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BackgroundThe pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is complex and multifactorial, with growing evidence indicating the involvement of hematologic disorders. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with increased risks of both hematologic malignancies and cardiovascular diseases. The CHIP in patients with CTEPH and its clinical relevance remain undetermined.MethodsWe performed a step-wise calling method on the next-generation sequencing data from 499 CTEPH patients referred to three centers between October 2006 and December 2021 to identify CHIP mutations. We associated CHIP with all-cause mortality in patients with CTEPH. To provide potential mechanistic insights, the associations between CHIP and inflammation characteristics reflected by circulating cytokines and IgG galactosylation, a hallmark of inflammatory state in diseases were also determined.ResultsTotal 51 (10.2%) patients with CTEPH carried at least one CHIP mutation at a variant allele frequency of ≥ 2%, and the most common mutations were amongDNMT3A,RUN1andSTAG2. During a mean follow-up time of 55 months, deaths occurred in 21 patients (42.9%) in the CHIP group and 105 patients (24.3%) in the non-CHIP group, contributing to the 5-year survival rate of 65.3% in the CHIP group and 81.9% in the non-CHIP group (P< 0.001 for log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (HR: 3.447; 95% CI: 1.747 – 6.803;P< 0.001). Besides, patients in the CHIP group showed higher circulating IL-1beta and IL-6 and lower IL-4 and IgG galactosylation compared with the non-CHIP group.ConclusionsCHIP is enriched in CTEPH patients and is associated with a worse prognosis in CTEPH. Mechanically, patients in the CHIP group showed a more severe inflammatory state.Clinical PerspectiveWhat is new?Clonal hematopoiesis of indeterminate potential (CHIP) mutations are enriched in chronic thromboembolic pulmonary hypertension (CTEPH) patients, with most common mutated genes beingDNMT3A,RUN1andSTAG2.CHIP is associated with worse clinical outcomes in CTEPH.CHIP is associated with more severe inflammation state mediated by myeloid as well as lymphoid cells in patients with CTEPH.What are the clinical implications?CHIP might be a risk factor for CTEPH, suggesting a relationship between CTEPH and hematopoietic disorders.CHIP represented an additional disease component in CTEPH that independently impacts prognosis.CHIP might be a potential target for personalized medicine and an indicator of benefit from anti-inflammatory therapies for CTEPH patients.

Background Subendocardial late gadolinium enhancement (LGE) detected with cardiac MRI in myocarditis represents a diagnostic dilemma, since it may resemble myocardial ischemia. Purpose To explore and compare the histopathologic characteristics and clinical features and outcomes in patients with myocarditis with and without subendocardial involvement at cardiac MRI. Materials and Methods This retrospective study evaluated 39 patients with myocarditis pathologically proven by means of either endomyocardial biopsy or explant pathologic findings between 2015 and 2020. Patients were divided into two groups according to cardiac MRI phenotype: 18 with subendocardial involvement (mean age ± standard deviation, 40 years ± 17; 10 women) and 21 with no subendocardial involvement (mean age, 35 years ± 11; six women). The median follow-up period was 784 days (interquartile range [IQR], 90-1123 days). The Student t test, Mann-Whitney U test, and univariable Cox regression were used for statistical analyses. Results In the 18 patients with subendocardial involvement, 12 (67%) had lymphocytic myocarditis and six (33%) had giant cell myocarditis. Patients with subendocardial involvement compared with those without subendocardial involvement had lower left ventricular ejection fraction (mean ± standard deviation, 27% ± 11 vs 41% ± 19; P = .004), larger LGE extent (median, 13% [IQR, 10%-22%] vs 5% [IQR, 2%-17%]; P < .001), higher rates of cardiac death or transplant (eight of 18 patients [44%] vs one of 21 patients [4.8%]; P = .006), higher probability of giant cell myocarditis (six of 18 [33%] vs one of 21 [4.8%]; P = .02), and more major adverse cardiovascular events (MACE) (15 of 18 [83%] vs seven of 21 [33%]; P = .002). In a subgroup of patients with comparable LGE extent (median, 15% vs 16%; P = .40) and left ventricular ejection fraction (median, 27% vs 31%; P = .26), the prognostic difference in terms of MACE remained (15 of 17 patients [88%] vs five of 10 [50%]; P = .02). Conclusion Subendocardial involvement detected with cardiac MRI in myocarditis indicated more severe clinical features, including a higher frequency of severe lymphocytic myocarditis or giant cell myocarditis and worse prognosis. © RSNA, 2021 See also the editorial by de Roos in this issue.

Detection and accurate delineation of tumor is important for the management of head and neck squamous cell carcinoma (HNSCC) but is challenging with current imaging techniques. In this study, we evaluated whether molecular immuno-imaging targeting myeloperoxidase (MPO) activity, an oxidative enzyme secreted by many myeloid innate immune cells, would be superior in detecting tumor extent compared to conventional contrast agent (DTPA-Gd) in a carcinogen-induced immunocompetent HNSCC murine model and corroborated in human surgical specimens. In C57BL/6 mice given 4-nitroquinoline-N-oxide (4-NQO), there was increased MPO activity in the head and neck region as detected by luminol bioluminescence compared to that of the control group. On magnetic resonance imaging, the mean enhancing volume detected by the MPO-targeting agent (MPO-Gd) was higher than that by the conventional agent DTPA-Gd. The tumor volume detected by MPO-Gd strongly correlated with tumor size on histology, and higher MPO-Gd signal corresponded to larger tumor size found by imaging and histology. On the contrary, the tumor volume detected by DTPA-Gd did not correlate as well with tumor size on histology. Importantly, MPO-Gd imaging detected areas not visualized with DTPA-Gd imaging that were confirmed histopathologically to represent early tumor. In human specimens, MPO was similarly associated with tumors, especially at the tumor margins. Thus, molecular immuno-imaging targeting MPO not only detects oxidative immune response in HNSCC, but can better detect and delineate tumor extent than nonselective imaging agents. Thus, our findings revealed that MPO imaging could improve tumor resection as well as be a useful imaging biomarker for tumor progression, and potentially improve clinical management of HNSCC once translated.

DNA topoisomerase II alpha (TOP2A) reportedly plays a crucial role in several cancers, however, the precise regulatory role of TOP2A in metastatic characteristics of glioma is still poorly understood. Herein, we sought to elucidate the mechanisms by which TOP2A affects the metastatic phenotypes of glioma. We observed that a high level of TOP2A expression was dramatically linked with inferior survival in glioma patients while silencing of TOP2A impaired glioma cell proliferation and aggressiveness. TOP2A was found to directly interact with β-catenin and facilitated its translocation into the nucleus. Mechanistically, TOP2A effectively induced glioma cell growth and invasion in a β-catenin-dependent manner. Overall, we pinpoint TOP2A as a critical activator of the Wnt/β-catenin pathway in glioma, promoting cell growth, migration, and invasion.

Background Despite advances in immunomodulatory agents, most current therapies for multiple sclerosis target lymphocytes or lymphocytic function. However, therapy response may be less than optimal due to demyelination and axonal damage caused by myeloid cells. Purpose To determine if myeloperoxidase (MPO) molecular MRI can evaluate whether combination therapy targeting both lymphoid and myeloid inflammation can improve autoimmune neuroinflammation compared with either drug alone, even at suboptimal doses. Materials and Methods Four groups of 94 female mice (8-10 weeks old) were induced with experimental autoimmune encephalomyelitis (EAE) from August 2, 2016, to March 30, 2018, and divided into saline control (n = 22), 4-aminobenzoic acid hydrazide (ABAH) therapy group (n = 19), glatiramer acetate (GA) therapy group (n = 22), and combination therapy group (n = 31). Mice were administered suboptimal doses of ABAH, an irreversible inhibitor of MPO; GA, a first-line multiple sclerosis drug; both ABAH and GA; or saline (control). Mice were imaged with bis-5-hydroxytryptamide-diethylenetriaminepentaacetate gadolinium (hereafter, MPO-Gd) MRI. One-way analysis of variance, two-way analysis of variance, Kurskal-Wallis, and log-rank tests were used. P < .05 was considered to indicate statistical significance. Results The combination-treated group showed delayed disease onset (day 11.3 vs day 9.8 for ABAH, day 10.4 for GA, day 9.9 for control; P < .05) and reduced disease severity (clinical score during the acute exacerbation period of 1.8 vs 3.8 for ABAH, 3.1 for GA, 3.9 for control; P < .05). The combination-treated group demonstrated fewer MPO-positive lesions (30.2 vs 73.7 for ABAH, 64.8 for GA, 67.2 for control; P < .05), smaller MPO-positive lesion volume (16.7 mm3 vs 65.2 mm3 for ABAH, 69.9 mm3 for GA, 66.0 mm3 for control; P < .05), and lower intensity of MPO-Gd lesion activation ratio (0.7 vs 1.9 for ABAH, 3.2 for GA, 2.3 for control; P < .05). Reduced disease severity in the combination group was confirmed at histopathologic analysis, where MPO expression (1779 vs 2673 for ABAH, 2898 for GA; P < .05) and demyelination (5.3% vs 9.0% for ABAH, 10.6% for GA; P < .05) were ameliorated. Conclusion Myeloperoxidase molecular MRI can track the treatment response from immunomodulatory drugs even if the drug does not directly target myeloperoxidase, and establishes that combination therapy targeting both myeloid and lymphocytic inflammation is effective for murine autoimmune neuroinflammation, even at suboptimal doses. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Walczak in this issue.

Recent exploration revealed a number of rare earth element (REE) deposits that are distributed along the Qinling Orogenic Belt, Central China. These deposits have an estimated total reserve of about 2 Mt. REE2O3, thus making this belt a world-class REE metallogenic province. Understanding the metallogenesis of the belt requires direct dating of REE minerals. In this study, LA-ICP-MS U-Th-Pb dating on bastnasite and monazite from the Huangshuian, Taipingzhen, and Miaoya deposits in different units of the belt was used to precisely determine the timing of the REE mineralization. The Huangshuian deposit in the north is a carbonatite-related Mo-(REE) deposit in which the REE minerals are closely associated with molybdenite. After correction for common Pb and excessed 206Pb decayed from 230Th, a weighted average 206Pb/238U age of 207 ± 4 Ma (n = 17; MSWD = 1.9) is obtained for bastnasite grains from this deposit. Such an age is slightly younger than that of the final collision (peak at 230–220 Ma) of the Qinling Orogenic Belt, thus indicating that the Mo-REE mineralization is likely related to a post-collisional extension setting. The Taipingzhen REE deposit in the middle contains sheet-like ore bodies composed of veins where bastnasite, the dominant REE mineral, is closely associated with quartz, fluorite, and barite. In situ bastnasite U-Th-Pb dating shows that the REE mineralization in this deposit has formed at 421 ± 7 Ma (n = 17; MSWD = 1.5), synchronous with extension-related magmatism in the region. The Miaoya deposit in the south is the largest one in the belt, and it is essentially a REE-mineralized syenite-carbonatite complex. In this deposit, the monazite grains are closely associated with major minerals of the syenites or carbonatites (e.g., K-feldspar or calcite), but commonly exhibit complex internal textures. Different domains of monazite yield two groups of U-Pb ages at 414 ± 11 Ma (n = 5; MSWD = 0.91) and 231 ± 2 Ma (n = 21; MSWD = 3.1), whereas the bastnasite has an age of 206 ± 4 Ma (n = 14; MSWD = 1.5). The early age of 414 Ma is obtained from homogenous monazite grains and in good agreement with zircon U-Pb ages of the Miaoya syenite-carbonatite complex, and thus is considered to represent the timing of the major REE mineralization in the deposit. The younger ages of 231–206 Ma are obtained from monazite grains with complex internal textures and bastnasite in late veinlets, thus recording secondary, consecutive REE remobilization events likely related to the compression process during formation of the Qinling Orogenic Belt. Our new U-Th-Pb ages, in combination with previously geochronological data, demonstrate that there are two episodes of REE mineralization at 440–410 Ma and 220–200 Ma in the Qinling Orogenic Belt.

Microglia activation and its mediated production of proinflammatory mediators play important roles in different neurodegenerative diseases; hence, modulation of microglia activation has been considered a potential therapeutic strategy to ameliorate neurodegeneration. This study was aimed to determine whether Gastrodin, a common herbal agent known to possess neuroprotective property, can attenuate production of proinflammatory mediators in activated microglia through the renin-angiotensin system (RAS) and Sirtuin3 (SIRT3). Expression of various members of the RAS including ACE, AT1, AT2, and SIRT3 in activated microglia was assessed by immunofluorescence and Western blot in hypoxic-ischemia brain damage (HIBD) in postnatal rats, and in BV-2 microglia in vitro challenged with lipopolysaccharide (LPS) with or without Gastrodin treatment. Expression of NOX-2, a subunit of NADPH oxidase, and proinflammatory mediators including iNOS and TNF-α, was also evaluated. The present results showed that expression of ACE, AT1, NOX-2, iNOS and TNF-α was markedly increased in activated microglia in the corpus callosum of HIBD rats, and in LPS stimulated BV-2 microglia. Remarkably, the expression was markedly attenuated following Gastrodin treatment. Conversely, Gastrodin enhanced AT2 and SIRT3 protein expression. In BV-2 microglia treated with Azilsartan, a specific inhibitor of AT1 (AT1I group), NOX-2 expression was decreased whereas that of SIRT3 in LPS + AT1I and LPS + Gastrodin group was increased when compared with the controls. In LPS + AT1I + Gastrodin group, SIRT3 expression was further augmented. More importantly, Gastrodin effectively reduced caspase 3 protein expression level in the HIBD rats coupled with a significant decrease in caspase 3 positive cells. We conclude that Gastrodin can exert its protective effects against the hypoxic-ischemia brain damage in the present experimental HIBD model. It is suggested that this is mainly through suppression of expression of RAS (except for AT2 and SIRT3) and proinflammatory mediators e.g. TNF-α in activated microglia.

Early brain development after birth is extremely dynamic, suggesting that potential functional changes occur during this period. In this study, the maximal electroshock seizure threshold (MEST) was used to explore the electrophysiological variation among three developmental stages in young mice (no more than 5 weeks old). The induced electroshock seizure (ES) behavior of early postnatal mice (1–2-weeks old) differed from that during weaning (3 weeks old) and early puberty (4–5-weeks old). Thus, we further explored their respective characteristic responses to the ES parameters. When the stimulation current (SC) was limited to 4.0 mA, only the 1–2-week-old mice were induced to exhibit ES behavior at voltages of 30 V and 40 V, indicating they were more sensitive to maximal electroshock seizure (MES) (response to lower voltage). Surprisingly, however, they showed substantially lower mortality than the older groups under higher voltage conditions (60, 100, 160, and 200 V), suggesting better tolerance to the SC. We also found that when the current limit decreased to 3.5 mA, the 4–5-week-olds mice exhibited stable ES behavior with low mortality, while for 3-week-olds mice, the SC limit required to be reduced to 1.5 mA. In conclusion, our findings showed that neural sensitivity to MES was significantly different in young mice before puberty. Thus, greater attention should be given to distinguishing the developmental period of mice, especially in electrophysiological examination.

Background: Right ventricle (RV) function is among the most important prognostic factors for pulmonary arterial hypertension (PAH) patients. Inhaled iloprost, an inhaled member of the prostacyclin family, is effective for the treatment of severe PAH and acute RV failure. However, the acute effects of iloprost on RV physiology have not been thoroughly explored in the past.Materials and Methods: This prospective study involved 69 incident PAH patients, including 23 idiopathic PAH (IPAH) patients, 26 patients with PAH associated with connective tissue disease (CTD-PAH) and 20 with PAH associated with congenital heart disease (CHD-PAH). All patients underwent both right heart catheterization and cardiac magnetic resonance imaging at baseline and 20 min after 5 μg iloprost inhalation.Results: Acute iloprost inhalation reduced PVR from 13 ± 7 to 10 ± 6 Wood U (P < 0.001), increased RV ejection fraction (RVEF) from 31 ± 11 to 35 ± 12 % (P < 0.001), increased RV stroke volume from 53 ± 21 to 57 ± 22 ml (P < 0.001) and decreased RV end-diastolic volume from 179 ± 67 to 172 ± 69 ml (P < 0.001). Acute iloprost inhalation-induced RVEF improvement was correlated with the degree of PVR reduction (P < 0.001) in IPAH patients, but not in CTD-PAH or CHD-PAH patients.Conclusion: Acute iloprost inhalation improved RVEF, RV stroke volume and decreased RV volume in IPAH and CTD-PAH patients. Iloprost-induced RVEF increase was proportional to PVR reduction in IPAH patients, but not in CTD-PAH or CHD-PAH patients.

Currently, there is no stable and flexible method to label and track cytotoxic T-lymphocytes (CTLs) in vivo in CTL immunotherapy. We aimed to evaluate whether the sulfo-hydroxysuccinimide (NHS)-biotin-streptavidin (SA) platform could chemically modify the cell surface of CTLs for in vivo tracking. CD8+ T lymphocytes were labeled with sulfo-NHS-biotin under different conditions and then incubated with SA-Alexa647. Labeling efficiency was proportional to sulfo-NHS-biotin concentration. CD8+ T lymphocytes could be labeled with higher efficiency with sulfo-NHS-biotin in DPBS than in RPMI (P

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with high heritability; however, the bone morphogenetic protein receptor 2 (BMPR2) gene only accounts for 17% of IPAH. The genetic basis of IPAH needs further investigation.To identify novel IPAH susceptibility genes other than BMPR2.This 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had no BMPR2 variants and were compared with 968 healthy control participants. Data were collected from January 1, 2000, to July 31, 2015, and analyzed from August 1, 2015, to May 30, 2018.PTGIS rare variants.Whole-genome sequencing was performed to identify putative IPAH genes in a discovery cohort, with validation in an independent referral cohort. Correlation of genotype and hemodynamic characteristics was then evaluated at baseline and after pulmonary vasodilator testing. Functional assessments were conducted to analyze the effects of identified genetic variants on transcript splicing, enzymatic activity, and endothelial cell phenotypes.Among 230 patients with IPAH (164 female [71.3%]; mean [SD] age, 34 [18] years), an enrichment of rare variants in a gene encoding prostacyclin synthase (PTGIS) was identified in the discovery cohort. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In the combined data set, PTGIS rare variants were found in 14 of 230 cases (6.1%) and 8 of 968 controls (0.8%) (odds ratio, 7.8; 95% CI, 3.2-18.8; P = 5 × 10-6, logistic regression). Compared with patients without PTGIS variants, inhaled iloprost induced a more significant decrease of pulmonary vascular resistance (difference in the least square mean, -21.7%; 95% CI, -31.4% to -12.0%; P .001, linear regression model) and an increase of cardiac index (difference in the least square mean, 18.3%; 95% CI, 8.8%-27.8%; P .001, linear regression model) in patients with PTGIS variants. The minigene assay indicated that the c.521 + 1GA variant resulted in aberrant messenger RNA transcripts. The functional studies showed that the 2 missense rare variants (R252Q and A447T) resulted in a decrease in prostacyclin production and increased cell death of pulmonary microvascular endothelial cells.This study identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation. These findings suggest that PTGIS variants may be involved in the pathogenesis of IPAH.

To investigate the change of apoptosis protein (Caspase 3) expression when RNA binding motif protein 3 (RBM3) overexpression in swine testicle (ST) cell line under cold stress (32℃) condition.In present study, RBM3 overexpression lentiviral vector (pLenti6/V5-GW/EmGFP-RBM3) and empty viral vector (pLenti6/V5-GW/EmGFP-DEST) with green fluorescent protein (GFP) that were successfully constructed in our laboratory were transfected into ST cells as overexpression virus group (OEV), empty vector virus (EVV) group and establishment of wildtype cell (WTC) group as the control group. The real-time fluorescence quantitative RCR (qPCR) and Western blot were used to detect expression of RBM3 mRNA and protein in each group, then cells in each group were cultured at 37℃ or 32℃ (2 h, 4 h, 8 h), the changes of Caspase 3 expression in each group were detected by enzyme linked immunosorbent assay (ELISA).Relative RBM3 gene and protein expression in OEV group were significantly higher than those in EVV group and WTC group. At the temperature of 37℃ and at 32℃ (2 h, 4 h, 8 h) in cold stress experiment, Caspase 3 expression in OEV group was significantly lower than those in EVV group and WTC group.RBM3 overexpression in ST cell line exposured to cold can significantly decreased the level of Caspase 3 expression, this study provides an experimental basis of RBM3 resistance against apoptosis of ST cells induced by low temperature.

The association of sex hormone (estradiol, testosterone, and progesterone) with cardiopulmonary disease has already attracted great attention, especially in pulmonary arterial hypertension (PAH). However, the impact of sex hormones and their pituitary stimulators (follicle-stimulating hormone and luteinizing hormone) on PAH in men remains unclear. We conducted a prospective cohort study recruiting 95 patients with idiopathic PAH from 2008 to 2014 and following up for a median of 65 months for death. Compared with control, abnormal plasma levels of sex hormones were more common in patients with PAH. Higher estradiol and estradiol/testosterone levels were associated with risk of PAH diagnosis (odds ratio per ln estradiol, 3.55;PPP=0.003; odds ratio per ln progesterone, 0.09;PP=0.007), even after adjustment for baseline characteristics and PAH treatment. According to receiver operating characteristic analysis, patients with PAH with higher estradiol level (≥145.55 pmol/L) had worse 5-year survival rate compared with those with lower estradiol (38.6% versus 68.2%; log-rank testP=0.001). Therefore, our data show higher estradiol, estradiol/testosterone ratio, lower testosterone, and progesterone were associated with increased risk of PAH. Meanwhile, higher estradiol was independently associated with higher mortality in men with PAH. Further studies are needed to explain the origin of these hormonal derangements and their potential pathophysiological implications in PAH.

Background: Genetic variants such as inactivating mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene account for approximately 15-20% of the etiology of idiopathic pulmonary arterial hypertension (IPAH). Increasing evidence indicates the existence of other IPAH susceptibility genes. Methods: The whole-genome sequencing was performed in a discovery cohort including 42 IPAH patients who are lacking BMPR2 mutations. Putative IPAH genes were validated in an independent cohort that included 188 IPAH patients and 968 healthy controls. Functional assessments were conducted to analyze the effects of candidate genetic variants on transcript splicing, enzymatic activity and function. Results: An enrichment of rare variants in the gene encoding prostacyclin synthase (PTGIS) was initially identified by the whole-genome sequencing. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In total, fourteen patients (6.1%) were heterozygous for three PTGIS rare variants, including one splice-site variant (c.521 1G>A) and two missense variants (R252Q, A447T). These rare variants conferred a 7.8-fold greater risk of IPAH (95% confidence interval (CI), 3.2 to 18.8; P=5 x 10-6). Inhaled iloprost induced more significantly decrease of pulmonary vascular resistance (P=0.001) and increase of cardiac index (P A variant resulted in aberrant mRNA transcripts. The functional studies showed that the two missense variants caused a decrease in prostacyclin production and increased cell death in pulmonary microvascular endothelial cells. Conclusions: We have identified three loss-of-function rare variants in the PTGIS gene from two independent IPAH cohorts. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation and cause deleterious effects. These results provide a novel finding that PTGIS rare variants are involved in the pathogenesis of IPAH. Funding: The work was supported by the following grants: the Beijing Natural Science Foundation (7181009, 7172180), the National Natural Science Foundation of China (81320108005), the National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2016-I2M-4-003), the National Key Research and Development Program of China (2016YFC0901502), Sanming Project of Medicine in Shenzhen-Professor Zhi-Cheng Jing's Group for Precise Medicine Research in Thrombosis and Vascular Disease (SZSM201502001) , and the fund from State Key Laboratory of Cardiovascular Disease (2016-kf04, 2018ZR-02). Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study protocol was approved by the ethics committees of Shanghai Pulmonary Hospital and FuWai Hospital. The participants, who were all of Chinese Han ancestry, provided written informed consent.

In this paper, we investigate the stationary probability current (or flux) of a Brownian ratchet model as a function of the flipping rate of the fluctuating potential barrier. It is shown that, with suitably selecting the parameters' values of the ratchet system, we can get the negative resonant activation, the positive resonant activation, the double resonant activation, and the current reversal, for the stationary probability current versus the flipping rate. The appearance of these phenomena is the result of the cooperative effects of the potential's dichotomous fluctuations and the internal thermal fluctuations on the evolution of the flux versus the flipping rate of the fluctuating potential barrier. In addition, some applications of our results to the motor proteins are discussed.

Sirtuin 3 (SIRT3) mediates cellular resistance toward various forms of stress. SIRT3 expression in the developing brain, especially its localization in various glial cell types, has not been fully explored. This study aimed to determine SIRT3 expression in the brain of neonatal rats subjected to hypoxia. By immunohistochemistry, immunofluorescence and Western blotting, we show here that SIRT3 expression in the periventricular white matter was up-regulated in hypoxia group compared with the control group at the corresponding time points. Intense SIRT3 expression was detected in microglia at early time points after hypoxia whose cell number was increased with reduced ramifications in hypoxia group compared with the control group. Furthermore, SIRT3 immunoreactivity was obviously enhanced at 24 h, 3 and 7d, but was declined at 14d after hypoxia so that SIRT3 expression between the two groups was comparable. SIRT3 immunofluorescence was also localized in astrocytes labeled with GFAP which was augmented at different time points in hypoxia group. GPAP positive astrocytes exhibited long extending processes being most pronounced at 3d. SIRT3 was moderately expressed at 24 h, 3 and 7d, but was markedly increased at 14d after hypoxia. Moderate SIRT3 expression was also localized in oligodendrocytes labeled with CNPase in the control group. The incidence of CNPase positive oligodendrocytes showing colocalization of SIRT3 increased significantly at 24 h, 3 and 7d after hypoxia. In conclusion, SIRT3 expression was differentially up-regulated in all three major glial cell types following hypoxia. It is suggested that increased SIRT3 expression in the respective glial cell types following hypoxia is involved in different signaling pathways that protect against hypoxic stress in the developing brain.

In order to process the abundant information in fuzzy clustering, one fault diagnosis method was proposed based on Rough Set reduction algorithm and Fuzzy equal relationship clustering. Not only the iteration numbers was reduced in the fuzzy equal relationship matrix, but also the clustering numbers was lower. Then the examples were applied to test its validity.

In this paper, we research and develop a new machine called large highland hydraulic intelligent pesticide spraying machine. The pesticide spraying machine adopts hydraulic electric control technology, and adapts to all tall or short crops for pesticide spraying. The machine employs large intelligent computer control technology, and adjusts the spraying dose according to the pest density measured by intelligent sensors. Furthermore, the machine adopts the technology of self-filter and dilutes the pesticide with absorption water automatically. This paper presents hydraulic control system, and puts forward the hydraulic control principle of the walking part, the hydraulic control principle of the work part and main technical parameters.

Optical coherence tomography (OCT) is an intravascular imaging modality capable of providing in situ images of tissues at near histologic resolution. In this study we examine the utility of OCT in identifying vascular changes related to pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).OCT of four different distal pulmonary arteries was performed during right heart catheterization in 87 patients, 64 patients with PAH and 23 patients with CTEPH. The mean luminal diameter measured by OCT for all patients was 2.26mm. Intimal thickening was significantly increased in all PAH patients (0.26±0.05mm in idiopathic PAH, 0.24±0.03mm in connective tissue disease related PAH, 0.26±0.06mm in congenital heart disease related PAH and 0.22±0.04mm in CTEPH, respectively) compared with controls (0.13±0.03mm) (all p0.05). An intimal thickness of ≥0.176mm had a 91% positive predictive value for pulmonary hypertension. The anatomic abnormalities revealed by OCT tended to be severe in the idiopathic PAH group and mild in the CTEPH group. Signs of intravascular webs were found in 60.9% of CTEPH patients, but no other patients. Intimal thickness was moderately correlated with pulmonary arterial pressure and pulmonary vascular resistance (r=0.423 and 0.439, respectively, p0.001).OCT provides important information for assessment of pulmonary arterial remodeling in patients with PAH and improves diagnostic capability of angiographically undetected distal-thrombotic lesions in patients with CTEPH.

The composite material is composed of low alkaline magnesium oxychloride cement as base material and plant straw fiber as reinforcement material. Further, the thermal conductivity was measured to characterize the thermal insulation properties of composite materials. The influence of straw fiber on the frost resistance of composite materials was investigated after 50 freeze-thaw cycles.

A theoretical model of cascaded terahertz (THz) difference-frequency generation is established based on one-dimensional coupled-wave equations. The relationships between sphalerite crystals’ wave vector mismatches and difference-frequency pump waves are analyzed. To produce terahertz wave with the frequency of 1.5 THz, 80-order cascaded difference-frequency is applied. By introducing crystal absorption, we calculate the optimum crystal length and pump frequency under actual circumstances. It is found that Stokes waves dominate the terahertz waves output in cascaded progress, and cascaded difference-frequency can increase the photon conversion efficiency obviously.

Statistical theory and fuzzy analysis are two primary methods of radar and ESM track association algorithms. Absolute-double-threshold rule was used to analyze these two association algorithms. Each algorithm was simulated in this paper. The simulation results show that both of these two track association algorithms have high probability of correct association, but the algorithm based on statistical theory has faster convergent speed and litter samples, while the other is simple, and has less calculation.