Inflammation caused by obesity,particularly in adipose tissue and the liver,can lead to insulin resistance(IR)and trigger type 2 diabetes mellitus(T2DM).It is crucial to identify therapeutic agents that alleviate IR b...Inflammation caused by obesity,particularly in adipose tissue and the liver,can lead to insulin resistance(IR)and trigger type 2 diabetes mellitus(T2DM).It is crucial to identify therapeutic agents that alleviate IR by reducing inflammation.Here,we report that isobavachromene(IB),a flavonoid derived from Psoralea corylifolia Linn.,ameliorates IR in 3T3-L1 adipocytes by inhibiting the mitogen-activated protein kinase(MAPK)and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway.We first found that IB could promote glucose uptake in 3T3-L1 adipocytes by activating the phosphoinositide 3-kinase(PI-3K)/protein kinase B(Akt)signaling pathway and was more effective than the positive control sodium orthovanadate at concentrations ranging from 25 to 100μmol/L.Additionally,IB inhibited RAW264.7 macrophage infiltration into 3T3-L1 adipocytes and suppressed the secretion of inflammatory factors from RAW264.7 macrophages,as well as the phosphorylation levels of key proteins(NF-κB p65,extracellular-signal-regulated kinase 1/2(ERK1/2),Jun N-terminal kinase(JNK),and mitogen-activated protein kinase 38(p38))in the NF-κB and MAPK signaling pathways.In summary,IB improves glucose uptake in IR adipocytes,activates the PI-3K/Akt signaling pathway,inhibits the JNK and NF-κB inflammatory signaling pathways,and reduces adipocyte inflammation,thereby improving of IR in 3T3-L1 adipocytes.展开更多
Parkinson's disease is a neurodegenerative disorder caused by loss of dopamine neurons in the substantia nigra pars compacta. Tremor, rigidity, and bradykinesia are the major symptoms of the disease. These motor i...Parkinson's disease is a neurodegenerative disorder caused by loss of dopamine neurons in the substantia nigra pars compacta. Tremor, rigidity, and bradykinesia are the major symptoms of the disease. These motor impairments are often accompanied by affective and emotional dysfunctions which have been largely studied over the last decade. The aim of this study was to investigate emotional processing organization in the brain of patients with Parkinson's disease and to explore whether there are differences between recognition of different types of emotions in Parkinson's disease. We examined 18 patients with Parkinson's disease(8 men, 10 women) with no history of neurological or psychiatric comorbidities. All these patients underwent identical brain blood oxygenation level-dependent functional magnetic resonance imaging for emotion evaluation. Blood oxygenation level-dependent functional magnetic resonance imaging results revealed that the occipito-temporal cortices, insula, orbitofrontal cortex, basal ganglia, and parietal cortex which are involved in emotion processing, were activated during the functional control. Additionally, positive emotions activate larger volumes of the same anatomical entities than neutral and negative emotions. Results also revealed that Parkinson's disease associated with emotional disorders are increasingly recognized as disabling as classic motor symptoms. These findings help clinical physicians to recognize the emotional dysfunction of patients with Parkinson's disease.展开更多
Cymbaria daurica L.has a long history as a folk medicine and tea for the treatment of diabetes.However,the biological activity and mechanism of its hypoglycemic effect have not been fully elucidated.In this study,the ...Cymbaria daurica L.has a long history as a folk medicine and tea for the treatment of diabetes.However,the biological activity and mechanism of its hypoglycemic effect have not been fully elucidated.In this study,the potential mechanism of C.daurica against type 2 diabetes mellitus(T2DM)was postulated via pharmacological network analysis.Based on data mining techniques involving topological parameters,gene ontology,and pathway enrichment,we established a compound-target,protein-protein interaction,and target-pathway network to identify central targets and pathways.Pathway enrichment analysis revealed that the most important pathway associated with C.daurica in treating T2DM is the PI3K-Akt signaling pathway.Molecular docking was performed to validate the predicted results.Then,a HepG2 cell insulin resistance model and a high-fat,high-glucose diet combined with a streptozotocin-induced T2DM rat model was established to assess the fasting glucose changes and lipid profile after C.daurica treatment,respectively.Finally,real-time PCR and western blotting were used to verify changes in key targets.The anti-diabetic mechanism of the active ingredient in C.daurica may involve the regulation of IRS-2,Akt1,GLUT4,and GSK3β.展开更多
Parkinson＇s disease （PD） is a complex neurode- generative disease with progressive loss of dopamine neurons. PD patients usually manifest a series of motor and non-motor symptoms. In order to provide better early d...Parkinson＇s disease （PD） is a complex neurode- generative disease with progressive loss of dopamine neurons. PD patients usually manifest a series of motor and non-motor symptoms. In order to provide better early diagnosis and subsequent disease-modifying therapies for PD patients, there is an urgent need to identify sensitive and specific biomarkers. Biomarkers can be divided into four categories： clinical, imaging, biochemical, and genetic. Ideal biomarkers not only improve our under- standing of PD pathogenesis and progression, but also provide benefits for early risk evaluation and clinical diagnosis of PD. Although many efforts have been made and several biomarkers have been extensively investigated, few if any have been found useful for early diagnosis. Here, we summarize recent developments in the discovered biomarkers of PD and discuss their merits and limitations for the early diagnosis of PD.展开更多
Leaf spot disease seriously affects the yield and quality of waxberry, but there is no registration agent for prevention and control of the disease. The field trials showed that the control efficacy of 33.5% oxine-cop...Leaf spot disease seriously affects the yield and quality of waxberry, but there is no registration agent for prevention and control of the disease. The field trials showed that the control efficacy of 33.5% oxine-copper SC against leaf spot disease on waxberry reached above 74% when used at the dosage of 167.5-223.3 mg/kg. 33.5% Oxine-copper SC could be used to control leaf spot disease on waxberry.展开更多
One hundred strains isolated from bovine raw milk, obtained from different farms, were subjected to different in vitro stress typical of gastrointestinal tract. Twelve strains were able to tolerate pepsin at pH 2, pan...One hundred strains isolated from bovine raw milk, obtained from different farms, were subjected to different in vitro stress typical of gastrointestinal tract. Twelve strains were able to tolerate pepsin at pH 2, pancreatin and bile salts (0.3%). These bacteria were identified using 16S rRNA gene sequencing. Eight isolates were Lactobacillus plantarum and four were Lactobacillus fermentum. They were not able to degrade mucin and they were γ-haemolytic. All strains had antibacterial activity against Staphylococcus aureus, Listeria monocytogenes and Salmonella thyphimirium. However, only six strains inhibited Escherchia coli. All these showed ability for autoaggregation and/or hydrophobicity properties. They were also characterized in respect to their technological properties. Important acidification and low proteolytic and lipolytic capacities were detected for all strains. In addition, they were able to produce exopolysaccharides and grow at hot and cold temperatures. These bacteria may be used further for manufacturing of functional foods and confirming their suitability as probiotic starter cultures.展开更多
Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria,are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strate...Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria,are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strategy. In this study, a series of constitutionally-pure pentavalent glycoclusters was prepared by conjugating assorted azido-carbohydrates onto a penta-propargyl rim-differentiated pillar[5]arene(RD-P[5])scaffold through Cu(I)-catalyzed azide–alkyne cycloaddition “click” reactions. Their binding towards therapeutically relevant bacterial lectins, such as Lec A and Lec B from Pseudomonas aeruginosa and concanavalin A(Con A), were evaluated subsequently by isothermal titration calorimetric studies. Most of these isomerfree RD-P[5] pentavalent glycoclusters, except the fucosylated ones, display good affinities to lectins.Nonetheless, the dissociation constants observed are similar to those displayed by an analogous pentavalent glycocluster consisting of four P[5] constitutional isomers, in which the RD-P[5] component merely accounts for 7% in the mixture. Our results revealed that high constitutional purity is not essential for achieving effective multivalent interactions between P[5]-based glycoclusters and lectins, presumably as a result of the conformationally labile nature of the P[5] scaffold. This information provides valuable design principles for low-cost and facile syntheses of glycosylated P[5]s for biomedical applications.展开更多
BACKGROUND Chronic kidney disease is associated with immunological disorders,presented as phenotypic alterations of T lymphocytes.These changes are expected to be restored after a successful renal transplantation;howe...BACKGROUND Chronic kidney disease is associated with immunological disorders,presented as phenotypic alterations of T lymphocytes.These changes are expected to be restored after a successful renal transplantation;however,additional parameters may contribute to this process.AIM To evaluate the impact of positive panel reactive antibodies(PRAs)on the restoration of T cell phenotype,after renal transplantation.METHODS CD4CD28null,CD8CD28null,natural killer cells(NKs),and regulatory T cells(Tregs)were estimated by flow cytometry at T0,T3,and T6 which were the time of transplantation,and 3-and 6-mo follow-up,respectively.Changes were estimated regarding the presence or absence of PRAs.RESULTS Patients were classified in two groups:PRA(-)(n=43)and PRA(+)(n=28)groups.Lymphocyte and their subtypes were similar between the two groups at T0,whereas their percentage was increased at T3 in PRA(-)compared to PRA(+)[23(10.9-47.9)vs 16.4(7.5-36.8)μ/L,respectively;P=0.03].Lymphocyte changes in PRA(-)patients included a significant increase in CD4 cells(P<0.0001),CD8 cells(P<0.0001),and Tregs(P<0.0001),and a reduction of NKs(P<0.0001).PRA(+)patients showed an increase in CD4(P=0.008)and CD8(P=0.0001),and a reduction in NKs(P=0.07).CD4CD28null and CD8CD28null cells,although initially reduced in both groups,were stabilized thereafter.CONCLUSION Our study described important differences in the immune response between PRA(+)and PRA(-)patients with changes in lymphocytes and lymphocyte subpopulations.PRA(+)patients seemed to have a worse immune profile after 6 mo follow-up,regardless of renal function.展开更多
Objective: The aim of this study was to determine the average values of width of the upper central incisor (WUCI) in Congolese Bantu and compare them to those of Caucasians and Asiatic. Material and Methods: It was a ...Objective: The aim of this study was to determine the average values of width of the upper central incisor (WUCI) in Congolese Bantu and compare them to those of Caucasians and Asiatic. Material and Methods: It was a prospective cross-sectional study carried out at the Université de Kinshasa on the Congolese Bantu, Department of Dental Medicine, from March 2020 to March 2021. A maxillary imprint was taken by Jeltrate-type alginate. The measurement of two healthy upper central incisors (UCI) was carried out by the hard plaster casting type 4, with a brand caliper, carbon fiver composite mark. The study was approved by the Ethics Committee of the School of Public Health in the Université de Kinshasa and verbal consent was obtained from each participant. Results: The Average Width of the UCI was 8.74 mm ± 0.56. The average width of the right Upper Central incisor (RUCI) and the left UCI (LUCI) was 8.71 mm ± 0.57 and 8.77 mm ± 0.56, respectively. The average width of the RUCI and LUCI was not the same for men and women (p 0.001). A significant difference was observed between the average of the RUCI and the 18 - 28 and 40 - 50 age group (p = 0.056) as well as for the average LUCI (p = 0.085). The width average of UCI between the Congolese Bantu with those of Caucasians and Asians was significantly different (p = 0.000 and p = 0.009). Conclusion: The average width of the RUCI and LUCI was different among sex and age group. The average width of UCI of the Congolese Bantu is different from that of Caucasians and Asians.展开更多
Annual haze in Northern Thailand has become increasingly severe,impacting health and the environment.How-ever,the sources of the haze remain poorly quantified due to limited observational data on aerosol molecular tra...Annual haze in Northern Thailand has become increasingly severe,impacting health and the environment.How-ever,the sources of the haze remain poorly quantified due to limited observational data on aerosol molecular tracers.This study comprehensively investigates chemical composition of PM_(2.5),including both inorganic and organic compounds throughout haze and post-haze periods in 2019 at a rural site of Northern Thailand.Average PM_(2.5) concentrations during haze and post-haze period were 87±36 and 21±11μg/m^(3),respectively.Organic matter was the dominant contributor in PM_(2.5) mass,followed by water soluble inorganic ions and mineral dust.Molecular markers,including levoglucosan,dehydroabietic acid,and 4-nitrocatechol,and ions(Cl^(-),and K^(+)),were used to characterize low haze(PM_(2.5)<100μg/m^(3))and episodic haze(PM_(2.5)>100μg/m^(3)).Low haze is associated with local aerosols from agricultural waste burning,while episodic haze is linked to aged aerosols from mixed agricultural waste,softwood,and hardwood burning.Source apportionment incorporating these molecular markers in receptor modelling(Positive matrix factorization),identified three distinct biomass burning sources:mixed,local,and aged biomass burnings,contributing 31,19 and 13%of PM_(2.5) during haze period.During post-haze period,contributions shifted,with local biomass burning(32%)comparable to secondary sulfate(34%)and mixed dust and traffic sources(26%).These findings demonstrate that both regional and local sources con-tribute to severe haze,highlighting the need for integrated policies for cross-border cooperation as well as stricter regulations to reduce biomass burning in Northern Thailand and Southeast Asia.展开更多
Accurately estimating power loss reduction from passive filters before installation is challenging due to variable loads and power quality conditions across grid points.Existing studies rely on simulation or analytica...Accurately estimating power loss reduction from passive filters before installation is challenging due to variable loads and power quality conditions across grid points.Existing studies rely on simulation or analytical models.These approaches often fail to capture real-world variability through data-driven methods.This gap limits effective,site-specific filter deployment decisions.We present a two-step machine learning approach to estimate energy efficiency gains from passive filters under variable conditions using high-resolution power analyzer data.Ridge Regression identifies key predictive variables,achieving baseline R^(2)=0.591.XGBoost then captures nonlinear interactions between load variability,power quality disturbances,and filter performance,improving accuracy to R^(2)=0.755.The methodology was validated through deployment at three industrial facilities in collaboration with Livarsa GmbH.Results demonstrate 9.9%average relative error across measured efficiency gains,confirming reliability under real-world conditions.Comprehensive validation through k-fold cross-validation,ensemble methods,and external testing quantified prediction uncertainty inherent in small indus-trial datasets(25 training samples).The approach offers a scalable,data-driven decision-support tool overcoming simulation-based limitations.Computational efficiency enables real-time assessment during client consultations without specialized software.Economic value derives from reduced performance guarantee margins,accelerated assessment timelines,and minimized warranty exposure.Limitations include statistical constraints from limited training data,reflected in cross-validation overfitting and wide confidence intervals.External validity requires site-specific validation for facilities with substantially different electrical characteristics.Despite these con-straints,the findings provide practical value for energy professionals seeking efficient power quality solutions,enabling confident passive filter deployment decisions based on quantified performance predictions.展开更多
Since the Cenozoic,a series of extensional south-north normal faults and gneiss-granite domes evolved in the southern Tibetan Plateau,the formation mechanism of which is of scientific interest and which has implicatio...Since the Cenozoic,a series of extensional south-north normal faults and gneiss-granite domes evolved in the southern Tibetan Plateau,the formation mechanism of which is of scientific interest and which has implications for the tectonic dynamics of the plateau.Typical of such features are the Xainza-Dinggye rift and the Mabja gneiss dome,which are located in the Xainza-Xietongmen-Dinggye region in the central Tibetan Plateau.In this study,Magnetotelluric measurements across this region are used to generate a high-resolution 3-D electrical resistivity model of the subsurface and to analyze the cause of the conductive zones.The large-scale conductive zones identified in the middle-lower crust may result from aqueous melt partial melting,whereas the smaller-scale conductive zones in the upper-middle crust may result from saline fluids,possibly with varying minor volumes of melts.Subsequently,based on the electrical resistivity model and combined with the spatiotemporal coupling of the geological,geochemical,and geophysical data,the state and migration features of crustal materials are discussed.The results show that the upwelling of mantle materials along subduction channels and slab-windows related to the tearing of the Indian lithospheric plate contributed to the partial melting of the middle-lower crust in the Lhasa terrane.Furthermore,partial melting of the upper-middle crust in the Tethys-Himalaya terrane resulted from southern extrusion of crustal materials in the Lhasa terrane.These two mechanisms can significantly reduce the effective viscosity.We speculate that the deformation of the brittle upper crust that is controlled by large-scale ductile layers characterized by weak rheology is the main dynamic mechanism of rift evolution.Meanwhile,the metamorphism and anatexis in the upper-middle crust of the Tethys-Himalaya terrane related to the southern extrusion of materials contributed to the evolution of the Mabja gneiss dome.During the middle Miocene,the southern extrusion of crustal materials may have been influenced by the cooling events beneath the Mabja gneiss dome,which can explain why the deep areas beneath the Mabja gneiss dome have middle-high resistivity.In addition,our study region is located in the Mediterranean-Himalayan seismic belt,and mainly includes shallow-focus earthquakes and intermediate-depth earthquakes.In the north,shallow-focus earthquakes are mainly controlled by the accumulation of stress in the brittle layer of the overlying crust related to the ductile layer of the middle and lower crust.In the south,shallow-focus earthquakes(e.g.,Dingri MS6.8 earthquake)mainly occur in the rigid,resistive block,which is surrounded by conductive zones,possibly because fluid migration may be hindered by these resistive blocks.The intermediate-depth earthquakes are mainly controlled by the response in the subsurface area,which is related to the detachment of the Indian lithospheric mantle from the Indian crust.展开更多
Heat stress(HS)at the reproductive stage detrimentally affects crop yields and seed quality.However,the molecular mechanisms that protect reproductive processes in plants under HS remain largely unknown.Here,we report...Heat stress(HS)at the reproductive stage detrimentally affects crop yields and seed quality.However,the molecular mechanisms that protect reproductive processes in plants under HS remain largely unknown.Here,we report that Acetylation Lowers Binding Affinity 3(ALBA3)is crucial for safeguarding male fertility against HS in Arabidopsis.ALBA 3 is highly expressed in pollen,and ALBA3 is localized in the cytoplasm of both sperm and vegetative cells.Mutants lacking functional ALBA3exhibit hypersensitivity to HS,with reduced silique length and fertility due to defects in pollen germination,pollination,pollen tube growth,and fertilization under HS.ALBA3 binds and stabilizes a subset of messenger RNAs(mRNAs)essential for pollen function,thereby protecting male fertility.Two residues in the Alba domain,K46 and L90,are critical for ALBA3's ability to bind and stabilize mRNAs and are necessary for its proper function.Interestingly,the loss of rice ALBA3 also leads to severe pollen abortion and male sterility under HS,highlighting the conserved role of ALBA3 in protecting male fertility across plant species.This study uncovers a conserved mechanism by which ALBA3 safeguards male fertility during HS by stabilizing specific mRNAs crucial for pollen function.展开更多
The nucleotide-binding domain leucine-rich repeat(NLR)receptor proteins play pivotal roles in plant disease resistance due to their extensive genetic diversity driven by long-term co-evolution with pathogens.In this s...The nucleotide-binding domain leucine-rich repeat(NLR)receptor proteins play pivotal roles in plant disease resistance due to their extensive genetic diversity driven by long-term co-evolution with pathogens.In this study,we present a comprehensive wheat pan-NLRome containing 8056 NLR genes,which display remarkable diversity in gene structure,nucleotide variation,and presence-absence polymorphisms across the A.E.Watkins landrace collection.Comparative analysis between the landraces and modern cultivars revealed that 1316 NLRs were gained,and 1179 NLRs were lost during wheat breeding.Furthermore,we identified 221 spatial pairs of NLR genes in the genome,which show co-evolutionary patterns similar to those of physical NLR pairs.Finally,we identified 1710 candidate NLR genes potentially involved in resistance to various diseases or environmental adaptation.Overall,our study establishes a comprehensive and diversified NLR gene resource that will facilitate the discovery and utilization of genes for disease resistance and climate adaptation in wheat.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is continuously evolving since 2019.Some monoclonal antibodies(mAbs)have been developed and widely used,such as etesevimab(CB6)developed by Eli-Lilly/Junshi.H...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is continuously evolving since 2019.Some monoclonal antibodies(mAbs)have been developed and widely used,such as etesevimab(CB6)developed by Eli-Lilly/Junshi.However,the mAb escaped from the variant of concern(VOC)ever since the emergence of Beta VOC,with a complete loss of efficacy against the Omicron subvariants.Here,we developed a broad-spectrum and affinity-mature antibody design(BAADesign)procedure to design CB6,enabling it to bind to the receptor-binding domains(RBDs)of multiple important Omicron subvariants,including the recent variant KP.2.Structural analysis confirmed the desired CB6-RBD interactions.Additionally,identical mutations in the complementarity determining regions(CDR)1 and CDR2 of the CB6 mutants also restored neutralizing potency for some RBD-1 group antibodies.Overall,the enhanced CB6 neutralizing capacity makes it a promising candidate against SARS-CoV-2 infection,and the BAADesign method has implications for the design of other antibodies.展开更多
Levodopa(L-DOPA),a precursor of dopamine,is commonly prescribed for the treatment of the Parkinson’s disease(PD).However,oral administration of levodopa results in a high level of homocysteine in the peripheral circu...Levodopa(L-DOPA),a precursor of dopamine,is commonly prescribed for the treatment of the Parkinson’s disease(PD).However,oral administration of levodopa results in a high level of homocysteine in the peripheral circulation,thereby elevating the risk of cardiovascular disease,and limiting its clinical application.Here,we report a non-invasive method to deliver levodopa to the brain by delivering L-DOPA-loaded sub-50 nm nanoparticles via brain-lymphatic vasculature.The hydrophilic L-DOPA was successfully encapsulated into nanoparticles of tannic acid(TA)/polyvinyl alcohol(PVA)via hydrogen bonding using the flash nanocomplexation(FNC)process,resulting in a high L-DOPA-loading capacity and uniform size in a scalable manner.Pharmacodynamics analysis in a PD rat model demonstrated that the levels of dopamine and tyrosine hydroxylase,which indicate the dopaminergic neuron functions,were increased by 2-and 4-fold,respectively.Movement disorders and cerebral oxidative stress of the rats were significantly improved.This formulation exhibited a high degree of biocompatibility as evidenced by lack of induced inflammation or other pathological changes in major organs.This antioxidative and drug-delivery platform administered through the brain-lymphatic vasculature shows promise for clinical treatment of the PD.展开更多
Functional neurological recovery remains the primary objective when treating ischemic stroke.However,current therapeutic approaches often fall short of achieving optimal outcomes.One of the most significant challenges...Functional neurological recovery remains the primary objective when treating ischemic stroke.However,current therapeutic approaches often fall short of achieving optimal outcomes.One of the most significant challenges in stroke treatment is the effective delivery of neuroprotective agents across the blood–brain barrier to ischemic regions within the brain.The blood–brain barrier,while essential for protecting the brain from harmful substances,also restricts the passage of many therapeutic compounds,thus limiting their efficacy.In this review,we summarizes the emerging role of nanoparticle-based therapies for the treatment of ischemic stroke and investigate their potential to revolutionize drug delivery,enhance neuroprotection,and promote functional recovery.Recent advancements in nanotechnology have led to the development of engineered nanoparticles specifically designed to overcome the blood–brain barrier,thus enabling the targeted delivery of therapeutic agents directly to the affected brain areas.Preclinical studies have demonstrated the remarkable potential of nanoparticle-based therapies to activate key neuroprotective pathways,such as the phosphoinositide 3-kinase/protein kinase B/c AMP response element-binding protein signaling cascade,which is crucial for neuronal survival,synaptic plasticity,and post-stroke recovery.By modulating these pathways,nanoparticles could mitigate neuronal damage,reduce inflammation,and promote tissue repair.Furthermore,nanoparticles offer a unique advantage by enabling multimodal therapeutic strategies that simultaneously target multiple pathological mechanisms of ischemic stroke,including oxidative stress,neuroinflammation,and apoptosis.This multifaceted approach enhances the overall efficacy of treatment,addressing the complex and interconnected processes that contribute to stroke-related brain injury.Surface modifications,such as functionalization with specific ligands or targeting molecules,further improve the precision of drug delivery,enhance targeting specificity,and prolong systemic circulation,thereby optimizing therapeutic outcomes.Nanoparticlebased therapeutics represent a paradigm shift for the management of stroke and provide a promising avenue for reducing post-stroke disability and improving the outcomes of long-term rehabilitation.By combining targeted drug delivery with the ability to modulate critical neuroprotective pathways,nanoparticles hold the potential to transform the treatment landscape for ischemic stroke.However,while preclinical data are highly encouraging,significant challenges remain in translating these advancements into clinical practice.Further research is needed to refine nanoparticle designs,optimize their safety profiles,and ensure their scalability for widespread application.Rigorous clinical trials are essential to validate their efficacy,assess long-term biocompatibility,and address potential off-target effects.The integration of interdisciplinary approaches,combining insights from nanotechnology,neuroscience,and pharmacology,will be critical if we are to overcome these challenges.Ultimately,nanoparticle-based therapies offer a foundation for innovative,precision-based treatments that could significantly improve outcomes for stroke patients,thus paving the way for a new era in stroke care and neurological rehabilitation.展开更多
Dear Editor,The purinergic receptors(P2YRs)are involved in a variety of physiological processes,including proliferation,chemotaxis,cancer metastasis,cardiovascular events,neurodegenerative diseases and aging(Weisman e...Dear Editor,The purinergic receptors(P2YRs)are involved in a variety of physiological processes,including proliferation,chemotaxis,cancer metastasis,cardiovascular events,neurodegenerative diseases and aging(Weisman et al.,2012).Thus far,eight human P2YRs have been characterized and are classified into two subfamilies based on their sequence homology and signal transduction mechanisms,including P2Y1 R-like receptors that signal preferentially through Gq/11 proteins and P2Y12R-like receptors that activate Gi/o proteins(Abbracchio et al.,2006).展开更多
Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic envi...Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.展开更多
Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we report...Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.展开更多
基金supported by National Key R&D Program of China(2022YFF1100300)the Central Guidance on Local Science and Technology Development Found of Shenzhen,China(2021Szvup030).
文摘Inflammation caused by obesity,particularly in adipose tissue and the liver,can lead to insulin resistance(IR)and trigger type 2 diabetes mellitus(T2DM).It is crucial to identify therapeutic agents that alleviate IR by reducing inflammation.Here,we report that isobavachromene(IB),a flavonoid derived from Psoralea corylifolia Linn.,ameliorates IR in 3T3-L1 adipocytes by inhibiting the mitogen-activated protein kinase(MAPK)and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway.We first found that IB could promote glucose uptake in 3T3-L1 adipocytes by activating the phosphoinositide 3-kinase(PI-3K)/protein kinase B(Akt)signaling pathway and was more effective than the positive control sodium orthovanadate at concentrations ranging from 25 to 100μmol/L.Additionally,IB inhibited RAW264.7 macrophage infiltration into 3T3-L1 adipocytes and suppressed the secretion of inflammatory factors from RAW264.7 macrophages,as well as the phosphorylation levels of key proteins(NF-κB p65,extracellular-signal-regulated kinase 1/2(ERK1/2),Jun N-terminal kinase(JNK),and mitogen-activated protein kinase 38(p38))in the NF-κB and MAPK signaling pathways.In summary,IB improves glucose uptake in IR adipocytes,activates the PI-3K/Akt signaling pathway,inhibits the JNK and NF-κB inflammatory signaling pathways,and reduces adipocyte inflammation,thereby improving of IR in 3T3-L1 adipocytes.
文摘Parkinson's disease is a neurodegenerative disorder caused by loss of dopamine neurons in the substantia nigra pars compacta. Tremor, rigidity, and bradykinesia are the major symptoms of the disease. These motor impairments are often accompanied by affective and emotional dysfunctions which have been largely studied over the last decade. The aim of this study was to investigate emotional processing organization in the brain of patients with Parkinson's disease and to explore whether there are differences between recognition of different types of emotions in Parkinson's disease. We examined 18 patients with Parkinson's disease(8 men, 10 women) with no history of neurological or psychiatric comorbidities. All these patients underwent identical brain blood oxygenation level-dependent functional magnetic resonance imaging for emotion evaluation. Blood oxygenation level-dependent functional magnetic resonance imaging results revealed that the occipito-temporal cortices, insula, orbitofrontal cortex, basal ganglia, and parietal cortex which are involved in emotion processing, were activated during the functional control. Additionally, positive emotions activate larger volumes of the same anatomical entities than neutral and negative emotions. Results also revealed that Parkinson's disease associated with emotional disorders are increasingly recognized as disabling as classic motor symptoms. These findings help clinical physicians to recognize the emotional dysfunction of patients with Parkinson's disease.
基金funded by the National Natural Science Foundation of China(81760776)the Natural Science Foundation of Inner Mongolia Autonomous Region(2018ZD13,2018LH08082,2019MS08208).
文摘Cymbaria daurica L.has a long history as a folk medicine and tea for the treatment of diabetes.However,the biological activity and mechanism of its hypoglycemic effect have not been fully elucidated.In this study,the potential mechanism of C.daurica against type 2 diabetes mellitus(T2DM)was postulated via pharmacological network analysis.Based on data mining techniques involving topological parameters,gene ontology,and pathway enrichment,we established a compound-target,protein-protein interaction,and target-pathway network to identify central targets and pathways.Pathway enrichment analysis revealed that the most important pathway associated with C.daurica in treating T2DM is the PI3K-Akt signaling pathway.Molecular docking was performed to validate the predicted results.Then,a HepG2 cell insulin resistance model and a high-fat,high-glucose diet combined with a streptozotocin-induced T2DM rat model was established to assess the fasting glucose changes and lipid profile after C.daurica treatment,respectively.Finally,real-time PCR and western blotting were used to verify changes in key targets.The anti-diabetic mechanism of the active ingredient in C.daurica may involve the regulation of IRS-2,Akt1,GLUT4,and GSK3β.
基金supported by grants from the National Natural Science Foundation of China (81430021 and 81370470)the Program for Liaoning Provincial Innovative Research Team in Universities (LT2015009)+1 种基金the Liaoning Provincial Science and Technology Project (2015225008)a Research Project of Dalian Science and Technology (2014E14SF175) of Liaoning Province, China
文摘Parkinson＇s disease （PD） is a complex neurode- generative disease with progressive loss of dopamine neurons. PD patients usually manifest a series of motor and non-motor symptoms. In order to provide better early diagnosis and subsequent disease-modifying therapies for PD patients, there is an urgent need to identify sensitive and specific biomarkers. Biomarkers can be divided into four categories： clinical, imaging, biochemical, and genetic. Ideal biomarkers not only improve our under- standing of PD pathogenesis and progression, but also provide benefits for early risk evaluation and clinical diagnosis of PD. Although many efforts have been made and several biomarkers have been extensively investigated, few if any have been found useful for early diagnosis. Here, we summarize recent developments in the discovered biomarkers of PD and discuss their merits and limitations for the early diagnosis of PD.
文摘Leaf spot disease seriously affects the yield and quality of waxberry, but there is no registration agent for prevention and control of the disease. The field trials showed that the control efficacy of 33.5% oxine-copper SC against leaf spot disease on waxberry reached above 74% when used at the dosage of 167.5-223.3 mg/kg. 33.5% Oxine-copper SC could be used to control leaf spot disease on waxberry.
文摘One hundred strains isolated from bovine raw milk, obtained from different farms, were subjected to different in vitro stress typical of gastrointestinal tract. Twelve strains were able to tolerate pepsin at pH 2, pancreatin and bile salts (0.3%). These bacteria were identified using 16S rRNA gene sequencing. Eight isolates were Lactobacillus plantarum and four were Lactobacillus fermentum. They were not able to degrade mucin and they were γ-haemolytic. All strains had antibacterial activity against Staphylococcus aureus, Listeria monocytogenes and Salmonella thyphimirium. However, only six strains inhibited Escherchia coli. All these showed ability for autoaggregation and/or hydrophobicity properties. They were also characterized in respect to their technological properties. Important acidification and low proteolytic and lipolytic capacities were detected for all strains. In addition, they were able to produce exopolysaccharides and grow at hot and cold temperatures. These bacteria may be used further for manufacturing of functional foods and confirming their suitability as probiotic starter cultures.
基金Financial supports from the National Natural Science Foundation of China (No. 21801184)the Tianjin Municipal Applied Basic and Key Research Scheme of China (No. 18JCQNJC06400)+3 种基金Xiamen University, Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (No. SN-ZJU-SIAS-006)Université de Lyon, the French Agence Nationale de la Recherche (Dyna Sweet, ANR-08-BLAN-0305)Glyco@Alps (ANR-15-IDEX-02)Labex Arcane/CBH-EUR-GS (ANR-17-EURE-0003) are gratefully acknowledged。
文摘Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria,are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strategy. In this study, a series of constitutionally-pure pentavalent glycoclusters was prepared by conjugating assorted azido-carbohydrates onto a penta-propargyl rim-differentiated pillar[5]arene(RD-P[5])scaffold through Cu(I)-catalyzed azide–alkyne cycloaddition “click” reactions. Their binding towards therapeutically relevant bacterial lectins, such as Lec A and Lec B from Pseudomonas aeruginosa and concanavalin A(Con A), were evaluated subsequently by isothermal titration calorimetric studies. Most of these isomerfree RD-P[5] pentavalent glycoclusters, except the fucosylated ones, display good affinities to lectins.Nonetheless, the dissociation constants observed are similar to those displayed by an analogous pentavalent glycocluster consisting of four P[5] constitutional isomers, in which the RD-P[5] component merely accounts for 7% in the mixture. Our results revealed that high constitutional purity is not essential for achieving effective multivalent interactions between P[5]-based glycoclusters and lectins, presumably as a result of the conformationally labile nature of the P[5] scaffold. This information provides valuable design principles for low-cost and facile syntheses of glycosylated P[5]s for biomedical applications.
文摘BACKGROUND Chronic kidney disease is associated with immunological disorders,presented as phenotypic alterations of T lymphocytes.These changes are expected to be restored after a successful renal transplantation;however,additional parameters may contribute to this process.AIM To evaluate the impact of positive panel reactive antibodies(PRAs)on the restoration of T cell phenotype,after renal transplantation.METHODS CD4CD28null,CD8CD28null,natural killer cells(NKs),and regulatory T cells(Tregs)were estimated by flow cytometry at T0,T3,and T6 which were the time of transplantation,and 3-and 6-mo follow-up,respectively.Changes were estimated regarding the presence or absence of PRAs.RESULTS Patients were classified in two groups:PRA(-)(n=43)and PRA(+)(n=28)groups.Lymphocyte and their subtypes were similar between the two groups at T0,whereas their percentage was increased at T3 in PRA(-)compared to PRA(+)[23(10.9-47.9)vs 16.4(7.5-36.8)μ/L,respectively;P=0.03].Lymphocyte changes in PRA(-)patients included a significant increase in CD4 cells(P<0.0001),CD8 cells(P<0.0001),and Tregs(P<0.0001),and a reduction of NKs(P<0.0001).PRA(+)patients showed an increase in CD4(P=0.008)and CD8(P=0.0001),and a reduction in NKs(P=0.07).CD4CD28null and CD8CD28null cells,although initially reduced in both groups,were stabilized thereafter.CONCLUSION Our study described important differences in the immune response between PRA(+)and PRA(-)patients with changes in lymphocytes and lymphocyte subpopulations.PRA(+)patients seemed to have a worse immune profile after 6 mo follow-up,regardless of renal function.
文摘Objective: The aim of this study was to determine the average values of width of the upper central incisor (WUCI) in Congolese Bantu and compare them to those of Caucasians and Asiatic. Material and Methods: It was a prospective cross-sectional study carried out at the Université de Kinshasa on the Congolese Bantu, Department of Dental Medicine, from March 2020 to March 2021. A maxillary imprint was taken by Jeltrate-type alginate. The measurement of two healthy upper central incisors (UCI) was carried out by the hard plaster casting type 4, with a brand caliper, carbon fiver composite mark. The study was approved by the Ethics Committee of the School of Public Health in the Université de Kinshasa and verbal consent was obtained from each participant. Results: The Average Width of the UCI was 8.74 mm ± 0.56. The average width of the right Upper Central incisor (RUCI) and the left UCI (LUCI) was 8.71 mm ± 0.57 and 8.77 mm ± 0.56, respectively. The average width of the RUCI and LUCI was not the same for men and women (p 0.001). A significant difference was observed between the average of the RUCI and the 18 - 28 and 40 - 50 age group (p = 0.056) as well as for the average LUCI (p = 0.085). The width average of UCI between the Congolese Bantu with those of Caucasians and Asians was significantly different (p = 0.000 and p = 0.009). Conclusion: The average width of the RUCI and LUCI was different among sex and age group. The average width of UCI of the Congolese Bantu is different from that of Caucasians and Asians.
文摘Annual haze in Northern Thailand has become increasingly severe,impacting health and the environment.How-ever,the sources of the haze remain poorly quantified due to limited observational data on aerosol molecular tracers.This study comprehensively investigates chemical composition of PM_(2.5),including both inorganic and organic compounds throughout haze and post-haze periods in 2019 at a rural site of Northern Thailand.Average PM_(2.5) concentrations during haze and post-haze period were 87±36 and 21±11μg/m^(3),respectively.Organic matter was the dominant contributor in PM_(2.5) mass,followed by water soluble inorganic ions and mineral dust.Molecular markers,including levoglucosan,dehydroabietic acid,and 4-nitrocatechol,and ions(Cl^(-),and K^(+)),were used to characterize low haze(PM_(2.5)<100μg/m^(3))and episodic haze(PM_(2.5)>100μg/m^(3)).Low haze is associated with local aerosols from agricultural waste burning,while episodic haze is linked to aged aerosols from mixed agricultural waste,softwood,and hardwood burning.Source apportionment incorporating these molecular markers in receptor modelling(Positive matrix factorization),identified three distinct biomass burning sources:mixed,local,and aged biomass burnings,contributing 31,19 and 13%of PM_(2.5) during haze period.During post-haze period,contributions shifted,with local biomass burning(32%)comparable to secondary sulfate(34%)and mixed dust and traffic sources(26%).These findings demonstrate that both regional and local sources con-tribute to severe haze,highlighting the need for integrated policies for cross-border cooperation as well as stricter regulations to reduce biomass burning in Northern Thailand and Southeast Asia.
基金supported by funding from the Carl-Zeiss Stiftung as part of iFEMA project.
文摘Accurately estimating power loss reduction from passive filters before installation is challenging due to variable loads and power quality conditions across grid points.Existing studies rely on simulation or analytical models.These approaches often fail to capture real-world variability through data-driven methods.This gap limits effective,site-specific filter deployment decisions.We present a two-step machine learning approach to estimate energy efficiency gains from passive filters under variable conditions using high-resolution power analyzer data.Ridge Regression identifies key predictive variables,achieving baseline R^(2)=0.591.XGBoost then captures nonlinear interactions between load variability,power quality disturbances,and filter performance,improving accuracy to R^(2)=0.755.The methodology was validated through deployment at three industrial facilities in collaboration with Livarsa GmbH.Results demonstrate 9.9%average relative error across measured efficiency gains,confirming reliability under real-world conditions.Comprehensive validation through k-fold cross-validation,ensemble methods,and external testing quantified prediction uncertainty inherent in small indus-trial datasets(25 training samples).The approach offers a scalable,data-driven decision-support tool overcoming simulation-based limitations.Computational efficiency enables real-time assessment during client consultations without specialized software.Economic value derives from reduced performance guarantee margins,accelerated assessment timelines,and minimized warranty exposure.Limitations include statistical constraints from limited training data,reflected in cross-validation overfitting and wide confidence intervals.External validity requires site-specific validation for facilities with substantially different electrical characteristics.Despite these con-straints,the findings provide practical value for energy professionals seeking efficient power quality solutions,enabling confident passive filter deployment decisions based on quantified performance predictions.
基金supported by the High-performance Computing Platform of China University of Geosciences,Beijingsupported by the National Natural Science Foundation of China(Grant No.42304087)+1 种基金the National Key R&D Program of China(Grant No.2022YFF0800901)the Fundamental Research Funds for the Central Universities(Grant No.29-2023-202)。
文摘Since the Cenozoic,a series of extensional south-north normal faults and gneiss-granite domes evolved in the southern Tibetan Plateau,the formation mechanism of which is of scientific interest and which has implications for the tectonic dynamics of the plateau.Typical of such features are the Xainza-Dinggye rift and the Mabja gneiss dome,which are located in the Xainza-Xietongmen-Dinggye region in the central Tibetan Plateau.In this study,Magnetotelluric measurements across this region are used to generate a high-resolution 3-D electrical resistivity model of the subsurface and to analyze the cause of the conductive zones.The large-scale conductive zones identified in the middle-lower crust may result from aqueous melt partial melting,whereas the smaller-scale conductive zones in the upper-middle crust may result from saline fluids,possibly with varying minor volumes of melts.Subsequently,based on the electrical resistivity model and combined with the spatiotemporal coupling of the geological,geochemical,and geophysical data,the state and migration features of crustal materials are discussed.The results show that the upwelling of mantle materials along subduction channels and slab-windows related to the tearing of the Indian lithospheric plate contributed to the partial melting of the middle-lower crust in the Lhasa terrane.Furthermore,partial melting of the upper-middle crust in the Tethys-Himalaya terrane resulted from southern extrusion of crustal materials in the Lhasa terrane.These two mechanisms can significantly reduce the effective viscosity.We speculate that the deformation of the brittle upper crust that is controlled by large-scale ductile layers characterized by weak rheology is the main dynamic mechanism of rift evolution.Meanwhile,the metamorphism and anatexis in the upper-middle crust of the Tethys-Himalaya terrane related to the southern extrusion of materials contributed to the evolution of the Mabja gneiss dome.During the middle Miocene,the southern extrusion of crustal materials may have been influenced by the cooling events beneath the Mabja gneiss dome,which can explain why the deep areas beneath the Mabja gneiss dome have middle-high resistivity.In addition,our study region is located in the Mediterranean-Himalayan seismic belt,and mainly includes shallow-focus earthquakes and intermediate-depth earthquakes.In the north,shallow-focus earthquakes are mainly controlled by the accumulation of stress in the brittle layer of the overlying crust related to the ductile layer of the middle and lower crust.In the south,shallow-focus earthquakes(e.g.,Dingri MS6.8 earthquake)mainly occur in the rigid,resistive block,which is surrounded by conductive zones,possibly because fluid migration may be hindered by these resistive blocks.The intermediate-depth earthquakes are mainly controlled by the response in the subsurface area,which is related to the detachment of the Indian lithospheric mantle from the Indian crust.
基金supported by the National Natural Science Foundation of China(32170285 to L.-M.F.and 32270288 to W.Q.)Beijing Life Science Academy(BLSA,2024500CA0010)。
文摘Heat stress(HS)at the reproductive stage detrimentally affects crop yields and seed quality.However,the molecular mechanisms that protect reproductive processes in plants under HS remain largely unknown.Here,we report that Acetylation Lowers Binding Affinity 3(ALBA3)is crucial for safeguarding male fertility against HS in Arabidopsis.ALBA 3 is highly expressed in pollen,and ALBA3 is localized in the cytoplasm of both sperm and vegetative cells.Mutants lacking functional ALBA3exhibit hypersensitivity to HS,with reduced silique length and fertility due to defects in pollen germination,pollination,pollen tube growth,and fertilization under HS.ALBA3 binds and stabilizes a subset of messenger RNAs(mRNAs)essential for pollen function,thereby protecting male fertility.Two residues in the Alba domain,K46 and L90,are critical for ALBA3's ability to bind and stabilize mRNAs and are necessary for its proper function.Interestingly,the loss of rice ALBA3 also leads to severe pollen abortion and male sterility under HS,highlighting the conserved role of ALBA3 in protecting male fertility across plant species.This study uncovers a conserved mechanism by which ALBA3 safeguards male fertility during HS by stabilizing specific mRNAs crucial for pollen function.
基金supported by the National Key R&D Program of China(2023YFF1000100)the National Natural Science Foundation of China(32022006)+1 种基金the Agricultural Science and Technology Innovation Program(CAAS-ASTIP-2021-AGIS-ZDRW202101)the Shenzhen Science and Technology Program(AGIS-ZDKY202002)awarded to S.C.
文摘The nucleotide-binding domain leucine-rich repeat(NLR)receptor proteins play pivotal roles in plant disease resistance due to their extensive genetic diversity driven by long-term co-evolution with pathogens.In this study,we present a comprehensive wheat pan-NLRome containing 8056 NLR genes,which display remarkable diversity in gene structure,nucleotide variation,and presence-absence polymorphisms across the A.E.Watkins landrace collection.Comparative analysis between the landraces and modern cultivars revealed that 1316 NLRs were gained,and 1179 NLRs were lost during wheat breeding.Furthermore,we identified 221 spatial pairs of NLR genes in the genome,which show co-evolutionary patterns similar to those of physical NLR pairs.Finally,we identified 1710 candidate NLR genes potentially involved in resistance to various diseases or environmental adaptation.Overall,our study establishes a comprehensive and diversified NLR gene resource that will facilitate the discovery and utilization of genes for disease resistance and climate adaptation in wheat.
基金supported by the National Natural Science Foundation of China(82225021)the National Key R&D Program of China(2022YFC2303403,2021YFA1300803,2021YFA1301404).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is continuously evolving since 2019.Some monoclonal antibodies(mAbs)have been developed and widely used,such as etesevimab(CB6)developed by Eli-Lilly/Junshi.However,the mAb escaped from the variant of concern(VOC)ever since the emergence of Beta VOC,with a complete loss of efficacy against the Omicron subvariants.Here,we developed a broad-spectrum and affinity-mature antibody design(BAADesign)procedure to design CB6,enabling it to bind to the receptor-binding domains(RBDs)of multiple important Omicron subvariants,including the recent variant KP.2.Structural analysis confirmed the desired CB6-RBD interactions.Additionally,identical mutations in the complementarity determining regions(CDR)1 and CDR2 of the CB6 mutants also restored neutralizing potency for some RBD-1 group antibodies.Overall,the enhanced CB6 neutralizing capacity makes it a promising candidate against SARS-CoV-2 infection,and the BAADesign method has implications for the design of other antibodies.
基金supported by Natural Science Foundation of China(No.51533009)the Guangdong Innovative and Entrepreneurial Research Team Program(No.2013S086)the key Area Research and Development of Guangzhou(No.202007020006).
文摘Levodopa(L-DOPA),a precursor of dopamine,is commonly prescribed for the treatment of the Parkinson’s disease(PD).However,oral administration of levodopa results in a high level of homocysteine in the peripheral circulation,thereby elevating the risk of cardiovascular disease,and limiting its clinical application.Here,we report a non-invasive method to deliver levodopa to the brain by delivering L-DOPA-loaded sub-50 nm nanoparticles via brain-lymphatic vasculature.The hydrophilic L-DOPA was successfully encapsulated into nanoparticles of tannic acid(TA)/polyvinyl alcohol(PVA)via hydrogen bonding using the flash nanocomplexation(FNC)process,resulting in a high L-DOPA-loading capacity and uniform size in a scalable manner.Pharmacodynamics analysis in a PD rat model demonstrated that the levels of dopamine and tyrosine hydroxylase,which indicate the dopaminergic neuron functions,were increased by 2-and 4-fold,respectively.Movement disorders and cerebral oxidative stress of the rats were significantly improved.This formulation exhibited a high degree of biocompatibility as evidenced by lack of induced inflammation or other pathological changes in major organs.This antioxidative and drug-delivery platform administered through the brain-lymphatic vasculature shows promise for clinical treatment of the PD.
基金supported by the National Natural Science Foundations of China,Nos.82272163,82472164(both MF)。
文摘Functional neurological recovery remains the primary objective when treating ischemic stroke.However,current therapeutic approaches often fall short of achieving optimal outcomes.One of the most significant challenges in stroke treatment is the effective delivery of neuroprotective agents across the blood–brain barrier to ischemic regions within the brain.The blood–brain barrier,while essential for protecting the brain from harmful substances,also restricts the passage of many therapeutic compounds,thus limiting their efficacy.In this review,we summarizes the emerging role of nanoparticle-based therapies for the treatment of ischemic stroke and investigate their potential to revolutionize drug delivery,enhance neuroprotection,and promote functional recovery.Recent advancements in nanotechnology have led to the development of engineered nanoparticles specifically designed to overcome the blood–brain barrier,thus enabling the targeted delivery of therapeutic agents directly to the affected brain areas.Preclinical studies have demonstrated the remarkable potential of nanoparticle-based therapies to activate key neuroprotective pathways,such as the phosphoinositide 3-kinase/protein kinase B/c AMP response element-binding protein signaling cascade,which is crucial for neuronal survival,synaptic plasticity,and post-stroke recovery.By modulating these pathways,nanoparticles could mitigate neuronal damage,reduce inflammation,and promote tissue repair.Furthermore,nanoparticles offer a unique advantage by enabling multimodal therapeutic strategies that simultaneously target multiple pathological mechanisms of ischemic stroke,including oxidative stress,neuroinflammation,and apoptosis.This multifaceted approach enhances the overall efficacy of treatment,addressing the complex and interconnected processes that contribute to stroke-related brain injury.Surface modifications,such as functionalization with specific ligands or targeting molecules,further improve the precision of drug delivery,enhance targeting specificity,and prolong systemic circulation,thereby optimizing therapeutic outcomes.Nanoparticlebased therapeutics represent a paradigm shift for the management of stroke and provide a promising avenue for reducing post-stroke disability and improving the outcomes of long-term rehabilitation.By combining targeted drug delivery with the ability to modulate critical neuroprotective pathways,nanoparticles hold the potential to transform the treatment landscape for ischemic stroke.However,while preclinical data are highly encouraging,significant challenges remain in translating these advancements into clinical practice.Further research is needed to refine nanoparticle designs,optimize their safety profiles,and ensure their scalability for widespread application.Rigorous clinical trials are essential to validate their efficacy,assess long-term biocompatibility,and address potential off-target effects.The integration of interdisciplinary approaches,combining insights from nanotechnology,neuroscience,and pharmacology,will be critical if we are to overcome these challenges.Ultimately,nanoparticle-based therapies offer a foundation for innovative,precision-based treatments that could significantly improve outcomes for stroke patients,thus paving the way for a new era in stroke care and neurological rehabilitation.
基金the National Science Foundation of China grants(31825010 and 82121005)National Key R&D Program of China(2018YFA0507000)+1 种基金CAS Strategic Priority Research Program(XDB37030100)Shanghai Pilot Program for Basic Research-Chinese Academy of Sciences,Shanghai Branch(JCYJ-SHFY-2021-008).
文摘Dear Editor,The purinergic receptors(P2YRs)are involved in a variety of physiological processes,including proliferation,chemotaxis,cancer metastasis,cardiovascular events,neurodegenerative diseases and aging(Weisman et al.,2012).Thus far,eight human P2YRs have been characterized and are classified into two subfamilies based on their sequence homology and signal transduction mechanisms,including P2Y1 R-like receptors that signal preferentially through Gq/11 proteins and P2Y12R-like receptors that activate Gi/o proteins(Abbracchio et al.,2006).
基金supported by the projects of National Natural Science Foundation of China(81874367 and 82074019)Guangdong Key Laboratory for Translational Cancer research of Chinese Medicine(2018B030322011,China)+3 种基金Natural Science Foundation for Distinguished Young Scholars of Guangdong Province,China(2017A030306033)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(2016,China)Project of Educational Commission of Guangdong Province of China(2016KTSCX012)Pearl River Nova Program of Guangzhou,China(201710010108)。
文摘Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.
基金supported by Beijing Natural Science Foundation(M21016)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-003 and 2021-CAMS-JZ004)+1 种基金Tsinghua-Peking Center for Life Sciences (045-61020100122)Beijing Advanced Innovation Center for Structural Biology
文摘Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral RNA.Here we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.
