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Liying Lu,1,2 Mengdan Pang,1,2 Tingting Chen,1,2 Yingying Hu,1,2 Likai Chen,3 Xiaoyue Tao,1,2 Shangqin Chen,1,2 Jianghu Zhu,1,2 Mingchu Fang,1,2 XiaoLing Guo,1,4 Zhenlang Lin1,2,4 1Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Key Laboratory of Perinatal Medicine of Wenzhou, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Elson S. Floyd College of Medicine at Washington State University, Spokane, WA, USA; 4Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: XiaoLing Guo; Zhenlang Lin, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang, 325027, People’s Republic of China, Tel +00-86-138-0668-9800, Fax +86-0577-88002198, Email guoxling@hotmail.com; linzhenlang@hotmail.comIntroduction: Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear.Methods: In this study, we established a CoCl2-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms.Results: Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro.Discussion: Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.Keywords: neonatal hypoxic-ischemic brain damage, protopine, reactive oxygen species, apoptosis, mitochondrial biogenesis

Zhengjia Zhang,1,* Xinyi Luo,1,* Xiaoxia Xue,1 Mingshi Pang,1 Xiangpeng Wang,1 Liuchunyang Yu,1 Jinxiu Qian,1 Xiaoyu Li,1 Meng Tian,1 Aiping Lu,2 Cheng Lu,3 Yuanyan Liu1 1School of Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, People’s Republic of China; 3Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanyan Liu; Cheng Lu, Email yyliu_1980@163.com; lv_cheng0816@163.comBackground: The morbidity and mortality of triple-negative breast cancer (TNBC) are still high, causing a heavy medical burden. CCL5, as a chemokine, can be involved in altering the composition of the tumor microenvironment (TME) as well as the immunosuppressive degree, and has become a very promising target for the treatment of TNBC. Dysregulation of microRNAs (miRNAs) in tumor tissues is closely related to tumor progression, and its utilization can be used to achieve therapeutic purposes. Engineered exosomes can avoid the shortcomings of miRNAs and also enhance their targeting and anti-tumor effects through engineering. Therefore, we aimed to create a cRGD-modified exosome for targeted delivery of miR-588 and to investigate its effect in remodeling immunosuppressive TME by anchoring CCL5 in TNBC.Methods: In this study, we loaded miR-588 into exosomes using electroporation and modified it with cRGD using post insertion to obtain cRGD-Exos/miR-588. Transmission electron microscopy (TEM), nanoparticle tracking assay technique (NTA), Western Blots, qPCR, and flow cytometry were applied for its characterization. CCK-8, qPCR and enzyme-linked immunosorbent assay (ELISA), in vivo fluorescence imaging system, immunohistochemistry and H&E staining were used to explore the efficacy as well as the mechanism at the cellular level as well as in subcutaneous graft-tumor nude mouse model.Results: The cRGD-Exos/miR-588 was successfully constructed and had strong TNBC tumor targeting in vitro and in vivo. Meanwhile, it has significant efficacy on TME components affected by CCL5 and the degree of immunosuppression, which can effectively control TNBC with good safety.Conclusion: In this experiment, cRGD-Exos/miR-588 was prepared to remodel immunosuppressive TME by anchoring CCL5, which is affected by the vicious cycle of immune escape. Overall, cRGD-Exos/miR-588 explored the feasibility of targeting TME for the TNBC treatment, and provided a competitive delivery system for the engineered exosomes to deliver miRNAs for antitumor therapy drug.Keywords: engineered exosome, triple negative breast cancer, miR-588, CCL5, tumor environment

Fang-fang Fan, Xiao Yu, Zi-wei Shuai, Xiao-yun Hu, Min Pang, Yi-wei Shi NHC Key Laboratory of Pneumoconiosis, Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Min Pang; Yi-wei Shi, Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, No. 85, Jiefang South Road, Taiyuan, Shanxi, 030001, People’s Republic of China, Tel +86-18734890328, Email pangmin2009@126.com; chinasyw225@163.comIntroduction: Although Legionella is not the most common pathogen of community-acquired pneumonia, the epidemiological distribution of pneumonia pathogens has changed in recent years, with a gradual increase in some rare pathogens. For example, pneumonia that occurs after water source contamination is mostly caused by Legionella infection. This paper reports the diagnosis and treatment process of a patient after Legionella infection, who had misdiagnosis at the beginning, rapidly progressed to severe disease and combined with fungal infection. This article focuses on the timely and effective treatment of rapidly progressing Legionella pneumonia, in anticipation of a better understanding of the diagnosis and treatment of the disease.Case Presentation: Here, we report a case of legionella infection with the nausea, vomiting as the first symptoms accompanied by weakness, chills, dizziness, abdominal discomfort in a 75-year-old female. The patient had a history of type 2 diabetes for 30 years, diabetic peripheral neuropathy for more than 20 years, arterial hypertension for 10 years, bone hyperplasia for more than 5 years, resection of right-sided thyroid cystadenoma in 1990. The patient had firstly been diagnosed with cholecystitis and gallbladder neck stones, diet abstinence, metronidazole, cefoperazone sulbactam, and rehydration were given. The patient responded poorly to these empiric treatments. The patient was given moxifloxacin in combination with azithromycin after the onset of respiratory symptoms, but the condition continued to deteriorate, and tigecycline was subsequently added. After the mechanical ventilation and the treatment plan adjusting, she improved significantly.Conclusion: Immunocompromised patient combined with underlying diseases are more susceptible to infection in an environment contaminated with Legionella, and the rapid onset and atypical respiratory symptoms make it easy to misdiagnose the disease, thus delaying treatment and leading to further deterioration. Timely diagnosis, early mechanical ventilation and rational drug administration were fundamental to treat Legionella pneumonia.Keywords: Legionella pneumonia, mechanical ventilation, digestive symptoms

Hardness is an essential mechanical indication of cemented carbides. The current work presents an approach to predict the hardness of three-phase WC–Co–Cubic cemented carbides, which establishes a relationship among composition, structure and mechanical performance. With the input of initial composition and grain sizes of carbides, structural parameters needed to predict the hardness can be calculated by thermodynamic calculations and diffusion simulations. The calculated hardness of a series of WC–Co–Cubic cemented carbides agrees reasonably with the experimental data. The present model is of reference to predict the hardness for multi-phase composites and design the new type of WC–Co-based cemented carbides.

Meng Pang,1 Chunyuan Li,1 Dong Zheng,1 Ying Wang,2 Jing Wang,1 Weilong Zhang,1 Fang Li,1 Hongmei Jing1 1Department of Hematology, Third Hospital of Peking University, Beijing, People’s Republic of China; 2Department of Immunology, Key Laboratory of Medical Immunology of Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaCorrespondence: Fang Li; Hongmei Jing Email lifang19611962@163.com; hongmeijing@bjmu.edu.cnBackground: The presence of circulating plasma cells (cPCs) was associated with a worse prognosis in multiple myeloma patients. However, the underlying mechanisms involved in the migration and invasion of bone marrow myeloma cells (BMMCs) to cPCs remains unclear. Here, we investigate the possible factors related to hematogenous myeloma cell dissemination and potential regulatory mechanisms.Methods: BMMCs and cPCs of five extramedullary plasmacytoma (EMP) patients were selected for single cell RNA sequencing, We found that the expression level of sphingosine-1-phosphate receptor 2 (S1RP2) was lower in cPCs compared with that in BMMCs. Then, we investigated the effect of S1PR2 in cell migration and invasion through pharmacologic inhibition with a S1PR2-selective antagonist JTE-013 or knockdown of S1PR2 expression in MM cell line U266.Results: The results showed that S1PR2 inhibition with JTE-013 or S1PR2-shRNA significantly promoted cell migration and invasion in U266 cells. We measured the expression of invasion-related proteins by Western blot and found that knockdown of S1PR2 could reduce MMP-9 expression in U266 cells. Furthermore, we found NF-κB pathway may mediate the inhibition effects of S1PR2 on cell migration and invasion in MM cells.Conclusion: Our findings demonstrated that S1PR2 downregulation may contribute to the initial extramedullary translocation by promoting cell migration and invasion through NF-κB pathway activation.Keywords: multiple myeloma, extramedullary plasmacytoma, circulating plasma cells, NF-κB, S1PR2

Copy number variation (CNV) is a main cause of male infertility, yet its influence still remains elusive in that of females. To investigate the correlation between CNV and female infertility, we applied whole-genome CNV analyses by next generation Sequencing (NGS), and analyzed 324 female infertility samples in Xinjiang Province, People's Republic of China. We identified 29 CNVs in total, of which 10 were novel CNVs. We found these CNVs mostly in chromosome X. The CNVs from one sample overlapped the POF1B gene that was related to premature ovarian failure (POF). The rest of these CNVs overlapped important functional genes related to neuropathy, brain, skin and retina, and the relationship between these CNVs and fertility needs to be studied further. We also found recurrent CNVs located on Xp22.31 and 22ql 1.21 in five and three cases, respectively. Our study first identified and characterized CNVs (CNVs preference, recurrent CNVs) in female infertility, also provided genetic evidence and references for future study and infertility etiology research.

Hf-N based alloys have been widely used and studied in the fields of electronic devices and cutting tools industry. A thermodynamic description of this system is essential for further materials development. By means of CALPHAD method, a thermodynamic modeling of the Hf-N system was carried out based on the available phase diagram data as well as thermodynamic property data. The Fcc phase is modeled as (Hf, Va)1(N, Va)1 to cover the composition range since the solubility of nitrogen in Fcc phase is reported up to about 52 at.%. A set of self-consistent thermodynamic parameters for the Hf-N system has been obtained. The computed phase diagrams and thermodynamic quantities using the present parameters agree well with the experimental data.

We have compared the decay rates of KL and KS toΠ+ Π- Π0Π0 final states using a subset of the data from the KTeV experiment (E832) at Fermilab. We find that the direct-CP-violation parameter Re (μ’/μ) is equal to [28.0±3.0(stat)±2.8(syst)]×10-4. This result definitively establishes the existence of CP violation in a decay process. © 1999 The American Physical Society.

We have compared the decay rates of KL and KS toΠ+ Π- Π0Π0 final states using a subset of the data from the KTeV experiment (E832) at Fermilab. We find that the direct-CP-violation parameter Re (μ’/μ) is equal to [28.0±3.0(stat)±2.8(syst)]×10-4. This result definitively establishes the existence of CP violation in a decay process. © 1999 The American Physical Society.

Thymic epithelial cells play a crucial role in the selection of developing thymocytes. Thymocyte-epithelial cell interactions involve a number of adhesion molecules, including members of the integrin and immunoglobulin superfamilies. We found that human thymic epithelial cells synthesize an endogenous lectin, galectin-1, which binds to oligosaccharide ligands on the surface of thymocytes and T lymphoblastoid cells. Binding of T lymphoblastoid cells to thymic epithelial cells was inhibited by antibody to galectin-1 on the epithelial cells, and by two antibodies, T305 and 2B11, that recognize carbohydrate epitopes on the T cell surface glycoproteins CD43 and CD45, respectively. T lymphoblastoid cells and thymocytes bound recombinant galectin-1, as demonstrated by flow cytometric analysis, and lectin binding was completely inhibited in the presence of lactose. The degree of galectin-1 binding to thymocytes correlated with the maturation stage of the cells, as immature thymocytes bound more galectin-1 than did mature thymocytes. Preferential binding of galectin-1 to immature thymocytes may result from regulated expression of preferred oligosaccharide ligands on those cells, since we found that the epitope recognized by the T305 antibody, the core 2 O-glycan structure on CD43, was expressed on cortical, but not medullary cells. The level of expression of the UDP-GlcNAc:Gal beta 1,3GalNAc-R beta 1, 6GlcNAc transferase (core 2 beta 1, 6 GlcNAc transferase, or C2GnT), which creates the core 2 O-glycan structure, correlated with the glycosylation change between cortical and medullary cells. Expression of mRNA encoding the C2GnT was high in subcapsular and cortical thymocytes and low in medullary thymocytes, as demonstrated by in situ hybridization. These results suggest that galectin-1 participates in thymocyte-thymic epithelial cell interactions, and that this interaction may be regulated by expression of relevant oligosaccharide ligands on the thymocyte cell surface.