BACKGROUND:Sepsis is a highly heterogeneous organ dysfunction syndrome.There is limited evidence regarding phenotypes and clinical outcomes in sepsis patients with initial normal lactate levels.We sought to identify t...BACKGROUND:Sepsis is a highly heterogeneous organ dysfunction syndrome.There is limited evidence regarding phenotypes and clinical outcomes in sepsis patients with initial normal lactate levels.We sought to identify the lactate-based clinical phenotypes and outcomes of sepsis patients.METHODS:The Medical Information Mart for Intensive Care IV(MIMIC-IV)and eICU databases were used to conduct a retrospective cohort study.Adult sepsis patients were included.Lactate was measured via blood gas,and the same assay type was used across both databases.Serial lactate measurements were analyzed via a two-point classification system based on the highest values recorded during two consecutive 24-hour periods following ICU admission.The fi rst measurement window(T1)comprised the initial 24 h post-admission,whereas the second window(T2)covered 24-48 h post-admission.The lactate diff erence was defi ned as the numerical change between the highest lactate level at T2 and the highest level at T1.The time interval between these two measurements was fi xed,with T2 commencing immediately after T1,together encompassing the fi rst 48 h post-ICU admission.A normal lactate level was defi ned as≤2 mmol/L,and an elevated level was defi ned as>2 mmol/L.Sepsis patients were stratifi ed into four trajectory phenotypes:(1)normal-normal(N-N);(2)normal-elevated(N-E);(3)elevated-normal(E-N);and(4)elevated-elevated(E-E).The primary outcome was in-hospital mortality.RESULTS:This study enrolled 6,926 sepsis patients.The clinical phenotypes of the sepsis patients were as follows:N-N(24.4%),N-E(3.8%),E-N(36.4%),and E-E(35.3%).The in-hospital mortality rates of sepsis patients with the four phenotypes from the MIMIC-IV and eICU databases were as follows(N-N:18.9%vs.17.6%,P=0.66;N-E:35.3%vs.29.2%,P=0.45;E-N:16.6%vs.14.2%,P=0.14;E-E:43.6%vs.37.8%,P=0.01).After adjusting for age,sex,Sequential Organ Failure Assessment(SOFA)score,vasopressor therapy,and infection sites,the N-E phenotype was associated with a higher risk of in-hospital mortality(odds ratio[OR]1.44;95%confidence intervals[95%CI]1.11-1.86;P=0.006;adjusted OR 1.61;95%CI 1.23-2.11;P<0.001).The E-N phenotype was associated with the most favorable outcomes for in-hospital mortality in the multivariable analysis(adjusted OR 0.41;95%CI 0.36-0.46;P<0.001).The E-E phenotype was associated with the highest risk of in-hospital mortality in the overall cohort(adjusted OR 3.00;95%CI 2.67-3.37;P<0.001).CONCLUSION:In sepsis patients with normal initial lactate levels,serial lactate measurements could be valuable for prognostic assessment.展开更多
Material phase-transition represents a significant phenomenon and mechanism in the context of hypervelocity protection.This study presents a thorough analysis of the phase-transition phenomena induced by shock pressur...Material phase-transition represents a significant phenomenon and mechanism in the context of hypervelocity protection.This study presents a thorough analysis of the phase-transition phenomena induced by shock pressure as the shock wave propagates initially to the rear of the projectile.The shock wave that induces a phase-transition is commonly referred to as a macroscopic phase-transition wave,whereas the interface that separates the distinct phases is referred to as macroscopic phase-boundary.The contact interface between the spherical projectile and the thin plate,characterized by its curved surface,plays a significant role in the nonlinear propagation and evolution of wave systems.The pressure distribution along the central axis of a spherical projectile is derived in accordance with the linear decay law observed for axial pressure.On this basis,a quadratic function is employed to characterize the trend of changes in wave front pressure,thereby facilitating the establishment of a model for wave front pressure distribution.Using the phase-transition pressure criterion for materials,the wave front phase evolution process is derived,and the macroscopic phase-boundary is determined.Based on the geometric propagation model(GPM)and the pressure distribution of the wave front,a phase geometric propagation model(PGPM)is proposed.The phase distribution of a spherical projectile impacting a thin plate is obtained by theoretical methods.The accuracy of the PGPM is subsequently validated through a comparison of its results with those obtained from numerical simulations.展开更多
Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling p...BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.展开更多
Friction rolling additive manufacturing(FRAM)is a solid-state additive manufacturing technology that plasticizes the feed and deposits a material using frictional heat generated by the tool head.The thermal efficiency...Friction rolling additive manufacturing(FRAM)is a solid-state additive manufacturing technology that plasticizes the feed and deposits a material using frictional heat generated by the tool head.The thermal efficiency of FRAM,which depends only on friction to generate heat,is low,and the thermal-accumulation effect of the deposition process must be addressed.An FRAM heat-balance-control method that combines plasma-arc preheating and instant water cooling(PC-FRAM)is devised in this study,and a temperature field featuring rapidly increasing and decreasing temperature is constructed around the tool head.Additionally,2195-T87 Al-Li alloy is used as the feed material,and the effects of heating and cooling rates on the microstructure and mechanical properties are investigated.The results show that water cooling significantly improves heat accumulation during the deposition process.The cooling rate increases by 11.7 times,and the high-temperature residence time decreases by more than 50%.The grain size of the PC-FRAM sample is the smallest,i.e.,3.77±1.03μm,its dislocation density is the highest,and the number density of precipitates is the highest,the size of precipitates is the smallest,which shows the best precipitation-strengthening effect.The hardness test results are consistent with the precipitation distribution.The ultimate tensile strength,yield strength and elongation of the PC-FRAM samples are the highest(351±15.6 MPa,251.3±15.8 MPa and 16.25%±1.25%,respectively)among the samples investigated.The preheating and water-cooling-assisted deposition simultaneously increases the tensile strength and elongation of the deposited samples.The combination of preheating and instant cooling improves the deposition efficiency of FRAM and weakens the thermal-softening effect.展开更多
PBQ[1-(4-chlorophenyl)-3-(pyridin-3-yl)urea],an enormous potent molluscicide,showed excellent Pomacea canaliculata(P.canaliculata)control activity and low toxicity for other aquatic organisms,but its snail-killing mec...PBQ[1-(4-chlorophenyl)-3-(pyridin-3-yl)urea],an enormous potent molluscicide,showed excellent Pomacea canaliculata(P.canaliculata)control activity and low toxicity for other aquatic organisms,but its snail-killing mechanisms are still not fully understood.We employed an optical method to elucidate PBQ action via a novel fluorescent viscosity probe,NCV.As the viscosity in the test solutions increased,compared with that in pure ethanol,a 54-fold fluorescence intensity enhancement of NCV was observed in 310 cP of 90%glycerol.Furthermore,NCV successfully exhibited a selective fluorescence response towards monensin-induced cellular viscosity changes in HepG2 cells.The liver,stomach,and foot plantar of the tested snails were frozen and sectioned for fluorescent imaging experiments after the treatment with different PBQ concentrations over various times.A significant fluorescent increase in the snail's liver was observed upon exposure to 0.75 mg/L PBQ for 72 h,which highlighted an increase in viscosity.Hematoxylin and eosin(HE)staining further supported PBQ-induced liver damage with a viscosity increase in P.canaliculata.Our study provides a new rapid optical visualization method to study the killing mechanisms of PBQ and may help discover new chemicals that control snail populations.展开更多
Pepper(Capsicum annuum L.)is a typical self-pollinating crop with obvious heterosis in hybrids.Consequently,the use of morphological markers during the pepper seedling stage is crucial for pepper breeding.The color of...Pepper(Capsicum annuum L.)is a typical self-pollinating crop with obvious heterosis in hybrids.Consequently,the use of morphological markers during the pepper seedling stage is crucial for pepper breeding.The color of hypocotyl is widely used as a phenotypic marker in crossing studies of pepper.Pepper accessions generally have purple hypocotyls,which are mainly due to the anthocyanin accumulation in seedlings,and green hypocotyls are rarely observed in pepper.Here we reported the characterization of a green hypocotyl mutant of pepper,Cha1,which was identified from a pepper ethyl methanesulfonate(EMS)mutant library.Fine mapping revealed that the causal gene,CaTTG1,belonging to the WD40 repeat family,controlled the green hypocotyl phenotype of the mutant.Virus-induced gene silencing(VIGS)confirmed that CaTTG1 regulated anthocyanin accumulation.RNA-seq data showed that expression of structural genes CaDFR,CaANS,and CaUF3GT in the anthocyanin biosynthetic pathway was significantly decreased in Cha1 compared to the wild type.Yeast two-hybrid(Y2H)experiments also confirmed that CaTTG1 activated the synthesis of anthocyanin structural genes by forming a MBW complex with CaAN1 and CaGL3.In summary,this study provided a green hypocotyl mutant of pepper,and the Kompetitive Allele Specific PCR(KASP)marker developed based on the mutation site of the underlying gene would be helpful for pepper breeding.展开更多
Background The emergence of antibiotic resistant microorganisms associated with conventional swine production practices has increased interest in acid-based compounds having antimicrobial properties and other biologic...Background The emergence of antibiotic resistant microorganisms associated with conventional swine production practices has increased interest in acid-based compounds having antimicrobial properties and other biological functions as nutritional interventions.Despite the interest in organic acids and monoglycerides,few studies have examined the effects of the combination of these acid-based additives in weaned pigs under disease challenge conditions.Therefore,this study aimed to investigate the effects of dietary supplementation with blend of organic acids and/or medium-chain fatty acid monoglycerides on intestinal health and systemic immunity of weaned pigs experimentally infected with an enterotoxigenic Escherichia coli(ETEC)F18 at 4-week of age.Results Dietary supplementation of organic acids,monoglycerides,or both organic acids and monoglycerides(combination)reduced(P<0.05)the diarrhea frequency of ETEC F18-infected pigs throughout the experimental period(d−7 to 21 post-inoculation).This is consistent with the reduced(P<0.05)proportion ofβ-hemolytic coliforms in feces observed for the organic acid and combination treatments on d 10 post-inoculation.Supplementation of organic acids,monoglycerides,or combination also reduced(P<0.05)bacterial translocation in mesenteric lymph nodes on d 21 post-inoculation.Pigs fed with monoglycerides or combination had lower(P<0.05)white blood cells on d 5 post-inoculation,and pigs fed the combination also had lower(P<0.05)lymphocytes than pigs in control group.Monoglyceride supplementation increased(P<0.05)white blood cells and neutrophils compared with control group on d 14 post-inoculation.However,supplementation with organic acid blend,monoglyceride blend,or combination did not affect growth performance in this experiment.Conclusions Supplementation with monoglycerides or organic acids alone or in combination improves the detrimental effects of ETEC F18 infection in weaned pigs,as indicated by reduced diarrhea,fecal shedding ofβ-hemolytic coliforms,and bacterial translocation,and thus enhancing disease resistance.Monoglycerides reduced the inflammatory response during peak infection,but their immunomodulatory and possible synergistic effects with organic acids need to be further investigated.展开更多
Developing efficient and stable non-precious metal catalysts is essential for replacing platinum-based catalysts in polymer electrolyte membrane fuel cells(PEMFCs).The transition metal and nitrogen co-doped carbon ele...Developing efficient and stable non-precious metal catalysts is essential for replacing platinum-based catalysts in polymer electrolyte membrane fuel cells(PEMFCs).The transition metal and nitrogen co-doped carbon electrocatalyst(M-N-C)is considered an effective alternative to precious metal catalysts.However,its relatively poor performance in acidic environments has always been a problem plaguing its practical application in PEMFCs.This study presents a sequential deposition methodology for constructing a composite catalytic system of Fe-N-C and ionic liquid(IL),which exhibits improved performance at both half-cell and membrane electrode assembly scales.The presence of IL significantly inhibits H_(2)O_(2)production,preferentially promoting the 4e–O_(2)reduction reaction,resulting in improved electrocatalytic activity and stability.Additionally,the enhanced PEMFC performance of IL containing electrodes is a direct result of the improved ionic and reactant accessibility of the pore confined Fe-N-C catalysts where the IL minimizes local resistive transport losses.This study establishes a strategic foundation for the practical utilization of non-precious metal catalysts in PEMFCs and other energy converting technologies.展开更多
Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.S...Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.Skeletal muscle,as a major metabolic organ system,undergoes significant remodeling during ALI.However,its specific regulatory contributions remain largely uncharacterized.Methods:Partial(2/3)hepatectomy and acetaminophen were used to induce ALI in male mice.RNA-sequencing(RNA-seq),assay for transposase-accessible chromatin by sequencing(ATAC-seq),chromatin immunoprecipitation,luciferase assay,Western blotting,TUNEL assay,immunohistochemistry,and phase separation assays were performed to reveal the transcriptional axis involved.Serum fibroblast growth factor binding protein 1(FGFBP1)protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.Results:Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid(GC)signaling-mediated regulation of fibroblast growth factor 6(FGF6)in skeletal muscle metabolism.Muscle-specific knockdown of GC receptor(GR)exacerbates ALI and suppresses liver regeneration.Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration,with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown.Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling.Moreover,FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation(LLPS)-driven condensate dynamics at the plasma membrane.Circulating FGFBP1 subsequently interacts with hepatic FGF5 through LLPS mechanisms to regulate liver regeneration.Conclusion:Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis,providing a potential therapeutic target and treatment strategy for ALI.展开更多
Cancer vaccines are a notable area of immunotherapy due to their capacity to elicit specific antitumor immune responses and to create immune memory.However,they encounter challenges in clinical practice due to several...Cancer vaccines are a notable area of immunotherapy due to their capacity to elicit specific antitumor immune responses and to create immune memory.However,they encounter challenges in clinical practice due to several bottlenecks,including tumor heterogeneity,low immunogenicity,immunosuppressive tumor environment,and delivery obstacles,which collectively impact their clinical effectiveness.In this study,we developed nanocomposites containing positively charged melittin(MEL)and negatively charged photosensitizer indocyanine green(ICG),embedded in dissolving microneedles(MEL/ICG-HA@DMNs).This approach allows precise drug delivery by creating microchannels that bypass the stratum corneum barrier,targeting superficial lesions directly.Our results demonstrated that the complexation of MEL and ICG significantly reduced the hemolytic activity of MEL while maintaining its ability to disrupt cell membranes.After loading MEL/ICG-HA into the microneedle,MEL/ICG-HA@DMNs not only effectively concentrated the drug at the tumor site,inducing localized hyperthermia and successfully ablating the tumor,but also formed an in situ whole-cell vaccine containing a rich source of tumor-associated antigens.Moreover,the system promoted dendritic cell maturation and increased the M1/M2 macrophage ratio,enhancing the immune response.By overcoming the limitations of traditional cancer vaccines,this system ensures precise drug delivery and robust immune activation.This innovative approach holds the potential to revolutionize cancer treatment,offering a new paradigm in precision oncology.展开更多
The increased demand for personalized customization calls for new production modes to enhance collaborations among a wide range of manufacturing practitioners who unnecessarily trust each other.In this article,a block...The increased demand for personalized customization calls for new production modes to enhance collaborations among a wide range of manufacturing practitioners who unnecessarily trust each other.In this article,a blockchain-enabled manufacturing collaboration framework is proposed,with a focus on the production capacity matching problem for blockchainbased peer-to-peer(P2P)collaboration.First,a digital model of production capacity description is built for trustworthy and transparent sharing over the blockchain.Second,an optimization problem is formulated for P2P production capacity matching with objectives to maximize both social welfare and individual benefits of all participants.Third,a feasible solution based on an iterative double auction mechanism is designed to determine the optimal price and quantity for production capacity matching with a lack of personal information.It facilitates automation of the matching process while protecting users'privacy via blockchainbased smart contracts.Finally,simulation results from the Hyperledger Fabric-based prototype show that the proposed approach increases social welfare by 1.4%compared to the Bayesian game-based approach,makes all participants profitable,and achieves 90%fairness of enterprises.展开更多
Photoinduced[2+2]cycloaddition of biomass-derived cycloolefin is a promising approach to synthesize high-energy bio-fuels,however,the conversion efficiency and selectivity are still low.Herein,we provide an acid-promo...Photoinduced[2+2]cycloaddition of biomass-derived cycloolefin is a promising approach to synthesize high-energy bio-fuels,however,the conversion efficiency and selectivity are still low.Herein,we provide an acid-promoted photocycloaddition approach to synthesize a new kind of spiral fuel from biomass-derived cyclohexanone (CHOE) and camphene (CPE).BrΦnsted acids show higher catalytic activity than Lewis acids,and acetic acid (HOAc) possesses the best catalytic performance,with CHOE conversion up to 99.1%.Meanwhile,the HOAc-catalytic effect has been confirmed for[2+2]photocycloaddition of other biomass-derived ketenes and olefins.The catalytic mechanism and dynamics have been investigated,and show that HOAc can bond with C=O groups of CHOE to form H–CHOE complex,which leads to higher light adsorption and longer triplet lifetime.Meanwhile,H–CHOE complex reduces the energy gap between CHOE LUMO and CPE HOMO,shortens the distance of ring-forming atoms,and then decreases the energy barrier (from 103.3 kcal mol^(-1)to 95.8 kcal mol^(-1)) of rate-limiting step.After hydrodeoxygenation,the targeted bio-spiral fuel shows high density of 0.992 g cm^(-3),high neat heat of combustion of 41.89 MJ L^(-1),low kinetic viscosity of 5.69 mm^(2)s^(-1)at 20℃,which is very promising to serve as high-performance aerospace fuel.展开更多
基金supported by grants from National Natural Science Foundation of China (82402543)National High Level Hospital Clinical Research Funding (2022-PUMCH-B-109)+2 种基金CAMS Innovation Fund for Medical Sciences (CIFMS)(2021-I2M-1-020)Opening Foundation of Agile and Intelligent Computing Key Laboratory of Sichuan ProvinceSpecial Research Fund for Central Universities,Peking Union Medical College (3332024120)
文摘BACKGROUND:Sepsis is a highly heterogeneous organ dysfunction syndrome.There is limited evidence regarding phenotypes and clinical outcomes in sepsis patients with initial normal lactate levels.We sought to identify the lactate-based clinical phenotypes and outcomes of sepsis patients.METHODS:The Medical Information Mart for Intensive Care IV(MIMIC-IV)and eICU databases were used to conduct a retrospective cohort study.Adult sepsis patients were included.Lactate was measured via blood gas,and the same assay type was used across both databases.Serial lactate measurements were analyzed via a two-point classification system based on the highest values recorded during two consecutive 24-hour periods following ICU admission.The fi rst measurement window(T1)comprised the initial 24 h post-admission,whereas the second window(T2)covered 24-48 h post-admission.The lactate diff erence was defi ned as the numerical change between the highest lactate level at T2 and the highest level at T1.The time interval between these two measurements was fi xed,with T2 commencing immediately after T1,together encompassing the fi rst 48 h post-ICU admission.A normal lactate level was defi ned as≤2 mmol/L,and an elevated level was defi ned as>2 mmol/L.Sepsis patients were stratifi ed into four trajectory phenotypes:(1)normal-normal(N-N);(2)normal-elevated(N-E);(3)elevated-normal(E-N);and(4)elevated-elevated(E-E).The primary outcome was in-hospital mortality.RESULTS:This study enrolled 6,926 sepsis patients.The clinical phenotypes of the sepsis patients were as follows:N-N(24.4%),N-E(3.8%),E-N(36.4%),and E-E(35.3%).The in-hospital mortality rates of sepsis patients with the four phenotypes from the MIMIC-IV and eICU databases were as follows(N-N:18.9%vs.17.6%,P=0.66;N-E:35.3%vs.29.2%,P=0.45;E-N:16.6%vs.14.2%,P=0.14;E-E:43.6%vs.37.8%,P=0.01).After adjusting for age,sex,Sequential Organ Failure Assessment(SOFA)score,vasopressor therapy,and infection sites,the N-E phenotype was associated with a higher risk of in-hospital mortality(odds ratio[OR]1.44;95%confidence intervals[95%CI]1.11-1.86;P=0.006;adjusted OR 1.61;95%CI 1.23-2.11;P<0.001).The E-N phenotype was associated with the most favorable outcomes for in-hospital mortality in the multivariable analysis(adjusted OR 0.41;95%CI 0.36-0.46;P<0.001).The E-E phenotype was associated with the highest risk of in-hospital mortality in the overall cohort(adjusted OR 3.00;95%CI 2.67-3.37;P<0.001).CONCLUSION:In sepsis patients with normal initial lactate levels,serial lactate measurements could be valuable for prognostic assessment.
基金supported by National Natural Science Foundation of China(Nos.12432018,12372346)the Innovative Research Groups of the National Natural Science Foundation of China(No.12221002)National Natural Science Foundation of China(No.12302493)。
文摘Material phase-transition represents a significant phenomenon and mechanism in the context of hypervelocity protection.This study presents a thorough analysis of the phase-transition phenomena induced by shock pressure as the shock wave propagates initially to the rear of the projectile.The shock wave that induces a phase-transition is commonly referred to as a macroscopic phase-transition wave,whereas the interface that separates the distinct phases is referred to as macroscopic phase-boundary.The contact interface between the spherical projectile and the thin plate,characterized by its curved surface,plays a significant role in the nonlinear propagation and evolution of wave systems.The pressure distribution along the central axis of a spherical projectile is derived in accordance with the linear decay law observed for axial pressure.On this basis,a quadratic function is employed to characterize the trend of changes in wave front pressure,thereby facilitating the establishment of a model for wave front pressure distribution.Using the phase-transition pressure criterion for materials,the wave front phase evolution process is derived,and the macroscopic phase-boundary is determined.Based on the geometric propagation model(GPM)and the pressure distribution of the wave front,a phase geometric propagation model(PGPM)is proposed.The phase distribution of a spherical projectile impacting a thin plate is obtained by theoretical methods.The accuracy of the PGPM is subsequently validated through a comparison of its results with those obtained from numerical simulations.
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
文摘BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.
基金supported by the National Natural Science Foundation of China(Nos.52275299,52105313)R&D Program of Beijing Municipal Education Commission(No.KM202210005036)+1 种基金Natural Science Foundation of Chongqing,China(No.CSTB2023NSCQ-MSX0701)National Defense Basic Research Projects of China(No.JCKY2022405C002).
文摘Friction rolling additive manufacturing(FRAM)is a solid-state additive manufacturing technology that plasticizes the feed and deposits a material using frictional heat generated by the tool head.The thermal efficiency of FRAM,which depends only on friction to generate heat,is low,and the thermal-accumulation effect of the deposition process must be addressed.An FRAM heat-balance-control method that combines plasma-arc preheating and instant water cooling(PC-FRAM)is devised in this study,and a temperature field featuring rapidly increasing and decreasing temperature is constructed around the tool head.Additionally,2195-T87 Al-Li alloy is used as the feed material,and the effects of heating and cooling rates on the microstructure and mechanical properties are investigated.The results show that water cooling significantly improves heat accumulation during the deposition process.The cooling rate increases by 11.7 times,and the high-temperature residence time decreases by more than 50%.The grain size of the PC-FRAM sample is the smallest,i.e.,3.77±1.03μm,its dislocation density is the highest,and the number density of precipitates is the highest,the size of precipitates is the smallest,which shows the best precipitation-strengthening effect.The hardness test results are consistent with the precipitation distribution.The ultimate tensile strength,yield strength and elongation of the PC-FRAM samples are the highest(351±15.6 MPa,251.3±15.8 MPa and 16.25%±1.25%,respectively)among the samples investigated.The preheating and water-cooling-assisted deposition simultaneously increases the tensile strength and elongation of the deposited samples.The combination of preheating and instant cooling improves the deposition efficiency of FRAM and weakens the thermal-softening effect.
基金the financial support of this work by the National Natural Science Foundation of China(Nos.82072309,22067019 and 22367023)the Major Science and Technology Projects in Yunnan Province(No.202402AE090006)+3 种基金the Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform(No.2022YKZY001)Yunnan Provincial Science and Technology Department Yunnan University Joint Special Project(No.202201BF070001-001)the Postgraduate Research Innovation Foundation of Yunnan University(No.KC-23234403)the Scientific Research Foundation Project of Yunnan Provincial Department of Education(No.2023Y0240)。
文摘PBQ[1-(4-chlorophenyl)-3-(pyridin-3-yl)urea],an enormous potent molluscicide,showed excellent Pomacea canaliculata(P.canaliculata)control activity and low toxicity for other aquatic organisms,but its snail-killing mechanisms are still not fully understood.We employed an optical method to elucidate PBQ action via a novel fluorescent viscosity probe,NCV.As the viscosity in the test solutions increased,compared with that in pure ethanol,a 54-fold fluorescence intensity enhancement of NCV was observed in 310 cP of 90%glycerol.Furthermore,NCV successfully exhibited a selective fluorescence response towards monensin-induced cellular viscosity changes in HepG2 cells.The liver,stomach,and foot plantar of the tested snails were frozen and sectioned for fluorescent imaging experiments after the treatment with different PBQ concentrations over various times.A significant fluorescent increase in the snail's liver was observed upon exposure to 0.75 mg/L PBQ for 72 h,which highlighted an increase in viscosity.Hematoxylin and eosin(HE)staining further supported PBQ-induced liver damage with a viscosity increase in P.canaliculata.Our study provides a new rapid optical visualization method to study the killing mechanisms of PBQ and may help discover new chemicals that control snail populations.
基金supported by grants from the Special Funds for Construction of Innovative Provinces in Hunan Province(Grant No.2021NK1006)the Science and Technology Innovation Program of Hunan Province(Grant No.2021JC0007)+2 种基金China Agriculture Research System of MOF and MARA(Grant No.CARS-24-A-15)National Natural Science Foundation of China(Grant No.32130097)National Natural Science Foundation of China(Grant No.U19A2028)。
文摘Pepper(Capsicum annuum L.)is a typical self-pollinating crop with obvious heterosis in hybrids.Consequently,the use of morphological markers during the pepper seedling stage is crucial for pepper breeding.The color of hypocotyl is widely used as a phenotypic marker in crossing studies of pepper.Pepper accessions generally have purple hypocotyls,which are mainly due to the anthocyanin accumulation in seedlings,and green hypocotyls are rarely observed in pepper.Here we reported the characterization of a green hypocotyl mutant of pepper,Cha1,which was identified from a pepper ethyl methanesulfonate(EMS)mutant library.Fine mapping revealed that the causal gene,CaTTG1,belonging to the WD40 repeat family,controlled the green hypocotyl phenotype of the mutant.Virus-induced gene silencing(VIGS)confirmed that CaTTG1 regulated anthocyanin accumulation.RNA-seq data showed that expression of structural genes CaDFR,CaANS,and CaUF3GT in the anthocyanin biosynthetic pathway was significantly decreased in Cha1 compared to the wild type.Yeast two-hybrid(Y2H)experiments also confirmed that CaTTG1 activated the synthesis of anthocyanin structural genes by forming a MBW complex with CaAN1 and CaGL3.In summary,this study provided a green hypocotyl mutant of pepper,and the Kompetitive Allele Specific PCR(KASP)marker developed based on the mutation site of the underlying gene would be helpful for pepper breeding.
基金supported by Animal Nutrition,Eastman Chemical Company,Kingsport,TN,USA.
文摘Background The emergence of antibiotic resistant microorganisms associated with conventional swine production practices has increased interest in acid-based compounds having antimicrobial properties and other biological functions as nutritional interventions.Despite the interest in organic acids and monoglycerides,few studies have examined the effects of the combination of these acid-based additives in weaned pigs under disease challenge conditions.Therefore,this study aimed to investigate the effects of dietary supplementation with blend of organic acids and/or medium-chain fatty acid monoglycerides on intestinal health and systemic immunity of weaned pigs experimentally infected with an enterotoxigenic Escherichia coli(ETEC)F18 at 4-week of age.Results Dietary supplementation of organic acids,monoglycerides,or both organic acids and monoglycerides(combination)reduced(P<0.05)the diarrhea frequency of ETEC F18-infected pigs throughout the experimental period(d−7 to 21 post-inoculation).This is consistent with the reduced(P<0.05)proportion ofβ-hemolytic coliforms in feces observed for the organic acid and combination treatments on d 10 post-inoculation.Supplementation of organic acids,monoglycerides,or combination also reduced(P<0.05)bacterial translocation in mesenteric lymph nodes on d 21 post-inoculation.Pigs fed with monoglycerides or combination had lower(P<0.05)white blood cells on d 5 post-inoculation,and pigs fed the combination also had lower(P<0.05)lymphocytes than pigs in control group.Monoglyceride supplementation increased(P<0.05)white blood cells and neutrophils compared with control group on d 14 post-inoculation.However,supplementation with organic acid blend,monoglyceride blend,or combination did not affect growth performance in this experiment.Conclusions Supplementation with monoglycerides or organic acids alone or in combination improves the detrimental effects of ETEC F18 infection in weaned pigs,as indicated by reduced diarrhea,fecal shedding ofβ-hemolytic coliforms,and bacterial translocation,and thus enhancing disease resistance.Monoglycerides reduced the inflammatory response during peak infection,but their immunomodulatory and possible synergistic effects with organic acids need to be further investigated.
基金国家自然科学基金(22202124,22208376)山西省科技创新团队专项资金(202304051001023)+3 种基金山西省重点研发计划(202302060301009)山西省国家留学基金委(2023-008,2023-009)山东省自然科学基金(ZR2023LFG005)青岛新能源山东实验室开放项目(QNESL OP 202303).
文摘Developing efficient and stable non-precious metal catalysts is essential for replacing platinum-based catalysts in polymer electrolyte membrane fuel cells(PEMFCs).The transition metal and nitrogen co-doped carbon electrocatalyst(M-N-C)is considered an effective alternative to precious metal catalysts.However,its relatively poor performance in acidic environments has always been a problem plaguing its practical application in PEMFCs.This study presents a sequential deposition methodology for constructing a composite catalytic system of Fe-N-C and ionic liquid(IL),which exhibits improved performance at both half-cell and membrane electrode assembly scales.The presence of IL significantly inhibits H_(2)O_(2)production,preferentially promoting the 4e–O_(2)reduction reaction,resulting in improved electrocatalytic activity and stability.Additionally,the enhanced PEMFC performance of IL containing electrodes is a direct result of the improved ionic and reactant accessibility of the pore confined Fe-N-C catalysts where the IL minimizes local resistive transport losses.This study establishes a strategic foundation for the practical utilization of non-precious metal catalysts in PEMFCs and other energy converting technologies.
基金supported by the NSFC Distinguished Young Scholars Fund(82325010)the National Natural Science Foundation of China(82370874)+4 种基金the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212700)the Major Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of Education(2023ZKZD17)the Shanghai Research Center for Endocrine and Metabolic Diseases(2022ZZ01002)the Shanghai Key Discipline of Public Health Grants Award(GWVI-11.1-20)the Basic Scientific Research Project(General Cultivation Program)of Shanghai Sixth People’s Hospital(ynms202203).
文摘Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.Skeletal muscle,as a major metabolic organ system,undergoes significant remodeling during ALI.However,its specific regulatory contributions remain largely uncharacterized.Methods:Partial(2/3)hepatectomy and acetaminophen were used to induce ALI in male mice.RNA-sequencing(RNA-seq),assay for transposase-accessible chromatin by sequencing(ATAC-seq),chromatin immunoprecipitation,luciferase assay,Western blotting,TUNEL assay,immunohistochemistry,and phase separation assays were performed to reveal the transcriptional axis involved.Serum fibroblast growth factor binding protein 1(FGFBP1)protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.Results:Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid(GC)signaling-mediated regulation of fibroblast growth factor 6(FGF6)in skeletal muscle metabolism.Muscle-specific knockdown of GC receptor(GR)exacerbates ALI and suppresses liver regeneration.Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration,with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown.Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling.Moreover,FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation(LLPS)-driven condensate dynamics at the plasma membrane.Circulating FGFBP1 subsequently interacts with hepatic FGF5 through LLPS mechanisms to regulate liver regeneration.Conclusion:Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis,providing a potential therapeutic target and treatment strategy for ALI.
基金supported by the National Natural Science Foundation of China(Nos.82173747,82373803)the Special Fund Project for Science and Technology Innovation Strategy of Guangdong Province(No.2021TQ060944)。
文摘Cancer vaccines are a notable area of immunotherapy due to their capacity to elicit specific antitumor immune responses and to create immune memory.However,they encounter challenges in clinical practice due to several bottlenecks,including tumor heterogeneity,low immunogenicity,immunosuppressive tumor environment,and delivery obstacles,which collectively impact their clinical effectiveness.In this study,we developed nanocomposites containing positively charged melittin(MEL)and negatively charged photosensitizer indocyanine green(ICG),embedded in dissolving microneedles(MEL/ICG-HA@DMNs).This approach allows precise drug delivery by creating microchannels that bypass the stratum corneum barrier,targeting superficial lesions directly.Our results demonstrated that the complexation of MEL and ICG significantly reduced the hemolytic activity of MEL while maintaining its ability to disrupt cell membranes.After loading MEL/ICG-HA into the microneedle,MEL/ICG-HA@DMNs not only effectively concentrated the drug at the tumor site,inducing localized hyperthermia and successfully ablating the tumor,but also formed an in situ whole-cell vaccine containing a rich source of tumor-associated antigens.Moreover,the system promoted dendritic cell maturation and increased the M1/M2 macrophage ratio,enhancing the immune response.By overcoming the limitations of traditional cancer vaccines,this system ensures precise drug delivery and robust immune activation.This innovative approach holds the potential to revolutionize cancer treatment,offering a new paradigm in precision oncology.
基金supported in part by the National Natural Science Foundation of China(62273310)the Natural Science Foundation of Zhejiang Province of China(LY22F030006,LZ24F030009)
文摘The increased demand for personalized customization calls for new production modes to enhance collaborations among a wide range of manufacturing practitioners who unnecessarily trust each other.In this article,a blockchain-enabled manufacturing collaboration framework is proposed,with a focus on the production capacity matching problem for blockchainbased peer-to-peer(P2P)collaboration.First,a digital model of production capacity description is built for trustworthy and transparent sharing over the blockchain.Second,an optimization problem is formulated for P2P production capacity matching with objectives to maximize both social welfare and individual benefits of all participants.Third,a feasible solution based on an iterative double auction mechanism is designed to determine the optimal price and quantity for production capacity matching with a lack of personal information.It facilitates automation of the matching process while protecting users'privacy via blockchainbased smart contracts.Finally,simulation results from the Hyperledger Fabric-based prototype show that the proposed approach increases social welfare by 1.4%compared to the Bayesian game-based approach,makes all participants profitable,and achieves 90%fairness of enterprises.
基金the support from National Key R&D Program of China (2021YFC2103704)the National Natural Science Foundation of China (22222808)+4 种基金the Natural Science Foundation of Shandong Province (ZR2023QB152)the Youth Innovation Team Plan of Shandong Province (2022KJ270)the China National Postdoctoral Program for Innovative Talents (BX20240251)the Aeronautical Science Foundation of China (2023Z073048003)the Haihe Laboratory of Sustainable Chemical Transformations。
文摘Photoinduced[2+2]cycloaddition of biomass-derived cycloolefin is a promising approach to synthesize high-energy bio-fuels,however,the conversion efficiency and selectivity are still low.Herein,we provide an acid-promoted photocycloaddition approach to synthesize a new kind of spiral fuel from biomass-derived cyclohexanone (CHOE) and camphene (CPE).BrΦnsted acids show higher catalytic activity than Lewis acids,and acetic acid (HOAc) possesses the best catalytic performance,with CHOE conversion up to 99.1%.Meanwhile,the HOAc-catalytic effect has been confirmed for[2+2]photocycloaddition of other biomass-derived ketenes and olefins.The catalytic mechanism and dynamics have been investigated,and show that HOAc can bond with C=O groups of CHOE to form H–CHOE complex,which leads to higher light adsorption and longer triplet lifetime.Meanwhile,H–CHOE complex reduces the energy gap between CHOE LUMO and CPE HOMO,shortens the distance of ring-forming atoms,and then decreases the energy barrier (from 103.3 kcal mol^(-1)to 95.8 kcal mol^(-1)) of rate-limiting step.After hydrodeoxygenation,the targeted bio-spiral fuel shows high density of 0.992 g cm^(-3),high neat heat of combustion of 41.89 MJ L^(-1),low kinetic viscosity of 5.69 mm^(2)s^(-1)at 20℃,which is very promising to serve as high-performance aerospace fuel.
