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Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVRREFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVRBetween Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVRThese biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy.AbbVie.

Towards understanding the trend and variability in the bottom water salinity in the Ross Sea, this study focuses on the seasonality of the salinity budget over the Ross Sea continental shelf, using a new coupled regional ocean-sea ice-ice shelf model. Owing to the sea ice production, the upstream advection, and the glacial melting, the Ross Sea continental shelf is characterized by the relatively saltier water on the western shelf than on the eastern shelf, with the saltiest water in the Terra Nova Bay Polynya. During the early freezing season (March-April), there is a remarkable sea ice production over the broad continental shelf, which makes a significant contribution to the production of High Salinity Shelf Water (HSSW). The brine rejection in the polynyas leads to the salinification and deepening of the mixed layer, yet the upstream advection acts to decrease the salinity below the mixed layer until the deep convection is fully developed throughout the water column. The seasonal cycle of the salinity budget in the Ross Sea continental shelf is largely determined by the formation/melting of sea ice, the intrusion of modified Circumpolar Deep Water, and the outflow of HSSW, while the contribution of the Ross Ice Shelf melting is relatively small., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Xiaoyan Huang,1– 3,* Yingyi Kuang,1– 3,* Qiyuan Qin,1– 3,* Miaomiao Zhu,1– 3 Yanjiong He,1– 3 Zixu Yuan,1– 3 Huaiming Wang,1– 3 Qinghua Zhong,1,2,4 Qi Guan,1– 3 Hui Wang,1– 3,* Tenghui Ma,1– 3,* Xinjuan Fan1,2,5,* 1Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 3Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 4Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 5Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinjuan FanDepartment of Pathology, Sun Yat-sen University Sixth Affiliated Hospital, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, People’s Republic of ChinaFax +86 20-38737621Email fanxjuan@mail.sysu.edu.cnTenghui MaDepartment of Colorectal Surgery, Sun Yat-sen University Sixth Affiliated Hospital, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong, People’s Republic of ChinaFax +86 20-38737621Email matengh@mail.sysu.edu.cnBackground: Chronic radiation intestinal injury (CRII) is the most common complication after pelvic malignancy radiation. Once hemorrhagic CRII patients suffer from lower extremity deep venous thrombosis (LE-DVT), hemostasis and anticoagulation therapy will be adopted simultaneously, but the treatment strategy is a paradox, as the condition is extremely intractable and serious. The aim of this study was to investigate the prevalence of and risk factors for LE-DVT in CRII patients and explore the treatment of hemorrhagic CRII patients with LE-DVT.Methods: This was a retrospective study, and a total of 608 hospitalized CRII patients after pelvic radiotherapy were included from November 2011 to October 2018. Univariate and multivariate analyses were conducted to investigate the potential risk factors for LE-DVT in CRII patients. Furthermore, the treatment of hemorrhagic CRII patients with LE-DVT was explored.Results: Among the CRII patients, 94 (15.5%) were with suspicious symptoms of LE-DVT in the lower limbs, and 32 (5.3%) were diagnosed with LE-DVT. Among the patients with LE-DVT, 65.6% (21/32) had bleeding simultaneously, and 29 (90.6%) had anemia with 24 (75.0%) having moderate to severe anemia. Multivariate analysis showed that a recent surgical history (≤ 6 months) (OR = 5.761, 95% CI: 2.506∼ 13.246, p < 0.001), tumor recurrence or metastasis (OR = 3.049, 95% CI: 1.398∼ 6.648, p = 0.005) and the hemoglobin (Hb) level (OR = 0.960, 95% CI: 0.942∼ 0.979, p < 0.001) were significantly associated with the development of LE-DVT. ROC curve analysis showed that the AUC of the merged risk score of the independent risk factors was 0.822 (95% CI: 0.789∼ 0.852), and the optimal Hb cutoff was 82.5 g/L. After colostomy, obvious bleeding remission was rapidly found in 84.6% of hemorrhagic CRII patients with LE-DVT.Conclusion: The prevalence of LE-DVT in hospitalized CRII patients was 5.3%. A recent surgical history, tumor recurrence or metastasis and a lower Hb level were independently associated with LE-DVT development in CRII patients. Colostomy could be a good choice for intractable hemorrhagic CRII patients with LE-DVT.Keywords: chronic radiation intestinal injury, lower extremity deep venous thrombosis, pelvic malignancy radiation, risk factor, colostomy, hemorrhagic

In 2020-2022, extensive discussions and deliberations have taken place in corresponding topical working groups of the Snowmass Accelerator Frontier (AF) and in numerous joint meetings with other Frontiers, Snowmass-wide meetings, a series of Colloquium-style Agoras, cross-Frontier Forums on muon and electron-positron colliders and the collider Implementation Task Force (ITF). The outcomes of these activities are summarized in this Accelerator Frontier report., contribution to Snowmass'21, v.2 (final)

We discuss the goals, the designs, the state of technical readiness, and the critical R&D needs of the accelerators that are currently under discussion as Higgs and electroweak factories. We also address the respective staging options enabling future energy-frontier colliders. The accelerators covered are based on many different techniques and approaches. They include several circular colliders, various linear colliders, colliders based on energy recovery linacs (ERLs), ERL-ring combinations, as well as gamma-gamma colliders. The linear colliders proposed consist of options for the International Linear Collider (ILC), for the Compact Linear Collider (CLIC), for the Cold Copper Collider (C^3), and for the more recent Higgs-Energy Lepton Collider (HELEN). ERLs are key components of the Recycling Linear e+e- Collider (ReLiC), of the Energy Recovery Linear Collider (ERLC), and of the Circular Energy Recovery Collider (CERC). Among the more conventional ring colliders, the following proposals are featured: the Future Circular Collider (FCC-ee), the Circular Electron Positron Collider (CEPC), the Electron Positron Circular Collider at Fermilab (EPCCF), and the Large Electron Positron collider $\#$3 (LEP-3). In addition, we consider the X-ray FEL based gamma-gamma Collider Higgs Factory (XCC) and the High-Energy High-Luminosity gamma-gamma collider (HE&HL gamma-gamma). Finally, a Higgs factory based on a circular muon collider is mentioned for completeness., Submitted to Snowmass 2021

This review article provides an overview of the current status of velocity-selective arterial spin labeling (VSASL) perfusion MRI and is part of a wider effort arising from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. Since publication of the 2015 consensus paper on arterial spin labeling (ASL) for cerebral perfusion imaging, important advancements have been made in the field. The ASL community has, therefore, decided to provide an extended perspective on various aspects of technical development and application. Because VSASL has the potential to become a principal ASL method because of its unique advantages over traditional approaches, an in-depth discussion was warranted. VSASL labels blood based on its velocity and creates a magnetic bolus immediately proximal to the microvasculature within the imaging volume. VSASL is, therefore, insensitive to transit delay effects, in contrast to spatially selective pulsed and (pseudo-) continuous ASL approaches. Recent technical developments have improved the robustness and the labeling efficiency of VSASL, making it a potentially more favorable ASL approach in a wide range of applications where transit delay effects are of concern. In this review article, we (1) describe the concepts and theoretical basis of VSASL; (2) describe different variants of VSASL and their implementation; (3) provide recommended parameters and practices for clinical adoption; (4) describe challenges in developing and implementing VSASL; and (5) describe its current applications. As VSASL continues to undergo rapid development, the focus of this review is to summarize the fundamental concepts of VSASL, describe existing VSASL techniques and applications, and provide recommendations to help the clinical community adopt VSASL.

Maojian Chen,1,* Chanchan Xiao,2,* Wei Jiang,3 Weiping Yang,4 Qinghong Qin,1 Qixing Tan,1 Bin Lian,1 Zhijie Liang,5 Changyuan Wei1 1Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Microbiology and Immunology, School of Medicine and Public Health, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 3Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 4Department of Ultrasound Diagnosis, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 5Department of Gland Surgery, The Fifth Affiliated Hospital of Guangxi Medical University & The First People’s Hospital of Nanning, Nanning, Guangxi 530022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changyuan WeiDepartment of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of ChinaTel/Fax +86 0771 5308593Email changyuanwei@gxmu.edu.cnBackground: As a natural compound extracted from a variety of hot peppers, capsaicin has drawn increasing attention to its anti-cancer effects against multiple human cancers including breast cancer. FBI-1 is a major proto-oncogene negatively regulating the transcription of many tumor suppressor genes, and plays a vital role in tumorigenesis and progression. However, whether FBI-1 is involved in capsaicin-induced breast cancer suppression has yet to be ascertained. This study aimed to investigate the effects of capsaicin on proliferation and apoptosis and its association with FBI-1 expression in breast cancer.Methods: CCK-8 and morphological observation assay were employed to detect cell proliferation. Flow cytometry and TUNEL assay were conducted to detect cell apoptosis. RNA interference technique was used to overexpress or silence FBI-1 expression. qRT-PCR and/or Western blot analysis were applied to detect the protein expression of FBI-1, Ki-67, Bcl-2, Bax, cleaved-Caspase 3, Survivin and NF-κB p65. Xenograft model in nude mice was established to assess the in vivo effects.Results: Capsaicin significantly inhibited proliferation and induced apoptosis in breast cancer in vitro and in vivo, along with decreased FBI-1, Ki-67, Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Furthermore, FBI-1 overexpression obviously attenuated the capsaicin-induced anti-proliferation and pro-apoptosis effect, accompanied with the above-mentioned proteins reversed, whereas FBI-1 silencing generated exactly the opposite response. In addition, as a target gene of FBI-1, NF-κB was inactivated by p65 nuclear translocation suppressed with capsaicin treatment, which was perceptibly weakened with FBI-1 overexpression or enhanced with FBI-1 silencing.Conclusion: This study reveals that FBI-1 is closely involved in capsaicin-induced anti-proliferation and pro-apoptosis of breast cancer. The underlying mechanism may be related to down-regulation of FBI-1-mediated NF-κB pathway. Targeting FBI-1 with capsaicin may be a promising therapeutic strategy in patients with breast cancer.Keywords: capsaicin, breast cancer, proliferation, apoptosis, FBI-1, NF-κB

Chengxin Shi,1,* Fengli Yue,2,* Feiyu Shi,1 Qian Qin,1 Lizhao Wang,1 Guanghui Wang,1 Lijun Mu,1 Dan Liu,1 Yaguang Li,1 Tianyu Yu,1 Junjun She1 1Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China; 2College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junjun SheDepartment of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, Yanta West Road, Xi’an, Shaanxi 710061, People’s Republic of ChinaTel +86-17765856985Email shejunjun@mail.xjtu.edu.cnBackground: Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. Oxidative stress plays a pivotal role in the pathogenesis of IBD. Selenium-containing amino acids reportedly have anti-oxidative and anti-inflammatory properties, but it remains unknown if selenium-containing amino acids can be used to treat IBD. This study aimed to investigate the effects of two selenium-containing amino acids – selenocysteine and selenocystine – on oxidative stress and chronic inflammation in a mouse model of dextran sulfate sodium (DSS)-induced IBD.Methodology: C57BL/6 mice were randomly assigned to the following six groups: control, DSS, DSS+selenocysteine, DSS+selenocystine, DSS+sodium selenite, and DSS+N-acetylcysteine (NAC). IBD was induced by 3% DSS. Pro-inflammatory cytokines [interleukin-1β (IL-1β), monocyte chemotactic protein 1 (MCP-1), IL-6, and tumor necrosis factor-α (TNF-α)] and markers for oxidative and anti-oxidative stress [malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were measured using immunohistochemical analysis.Results: Selenocysteine and selenocystine significantly attenuated IBD-related symptoms, including preventing weight loss, decreasing disease activity index (DAI) scores, and increasing colon length. Selenocysteine and selenocystine significantly ameliorated the DSS-induced oxidative stress, as demonstrated by a reduction in ROS and MDA activity and an increase in SOD and GPx activity. IL-1, MCP-1, IL-6, and TNF-α levels were significantly increased in the IBD mice, while treatment with the selenium-containing amino acids significantly reduced the levels of these pro-inflammatory cytokines. In vivo safety analysis showed minimal side effects of the selenium-containing amino acids.Conclusion: We found that selenocysteine and selenocystine ameliorated DSS-induced IBD via reducing oxidative stress and intestinal inflammation, indicating that selenium-containing amino acids could be a novel therapeutic option for patients with IBD.Keywords: Inflammatory bowel diseases, colitis, selenium-containing amino acids, selenocysteine, selenocystine, oxidative stress, inflammation

Zhen Huang,* Qinghong Qin,* Longjie Xia,* Bin Lian, Qixing Tan, Yinghua Yu, Qinguo Mo Department of Breast Surgery, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinguo MoDepartment of Breast Surgery, The Affiliated Tumor Hospital of Guangxi Medical University, No. 71 Hedi Road, Nanning 530021 Guangxi Province, People’s Republic of ChinaTel +86-771-530859Email qgmo135@263.netObjective: To investigate the association between the recurrence score (RS) obtained by Oncotype DX 21-gene test and long non-coding RNA (lncRNA) MALAT1 expression in early and estrogen receptor-positive (ER+) breast cancer.Materials and Methods: The Oncotype DX 21-gene test and MALAT1 expression detection were performed in tumor samples from 76 ER+ and early breast cancer patients with the Surplex liquid chip. The RS value was calculated based on the expression of total 21 genes. The level of MALAT1 was measured in both tumor tissue and para-tumor tissue, and relatively quantified with an internal control gene. Mann–Whitney U-test or Kruskal–Wallis test were used to analyze the association between MALAT1 level and different clinical pathological characteristics, including age, tumor stage, disease grade, lymph node status, Ki-67 expression, and progesterone receptor (PR) status. The association between the RS and different characteristics was analyzed by Wilcoxon rank-sum test. Correlation between two parameters was analyzed by Spearman’s rank correlation analysis.Results: The expression of MALAT1 was more abundant in tumor tissue (2.992 ± 2.256) than that in adjacent normal tissue (1.641± 1.438, Z=− 2.594, p= 0.009), and it was not correlated with any clinical pathological characteristics. According to the old criteria for RS stratification, 52.7% of patients were in low risk (RS< 18), 36.8% of patients were in medium risk (18≤RS≤ 30), and 10.5% of patients were in high risk (RS> 30). While under the new criteria, 18.4% were in low risk group (RS< 11), 63.2% were in a medium risk group (11≤RS≤ 26), and 18.4% were in a high risk group (RS> 26). The Oncotype DX 21-gene results only correlated with Ki-67 expression under both new and old criteria, and it was not related with other cancer characteristics. The expression of lncRNA MALAT1 was significantly correlated with the Oncotype DX 21-gene results under the old criteria.Conclusion: MALAT1 is a novel breast cancer biomarker independent of tumor stage, disease grade and lymph node status. MALAT1 level is associated with the Oncotype DX 21-gene RS value. Therefore, combination of MALAT1 and the Oncotype DX 21-gene test may be used to predict prognosis in ER+ and early stage breast cancer.Keywords: Oncotype DX 21-gene test, MALAT1, long non-coding RNA; lncRNA, breast cancer, risk of recurrence

Suzhen Fan,1,* Shujun Zhao,1,* Xiang Gao,1 Qiaohong Qin,1 Yan Guo,1 Zhongfu Yuan,2 Min Zhang,1 Qing Liu,1 Hongyu Li1 1Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongyu LiDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, 7 Kangfu Front Street, Erqi, Zhengzhou, Henan 450052, People’s Republic of ChinaEmail fkzlzdsys@163.comBackground: A growing number of studies have identified that circular RNAs (circRNAs) play a vital role in the progression of various tumors. However, the underlying functions and mechanisms of circRNAs in cervical cancer have not been clarified.Methods: qRT-PCR was used to detect the level of circGSE1 in cervical cancer tissues and matched normal tissues. In vitro cell wound healing, transwell migration and invasion assays were employed to assess the effects of circGSE1 on cell mobility. The pull-down, luciferase reporter, RIP and rescue assays were performed to evaluate the interaction between circGSE1and miR-138-5p and the regulation of miR-138-5p on Vimentin.Results: We found that circGSE1 was significantly higher in cervical cancer tissues than that in matched normal tissues. Further analyses revealed that the level of circGSE1 was positively correlated with tumor differentiation, FIGUREO stage, depth of stromal invasion, lymph node metastasis and infiltration of parauterine organ. Kaplan–Meier survival analysis showed that high circGSE1 predicted worse overall survival and disease-free survival. Down-regulated circGSE1 evidently inhibited cell migration and metastasis of cervical cancer, while up-regulated circGSE1 significantly promoted cell migration and metastasis. The pull-down, luciferase reporter and RIP assays revealed that circGSE1 directly bound to and sponge miR-138-5p. MiR-138-5p inhibited the expression of Vimentin through directly binding to 3ʹUTR of Vimentin mRNA. In addition, miR-138-5p suppressed cell migration and invasion through inhibiting Vimentin expression, and circGSE1 promoted cell migration and invasion through sponging miR-138-5p and enhancing Vimentin expression.Conclusion: CircGSE1 promotes the progression and may act as a novel diagnostic biomarker for disease progression of cervical cancer.Keywords: circGSE1, miR-138-5p, Vimentin, cervical cancer, migration and metastasis

Ting Guo,1– 3,* Qinxue Shen,1– 3,* Zhiguo Zhou,4 Jinhua Li,1– 3 Wei Guo,1– 3 Wenlong He,1– 3 Yunnian Wang,5 Zhi Xiang,6 Peng Huang,7 Nanyang Zeng,8 Qingwu Qin,1– 3 Ping Chen,1– 3 Hong Luo,1– 3 Hong Peng1– 3 1Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central-South University, Changsha, Hunan, People’s Republic of China; 2Research Unit of Respiratory Disease, Central-South University, Changsha, Hunan, People’s Republic of China; 3The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The First Hospital of Changsha, Changsha, Hunan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, The Traditional Chinese Medicine Hospital of Liling, Zhuzhou, Hunan, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Huaihua, Huaihua, Hunan, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, The Central Hospital of Zhuzhou, Zhuzhou, Hunan, People’s Republic of China; 8Department of Infectious Disease, The Lvkou People’s Hospital of Zhuzhou, Zhuzhou, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong PengDepartment of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central-South University, No. 139 Renmin Middle Road, Changsha, Hunan 410011, People’s Republic of ChinaTel +86 13807494486Email penghong66@csu.edu.cnPurpose: To summarize the clinical features and effective therapy of severe COVID-19 patients.Patients and Methods: In this retrospective, multicenter study, the medical records of COVID-19 patients in Hunan, from January 21, 2020 to February 19, 2020 were reviewed.Results: Of the 350 COVID-19 patients, 13.7% were severe cases. On admission, compared with non-severe patients, more severe patients had a neutrophil/lymphocyte ratio > 3 (58.3% vs 33.8%, P=0.001), D-dimer > 1 mg/L (41.7% vs 13.6%, P< 0.0001), higher level of CRP (39.1 mg/L, IQR18.1– 75.9 vs 13.4 mg/L, IQR5.0– 32.8, P< 0.0001), and multiple pneumonia on CT (77.1% vs 18.2%, P< 0.0001). All severe patients received oxygen support. 95.8% of them received antivirals, and the most frequent therapy was lopinavir and ritonavir plus human interferon-α 2b. Moxifloxacin was used in 70.8% severe patients. The total dosage of methylprednisolone sodium succinate was 640 mg (IQR 360– 960) in severe patients, and the duration of use was 8.5 days (IQR 6.8– 11.3). The total dosage of immunoglobulin was 80 g (IQR, 60– 140) in severe patients, and the duration was 8.0 days (IQR, 6.0– 11.5). As of March 15, 2020, 95.8% of the severe patients had been discharged and only two deaths occurred.Conclusion: The rate of severe cases and mortality of COVID-19 in Hunan are lower than those in Wuhan. In addition to antivirals and oxygen support, timely interventions including corticosteroids, immunoglobulin, and antibiotics, contribute to improving the prognosis of severe COVID-19 patients.Keywords: coronavirus disease 2019, SARS-CoV-2, severe disease, corticosteroid, immunoglobulin

To solve the technical, economic and environmental problems in the remanufacturing process of decommissioned machine tools, this study proposes a module partition method for remanufacturing retired machine tools. Through an analysis of the economic, accuracy, environment-friendly, and functional and physical interactivity principles, this study applies the fuzzy cluster method (FCM) to analyse the modularity of the components to be assembled. It establishes the correlation matrix between the parts, from which a module division scheme is obtained. Finally, a case study is presented to verify the feasibility of the module division method. Om die tegniese, ekonomiese en omgewingsprobleme in die hervervaardigingsproses van masjiengereedskap wat buite gebruik geraak het, op te los, stel hierdie studie 'n moduleverdelingsmetode voor vir die hervervaardiging van sulke masjiengereedskap. Deur 'n ontleding van die ekonomiese, akkuraatheid, omgewingsvriendelike en funksionele en fisiese interaktiwiteitsbeginsels, pas hierdie studie die "fuzzy cluster" metode (FCM) toe om die modulariteit van die komponente wat saamgestel moet word, te analiseer. Dit bepaal die korrelasiematriks tussen die dele, waaruit 'n module-verdelingskema verkry word. Ten slotte word 'n gevallestudie aangebied om die uitvoerbaarheid van die module-indelingsmetode te verifieer.

Maojian Chen,1,* Wei Jiang,2,* Chanchan Xiao,3 Weiping Yang,4 Qinghong Qin,1 Anyun Mao,1 Qixing Tan,1 Bin Lian,1 Changyuan Wei1 1Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 3Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, People’s Republic of China; 4Department of Ultrasound Diagnosis, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changyuan Wei Department of Breast SurgeryGuangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of ChinaTel/Fax +86 771 5308593Email changyuanwei@gxmu.edu.cnPurpose: This study is aimed to investigate the combined treating efficacy of sodium butyrate and docetaxel on proliferation and apoptosis of the lung adenocarcinoma A549 cell line based on Gli1 regulation in vitro and in vivo.Materials and Methods: RNA interference method was used to overexpress Gli1 in A549 cells. Cells were treated with varying concentrations of sodium butyrate, docetaxel or both in combination. CCK-8, colony formation assay, Hoechst 33258 staining, flow cytometry and TUNEL assay were employed to detect proliferation, cell cycle and apoptosis. qRT-PCR and Western blot analysis were applied to detect the mRNA and protein expression of Gli1. In vivo tumorigenicity was detected by tumor transplantation in nude mice. Downstream protein levels of Gli1 were detected using Western blot assay.Results: It was found that sodium butyrate or docetaxel alone, respectively, inhibited proliferation and promoted apoptosis of A549 cells in vitro and in vivo, while the combination of the two generated significantly higher responses, which were also effective in another lung adenocarcinoma cell line H1299. Furthermore, the combined therapy had an additive effect in suppressing Gli1 expression and regulating the expression of its downstream proteins that involve in proliferation, cell cycle and apoptosis of A549 cells in vitro and in vivo, including decreased protein expression of Ki-67, CDK1, CDK2, Cyclin D1, Bcl-2 and Survivin, and increased protein expression of Cyclin A, p21, Bax and cleaved-Caspase 3. On the other hand, Gli1 overexpression perceptibly reversed the above-mentioned additive effect in vitro and in vivo.Conclusion: This study demonstrates that the combined therapy of sodium butyrate and docetaxel additively inhibits proliferation and promotes apoptosis of A549 lung adenocarcinoma cells via suppressing Gli1 expression in vitro and in vivo. Targeting Gli1 by the combined therapy may provide new insights into the therapeutic management of patients with lung adenocarcinoma.Keywords: sodium butyrate, docetaxel, lung adenocarcinoma, A549, Gli1

Lan Cui,1,* Wentao Liu,1,* Hao Liu,1 Qian Qin,1,2 Shuangxia Wu,1 Suqin He,1,3 Zhenya Zhang,4 Xinchang Pang,1 Chengshen Zhu1 1School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450001, People’s Republic of China; 2Bio & Soft Matter, Institute of Condensed Matter and Nanosciences, Universite Catholique de Louvain, Louvain-la-Neuve B-1348, Belgium; 3Henan Key Laboratory of Advanced Nylon Materials and Application, Zhengzhou University, Zhengzhou 450001, People’s Republic of China; 4Department of Chemistry, Changwon National University of Korea, Changwon-city, Gyeongnam-do 51140, Republic of Korea*These authors contributed equally to this workCorrespondence: Wentao Liu; Hao LiuSchool of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450001, Henan Province, People’s Republic of ChinaEmail wtliu@zzu.edu.cn; hliu@zzu.edu.cnBackground: Although pH and redox sensitiveness have been extensively investigated to improve therapeutic efficiency, the effect of disulfide bonds location and pH-triggered charge-reversal on cascade-targeting still need to be further evaluated in cancer treatment with multi-responsive nanoparticles.Purpose: The aim of this study was to design multi-responsive DOX@MSNs-COS-NN-CMC, DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS and systematically investigate the effects of disulfide bonds location and charge-reversal on the cancer cell specificity, endocytosis mechanisms and antitumor efficiency.Results: In vitro drug release rate of DOX@MSNs-COS-SS-CMC in tumor environments was 7-fold higher than that under normal physiological conditions after 200 h. Furthermore, the fluorescence intensity of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS was 1.9-fold and 1.3-fold higher than free DOX at pH 6.5 and 10 mM GSH. In addition, vesicular transport might be a factor that affects the uptake efficiency of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS. The clathrin-mediated endocytosis and endosomal escape of DOX@MSNs-COS-SS-CMC enhanced cellular internalization and preserved highly controllable drug release into the perinuclear of HeLa cells. DOX@MSNs-COS-SS-CMC exhibited a synergistic chemotherapy in preeminent tumor inhibition and less side effects of cardiotoxicity.Conclusion: The cascade-targeting of charge-reversal and disulfide bonds shielding would be a highly personalized strategy for cervical cancer treatment.Keywords: disulfide bonds, pH-triggered charge-reversal, redox sensitive, chitosan oligosaccharide, human cervical carcinoma therapy

Qiaoji Qin, Nan Lin, Huan Huang, Xuezhi Zhang, Xuelei Cao, Yongbin Wang, Peng LiEmergency Department, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong, People’s Republic of ChinaBackground and purpose: Ginsenoside Rg1 (GS Rg1), as an important active substance of Panax ginseng, has been proven to have elaborate cardioprotective effects. The purpose of this study was to detect that GS Rg1 attenuates cardiac oxidative stress and inflammation in streptozotocin (STZ)-induced diabetic rats (DM).Methods: Cardiac function was assessed by heart rate and blood pressure. Markers relevant to myocardial oxidative stress and antioxidant capacity, and inflammatory reaction factors were detected. The mRNA and protein expression were detected by RT-qPCR and Western blot, respectively.Results: GS Rg1 treatment significantly reduced the symptoms of cardiac hypertrophy and hypertension, and also decreased oxidative stress, inflammation response, NF-κB expression and NLRP3 inflammasome expression. GS Rg1 enhanced mitochondrial biogenesis by increasing PGC-1α, complex III and complex Ⅳ expression. GS Rg1 treatment significantly increased the expression of AMPK, Nrf2 and HO-1 in cardiac tissues.Conclusion: GS Rg1 exhibited protective effect against STZ-induced cardiac dysfunction, which is potentially associated with AMPK/Nrf2/HO-1 signal pathway.Keywords: Ginsenoside Rg1, oxidative stress, inflammation, AMPK, Nrf, HO-1

Lingling Yu,1,2 Wei Wang,1 Liang Li,2 Qingguang Qin,2 Yutian Yu,2 Kun Liu,2 Yufeng Zhao,2 Peijing Rong,2 Bing Zhu2 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 2Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China Background: The transmission of visceral nociception can be inhibited by electroacupuncture (EA) at the spinal level. However, relationships between current intensity and EA-induced analgesia are still lacking. This study compares the effects of different intensities of EA at local acupoints and heterotopic acupoints on nociceptive responses of spinal wide dynamic range (WDR) neurons induced by noxious colorectal distension (CRD). Materials and methods: Experiments were conducted on 40 Sprague Dawley rats anesthetized with 10% urethane. Discharges of WDR neurons in the L1–L3 segments of the dorsal horn of the spinal cord were recorded extracellularly by glass micropipettes. Different intensities of EA (0.5, 1, 2, 4, 6, and 8 mA, 0.5 ms, 2 Hz) were applied to contralateral “Zusanli” (ST 36) or “Neiguan” (PC 6), with either the same or different segmental innervation of the colon. Results: In local acupoints, the increased discharges of WDR neurons evoked by CRD were significantly inhibited by EA at 0.5–8 mA. A positive relationship between current intensity and the inhibiting rate was observed within 0.5–4 mA, but the inhibiting rate reached a plateau when EA exceeded 4 mA. In heterotopic acupoints, the increased discharges of WDR neurons evoked by CRD were significantly inhibited by EA at 2–8 mA. A positive relationship between current intensity and the inhibiting rate was observed within 2–6 mA. Further increase in the current beyond 6 mA also resulted in a plateau effect. Conclusion: Within a certain range, the nociceptive responses of dorsal horn neurons induced by CRD could be inhibited by EA in an intensity-dependent manner. Keywords: electroacupuncture, current intensity, wide dynamic range, colorectal distension

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-XL and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 109/L or >150 × 109/L, respectively. RUX was given BID with starting dose based on BL platelet count per local label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow (BM) fibrosis reduction, and anemia response. Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 pts received NAV+RUX. Median duration of f/u was 6.1 (range, 1.9 ─ 18.6) mos. 28 (88%) pts received NAV 200 mg and 4 (13%) received 100 mg OD. Median age was 69 (44 ─ 83) yrs, and median spleen volume was 1889.08 cm3 (645.6 ─ 7339.6). Median NAV and RUX exposures were 24.1 (5.1 ─ 80.9) and 20.1 (0.1 ─ 80.1) wks, respectively. 31 (97%) pts reported ≥1 AE (Grade ≥3 AEs, 25 [78%]; serious AEs, 6 [19%]). Most common Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). 3 (9%) and 2 (6%) pts reported an AE leading to NAV and RUX discontinuation, respectively, and 2 (6%; 1 PD, 1 cardiac disorder unrelated to NAV) AEs led to death ≤30 days after last NAV dose. SVR35 was achieved by 52% of evaluable pts at wk 24 (SVR35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR35 was 12.1 (11 ─ 47) wks. Conclusions: The combination of NAV+RUX was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in pts without prior JAK-2 inhibitor exposure. SVR35, TSS50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]

The beam-ion interaction is one of the potential limitations of beam performance in ultra-low emittance electron rings. The High Energy Photon Source (HEPS), under construction in Beijing, is one example for which the beam-ion effect has to be carefully evaluated. In this paper, we will introduce the beam-ion interaction models applied in HEPS. Based on these models, a new numerical simulation code is developed. Currently, the code includes modules such as ionization, beam-ion interaction, synchrotron radiation damping, quantum excitation, bunch-by-bunch feedback etc. Settings such as weak-strong, strong-strong and arbitrary number of interaction points can be launched in the code. It will be shown that the beam instability excited by the beam-ion interaction can be effectively suppressed by the bunch-by-bunch feedback system., CERN Yellow Reports: Conference Proceedings, Vol. 9 (2020): Proceedings of the ICFA mini-Workshop on Mitigation of Coherent Beam Instabilities in Particle Accelerators, Zermatt, Switzerland, 23–27 September 2019

Background Acupuncture therapy is well known. But there is no report that acupuncture in patients with coagulation dysfunction in stroke may lead to severe soft tissue injury. we report a case of acupuncture leading to severe soft tissue injury.Methods A 63-year-old female patient was hospitalized for stroke rehabilitation. After 2 years of discharge, severe subcutaneous hematoma caused by acupuncture was readmitted to hospital. She received medication and physical rehabilitation. we monitored the international standardized ratio (INR) in plasma and observed the degree of dissipation of subcutaneous hematoma. the changes of patients during treatment were explored by data analysis.Findings Subcutaneous hematoma (area 20×20 cm) disappeared completely after 3 weeks of physical factor therapy. Small range (area ≤3×3 cm) subcutaneous hematoma can heal itself within 2 weeks. Improper acupuncture is only one of the causes of soft tissue injury. Stroke with coagulation dysfunction is not a contraindication of acupuncture treatment.Interpretation Our report suggests that previously unanticipated acupuncture treatment for stroke patients with coagulation dysfunction may lead to severe multiple soft tissue injuries. Although coagulation dysfunction is not a contraindication of acupuncture treatment, acupuncture treatment for stroke patients with coagulation dysfunction should be vigilant, strengthen the level of acupuncture operation, and fundamentally eliminate the problem. These cases are validation and supplement of adverse clinical reactions caused by improper acupuncture.

Nian Chen, Qin Qin, Ke-Dai Sun, Dan Luo, Qiong-Hui Cheng Department of Dermatology, Daping Hospital, Army Medical University, Chongqing 400042, China Introduction: Primary cutaneous nocardiosis is a rare suppurative or granulomatous inflammation disease caused by Nocardia infection. Because of nonspecific clinical findings, it is always misdiagnosed as common pyogenic infection. Sulfonamides have been the standard treatment for nocardiosis, but the outcome is always poor due to the high rates of misdiagnosis and refractoriness of the disease. Cases presentations: The presented cases are patients of acute suppurative cutaneous infection without involvement of other organs. We report four cases, of which two cases were localized cutaneous nocardiosis and the other two were lymphocutaneous type of nocardiosis. All cases were diagnosed with pus culture which turned out to be Nocardia brasiliensis. We report an improvement of primary cutaneous nocardiosis symptoms in the four patients treated with non-sulfonamides. All patients were cured and recovered without recurrence during follow-up. Conclusion: Our results suggest that non-sulfonamides are effective treatment for the patients with primary cutaneous nocardiosis who are resistant or intolerant to sulfonamides. Keywords: primary cutaneous nocardiosis, treatment, non-sulfonamides

Jiaqi Li,1,2 Jing Zhao,2 Huan Wang,2 Xiaohan Li,2 Aixia Liu,2 Qin Qin,1,3 Boan Li1,2 1Basic Medicine College, Navy Military Medical University of Chinese PLA, Shanghai 200433, People’s Republic of China; 2Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing 100039, People’s Republic of China; 3Department of Laboratory Medicine, Changhai Hospital, Navy Military Medical University of Chinese PLA, Shanghai 200433, People’s Republic of China Background: Pregnane X receptor (PXR), which is a member of the nuclear receptor protein family (nuclear receptor subfamily 1 group I member 2 [NR 1I2]), mediates the drug-resistance in the hepatocellular carcinoma (HCC) via enhancing the expression of drug-resistance-related genes which accelerate the clearance of antitumor drugs, eg, sorafenib. However, there are few reports on miRNA targeting PXR participating in the epigenetic regulation of PXR in HCC cells. Materials and methods: TargetScan 7.2, an online method, was used to predict the miRNAs potentially targeting PXR. The expression of PXR and PXR downstream genes was detected by quantitative real-time PCR (qPCR) and Western blot. The clearance of sorafenib in HCC cells was monitored by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS). The effects of miRNA on sorafenib’s efficacy were examined by in vitro methods, eg, MTT, and in vivo methods, eg, subcutaneous or intrahepatic tumor model. Results: By virtual screening, we identified that miR-140-3p possibly targets PXR and then confirmed that the overexpression of miR-140-3p via lentiviral particles inhibited the expression of PXR in HCC cells. The downregulation of PXR’s expression by miR-140-3p led to the reduction of PXR downstream genes’ expression, which finally resulted in the decelerating clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. The effect of miR-140-3p could not modulate the expression of mutated PXR and the effect of miR-140-3p could also be inhibited by miR-140-3p’s inhibitor. Moreover, miR-140-3p enhanced the antitumor effect of sorafenib in both the subcutaneous and intrahepatic HCC tumor models. Conclusion: Our study suggests that targeting PXR by miR-140-3p is a promising strategy for enhancing sorafenib’s efficacy during HCC treatment. Keywords: hepatocellular carcinoma, microRNA, pregnenolone X receptor, sorafenib

The analytical expression of the magnetic field distribution within the aperture of a circular vacuum chamber due to the induced eddy is derived. Two cases are discussed, one is the absence of iron, the other is that the vacuum chamber is between the iron poles, that implies the use of the image current methods. The current angular distribution in the vacuum chamber can be calculated from the ramping rate of the exposed field, then the contour integration is applied to the circular current to obtain the field distribution. The formula can be used to estimate the undesired fields from a circular beam box when it is exposed to a ramping field., Comment: 6 pages, 3 figures

The central motivation of the thesis was to provide possible solutions and concepts to improve the performance (e.g. activity and selectivity) of electrochemical N2 reduction reaction (NRR). Given that porous carbon-based materials usually exhibit a broad range of structural properties, they could be promising NRR catalysts. Therefore, the advanced design of novel porous carbon-based materials and the investigation of their application in electrocatalytic NRR including the particular reaction mechanisms are the most crucial points to be addressed. In this regard, three main topics were investigated. All of them are related to the functionalization of porous carbon for electrochemical NRR or other electrocatalytic reactions. In chapter 3, a novel C-TixOy/C nanocomposite has been described that has been obtained via simple pyrolysis of MIL-125(Ti). A novel mode for N2 activation is achieved by doping carbon atoms from nearby porous carbon into the anion lattice of TixOy. By comparing the NRR performance of M-Ts and by carrying out DFT calculations, it is found that the existence of (O-)Ti-C bonds in C-doped TixOy can largely improve the ability to activate and reduce N2 as compared to unoccupied OVs in TiO2. The strategy of rationally doping heteroatoms into the anion lattice of transition metal oxides to create active centers may open many new opportunities beyond the use of noble metal-based catalysts also for other reactions that require the activation of small molecules as well. In chapter 4, a novel catalyst construction composed of Au single atoms decorated on the surface of NDPCs was reported. The introduction of Au single atoms leads to active reaction sites, which are stabilized by the N species present in NDPCs. Thus, the interaction within as-prepared AuSAs-NDPCs catalysts enabled promising performance for electrochemical NRR. For the reaction mechanism, Au single sites and N or C species can act as Frustrated Lewis pairs (FLPs) to enhance the electron donation and back-donation process to activate N2 molecules. This work provides new opportunities for catalyst design in order to achieve efficient N2 fixation at ambient conditions by utilizing recycled electric energy. The last topic described in chapter 5 mainly focused on the synthesis of dual heteroatom-doped porous carbon from simple precursors. The introduction of N and B heteroatoms leads to the construction of N-B motives and Frustrated Lewis pairs in a microporous architecture which is also rich in point defects. This can improve the strength of adsorption of different reactants (N2 and HMF) and thus their activation. As a result, BNC-2 exhibits a desirable electrochemical NRR and HMF oxidation performance. Gas adsorption experiments have been used as a simple tool to elucidate the relationship between the structure and catalytic activity. This work provides novel and deep insights into the rational design and the origin of activity in metal-free electrocatalysts and enables a physically viable discussion of the active motives, as well as the search for their further applications. Throughout this thesis, the ubiquitous problems of low selectivity and activity of electrochemical NRR are tackled by designing porous carbon-based catalysts with high efficiency and exploring their catalytic mechanisms. The structure-performance relationships and mechanisms of activation of the relatively inert N2 molecules are revealed by either experimental results or DFT calculations. These fundamental understandings pave way for a future optimal design and targeted promotion of NRR catalysts with porous carbon-based structure, as well as study of new N2 activation modes. Die zentrale Motivation der Arbeit war es, mögliche Lösungen und Konzepte zur Verbesserung der Leistung (z.B. Aktivität und Selektivität) der elektrochemischen N2-Reduktionsreaktion (NRR) anzubieten. Da poröse Materialien auf Kohlenstoffbasis in der Regel ein breites Spektrum an strukturellen Eigenschaften aufweisen, könnten sie vielversprechende NRR-Katalysatoren sein. Daher sind das fortgeschrittene Design neuartiger poröser Materialien auf Kohlenstoffbasis und die Untersuchung ihrer Anwendung in der elektrokatalytischen NRR einschließlich der besonderen Reaktionsmechanismen die wichtigsten Punkte, die angegangen werden müssen. In diesem Zusammenhang wurden drei Hauptthemen untersucht. Alle von ihnen stehen im Zusammenhang mit der Funktionalisierung von porösem Kohlenstoff für elektrochemische NRR oder andere elektrokatalytische Reaktionen. In Kapitel 3 wurde ein neuartiger C-TixOy/C-Nanokomposit beschrieben, der durch einfache Pyrolyse von MIL-125(Ti) gewonnen wurde. Ein neuartiger Modus für die N2-Aktivierung wird durch Dotierung von Kohlenstoffatomen aus nahegelegenem porösem Kohlenstoff in das Aniongitter von TixOy erreicht. Durch den Vergleich der NRR-Leistung von M-Ts und die Durchführung von DFT-Berechnungen wird festgestellt, dass die Existenz von (O-)Ti-C-Bindungen in C-dotiertem TixOy die Fähigkeit zur Aktivierung und Reduktion von N2 im Vergleich zu unbesetzten OVs in TiO2 erheblich verbessern kann. Die Strategie, Heteroatome rational in das Aniongitter von Übergangsmetalloxiden zu dotieren, um aktive Zentren zu schaffen, kann viele neue Möglichkeiten eröffnen, die über den Einsatz von edelmetallbasierten Katalysatoren hinausgehen, auch für andere Reaktionen, die ebenfalls die Aktivierung von kleinen Molekülen erfordern. In Kapitel 4 wurde über eine neuartige Katalysatorkonstruktion aus Au-Einzelatomen berichtet, die auf der Oberfläche von NDPCs dekoriert sind. Die Einführung von Au-Einzelatomen führt zu aktiven Reaktionsstellen, die durch die in NDPCs vorhandenen N-Spezies stabilisiert werden. So ermöglichte die Interaktion innerhalb von hergestellten AuSAs-NDPCs-Katalysatoren eine vielversprechende Leistung für die elektrochemische NRR. Für den Reaktionsmechanismus können Au-Einzelstandorte und N- oder C-Spezies als frustrierte Lewis-Paare (FLPs) fungieren, um den Elektronenabgabe- und Rückgabeprozess zur Aktivierung von N2-Molekülen zu verbessern. Diese Arbeit bietet neue Möglichkeiten für das Design von Katalysatoren, um eine effiziente N2-Fixierung unter Umgebungsbedingungen durch die Nutzung recycelter elektrischer Energie zu erreichen. Das letzte in Kapitel 5 beschriebene Thema konzentrierte sich hauptsächlich auf die Synthese von dualem heteroatomdotiertem porösem Kohlenstoff aus einfachen Vorläufern. Die Einführung von N- und B-Heteroatomen führt zur Konstruktion von N-B-Motiven und frustrierten Lewis-Paaren in einer mikroporösen Architektur, die ebenfalls reich an Punktdefekten ist. Dies kann die Adsorptionskraft verschiedener Reaktanden (N2 und HMF) und damit deren Aktivierung verbessern. Infolgedessen weist BNC-2 eine wünschenswerte elektrochemische NRR- und HMF-Oxidationsleistung auf. Gasadsorptionsexperimente wurden als einfaches Werkzeug zur Aufklärung des Zusammenhangs zwischen Struktur und katalytischer Aktivität eingesetzt. Diese Arbeit liefert neue und tiefe Einblicke in das rationale Design und den Ursprung der Aktivität bei metallfreien Elektrokatalysatoren und ermöglicht eine physikalisch tragfähige Diskussion der aktiven Motive, sowie die Suche nach deren weiteren Anwendungen. Während dieser Arbeit, die allgegenwärtigen Probleme der niedrigen Selektivität und Aktivität der elektrochemischen NRR werden durch die Gestaltung poröser Katalysatoren auf Kohlenstoffbasis mit hoher Effizienz und die Erforschung ihrer katalytischen Mechanismen. Die Struktur-Leistungsbeziehungen und Aktivierungsmechanismen der relativ inerten N2-Moleküle werden entweder durch experimentelle Ergebnisse oder DFT-Berechnungen aufgezeigt. Diese grundlegenden Erkenntnisse ebnen den Weg für ein zukünftiges optimales Design und eine gezielte Förderung von NRR-Katalysatoren mit poröser Kohlenstoffstruktur, sowie für die Untersuchung neuer N2-Aktivierungsmodi.

Liping Xu,* Xi Yang,* Jiayan Chen, Xiaolin Ge, Qin Qin, Hongcheng Zhu, Chi Zhang, Xinchen Sun Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Objective: Statins are widely used lipid-lowering drugs, which have pleiotropic effects, such as anti-inflammation, and vascular protection. In our study, we investigated the radioprotective potential of simvastatin (SIM) in a murine model of radiation-induced salivary gland dysfunction. Design: Ninety-six Institute of Cancer Research mice were randomly divided into four groups: solvent + sham irradiation (IR) (Group I), SIM + sham IR (Group II), IR + solvent (Group III), and IR + SIM (Group IV). SIM (10mg/kg body weight, three times per week) was administered intraperitoneally 1week prior to IR through to the end of the experiment. Saliva and submandibular gland tissues were obtained for biochemical, morphological (hematoxylin and eosin staining and Masson’s trichrome), and Western blot analysis at 8hours, 24hours, and 4weeks after head and neck IR. Results: IR caused a significant reduction of salivary secretion and amylase activity but elevation of malondialdehyde. SIM remitted the reduction of saliva secretion and restored salivary amylase activity. The protective benefits of SIM may be attributed to scavenging malondialdehyde, remitting collagen deposition, and reducing and delaying the elevation of transforming growth factor β1 expression induced by radiation. Conclusion: SIM may be clinically useful to alleviate side effects of radiotherapy on salivary gland. Keywords: simvastatin, radiation protection, submandibular gland, transforming growth factor-β1, mice

The road of a greenhouse is both damp and narrow, and there are both ground obstacles and space obstacles in a greenhouse, which easily cause the instability problem for a four-wheel independent driving greenhouse spraying mobile robot turning in the greenhouse. In order to improve the steering performance of the greenhouse spraying mobile robot, based on the characteristics that each wheel torque of the robot can be separately controlled, the dynamic model of the four-wheel independent steering system is firstly established by using the D'alembert’s Principle and choosing the sideslip angle and the yaw velocity as the state variables. Then, based on the theory of sliding mode control, a dynamic sliding mode control strategy with exponential approaching rate is proposed by adopting the sideslip angle and the yaw velocity as the joint control variables in order to make the sideslip angle be in the stable range and make the oyaw velocity track the desired value well. Finally, the simulation of the steering performance is performed using Matlab/Simulink. The control response curves of the yaw velocity and the sideslip angle of the robot’s mass-center in a step input and in a sinusoidal input are obtained respectively. It is shown from the simulation results that compared with the feedforward-feedback control method, the proposed dynamic sliding mode control strategy based on the established dynamic model is effective to improve the turning control stability of the mobile robot for greenhouse spraying. The experiment results further verify the feasibility of the proposed turning control strategy.

FT-03

Homo- and heterodimerization of the opioid receptors with functional consequences were reported previously. However, the exact nature of these putative dimers has not been identified. In current studies, the nature of the heterodimers was investigated by producing the phenotypes of the 1:1 heterodimers formed between the constitutively expressed mu-opioid receptor (MOR) and the ponasterone A-induced expression of delta-opioid receptor (DOR) in EcR293 cells. By examining the trafficking of the cell surface-located MOR and DOR, we determined that these two receptors endocytosed independently. Using cell surface expression-deficient mutants of MOR and DOR, we observed that the corresponding wild types of these receptors could not rescue the cell surface expression of the mutants, whereas the antagonist naloxone could. Furthermore, studies with constitutive or agonist-induced receptor internalization also indicated that MOR and DOR endocytosed independently and could not "drag in" the corresponding wild types or endocytosis-deficient mutants. Additionally, the heterodimer phenotypes could be eliminated by the pretreatment of the EcR293 cells with pertussis toxin and could be modulated by the deletion of the RRITR sequence in the third intracellular loop that is involved in the receptor-G protein interaction and activation. These data suggest that MOR and DOR heterodimerize only at the cell surface and that the oligomers of opioid receptors and heterotrimeric G protein are the bases for the observed MOR-DOR heterodimer phenotypes.

The falls incidence among the elderly is important and frequency risk factors. The consequences of falls are broad and contribute to immobility and premature institutionalization. To investigate the association between cognitive function and falling in the elderly living at home we designed a case-control study. 1,576 elderly adults in this study completed interviews, and 274 of them who had falls last year were screened out as the case group. The results showed that mild cognitive impairment was associated with fall in the elderly living at home. After adjustment for marital status, level of education, the number of co-morbid conditions and living situation, the relationship was still significant (OR=1.747, 95%CI [1.099, 2.777]). Multivariate logistic regression revealed that orientation and recall impairment, memory and calculation impairment were independently associated with higher rates of falling in the elderly. For elderly, orientation and recall impairment could predict falling in elderly living at home.

Melanin-concentrating hormone receptor 2 (MCHR2), a second G protein-coupled receptor for melanin-concentrating hormone (MCH), has been known for many years. However, its physiological function is poorly understood. To identify the proteins involved in MCHR2 physiological function, a comparative proteomic analysis of protein expression in SH-SY5Y cells stably expressing human MCHR2 (SH-SY5Y-MCHR2) and control SH-SY5Y cells (SH-SY5Y-mock) - both treated with MCH - was conducted. Significant changes were observed in the expression of 34 proteins, including isocitrate dehydrogenase (NAD) subunit alpha, mitochondrial (IDH3A), phosphoenolpyruvate carboxykinase 1 (PCK1), 6-phosphofructo-2-kinase/fructose-2.6-biphosphatase 4 (PFKFB4), insulin-induced gene 2 protein (INSIG2), and acyl-coenzyme A thioesterase 8 (ACOT8). Among the proteins, IDH3A, PCK1, PFKFB4 increased significantly, and INSIG2, ACOT8 decreased significantly in experimental cells compared with control cells; these findings were further confirmed by semi-quantitative RT-PCR and Western blot analysis. The comparative proteome data may provide a valuable clue to further understand MCHR2 physiological function, and several differentially regulated proteins may be used as target proteins for the development of novel drugs.

Francesco Ruggiero (1957–2007)was a brilliant accelerator physicist, an inventive researcher, a great collaborator, an excellent mentor, and a true gentleman. We here take a look at Francesco’s scientific work, and highlight some of his contributions to accelerator physics. More details can be found in the slides presented by the speakers of the Francesco Ruggiero Memorial Symposium held at CERN on 3 October 2007

A new version of the accelerator design code, MAD, was developed by Francesco Ruggiero in 1996. It can provide the function of automatically searching for the dynamic aperture of a synchrotron. With this MAD, we optimized the dynamic aperture of the upgrade project of Beijing Electron Positron Collider (BEPCII) at its R&D stage.

Experimental study using nude mice human hepatocellular carcinoma (HCC) xenograft indicated that the combination treatment with iodine 131 (131I)-anti-human HCC isoferritin (131I-isoFtAb), cisplatin, and mixed bacterial vaccine (MBV) yielded better inhibition rate as compared with double combination or 131I-isoFtAb alone. Based on these findings, 25 patients with surgically proven nonresectable and pathologically proven HCC have been treated by radioimmunotherapy using 131I-isoFtAb intrahepatic arterial infusion as a part of multimodality treatment. Of the 25 patients, seven (28.0%) received second-look resection after marked shrinkage of tumor. The 1-year survival was 52.5% (12/23) and 2-year survival 27.7% (five of 18) in the entire series. Of the five patients with 2-year survival, four were in the second-look resection group. Patients with tumor less than or equal to 8 cm showed higher second-look resection rate (62.5% versus 11.8%) and 1-year survival (85.7% versus 37.5%) as compared with tumor greater than 8 cm. Mixed bacterial vaccine as adjuvant immunotherapy seemed effective to prolong survival. The 2-year survival was higher in patients with second-look resection as compared with those without (75.0% versus 14.3%). Thus, radioimmunotherapy using 131I-isoFtAb might be one of the modalities of choice, particularly in the conversion of nonresectable to resectable HCC in a well-designed multimodality treatment regimen.

Verticillium wilt, caused by Verticillium dahliae, poses a major threat to lettuce (Lactuca sativa) production in California. Incorporation of resistance into commercial lettuce cultivars offers the least expensive technique of sustaining production in infested areas. To test the breadth of the resistance identified in field experiments, a pair of susceptible ('Saunas' and 'Sniper') and resistant ('La Brillante' and 'Little Gem') lettuce cultivars were used as differentials and individually inoculated with 29 isolates of V. dahliae and two isolates of V. albo-atrum from several hosts, including lettuce, in replicated greenhouse experiments. The reactions of the four cultivars were determined based on the disease severity at maturity. None of the V. albo-atrum isolates or V. dahliae isolates from cruciferous hosts caused significant disease on lettuce. Both Salinas and Sniper were susceptible to many isolates of V. dahliae (21 of 23) from noncruciferous hosts, and the isolates varied in their overall virulence. However, of these, only three isolates caused significant disease on the resistant cvs. La Brillante' and Little Gem. These three isolates also were distinct from the other V. dahliae isolates based on sequence data from the intergenic spacer (IGS) region of the nuclear ribosomal RNA gene, suggesting that they form a phylogenetically distinct subgroup that differs in virulence toward specific lettuce genotypes. Accordingly, isolates of V. dahliae virulent on all tested cultivars, including the resistant La Brillante and Little Gem were designated as race 2, whereas those virulent only on the susceptible Salinas and Sniper were designated as race 1. Although a range of virulence among isolates has been described in other hosts, this is the first description of distinct virulence phenotypes in V. dahliae since a similar race structure was described in tomato in the 1960s.

To better understand the genetic relationships between Verticillium dahliae isolates from lettuce and other phytopathogenic Verticillium spp. isolates from various hosts and geographic locations, the complete intergenic spacer (IGS) region of the nuclear ribosomal RNA gene (rDNA) and the beta-tubulin gene were amplified and sequenced. The sequences of the complete IGS region and the P-tubulin gene were used alone and in combination to infer genetic relationships among different isolates of Verticillium with the maximum-likelihood distance method. Phylogenetic analyses set sequences into four distinct groups comprising isolates V. albo-atrum, V. tricorpus, and V. dahliae from cruciferous and noncruciferous hosts. Within the four Verticillium groups, isolates of V dahliae from cruciferous hosts displayed the closest affinity to V dahliae from noncruciferous hosts. Isolates of V dahliae from noncruciferous hosts could be further divided into four subgroups based on sequence similarities within the IGS region. Cross-pathogenicity tests demonstrated that most Verticillium isolates were as virulent on other hosts as on their hosts of origin. A phenogram based on the cross pathogenicity of individual isolates resembled those derived from the IGS and P-tubulin sequence comparisons. On the basis of the data presented, the potential origin of some isolates of V. dahliae pathogenic on lettuce is proposed.

Keratinocyte transglutaminase catalyzes isopeptide bond formation to yield the highly insoluble crosslinked envelope during terminal differentiation of epidermal cells, Transcriptional response elements were identified in the 5'-flanking DNA of the gene for this enzyme by a combination of transient transfection and electrophoretic mobility shift analyses, Since human keratinocytes transcribed ineffectively transfected transglutaminase flanking DNA, a key feature of these experiments was the use of rat bladder epithelial cells as recipients, Serial deletion experiments identified by transient transfection an important response region containing three putative AP2-like response elements approximately 0.5 kilobases from the transcription initiation site, Oligonucleotides, each containing a single one of the elements, formed specific complexes with keratinocyte nuclear proteins, Two of the response elements were found to be functional by transfection in site-specific deletion experiments, Of these one formed specific DNA-protein complexes with nuclear proteins only from cells exhibiting keratinocyte differentiation. UV cross-linking experiments estimated the protein component of the complex to be approximate to 85 kDa, This response element alone increased substantially the transcription of a minimal transglutaminase promoter in transient transfections. Further characterization of the putative transcription factor binding to this response element may provide insight into the regulation of keratinocyte transglutaminase.

The Beijing Electron-Positron Collider (BEPC) has been running for both high energy physics (HEP) and synchrotron radiation (SR) researches since 1989. Good performance of BEPC accomplishes a lot of achievements in the tau-charm region over the past decade, and in many fields of SR applications as well. As an upgrading scheme from BEPC, the BEPCII project was approved by the Chinese government in the early time of this year, with a micro-beta scheme and multi-bunch collision in a doublering machine installed in the current BEPC tunnel. The design work of the BEPCII is being carried on. This paper will describe the main progresses on the design of the BEPCII in the field of accelerator physics., Comment: Invited talk at the Workshop on e+e- in the 1-2 GeV range, Alghero, Italy, September 2003 (eConf C0309101)

Electron beams with the lowest, normalized transverse emittance recorded so far were produced and confirmed in single-bunch-mode operation of the Accelerator Test Facility at KEK. We established a tuning method of the damping ring which achieves a small vertical dispersion and small x-y orbit coupling. The vertical emittance was less than $1%$ of the horizontal emittance. At the zero-intensity limit, the vertical normalized emittance was less than $2.8\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}8}\mathrm{rad}\mathrm{m}$ at beam energy 1.3 GeV. At high intensity, strong effects of intrabeam scattering were observed, which had been expected in view of the extremely high particle density due to the small transverse emittance.

We present energy spread and bunch length measurements at the Accelerator Test Facility (ATF) at KEK, as functions of current, for different ring rf voltages, and with the beam both on and off the coupling resonance. We fit the on-coupling bunch shapes to those of an impedance model consisting of a resistor and an inductor connected in series. We find that the fits are reasonably good, but that the resulting impedance is unexpectedly large., Comment: 9 pages, 5 figures, presented at 10th International Symposium on Applied Electromagnetics and Mechanics (ISEM2001)

The limitations of the dynamic aperture due to field errors of the super-conducting magnets is a notorious problem for the LHC. Given the large amount of independent studies performed by a sizeable research team it becomes necessary to define a common tracking strategy. The emphasis is placed on an elaborate on - and off - line processing of the tracking data making use of all tools presently available. To manage the very time-comsuming investigations our approach is two-fold: firstly we are maximising the computing power running optimised code on state of the art equipment which is continuously upgraded and secondly we speed up the studies by using reliable and automated early indicators for long-term losses. The procedure is exemplified with a series of tracking runs for the LHC version 4 at injection.

The waxy (Wx) gene of rice encodes a granule-bound starch synthase (GBSS = waxy protein) required for the synthesis of amylose in endosperm. An analysis of Wx transcripts, Wx protein, and amylose content of 31 rice cultivars revealed that endosperm amylose and Wx protein contents are correlated with the ability of the cultivar to excise intron I from the leader sequence of the Wx transcript. Cultivars with high endosperm amylose content (group I) contain high levels of amylose, Wx protein, and the mature 2.3 kb Wx mRNA. Cultivars with intermediate amylose content (group II) produce substantial amounts of a large 3.3 kb Wx pre-mRNA, with intron I still present, in addition to the mature Wx mRNA, and intermediate levels of Wx protein. Glutinous rice (group III cultivars) contains no amylose, no Wx protein, and no mature Wx mRNA; only the incompletely spliced 3.3 kb Wx pre-mRNA is present in group III cultivars. Based on these results, it is hypothesized that the amylose content of rice endosperm is regulated at the level of Wx transcript processing, and, more specifically, at the stage of intron I excision from the Wx pre-mRNA.