Intrinsic brain activity alterations in patients with Parkinson's disease.

OBJECTIVE:The objective of this study is to explore the brain activity alterations in Parkinson's disease (PD) from the perspectives of neuronal activity, synchronization of neuronal activity, and coordination of whole-brain activity.METHODS:In this study, we recruited 38 PD patients and 35 matched healthy controls (HCs). We explored intrinsic brain activity alterations in PD by comparing resting-state functional magnetic resonance imaging (rs-fMRI) metrics of the amplitude of low-frequency of fluctuation (ALFF), the fractional amplitude of low-frequency fluctuation (fALFF), percent amplitude of fluctuation (PerAF), regional homogeneity (ReHo), and degree centrality (DC). Two-sample t-tests were used to determine the differences between the two groups. Spearman correlation analysis was used to explore the relationships between abnormal ALFF, fALFF, PerAF, ReHo, and DC values and clinical indicators such as the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (H&Y) stage, and duration of disease.RESULTS:Compared with the HCs, PD had increased ALFF,fALFF, and PerAF in the temporal lobe and cerebellum, and decreased ALFF,fALFF, and PerAF in the occipital-parietal lobe in the neuronal activity. In the synchronization of neuronal activity, PD patients had increased ReHo in the right inferior parietal lobule and decreased ReHo in the caudate. In the coordination of whole-brain activity, PD patients had increased DC in the cerebellum and decreased DC in the occipital lobe. Correlation analysis showed that there is a correlation between abnormal brain regions and clinical indicators in PD. Notably, the changes in occipital lobe brain activity were found in ALFF, fALFF, PerAF, and DC, and were most correlated with the clinical indicators of PD patients.CONCLUSIONS:This study found that intrinsic brain function in several occipital-temporal-parietal and cerebellum regions was altered in PD patients, potentially related to the clinical indicators of PD. These results may enhance our understanding of the underlying neural mechanisms of PD and may contribute to further exploring the selection of therapeutic targets in PD patients.

DNMT1 determines osteosarcoma cell resistance to apoptosis by associatively modulating DNA and mRNA cytosine-5 methylation.

Cellular apoptosis is a central mechanism leveraged by chemotherapy to treat human cancers. 5-Methylcytosine (m5C) modifications installed on both DNA and mRNA are documented to regulate apoptosis independently. However, the interplay or crosstalk between them in cellular apoptosis has not yet been explored. Here, we reported that promoter methylation by DNMT1 coordinated with mRNA methylation by NSun2 to regulate osteosarcoma cell apoptosis. DNMT1 was induced during osteosarcoma cell apoptosis triggered by chemotherapeutic drugs, whereas NSun2 expression was suppressed. DNMT1 was found to repress NSun2 expression by methylating the NSun2 promoter. Moreover, DNMT1 and NSun2 regulate the anti-apoptotic genes AXL, NOTCH2, and YAP1 through DNA and mRNA methylation, respectively. Upon exposure to cisplatin or doxorubicin, DNMT1 elevation drastically reduced the expression of these anti-apoptotic genes via enhanced promoter methylation coupled with NSun2 ablation-mediated attenuation of mRNA methylation, thus rendering osteosarcoma cells to apoptosis. Collectively, our findings establish crosstalk of importance between DNA and RNA cytosine methylations in determining osteosarcoma resistance to apoptosis during chemotherapy, shedding new light on future treatment of osteosarcoma, and adding additional layers to the control of gene expression at different epigenetic levels.

Dasabuvir suppresses esophageal squamous cell carcinoma growth in vitro and in vivo through targeting ROCK1.

Esophageal squamous cell carcinoma (ESCC) is an upper gastrointestinal cancer with high morbidity and mortality. New strategies are urgently needed to prolong patients' survival. Through screening FDA-approved drugs, we found dasabuvir, a drug approved for hepatitis C virus (HCV) treatment, suppressed ESCC proliferation. Dasabuvir could inhibit the growth of ESCC cells in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was further validated in vivo using patient-derived xenograft tumor models. In terms of mechanism, we unveil that dasabuvir is a Rho-associated protein kinase 1 (ROCK1) inhibitor. Dasabuvir can bind to ROCK1 and suppress its kinase activity, thus downregulating the phosphorylation of ERK1/2 by ROCK1 and the expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1. These results provide evidence that dasabuvir suppresses ESCC growth in vivo and in vitro through blocking ROCK1/ERK signaling pathway.

Osthole protects H9c2 cardiomyocytes against trastuzumab-induced damage by enhancing autophagy through the p38MAPK/mTOR signaling pathway.

Trastuzumab (TRZ) is a novel targeted anti-tumor agent that significantly improve the survival of patients with human epidermal growth factor receptor (HER2) positive breast cancer. However, its clinical application is limited due to the side effects of cardiotoxicity. Osthole (OST), a coumarin derivative isolated from Cnidium monnieri (L.) Cusson, has previously demonstrated cardioprotective effects. The aim of this study was to observe the protective effect of OST on TRZ-induced cardiomyocytes damage and to explore its potential mechanism. The results showed that OST pretreatment could significantly inhibit TRZ-induced cardiomyocytes damage, markedly increase the ratio of LC3II/I and Beclin-1 protein expression, and reduce the protein expression of p62. OST pretreatment significantly attenuated oxidative stress and apoptosis induced by TRZ, as evidenced by reducing intracellular ROS level, the Bax/Bcl-2 ratio, and Caspase-3 protein expression. Additionally, OST markedly increased the phosphorylation level of p38MAPK and decreased the mTOR phosphorylation level. However, the effects of OST on enhancing autophagy, reducing oxidative stress, apoptosis, and the phosphorylation level of mTOR were reversed after the addition of 3-MA or SB203580. Molecular docking results indicated that OST exerted a good binding ability with the p38MAPK protein. Our findings suggested that OST could protect TRZ-induced cardiomyocytes damage by enhancing autophagy via the p38MAPK/mTOR signaling pathway.

Preliminary Study of Genome-Wide Association Identified Novel Susceptibility Genes for Hemorheological Indexes in a Chinese Population.

Background:Genome-wide association studies for various hemorheological characteristics have not been reported. We aimed to identify genetic loci associated with hemorheological indexes in a cohort of healthy Chinese Han individuals.Methods:Genotyping was performed using Applied Biosystems Axiom™ Precision Medicine Diversity Array in 838 individuals, and 6,423,076 single nucleotide polymorphisms were available for genotyping. The relations were examined in an additive genetic model using mixed linear regression and combined with identical by descent matrix.Results:We identified 38 genetic loci (p < 5 × 10-6) related to hemorheological traits. In which, LOC102724502-OLIG2 rs28371438 was related to the levels of nd30 (p = 8.58 × 10-07), nd300 (p = 1.89 × 10-06), erythrocyte rigidity (p = 1.29 × 10-06), assigned viscosity (p = 6.20 × 10-08) and whole blood high cut relative (p = 7.30 × 10-08). The association of STK32B rs4689231 for nd30 (p = 3.85 × 10-06) and nd300 (p = 2.94 × 10-06) and GTSCR1-LINC01541 rs11661911 for erythrocyte rigidity (p = 9.93 × 10-09) and whole blood high cut relative (p = 2.09 × 10-07) was found. USP25-MIR99AHG rs1297329 was associated with erythrocyte rigidity (p = 1.81 × 10-06) and erythrocyte deformation (p = 1.14 × 10-06). Moreover, the association of TMEM232-SLC25A46 rs3985087 and LINC00470-METTL4 rs9966987 for fibrinogen (p = 1.31 × 10-06 and p = 4.29 × 10-07) and plasma viscosity (p = 1.01 × 10-06 and p = 4.59 × 10-07) was found.Conclusion:These findings may represent biological candidates for hemorheological indexes and contribute to hemorheological study.

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy.

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

Contingency Measures During the COVID-19 Pandemic in China: An Analysis Based on a New Ethical Framework.

Effect of different reconstruction algorithms on coronary artery calcium scores using the reduced radiation dose protocol: a clinical and phantom study.

BACKGROUND:This study aimed to evaluate the effects of different iterative reconstruction (IR) algorithms on coronary artery calcium (CAC) score quantification using the reduced radiation dose (RRD) protocol in an anthropomorphic phantom and in patients.METHODS:A thorax phantom, containing 9 calcification inserts with varying hydroxyapatite (HA) densities, was scanned with the reference protocol [120 kv, 80 mAs, filtered back projection (FBP)] and RRD protocol (120 kV, 20-80 mAs, 5 mAs interval) using a 256-slice computed tomography (CT) scanner. Raw data were reconstructed with different reconstruction algorithms [iDose4 levels 1-7 and iterative model reconstruction (IMR) levels 1-3]. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and Agatston score (AS) were calculated for each image series. The correction factor was derived from linear regression analysis between the reference image series and other image series with different parameters. Additionally, 40 patients were scanned with the RRD protocol (50 mAs) and reconstructed with FBP, iDose4 level 4, and IMR level 2. AS was calculated for the 3-group image series, and was corrected by applying a correction factor for the IMR group. The agreement of risk stratification with different reconstruction algorithms was also analyzed.RESULTS:For the phantom study, the iDose4 and IMR groups had significantly higher SNR and CNR than the FBP group (all P<0.05). There were no significant differences in the total AS after comparing image series reconstructed with iDose4 (level 1-7) and FBP (all P>0.05), while AS from the IMR (level 1-3) image series were lower than the FBP group (all P<0.05). The tube current of 50 mAs was determined for the clinical study, and the correction factor was 1.14. For the clinical study, the median AS from the iDose4 and IMR groups were both significantly lower compared to the FBP image series [(112.89 (63.01, 314.09), 113.22 (64.78, 364.95) vs. 118.59 (65.05, 374.48), both P<0.05]. After applying the correction factor, the adjusted AS from the IMR group was not significantly different from that of the FBP group [126.48 (69.62, 355.85) vs. 118.59 (65.05, 374.48), P=0.145]. Moreover, the agreement in risk stratification between FBP and IMR improved from 0.81 to 0.85.CONCLUSIONS:The RRD CAC scoring scan using the IMR reconstruction algorithm is clinically feasible, and a correction factor can help reduce the AS underestimation effect.

What Can We Learn from COVID-19 Drug Development and Access for Non-Pandemic Diseases? A Chinese Perspective.

Artificial Intelligence, Social Media, and Suicide Prevention: Principle of Beneficence Besides Respect for Autonomy.

Intrinsic brain activity alterations in patients with Parkinson's disease.

OBJECTIVE:The objective of this study is to explore the brain activity alterations in Parkinson's disease (PD) from the perspectives of neuronal activity, synchronization of neuronal activity, and coordination of whole-brain activity.METHODS:In this study, we recruited 38 PD patients and 35 matched healthy controls (HCs). We explored intrinsic brain activity alterations in PD by comparing resting-state functional magnetic resonance imaging (rs-fMRI) metrics of the amplitude of low-frequency of fluctuation (ALFF), the fractional amplitude of low-frequency fluctuation (fALFF), percent amplitude of fluctuation (PerAF), regional homogeneity (ReHo), and degree centrality (DC). Two-sample t-tests were used to determine the differences between the two groups. Spearman correlation analysis was used to explore the relationships between abnormal ALFF, fALFF, PerAF, ReHo, and DC values and clinical indicators such as the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (H&Y) stage, and duration of disease.RESULTS:Compared with the HCs, PD had increased ALFF,fALFF, and PerAF in the temporal lobe and cerebellum, and decreased ALFF,fALFF, and PerAF in the occipital-parietal lobe in the neuronal activity. In the synchronization of neuronal activity, PD patients had increased ReHo in the right inferior parietal lobule and decreased ReHo in the caudate. In the coordination of whole-brain activity, PD patients had increased DC in the cerebellum and decreased DC in the occipital lobe. Correlation analysis showed that there is a correlation between abnormal brain regions and clinical indicators in PD. Notably, the changes in occipital lobe brain activity were found in ALFF, fALFF, PerAF, and DC, and were most correlated with the clinical indicators of PD patients.CONCLUSIONS:This study found that intrinsic brain function in several occipital-temporal-parietal and cerebellum regions was altered in PD patients, potentially related to the clinical indicators of PD. These results may enhance our understanding of the underlying neural mechanisms of PD and may contribute to further exploring the selection of therapeutic targets in PD patients.

DNMT1 determines osteosarcoma cell resistance to apoptosis by associatively modulating DNA and mRNA cytosine-5 methylation.

Cellular apoptosis is a central mechanism leveraged by chemotherapy to treat human cancers. 5-Methylcytosine (m5C) modifications installed on both DNA and mRNA are documented to regulate apoptosis independently. However, the interplay or crosstalk between them in cellular apoptosis has not yet been explored. Here, we reported that promoter methylation by DNMT1 coordinated with mRNA methylation by NSun2 to regulate osteosarcoma cell apoptosis. DNMT1 was induced during osteosarcoma cell apoptosis triggered by chemotherapeutic drugs, whereas NSun2 expression was suppressed. DNMT1 was found to repress NSun2 expression by methylating the NSun2 promoter. Moreover, DNMT1 and NSun2 regulate the anti-apoptotic genes AXL, NOTCH2, and YAP1 through DNA and mRNA methylation, respectively. Upon exposure to cisplatin or doxorubicin, DNMT1 elevation drastically reduced the expression of these anti-apoptotic genes via enhanced promoter methylation coupled with NSun2 ablation-mediated attenuation of mRNA methylation, thus rendering osteosarcoma cells to apoptosis. Collectively, our findings establish crosstalk of importance between DNA and RNA cytosine methylations in determining osteosarcoma resistance to apoptosis during chemotherapy, shedding new light on future treatment of osteosarcoma, and adding additional layers to the control of gene expression at different epigenetic levels.

Dasabuvir suppresses esophageal squamous cell carcinoma growth in vitro and in vivo through targeting ROCK1.

Esophageal squamous cell carcinoma (ESCC) is an upper gastrointestinal cancer with high morbidity and mortality. New strategies are urgently needed to prolong patients' survival. Through screening FDA-approved drugs, we found dasabuvir, a drug approved for hepatitis C virus (HCV) treatment, suppressed ESCC proliferation. Dasabuvir could inhibit the growth of ESCC cells in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was further validated in vivo using patient-derived xenograft tumor models. In terms of mechanism, we unveil that dasabuvir is a Rho-associated protein kinase 1 (ROCK1) inhibitor. Dasabuvir can bind to ROCK1 and suppress its kinase activity, thus downregulating the phosphorylation of ERK1/2 by ROCK1 and the expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1. These results provide evidence that dasabuvir suppresses ESCC growth in vivo and in vitro through blocking ROCK1/ERK signaling pathway.

Osthole protects H9c2 cardiomyocytes against trastuzumab-induced damage by enhancing autophagy through the p38MAPK/mTOR signaling pathway.

Trastuzumab (TRZ) is a novel targeted anti-tumor agent that significantly improve the survival of patients with human epidermal growth factor receptor (HER2) positive breast cancer. However, its clinical application is limited due to the side effects of cardiotoxicity. Osthole (OST), a coumarin derivative isolated from Cnidium monnieri (L.) Cusson, has previously demonstrated cardioprotective effects. The aim of this study was to observe the protective effect of OST on TRZ-induced cardiomyocytes damage and to explore its potential mechanism. The results showed that OST pretreatment could significantly inhibit TRZ-induced cardiomyocytes damage, markedly increase the ratio of LC3II/I and Beclin-1 protein expression, and reduce the protein expression of p62. OST pretreatment significantly attenuated oxidative stress and apoptosis induced by TRZ, as evidenced by reducing intracellular ROS level, the Bax/Bcl-2 ratio, and Caspase-3 protein expression. Additionally, OST markedly increased the phosphorylation level of p38MAPK and decreased the mTOR phosphorylation level. However, the effects of OST on enhancing autophagy, reducing oxidative stress, apoptosis, and the phosphorylation level of mTOR were reversed after the addition of 3-MA or SB203580. Molecular docking results indicated that OST exerted a good binding ability with the p38MAPK protein. Our findings suggested that OST could protect TRZ-induced cardiomyocytes damage by enhancing autophagy via the p38MAPK/mTOR signaling pathway.

Preliminary Study of Genome-Wide Association Identified Novel Susceptibility Genes for Hemorheological Indexes in a Chinese Population.

Background:Genome-wide association studies for various hemorheological characteristics have not been reported. We aimed to identify genetic loci associated with hemorheological indexes in a cohort of healthy Chinese Han individuals.Methods:Genotyping was performed using Applied Biosystems Axiom™ Precision Medicine Diversity Array in 838 individuals, and 6,423,076 single nucleotide polymorphisms were available for genotyping. The relations were examined in an additive genetic model using mixed linear regression and combined with identical by descent matrix.Results:We identified 38 genetic loci (p < 5 × 10-6) related to hemorheological traits. In which, LOC102724502-OLIG2 rs28371438 was related to the levels of nd30 (p = 8.58 × 10-07), nd300 (p = 1.89 × 10-06), erythrocyte rigidity (p = 1.29 × 10-06), assigned viscosity (p = 6.20 × 10-08) and whole blood high cut relative (p = 7.30 × 10-08). The association of STK32B rs4689231 for nd30 (p = 3.85 × 10-06) and nd300 (p = 2.94 × 10-06) and GTSCR1-LINC01541 rs11661911 for erythrocyte rigidity (p = 9.93 × 10-09) and whole blood high cut relative (p = 2.09 × 10-07) was found. USP25-MIR99AHG rs1297329 was associated with erythrocyte rigidity (p = 1.81 × 10-06) and erythrocyte deformation (p = 1.14 × 10-06). Moreover, the association of TMEM232-SLC25A46 rs3985087 and LINC00470-METTL4 rs9966987 for fibrinogen (p = 1.31 × 10-06 and p = 4.29 × 10-07) and plasma viscosity (p = 1.01 × 10-06 and p = 4.59 × 10-07) was found.Conclusion:These findings may represent biological candidates for hemorheological indexes and contribute to hemorheological study.

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy.

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

Contingency Measures During the COVID-19 Pandemic in China: An Analysis Based on a New Ethical Framework.

Effect of different reconstruction algorithms on coronary artery calcium scores using the reduced radiation dose protocol: a clinical and phantom study.

BACKGROUND:This study aimed to evaluate the effects of different iterative reconstruction (IR) algorithms on coronary artery calcium (CAC) score quantification using the reduced radiation dose (RRD) protocol in an anthropomorphic phantom and in patients.METHODS:A thorax phantom, containing 9 calcification inserts with varying hydroxyapatite (HA) densities, was scanned with the reference protocol [120 kv, 80 mAs, filtered back projection (FBP)] and RRD protocol (120 kV, 20-80 mAs, 5 mAs interval) using a 256-slice computed tomography (CT) scanner. Raw data were reconstructed with different reconstruction algorithms [iDose4 levels 1-7 and iterative model reconstruction (IMR) levels 1-3]. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and Agatston score (AS) were calculated for each image series. The correction factor was derived from linear regression analysis between the reference image series and other image series with different parameters. Additionally, 40 patients were scanned with the RRD protocol (50 mAs) and reconstructed with FBP, iDose4 level 4, and IMR level 2. AS was calculated for the 3-group image series, and was corrected by applying a correction factor for the IMR group. The agreement of risk stratification with different reconstruction algorithms was also analyzed.RESULTS:For the phantom study, the iDose4 and IMR groups had significantly higher SNR and CNR than the FBP group (all P<0.05). There were no significant differences in the total AS after comparing image series reconstructed with iDose4 (level 1-7) and FBP (all P>0.05), while AS from the IMR (level 1-3) image series were lower than the FBP group (all P<0.05). The tube current of 50 mAs was determined for the clinical study, and the correction factor was 1.14. For the clinical study, the median AS from the iDose4 and IMR groups were both significantly lower compared to the FBP image series [(112.89 (63.01, 314.09), 113.22 (64.78, 364.95) vs. 118.59 (65.05, 374.48), both P<0.05]. After applying the correction factor, the adjusted AS from the IMR group was not significantly different from that of the FBP group [126.48 (69.62, 355.85) vs. 118.59 (65.05, 374.48), P=0.145]. Moreover, the agreement in risk stratification between FBP and IMR improved from 0.81 to 0.85.CONCLUSIONS:The RRD CAC scoring scan using the IMR reconstruction algorithm is clinically feasible, and a correction factor can help reduce the AS underestimation effect.

What Can We Learn from COVID-19 Drug Development and Access for Non-Pandemic Diseases? A Chinese Perspective.

Artificial Intelligence, Social Media, and Suicide Prevention: Principle of Beneficence Besides Respect for Autonomy.