).CD is a form of inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract,influenced by genetic predisposition,gut microbiota dysbiosis,and environmental factors.Gut microbiota plays a crucial role in modulating immune response and intestinal inflammation and is associated with the onset and progression of CD.Further,visceral adipose tissue,particularly creeping fat,a mesenteric adipose tissue characterized by hypertrophy and fibrosis,has been implicated in CD pathogenesis,inflammation,and fibrosis.The bacteria from the gut microbiota may translocate into mesenteric adipose tissue,contributing to the formation of creeping fat and influencing CD progression.Although creeping fat may be a protective barrier against bacterial invasion,its expansion can damage adjacent tissues,leading to complications.Modulating gut microbiota through interventions such as fecal microbiota transplantation,probiotics,and prebiotics has shown potential in managing CD.However,more research is needed to clarify the mechanisms linking gut dysbiosis,creeping fat,and CD progression and develop targeted therapies for microbiota modulation and fat-related complications in patients with CD.
基金supported by a grant from Ministry of Science,Technological Development and Innovation,Serbia,No.451-03-68/2022-14/200178(to NN)University of Defence,No.MFVMA/02/22-24(to MN)。
文摘An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.
基金supported by Fundação de AmparoàPesquisa do Estado do Rio de Janeiro(FAPERJ,E-26/010.002160/2019,E-26/203.227/2017,E-260003/001177/2020,and E-26/201.279/2021)Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,313757/2020-8,311188/2023-0)(to PMPC).
文摘Neonatal hypoxic-ischemic encephalopathy(HIE)is a significant cause of disability in children.Improving brain function and accelerating neurological recovery may require a combination of neuroprotective and pro-regenerative treatments at different stages of HIE.While the first hours after the neonatal insult are the most critical period for neuroprotection,the existence of secondary and tertiary mechanisms of brain injury offers the possibility of preventing delayed neurodegeneration in the subsequent days,weeks,or months(Levison et al.,2022).
基金supported by the National Natural Science Foundation of China(32161143021)the Iran National Science Foundation(4001873)+1 种基金the Henan Province Natural Science Foundation of China(182300410313)Henan University graduate Talent Program of Henan Province(SYLYC2023092).
文摘Parkinson's disease(PD),a chronic and com-mon neurodegenerative disease,is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein.Type 2 diabetes mellitus(T2DM)is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion.Extensive evidence has con-firmed shared pathogenic mechanisms underlying PD and T2DM,such as oxidative stress caused by insulin resistance,mitochondrial dysfunction,inflammation,and disorders of energy metabolism.Conventional drugs for treating T2DM,such as metformin and glucagon-like peptide-1 receptor ago-nists,affect nerve repair.Even drugs for treating PD,such as levodopa,can affect insulin secretion.This review sum-marizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
基金supported by the Brain&Behavior Research Foundation(30233).
文摘Depressive disorder is a chronic,recurring,and potentially life-endangering neuropsychiatric disease.According to a report by the World Health Organization,the global population suffering from depression is experiencing a significant annual increase.Despite its prevalence and considerable impact on people,little is known about its pathogenesis.One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression.Furthermore,the neural circuit mechanism of depression induced by various factors is particularly complex.Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression,a comparison between the neural circuits of depression induced by various factors is essential for its treatment.In this review,we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression,aiming to provide a theoretical basis for depression prevention.
文摘Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.
基金Dean's Office Howard University College of Medicine,Grant/Award Number:Bridge Fund/Pilot Study AwardNational Center on Minority Health and Health Disparities,Grant/Award Number:RCMI/IDC Award U54MD007597National Institute of Child Health and Human Development,Grant/Award Number:R03HD095417 and R16HD116702。
文摘Background:How AMP activated protein kinase(AMPK)signaling regulates mito-chondrial functions and mitophagy in human trophoblast cells remains unclear.This study was designed to investigate potential players mediating the regulation of AMPK on mitochondrial functions and mitophagy by next generation RNA-seq.Methods:We compared ATP production in protein kinase AMP-activated catalytic subunit alpha 1/2(PRKAA1/2)knockdown(AKD)and control BeWo cells using the Seahorse real-time ATP rate test,then analyzed gene expression profiling by RNA-seq.Differentially expressed genes(DEG)were examined by Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment.Then protein-protein interactions(PPI)among mitochondria related genes were fur-ther analyzed using Metascape and Ingenuity Pathway Analysis(IPA)software.Results:Both mitochondrial and glycolytic ATP production in AKD cells were lower than in the control BeWo cells(CT),with a greater reduction of mitochondrial ATP production.A total of 1092 DEGs were identified,with 405 upregulated and 687 downregulated.GO analysis identified 60 genes associated with the term‘mitochon-drion’in the cellular component domain.PPI analysis identified three clusters of mito-chondria related genes,including aldo-keto reductase family 1 member B10 and B15(AKR1B10,AKR1B15),alanyl-tRNA synthetase 1(AARS1),mitochondrial ribosomal protein S6(MRPS6),mitochondrial calcium uniporter dominant negative subunit beta(MCUB)and dihydrolipoamide branched chain transacylase E2(DBT).Conclusions:In summary,this study identified multiple mitochondria related genes regulated by AMPK in BeWo cells,and among them,three clusters of genes may po-tentially contribute to altered mitochondrial functions in response to reduced AMPK signaling.
文摘Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Iα-loop-helix Iβmotif which corresponds to helix I of other P 450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,theγ-domain.The structure reveals a homodimer in which theγ-domain of one molecule interacts with theβ-domain of another.The plane of heme group makes an angle of approximately 40°with the helix Iα-loop-helix Iβmotif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recognition.Phe-301,Ser-303 and Gly-305 from the helix Iα-loop-helix Iβmotif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.
文摘The article written by Zhao et al,which was recently accepted for publication,introduces an innovative method that combines deep learning-based feature extraction with a radiomics nomogram to create a noninvasive procedure for determining perineural invasion status in patients with rectal cancer.This method is an artificial intelligence application in which researchers segment their own datasets,derive features and analyze their weights.It was found that the support vector machine was the most effective model in the arterial and venous phases.A support vector machine is a machine learning algorithm based on a vector space that finds a decision boundary between the two classes furthest from any point in the training data.
基金Supported by DHR Women Scientist Fellowship,No.12013/53/2024.
文摘Non-alcoholic fatty liver disease(NAFLD)is the fastest-growing global contributor to the disease burden associated with the consequences of chronic liver disease,including cirrhosis and liver cancer.It is projected that more than fifty percent of the adult population,including women,smokers,and individuals without metabolic syndrome,will have NAFLD by 2040.Various mechanisms linking the gut microbiome to NAFLD and the consequent fibrosis have been discerned,which suggest the dysbiosis-induced impairment of gut endothelial barrier function,leading to hepatic inflammation through the translocation of bacterial components.NAFLD is progressively associated with environmental variables,especially exposure to heavy metals that impair liver metabolism,produce oxidative stress,and exacerbate inflammation,hence accelerating its progression.These toxicants also modify the composition of gut microbiota,hence intensifying liver damage.Comprehending the processes by which heavy metals contribute to NAFLD is essential for formulating tailored therapies.This review examines strategies to alleviate liver toxicity caused by heavy metals,including chelation therapy,dietary modifications(antioxidants and hepatoprotective nutrients),gut microbiome modulation via probiotics and postbiotics like short-chain fatty acids to restore intestinal barrier function and use of essential minerals like selenium,with potent antioxidant characteristics.Employing these measures may offer an integrated approach for addressing NAFLD in individuals subjected to heavy metal poisoning.
基金supported by the National Natural Science Foundation of China(No.12205112)financially supported by self-determined research funds of CCNU from the colleges’basic research and operation of MOE(CCNU24JC012)supported by Natural Science Foundation of Wuhan(No.2024040801020302).
文摘Nucleosomes play a vital role in chromatin organization and gene regulation,acting as key hubs that inter-act with various chromatin-associated factors through diverse binding mechanisms.Recent research has highlighted the prevalence of mutations in linker histones across different types of cancer,emphasizing their critical involvement in cancer progression.These cancer-associated mutations in linker histones have been shown to disrupt nucleosome stacking and the formation of higher-order chromatin structures,which in turn significantly affect epigenetic regulatory processes.In this review,we provide a comprehensive analysis of how cancer-associated linker histone mutations alter their physicochemical properties,influencing their binding to nucleosomes,and overall chromatin architecture.Additionally,we explore the significant impact of mutations near post-translational modification sites,which further modulate chromatin dynamics and regulatory functions,offering insights into their role in oncogenesis and potential therapeutic targets.
基金supported by the‘Korea National Institute of Health’research project(2022ER130502)a grant from by SMC-SKKU Future Convergence Academic Research Program,2024supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(RS-2024-00336758)。
文摘Biomedical scaffold fabrication has seen advancements in mimicking the native extracellular matrix through intricate three-dimensional(3D)structures conducive to tissue regeneration.Coiled fibrous scaffolds have emerged as promising substrates owing to their ability to provide unique topographical cues.In this study,coiled poly(ε-caprolactone)(PCL)fibrous bundles were fabricated using an alginate-based composite system,and processed with 3D printing.The unique structure was obtained through the die-swell phenomenon related to the release of residual stresses from the printed strut,thereby transforming aligned PCL fibers into coiled structures.The effects of printing parameters,such as pneumatic pressure and nozzle moving speed,on fiber morphology were investigated to ensure a consistent formation of coiled PCL fibers.The resulting coiled PCL fibrous scaffold demonstrated higher activation of mechanotransduction signaling as well as upregulation of osteogenic-related genes in human adipose stem cells(hASCs),supporting its potential in bone tissue engineering.
基金financially supported by the National Natural Science Foundation of China (Grants Nos. 11775019 and 11875086)。
文摘In this paper, we investigate the effect of exceptional points(EPs) on the violation of Leggett–Garg inequality(LGI) and no-signaling-in-time(NSIT) conditions and compare the different effects between the Hamiltonian EP(HEP) and Liouvillian EP(LEP) on those violations. We consider an open system consisting of two coupled qubits and each qubit is contacted with a thermal bath at a different temperature. In the case of omitting quantum jumps, we find that the system exhibits a second-order HEP, which separates the parameter space into an overdamped regime and an underdamped regime. In this situation, the LGI and NSIT conditions can be violated in both regimes and not violated at the HEP. In the case of without omitting quantum jumps, we find that the system exhibits a third-order LEP, which also separates the parameter space into an overdamped regime and an underdamped regime. In this situation, the LGI can only be violated in the underdamped regime with large coupling strength between the qubits.Conversely, the NSIT conditions can be violated in both regimes, as well as at the LEP, except in the overdamped regime with small coupling strength between the qubits. Comparing the violations of the LGI and NSIT conditions with HEP and LEP, we find that the quantum jumps would reduce the generation of coherence, enhance the decoherence, and lead to narrower parameter regimes that the LGI and NSIT conditions can be violated. Furthermore, in both cases,the NSIT conditions can be violated in a wider parameter regime than the LGI.
基金supported by the National Key R&D Program of China(No.2023YFE0105200)the National Natural Science Foundation of China(Nos.21905072,22077025,22207029,U20A20260)+3 种基金the Natural Science Foundation of Hebei Province(Nos.B2020202086,B2023202024,B2021202041,B2020202062)the Financial Support Project of Central Government for Promoting Development of Science and Technology of Hebei Province(No.236Z2705G)the Excellent Young Scientist Fund of the Natural Science Foundation of Hebei Province(No.B2022202027)the Science Research Project of Hebei Education Department(No.ZD2021032).
文摘With prolonged exposure in the human body,titanium alloy implants face challenges associated with bacterial attachment and proliferation,leading to implant failure and severe complications.Photothermal therapy(PTT)emerges as an efficient strategy for biofilm elimination.However,the local high temperature of PTT and incomplete bacteria ablation in low-temperature PTT pose risks of damage to normal tissues and biofilm recalcitrance,respectively.In this study,we synergistically combined photothermal therapy and chemotherapy to mildly disrupt biofilms of Staphylococcus aureus(S.aureus)to enhance the efficiency of biofilm ablation.The synergistic nanoplatform comprises near-infrared-light responsive con-jugated polymers,heat-sensitive liposomes,and the antibiotic daptomycin for biofilm elimination.The heat generated by conjugated polymers,stimulated with 808 nm light,alters biofilm permeability and releases antibiotics locally to eradicate biofilm.The nanoparticles exhibit biofilm dispersion activity and can effectively inhibit biofilm growth for up to 5 days.Consequently,this nanoplatform based on conjugated polymers offers a reliable method for ablating biofilms on titanium alloy implant and exhibits potential in drug-resistant clinical applications.
基金supported by the National Key R&D Program of China(2023YFC2706302)National Natural Science Foundation of China(81000079,81170165 and 81870959 to X.Z.)+1 种基金Program of HUST Academic Frontier Youth Team(2016QYTD02)Fundamental Research Funds for the Central Universities(HUST:2019JYCXJJ035)。
文摘Congenital disorders of glycosylation(CDG)are a cluster of monogenic disorders resulting from defects in glycosylation.FCSK encodes fucokinase,an enzyme that catalyzes the phosphorylation of L-fucose to generate fucose-1-phosphate,an important step in fucosylation.Mutations in FCSK lead to CDG with an autosomal recessive inheritance pattern,primarily manifesting as developmental delay,hypotonia,and brain abnormalities.However,no fcsk mutant animal models have yet been established.This study constructed the first fcsk knockout(fcsk^(-/-))zebrafish model using CRISPR/Cas9 technology.Notably,fcsk^(-/-)zebrafish exhibited impaired growth,characterized by delayed epiboly and DNA accumulation during early embryonic development,as well as brain atrophy in adulthood.Larval-stage fcsk^(-/-)zebrafish displayed locomotor deficits and increased susceptibility to pentylenetetrazole-induced seizures.In adulthood,fcsk^(-/-)zebrafish showed neurodevelopmental abnormalities,including increased anxiety,decreased aggression,reduced social preference,and impaired memory.Additionally,total protein fucosylation was markedly reduced in fcsk^(-/-)zebrafish,accompanied by decreased expression of pofut2,which encodes protein Ofucosyltransferase 2,an enzyme involved in the fucosylation salvage pathway.Apoptotic activity was elevated in the midbrain-hindbrain boundary(MHB)of fcsk^(-/-)zebrafish.Supplementation with GDP-L-fucose or the human FCSK gene restored developmental defects and total protein fucosylation in fcsk^(-/-)zebrafish.RNA sequencing revealed dysregulated gene expression associated with glycosylation,apoptosis,and neurodegenerative diseases.These findings suggest that fcsk^(-/-)zebrafish exhibit neurodevelopmental disorders,providing the first fcsk gene knockout animal model and offering a platform for investigating the molecular underpinnings of the disease and facilitating drug screening efforts.
基金supported by the Ministry of Science and Higher Education of the Russian Federation in the Framework of State Assignment of PSCBR RAS 075-00609-24-01(No.1022080100047-5-1.6.4,Neuroprotective drugs of a new generation).
文摘Objective:Activation of mitophagy is a promising option to overcome the mitochondrial malfunction that accompanies many diseases.Herein,we investigate the mechanisms underlying the ability of sodium lactate and pyruvate to initiate mitophagy,from the perspective of action on mitochondrial network and expression levels.Methods:Fluorescent and confocal microscopy was used to assess key cell parameters characterizing the state of the mitochondrial network and the level of mitophagy in human fibroblasts carrying mutations in genes encoding LRRK2 and PINK1 after the combined application of lactate and pyruvate and after direct acidification.qRT-PCR was used to study the expression levels of key mitophagy genes.Results:Cells with a mutation in the PINK1 gene showed a lower basal cytosolic pH.The application of sodium lactate and pyruvate to the cells with mutations associated with Parkinson’s disease caused intracellular acidification.Lowering extracellular pH to 6.0 led to a decrease in mitochondrial membrane potential,while the effect of lactate and pyruvate tended to increase this parameter.Extracellular acidification,as well as the effects of lactate and pyruvate,led to an increased level of mitophagy,and also affected such parameters of the mitochondrial network morphology as the ratio of individual to network mitochondria,branch length in mitochondrial network,number of mitochondrial junctions in the network,and also altered the expression of key mitophagy genes.Conclusion:Direct acidification and one induced by lactate and pyruvate do not differ in the efficiency of their effects on the mitochondrial network and mitophagy but change the cell fate differently.The mechanisms of acidification-induced activation of mitophagy differ in control and mutant fibroblasts.
文摘In contrast to the conventional spermiogram, metabolomics approaches give insights into the molecular composition of semen and mayprovide more detailed information on the fertility status of the respective donor. Given the intra-individual variability of spermiogramparameters between two donations, this study sought to elucidate the biological variability of the seminal plasma metabolome overan average period of 8 weeks. Two time-shifted semen samples from 15 healthy donors were compared by a targeted metabolomicsapproach utilizing the Biocrates AbsoluteIDQ p180 kit. Next to intraclass correlation coefficients (ICC), which represent a measureof reliability, coefficients of variation within individuals(CVW) and coefficients of variation between individuals (CVB) were calculatedfor each metabolite to demonstrate its stability. Furthermore, men were divided into two cohorts, a similar sperm concentration(SSC) and a differing sperm concentration (DSC) cohort, based on the observed variance in sperm concentration between the twosemen donations. The ICC was higher in the SSC compared to the DSC cohort. The levels of 18 metabolites, primarily acylcarnitines,varied between the initial and subsequent donations. After subdivision into subgroups, only ornithine and phosphatidylcholine 40:5exhibited differential levels between the two donations in the SSC group, compared to 14 metabolites in the DSCgroup.CVBwashigher than CVW but both differed between the metabolite subclasses. Biogenic amines were identified as the least reliable analytesover time, exhibiting the highest CVW,compared to sphingomyelins, which demonstrated the highest reliability with the lowestvariation.CVB was the highest for ether-bound glycerophosphatidylcholines and the lowest for amino acids.
基金funded by the budgetary funding to FRC FTM for the project“Post-Genomic High-Tech Research on the Mechanisms of Development of Socially Significant Diseases and Stress-Induced Conditions”(Grant No.125031203556-7).
文摘Background:Glucocorticoids are used as anti-inflammatory drugs for the treatment of various diseases,however,their side effects on normal brain tissue remain underinvestigated.Objectives:The study aimed to investigate dexamethasone(DXM)effects on cell composition and myelin content in the mouse brain tissue.Methods:C57Bl/6 male mice(n 60)received single and ten multiple intraperitoneal DXM injections(2.5 mg/kg),and the studied=parameters were analysed at 1,3,7,10 days after a single DXM injection and 15,30,60,and 90 days after the multiple injections.Oligodendrocytes,microglia,and astrocytes were assayed by immunohistochemistry with specific antibodies(Olig2,CD68,and GFAP,respectively)in the corpus callosum of the normal brain tissue.The myelin content was estimated by staining with LuxolFastBlue.The presence of GFAP isoforms was determined by western blotting.Results:DXM administration did not affect oligodendrocytes in the mouse brain but temporarily significantly decreased myelin content(1.2-fold,p 0.0058;1.4-fold,p 0.0001)at 3–15 days time points.At the same time,DXM significantly=<decreased the number of microglial cells(1.5–3.5-fold,p 0.0001)and significantly increased astrocytes(1.8-fold,p<<0.0001).Prolonged administration of DXM resulted in the decrease of the main GFAPα-isoform(50 kDa)and the appearance of shorter GFAP isoforms(30 kDa,42 kDa,44 kDa)similar to that in some neurodegenerative animal models.Conclusion:DXM can modify the cell composition of the normal mouse brain tissue by decreasing microglial cells and increasing astrocytes.Long-term use of DXM results in the inhibition of myelin formation and the appearance of truncated GFAP isoforms,suggesting its ability to induce neurodegeneration-like changes in the normal mouse brain.
