Every year, around the world, between 250,000 and 500,000 people suffer a spinal cord injury(SCI). SCI is a devastating medical condition that arises from trauma or disease-induced damage to the spinal cord, disruptin...Every year, around the world, between 250,000 and 500,000 people suffer a spinal cord injury(SCI). SCI is a devastating medical condition that arises from trauma or disease-induced damage to the spinal cord, disrupting the neural connections that allow communication between the brain and the rest of the body, which results in varying degrees of motor and sensory impairment. Disconnection in the spinal tracts is an irreversible condition owing to the poor capacity for spontaneous axonal regeneration in the affected neurons.展开更多
During the use of robotics in applications such as antiterrorism or combat,a motion-constrained pursuer vehicle,such as a Dubins unmanned surface vehicle(USV),must get close enough(within a prescribed zero or positive...During the use of robotics in applications such as antiterrorism or combat,a motion-constrained pursuer vehicle,such as a Dubins unmanned surface vehicle(USV),must get close enough(within a prescribed zero or positive distance)to a moving target as quickly as possible,resulting in the extended minimum-time intercept problem(EMTIP).Existing research has primarily focused on the zero-distance intercept problem,MTIP,establishing the necessary or sufficient conditions for MTIP optimality,and utilizing analytic algorithms,such as root-finding algorithms,to calculate the optimal solutions.However,these approaches depend heavily on the properties of the analytic algorithm,making them inapplicable when problem settings change,such as in the case of a positive effective range or complicated target motions outside uniform rectilinear motion.In this study,an approach employing a high-accuracy and quality-guaranteed mixed-integer piecewise-linear program(QG-PWL)is proposed for the EMTIP.This program can accommodate different effective interception ranges and complicated target motions(variable velocity or complicated trajectories).The high accuracy and quality guarantees of QG-PWL originate from elegant strategies such as piecewise linearization and other developed operation strategies.The approximate error in the intercept path length is proved to be bounded to h^(2)/(4√2),where h is the piecewise length.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in th...BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a ...BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.展开更多
Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells c...Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells could be generated from adult mouse fibroblasts is powerful proof that cell fate can be changed.An exciting extension of the discovery of cell fate impermanence is the direct cellular reprogram ming hypothesis-that terminally differentiated cells can be reprogrammed into other adult cell fates without first passing through a stem cell state.展开更多
The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functio...The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.展开更多
基金financially supported by Ministerio de Ciencia e Innovación projects SAF2017-82736-C2-1-R to MTMFin Universidad Autónoma de Madrid and by Fundación Universidad Francisco de Vitoria to JS+2 种基金a predoctoral scholarship from Fundación Universidad Francisco de Vitoriafinancial support from a 6-month contract from Universidad Autónoma de Madrida 3-month contract from the School of Medicine of Universidad Francisco de Vitoria。
文摘Every year, around the world, between 250,000 and 500,000 people suffer a spinal cord injury(SCI). SCI is a devastating medical condition that arises from trauma or disease-induced damage to the spinal cord, disrupting the neural connections that allow communication between the brain and the rest of the body, which results in varying degrees of motor and sensory impairment. Disconnection in the spinal tracts is an irreversible condition owing to the poor capacity for spontaneous axonal regeneration in the affected neurons.
基金supported by the National Natural Sci‐ence Foundation of China(Grant No.62306325)。
文摘During the use of robotics in applications such as antiterrorism or combat,a motion-constrained pursuer vehicle,such as a Dubins unmanned surface vehicle(USV),must get close enough(within a prescribed zero or positive distance)to a moving target as quickly as possible,resulting in the extended minimum-time intercept problem(EMTIP).Existing research has primarily focused on the zero-distance intercept problem,MTIP,establishing the necessary or sufficient conditions for MTIP optimality,and utilizing analytic algorithms,such as root-finding algorithms,to calculate the optimal solutions.However,these approaches depend heavily on the properties of the analytic algorithm,making them inapplicable when problem settings change,such as in the case of a positive effective range or complicated target motions outside uniform rectilinear motion.In this study,an approach employing a high-accuracy and quality-guaranteed mixed-integer piecewise-linear program(QG-PWL)is proposed for the EMTIP.This program can accommodate different effective interception ranges and complicated target motions(variable velocity or complicated trajectories).The high accuracy and quality guarantees of QG-PWL originate from elegant strategies such as piecewise linearization and other developed operation strategies.The approximate error in the intercept path length is proved to be bounded to h^(2)/(4√2),where h is the piecewise length.
基金Supported by the Natural Science Foundation of Gansu Province,No.21JR7RA373 and No.24JRRA295.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
基金supported by Canada First Research Excellence Fund,Medicine by Design(to CMM)。
文摘Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells could be generated from adult mouse fibroblasts is powerful proof that cell fate can be changed.An exciting extension of the discovery of cell fate impermanence is the direct cellular reprogram ming hypothesis-that terminally differentiated cells can be reprogrammed into other adult cell fates without first passing through a stem cell state.
基金supported by National Institute on Aging(NIH-NIA)R21 AG074152(to KMA)National Institute of Allergy and Infectious Diseases(NIAID)grant DP2 AI171150(to KMA)Department of Defense(DoD)grant AZ210089(to KMA)。
文摘The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.
