PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can l...PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease.However,there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration.Additionally,PINK1 knockout pigs(Sus scrofa)do not appear to exhibit neurodegeneration.In our recent work involving non-human primates,we found that PINK1 is selectively expressed in primate brains,while absent in rodent brains.To extend this to other species,we used multiple antibodies to examine the expression of PINK1 in pig tissues.In contrast to tissues from cynomolgus monkeys(Macaca fascicularis),our data did not convincingly demonstrate detectable PINK1expression in pig tissues.Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation,as observed in cultured monkey cells.A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain.Consistently,PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD.These findings provide new evidence that PINK1expression is specific to primates,underscoring the importance of non-human primates in investigating PINK1function and pathology related to PINK1 deficiency.展开更多
AIM: To investigate clinical outcomes of chronic hepatitis B(CHB) and liver cirrhosis(LC) patients under whole-course management with lamivudine(LAM). METHODS: This was a retrospective-prospective cohort study based o...AIM: To investigate clinical outcomes of chronic hepatitis B(CHB) and liver cirrhosis(LC) patients under whole-course management with lamivudine(LAM). METHODS: This was a retrospective-prospective cohort study based on two nonrandom cohorts of Chinese patients(LAM group and history control group). Two hundred thirty-eight patients with LAM treatment for at least 12 mo under whole-course management were included in the LAM group. The management measures included regular follow-up and timely adjustment of the therapeutic regimen according to drug-resistance and relapse. Two hundred thirtyeight patients with CHB or LC without any antiviral treatment and with follow-up over 12 mo were included in the history control group. The LAM and control group patients were 1:1 matched by propensity score method to ensure both patients were similar in general datum,sex,age,E antigen,and diagnosis. The incidence rates of endpoint events [LC,hepatocellular carcinoma(HCC),and death] were compared between the LAM and control groups.RESULTS: Hepatitis B virus-DNA < 1000 copies per m L rate and rate of alanine transaminase < 1.3 of theupper normal limit in LAM and control groups were 89.1% vs 18.5%(P < 0.05) and 89.8% vs 31.1%(P < 0.05),respectively. Viral breakthrough occurred in 77 patients(32.4%); the one-,three-,and fiveyear cumulative rates were 6.8%,33.1%,and 41.3%,respectively. In total,44.5%(106/238) of patients had once stopped LAM,and 63(59.4%) of them developed virologic relapse; the relapse rate of patients with and without reaching Asian Pacific Association for the Study of the Liver endpoint criteria were 52.4% and 69.8%,respectively. Six CHB patients in the LAM group developed LC compared to 47 patients in the control group; the three-,and five-year cumulative rates of CHB at baseline of LAM were lower than those of the control group: 0.7% vs 12.0% and 1.8% vs 23.8%(P < 0.01),respectively. The incidence of HCC in CHB at baseline of LAM was lower than that of the control group; the three-,and five-year cumulative rates were 0% vs 3.2% and 1.1% vs 3.2%(P = 0.05),respectively. The incidence of HCC in LC at baseline of LAM was lower than that of the control group: 9.8%(5/51) vs 25.0%(12/48),and the three-,and five-year cumulative rates were 4.5% vs 20.7% and 8.1% vs 37.5%(P < 0.01),respectively. The mortality rate in the LAM group was lower than the control group. CONCLUSION: Standardized long-term LAM treatment in combination with comprehensive management can reduce the incidence rates of LC and HCC as well as hepatitis B virus-related deaths.展开更多
The contact sti ness of a mechanical bonding surface is an important parameter in determining the normal and radial contact force. To improve the calculation accuracy of the contact force model, the surface roughness ...The contact sti ness of a mechanical bonding surface is an important parameter in determining the normal and radial contact force. To improve the calculation accuracy of the contact force model, the surface roughness of the bonding surface and the energy loss that necessarily occurs during the impact process should be considered com?prehensively. To study the normal contact force of a revolute joint with clearance more accurately in the case of dry friction, a nonlinear sti ness coe cient model considering the surface roughness was established based on fractal theory, which considers the elastic, elastic?plastic, and plastic deformations of the asperities of the contact surface during the contact process. On this basis, a modified nonlinear spring damping model was established based on the Lankarani–Nikravesh contact force model. The laws influencing the surface roughness, recovery coe cient, initial velocity, and clearance size on the impact force were revealed, and were compared with the Lankarani–Nikravesh model and a hybrid model using MATLAB. The maximum impact force was obtained using a modified contact force model under di erent initial velocities, di erent clearances, and di erent degrees of surface roughness, and the calculated results were then compared with the experiment results. This study indicates that the modified model can be used more widely than other models, and is suitable for both large and small clearances. In particular, the modified model is more accurate when calculating the contact force of a revolute joint with a small clearance.展开更多
The development of stimuli-responsive theranostic platforms is of great demand for efficient cancer treatment because they can enhance diagnostic specificity and sensitivity.In this work,we report a p H-responsive the...The development of stimuli-responsive theranostic platforms is of great demand for efficient cancer treatment because they can enhance diagnostic specificity and sensitivity.In this work,we report a p H-responsive theranostic nanoplatform based on Fe OOH clusters loaded mesoporous silica nanoparticles(Fe@MSNs).The as-synthesized Fe@MSNs possess activatable T_1magnetic resonance imaging(MRI)performance that can respond to the acidic microenvironment of solid tumor to turn on T_1singals by releasing paramagnetic Fe^(3+)ions.The Fe@MSNs are biocompatible without appreciable cytotoxicity.Moreover,the unique mesoporous structure endows the Fe@MSNs with significant advantages to effectively deliver chemotherapeutic drug for inhibiting the growth of solid tumor.We believe that this novel p H-responsive theranostic nanoplatform holds great promise in cancer treatment.展开更多
The promising potential of photodynamic therapy （PDT） has fueled the development of minimally invasive therapeutic approaches for cancer therapy However, overcoming limitations in PDT efficacy in the hypoxic tumor e...The promising potential of photodynamic therapy （PDT） has fueled the development of minimally invasive therapeutic approaches for cancer therapy However, overcoming limitations in PDT efficacy in the hypoxic tumor environment and light penetration depth remains a challenge. We report the engineering of tungsten carbide nanopartides （W2C NPs） for 1,064 run laser-activated dual-type PDT and combined theranostics. The synthesized W2C NPs allow the robust generation of dual-type reactive oxygen species, including hydroxyl radicals （type I） and singlet oxygen （type II）, using only single 1,064 run laser activation, enabling effective PDT even in the hypoxic tumor environment. The W2C NPs also possess high photothermal performance under 1,064 nm laser irradiation, thus enabling synergistically enhanced cancer therapeutic efficacy of PDT and photothermal therapy. Additionally, the photoacoustic and X-ray computed tomography bioimaging properties of W2C NPs facilitate the integration of tumor diagnosis and therapy. The developed W2C based theranostic nanoagents increase the generation of reactive oxygen species in hypoxic tumors, improve the light penetration depth, and facilitate combined photothermal therapy and photoacoustic/computed tomography dual-mode bioimaging. These attributes could spur the exploration of transition metal carbides for advanced biomedical applications.展开更多
基金supported by the National Natural Science Foundation of China (32070534,32370567,82371874,81830032,31872779,82071421,81873736)Key Field Research and Development Program of Guangdong Province (2018B030337001)+3 种基金Guangzhou Key Research Program on Brain Science (202007030008)Department of Science and Technology of Guangdong Province (2021ZT09Y007,2020B121201006)Guangdong Basic and Applied Basic Research Foundation (2023B1515020031,2022A1515012301)Fundamental Research Funds for the Central Universities (Jinan University,21620358)。
文摘PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease.However,there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration.Additionally,PINK1 knockout pigs(Sus scrofa)do not appear to exhibit neurodegeneration.In our recent work involving non-human primates,we found that PINK1 is selectively expressed in primate brains,while absent in rodent brains.To extend this to other species,we used multiple antibodies to examine the expression of PINK1 in pig tissues.In contrast to tissues from cynomolgus monkeys(Macaca fascicularis),our data did not convincingly demonstrate detectable PINK1expression in pig tissues.Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation,as observed in cultured monkey cells.A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain.Consistently,PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD.These findings provide new evidence that PINK1expression is specific to primates,underscoring the importance of non-human primates in investigating PINK1function and pathology related to PINK1 deficiency.
基金Supported by the Natural Science Foundation of GuangxiNo.2014GXNSFDA118023
文摘AIM: To investigate clinical outcomes of chronic hepatitis B(CHB) and liver cirrhosis(LC) patients under whole-course management with lamivudine(LAM). METHODS: This was a retrospective-prospective cohort study based on two nonrandom cohorts of Chinese patients(LAM group and history control group). Two hundred thirty-eight patients with LAM treatment for at least 12 mo under whole-course management were included in the LAM group. The management measures included regular follow-up and timely adjustment of the therapeutic regimen according to drug-resistance and relapse. Two hundred thirtyeight patients with CHB or LC without any antiviral treatment and with follow-up over 12 mo were included in the history control group. The LAM and control group patients were 1:1 matched by propensity score method to ensure both patients were similar in general datum,sex,age,E antigen,and diagnosis. The incidence rates of endpoint events [LC,hepatocellular carcinoma(HCC),and death] were compared between the LAM and control groups.RESULTS: Hepatitis B virus-DNA < 1000 copies per m L rate and rate of alanine transaminase < 1.3 of theupper normal limit in LAM and control groups were 89.1% vs 18.5%(P < 0.05) and 89.8% vs 31.1%(P < 0.05),respectively. Viral breakthrough occurred in 77 patients(32.4%); the one-,three-,and fiveyear cumulative rates were 6.8%,33.1%,and 41.3%,respectively. In total,44.5%(106/238) of patients had once stopped LAM,and 63(59.4%) of them developed virologic relapse; the relapse rate of patients with and without reaching Asian Pacific Association for the Study of the Liver endpoint criteria were 52.4% and 69.8%,respectively. Six CHB patients in the LAM group developed LC compared to 47 patients in the control group; the three-,and five-year cumulative rates of CHB at baseline of LAM were lower than those of the control group: 0.7% vs 12.0% and 1.8% vs 23.8%(P < 0.01),respectively. The incidence of HCC in CHB at baseline of LAM was lower than that of the control group; the three-,and five-year cumulative rates were 0% vs 3.2% and 1.1% vs 3.2%(P = 0.05),respectively. The incidence of HCC in LC at baseline of LAM was lower than that of the control group: 9.8%(5/51) vs 25.0%(12/48),and the three-,and five-year cumulative rates were 4.5% vs 20.7% and 8.1% vs 37.5%(P < 0.01),respectively. The mortality rate in the LAM group was lower than the control group. CONCLUSION: Standardized long-term LAM treatment in combination with comprehensive management can reduce the incidence rates of LC and HCC as well as hepatitis B virus-related deaths.
基金Supported by National Natural Science Foundation of China(Grant No.51775475)Hebei Provincial Natural Science Foundation of China(Grant No.E2016203463)
文摘The contact sti ness of a mechanical bonding surface is an important parameter in determining the normal and radial contact force. To improve the calculation accuracy of the contact force model, the surface roughness of the bonding surface and the energy loss that necessarily occurs during the impact process should be considered com?prehensively. To study the normal contact force of a revolute joint with clearance more accurately in the case of dry friction, a nonlinear sti ness coe cient model considering the surface roughness was established based on fractal theory, which considers the elastic, elastic?plastic, and plastic deformations of the asperities of the contact surface during the contact process. On this basis, a modified nonlinear spring damping model was established based on the Lankarani–Nikravesh contact force model. The laws influencing the surface roughness, recovery coe cient, initial velocity, and clearance size on the impact force were revealed, and were compared with the Lankarani–Nikravesh model and a hybrid model using MATLAB. The maximum impact force was obtained using a modified contact force model under di erent initial velocities, di erent clearances, and di erent degrees of surface roughness, and the calculated results were then compared with the experiment results. This study indicates that the modified model can be used more widely than other models, and is suitable for both large and small clearances. In particular, the modified model is more accurate when calculating the contact force of a revolute joint with a small clearance.
基金supported by the National Natural Science Foundation of China (81501461, 21635002)the Open Research Fund for Expensive Instrument Testing of Fuzhou University (2017T026, 2017T028)
文摘The development of stimuli-responsive theranostic platforms is of great demand for efficient cancer treatment because they can enhance diagnostic specificity and sensitivity.In this work,we report a p H-responsive theranostic nanoplatform based on Fe OOH clusters loaded mesoporous silica nanoparticles(Fe@MSNs).The as-synthesized Fe@MSNs possess activatable T_1magnetic resonance imaging(MRI)performance that can respond to the acidic microenvironment of solid tumor to turn on T_1singals by releasing paramagnetic Fe^(3+)ions.The Fe@MSNs are biocompatible without appreciable cytotoxicity.Moreover,the unique mesoporous structure endows the Fe@MSNs with significant advantages to effectively deliver chemotherapeutic drug for inhibiting the growth of solid tumor.We believe that this novel p H-responsive theranostic nanoplatform holds great promise in cancer treatment.
文摘The promising potential of photodynamic therapy （PDT） has fueled the development of minimally invasive therapeutic approaches for cancer therapy However, overcoming limitations in PDT efficacy in the hypoxic tumor environment and light penetration depth remains a challenge. We report the engineering of tungsten carbide nanopartides （W2C NPs） for 1,064 run laser-activated dual-type PDT and combined theranostics. The synthesized W2C NPs allow the robust generation of dual-type reactive oxygen species, including hydroxyl radicals （type I） and singlet oxygen （type II）, using only single 1,064 run laser activation, enabling effective PDT even in the hypoxic tumor environment. The W2C NPs also possess high photothermal performance under 1,064 nm laser irradiation, thus enabling synergistically enhanced cancer therapeutic efficacy of PDT and photothermal therapy. Additionally, the photoacoustic and X-ray computed tomography bioimaging properties of W2C NPs facilitate the integration of tumor diagnosis and therapy. The developed W2C based theranostic nanoagents increase the generation of reactive oxygen species in hypoxic tumors, improve the light penetration depth, and facilitate combined photothermal therapy and photoacoustic/computed tomography dual-mode bioimaging. These attributes could spur the exploration of transition metal carbides for advanced biomedical applications.
