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© 2023 European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration. JAMA Network Open. Open Access: This is an open access article distributed under the terms of the CC-BY License, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., Dr Frikke-Schmidt was funded by grants from the Lundbeck Foundation (grant No. R278-2018-804), the Danish Heart Foundation, and Innovation Fund Denmark (grant No. 9084-00020B).

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., JAMA Network Open, 6 (5)

Importance An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.Objective To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.Design, Setting, and Participants This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.Exposures Genetically determined modifiable risk factors.Main Outcomes and Measures Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.Results The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.23 [95% CI, 1.01-1.50]).Conclusions and Relevance This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation. Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Additional file 2: Table S1. Effect of CAFs on popliteal lymph nodes (LNs) metastasis in vivo. Table S2. Primers for real-time RT-PCR.

17 páginas, 3 figuras, 2 tablas. Material suplementario accesible en : https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805006, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., The work for this manuscript was further supported by the CoSTREAM project (www.costream.eu) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’).

Additional file 1: Figure S1. HDLEC monolayers incubated with the indicated CM for 24 h were analysed by immunofluorescence (IF) staining of VE-cadherin (red). Blue indicates the nucleus. Figure S2. siLRP1 abolished the biological effects of PAI-1 on HDLECs, related to Fig 5C. Figure S3. Suppression of ERK1/2 phosphorylation by U0126 in HDLECs affected the biological behaviour of PAI-1, related to Fig 5F. Figure S4. Suppression of AKT phosphorylation by MK2206 in HDLECs affected the biological behaviour of PAI-1, related to Fig 5G. Figure S5. Validation and efficacy of LRP1 gene silencing was performed by qPCR. Normalized gene expression over GAPDH is shown with the means ± SD of three independent experiments. *P < 0.05.

In this paper, the chain structure of magnetorheological fluid (MRF) magnetic particles was studied and analyzed, the mechanical model of MRF with different diameter ferromagnetic particles was established, silicone oil-based MRF with different particle volume fractions was prepared, the shear properties of the MRF were tested, and the theoretical and experimental data were compared. The experimental results show that the shear stress is stable with the increase of shear strain rate under the action of the magnetic field, and it has a shear thinning effect. The shear stress increases linearly with the increase of particle volume fraction. The shear stress increases with the increase of magnetic induction intensity. After data analysis and in the case of control variables, the average error of improved theoretical data and experimental data is lower than that of previous theoretical data and experimental data, which verifies that the improved theory (mechanical model) has a certain accuracy.

Lymphatic remodelling in the hypoxic tumour microenvironment (TME) is critically involved in the metastasis of cervical squamous cell carcinoma (CSCC); however, its underlying mechanisms remain unclear. Here, we uncovered a novel lymphatic pattern in the hypoxic TME, wherein lymphatic vessels (LVs) are encapsulated by tumour-associated macrophages (TAMs) to form an interconnected network. We describe these aggregates as LVEM (LVs encapsulated by TAMs) considering their advantageous metastatic capacity and active involvement in early lymph node metastasis (LNM). Mechanistic investigations revealed that interleukin-10 (IL-10) derived from hypoxic TAMs adjacent to LVs was a prerequisite for lymphangiogenesis and LVEM formation through its induction of Sp1 upregulation in lymphatic endothelial cells (LECs). Interestingly, Sp1high LECs promoted the transactivation of C–C motif chemokine ligand 1 (CCL1) to facilitate TAM and tumour cell recruitment, thereby forming a positive feedback loop to strengthen the LVEM formation. Knockdown of Sp1 or blockage of CCL1 abrogated LVEM and consequently attenuated LNM. Notably, CSCCnon-LNM is largely devoid of hypoxic TAMs and the resultant LVEM, which might explain its metastatic delay. These findings identify a novel and efficient metastasis-promoting lymphatic pattern in the hypoxic TME, which might provide new targets for anti-metastasis therapy and prognostic assessment. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-020-09766-2.

Lymph node metastasis (LNM), a critical prognostic determinant in cancer patients, is critically influenced by the presence of numerous heterogeneous cancer-associated fibroblasts (CAFs) in the tumor microenvironment. However, the phenotypes and characteristics of the various pro-metastatic CAF subsets in cervical squamous cell carcinoma (CSCC) remain unknown. Here, we describe a CAF subpopulation with elevated periostin expression (periostin+ CAFs), located in the primary tumor sites and metastatic lymph nodes, that positively correlated with LNM and poor survival in CSCC patients. Mechanistically, periostin+ CAFs impaired lymphatic endothelial barriers by activating the integrin-FAK/Src-VE-cadherin signaling pathway in lymphatic endothelial cells and consequently enhanced metastatic dissemination. In contrast, inhibition of the FAK/Src signaling pathway alleviated periostin-induced lymphatic endothelial barrier dysfunction and its related effects. Notably, periostin- CAFs were incapable of impairing endothelial barrier integrity, which may explain the occurrence of CAF-enriched cases without LNM. In conclusion, we identified a specific periostin+ CAF subset that promotes LNM in CSCC, mainly by impairing the lymphatic endothelial barriers, thus providing the basis for potential stromal fibroblast-targeted interventions that block CAF-dependent metastasis.

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8+ T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2–DNMT1–IFN-γ signalling to suppress and exhaust CD8+ T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.

The accumulation of tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is associated with malignant progression in cancer. However, the mechanisms by which the hypoxic TME facilitates TAM infiltration are not fully understood. This study showed that high ZEB1 expression in hypoxic cervical cancer cell islets was positively correlated with CD163+ TAM accumulation. ZEB1 in hypoxic cancer cells promoted the migration of TAMs in vitro and altered the expression of multiple chemokines, especially CCL8. Mechanistically, hypoxia-induced ZEB1 activated the transcription of CCL8, which attracted macrophages via the CCR2–NF-κB pathway. Furthermore, ZEB1 and CCL8 were independent prognostic factors in cervical cancer patients based on The Cancer Genome Atlas (TCGA) data analysis. In conclusion, hypoxia-induced ZEB1 exerts unexpected functions in cancer progression by fostering a prometastatic environment through increased CCL8 secretion and TAM recruitment; thus, ZEB1 may serve as a candidate biomarker of tumour progression and provide a potential target for disrupting hypoxia-mediated TME remodelling.

Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis. miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p. Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.

The activation of stromal fibroblasts into cancer-associated fibroblasts (CAFs) has been suggested to promote primary tumor growth and progression; however, the mechanisms underlying the crosstalk between tumors and fibroblasts that drives stromal heterogeneity remain unknown. Here, we show that high Wnt2B levels were positively correlated with the number of CAFs in cervical cancer (CC). More importantly, Wnt2B was characteristically enriched in CC cell-secreted exosomes and transferred into fibroblasts to promote fibroblast activation via Wnt/β-catenin signaling, and inhibiting exosomal release or the Wnt/β-catenin signaling pathway diminished the activation induced by exosomal Wnt2B. Moreover, circulating exosomal Wnt2B also promoted CAF conversion in vitro and its expression was significantly higher in CC patients. In conclusion, our findings indicate that CC cell-derived Wnt2B can induce the activation of fibroblasts into CAFs, mainly via exosome-dependent secretion, thus providing directions for the development of diagnostic and therapeutic targets for CC progression.

Supplemental material, sj-pdf-1-ade-10.1177_1687814021992153 for Fatigue life prediction of train wheel shaft based on load spectrum characteristics by Jiao Luo, Shuci Wang, Xintian Liu and Shuanglong Geng in Advances in Mechanical Engineering

Bupleuri Radix is a traditional staple Chinese medicinal material which has a wide range of medicinal values. However, with the increase of the international trade of Bupleuri Radix, its quality and safety issues have attracted much attention. Therefore, the establishment of international standards for Bupleuri Radix has important practical significance. In view of this, based on our foundation work on the standardization of Chinese medicine and international standards, this review systematically collates the quality standards of the major countries(regions) in which Bupleuri Radix is used, including the origin, macroscopic characteristics, microscopic characteristics, determination of marker compounds and extrinsic harmful contaminants. The existing problems and suggestions are also discussed in this review, which may provide reference for the study of the quality standard of Bupleuri Radix.

Cancer-associated lymphatic endothelial cells (LECs) are an active barrier to the effector arm of the anti-tumor immune response; however, it remains unclear how LECs become immunosuppressive in the tumor microenvironment (TME). Exosomal microRNAs (miRNAs) have recently been implicated in intercellular crosstalk within the TME. Here, we report a mechanistic model via which cervical cancer-secreted, exosome-encapsulated microRNA (miR)-1468-5p promotes lymphatic PD-L1 upregulation and lymphangiogenesis to impair T cell immunity. Subsequently, exosomal miR-1468-5p epigenetically activates the JAK2/STAT3 pathway in LECs by directly targeting homeobox containing 1 (HMBOX1) in the SOCS1 promoter, activating an immunosuppressive program that allows cancer cells to escape anti-cancer immunity. Furthermore, clinical data reveal that high serum exosomal miR-1468-5p levels correlate with TME immunosuppressive status and poor prognosis in cervical cancer (CCa) patients. Taken together, our results suggest that cancer-secreted exosomal miR-1468-5p instructs LECs to form an integrated immunosuppressive TME component and may be a prognostic biomarker and therapeutic target for CCa.

BackgroundGS-5734 as a novel and promising medicine for COVID-2019, its biological impact on the mammalian reproductive system has not been systematically studied. The aim of this study was to evaluate the effects of GS-5734 on sperm parameters and spermatogenesis in mice.Materials and MethodsIn this study, GS-5734 was synthesized according to the report. 28 adult male mice were randomly segregated into four groups (n=7 for each group). The group 1 was set as the control group, the group 1, 2, 3 and 4 were administered with GS-5734 at a daily dose of 0, 10, 50, 150 μg/mouse respectively, by intraperitoneal injection for 10 days. On the 7th day after the last injection, the testes and cauda epididymides were collected for HE staining and sperm concentration, motility, morphology analysis.ResultsThe results indicated that after treated with GS-5734, the total sperm count and motile sperm rate showed downward trends, the abnormal sperm rate showed an increasing trend. As compared with the control group, GS-5734 at a daily dose of 150 μg/mouse caused a significant decrease in sperm concentration and motility, and a significant increased of abnormal sperm rate; the 50 μg/mouse drug treatment lead to a significant decrease in sperm motility and an increase in abnormal sperm rate. The HE staining of testicular and epididymal tissues showed that the spermatogenesis of mice was significantly deteriorated with the increasing dosage of GS-5734, especially in the 150 μg/mouse group.ConclusionOur findings suggest that a high dosage of GS-5734 may induce testicular toxicity and result in deterioration of sperm parameters in mice. More investigation on the reproductive toxicity of GS-5734 is required.

Supplemental material, Luo_Chen_Chen_online_supp for Coming Back and Giving Back: Transposition, Institutional Actors, and the Paradox of Peripheral Influence* by Jiao Luo, Dongjie Chen and Jia Chen in Administrative Science Quarterly

A Pi-sigma fuzzy neural network (FNN), in which the layers of neural networks were organized into a feed-forward system, was used to predict the flow stress and the grain size during isothermal compression of Ti-6Al-2Zr-2Sn-2Mo-1.5Cr-2Nb alloy. After the optical micrography (OM) and scanning electron microscopy (SEM) observations, the grain size of primary α phase was measured via a quantitative metallography image analysis software. The effect of deformation temperature and strain rate on the microstructure was discussed. The comparisons of the predicted flow stress and grain size for the sample data or the non-sample data with the experimental results were given to train the models and confirm the validity in present study. The results show that the accuracy of prediction from the Pi-sigma FNN models is much high, and the Pi-sigma FNN approach can efficiently describe the non-linear and complex relationship of titanium alloys.

Background: G-protein coupled receptors are the largest super family of integral membrane proteins in human. Systemic lupus erythematosus (SLE) is multisystem autoimmune disease characterized by chronic immune activation and the presence of a plethora of autoantibodies. Our hypothesis is that autoantibodies[for full text, please go to the a.m. URL], 47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Currently, the majority of studies using metabolomics data assume that missing values are due to low concentration and impute the missing values to a single value, e.g. half detection threshold, which was shown very high bias4. Furthermore, metabolites with more than an arbitrary cutoff of 20-30% missingness are often excluded from the analyses. However, these solutions do not consider the complex nature of untargeted metabolomics data and may cause biases. We set out to evaluate alternative imputation methods for untargeted metabolomics using the MICE and KNN methods.

Magnetorheological Fluids (MRFs) is rapidly emerging as a type of new fluid intelligence material that is controllable and low-energy consuming with high output and fast response. It has already received widespread attention from many international scholars. In this paper, the orthogonal test of MRFs configuration with six different types of lubricating additives (oleic acid, hydrogenated castor oil, teflon, boron nitride, molybdenum disulfide, graphite) is conducted to study the wettability, zero-field viscosity and yield stress of MRFs under different solid lubricants. According to the size of contact angle, the ability of anti-sedimentation stability of MRFs under different lubricants is compared. The zero-field viscosity of MRFs is tested by viscometer, and the strength of viscosity under the zero-field condition is compared. The yield stress is measured by a self-made yield stress device, and then the sedimentation stability characteristics of MRFs are analyzed. Finally, through the analysis and evaluation of experimental data, it is concluded that molybdenum disulfide as a lubricating additive can effectively improve the anti-sedimentation stability of MRFs, and the general rules of lubricating additives used in MRFs formulations with excellent performance are summarized.

Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis.miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p.Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.

To clarify clinical characteristics of immune thrombocytopenia (ITP) subsets associated with autoimmune diseases (AIDs). Five thousand five hundred twenty patients were reviewed retrospectively. One hundred four ITP patients were included for analysis. Clinical manifestations at first thrombocytopenic episode were recorded. Systemic lupus erythematosus (SLE) and primary Sjogren syndrome (pSS) accounted for a large part in AIDs associated with secondary ITP. SLE-ITP, pSS-ITP, and primary ITP (pITP) patients were different in several aspects in clinical and immunological characteristics. A subgroup of patients in pITP patients with some obvious autoimmune features (defined as AIF-ITP) such as positive ANA but failing to meet the diagnosis criteria now used for a specific kind of connective tissue diseases were also different with other pITP patients in some immunological features, indicating the difference in the pathogenesis mechanism of those autoimmune featured ITP patients. ITP patients were heterogeneous in clinical characteristics. Further study about the different pathogenesis of ITP subsets especially those AIF-ITP patients who only presented with thrombocytopenia will help us have a better understanding of pathogenesis of ITP and a better management of ITP patients.

The effect of processing parameters, including deformation temperature, strain rate and deformation degree on the microstructure evolution and the microstructure variables (grain size and volume fraction of primary α phase) was investigated based on the microstructure observation and the quantitative metallography of the isothermally compressed Ti-6Al-4V alloy. The results show that the curves of grain size of primary α phase are oscillatory in the α+β two-phase region with increasing of the deformation temperature, and meanwhile the volume fraction of primary α phase decreases. The effect of the strain rate on the morphology of primary α phase is significant, while its effect on the microstructure variables of isothermally compressed Ti-6Al-4V alloy is dependent on deformation temperature. The grain size of primary α phase decreases with increasing of strain rate above 1203 K, but below 1203 K it fluctuates. The curves of volume fraction of primary α phase are oscillatory with increasing of strain rate above 1223 K, but below 1223 K the volume fraction decreases. The grain size of primary α phase increases slightly after a drop with increasing of the deformation degree, and meanwhile the secondary α phase decreases gradually. The effect of deformation degree on the volume fraction of primary α phase is not significant.

Organizational participation in morally contested markets, that is, markets surrounded by controversy reflecting values-led beliefs, is an understudied topic (Zelizer, 1978, 1979; Healy, 2006; Quinn, 2008; Anteby, 2010). The extant research has tended to focus on the genesis and evolution of contestation toward certain categories of trades, to the relative neglect of attention toward the responses of organizations, to such contestations. Yet the market exchange outcomes of organizations hinge not only upon social relations (Granovetter, 1985; Uzzi 1996, 1997) and power distribution (Blau, 1964; Emerson, 1976) but also upon the legitimacy benefit that exchange might render (Jensen, 2006). In deciding whether and how to engage in markets associated with debated legitimacy, organizations establish and express their meaning, status and identity (Phillips and Owens, 2004; Jensen, 2010). Particularly in markets that are morally contested, firms inevitably balance two competing sources of institutional demands: the rationale for economic efficiency, and the defense of values and norms. In weighing and negotiating these interests, how do firms behave and choose in response to institutional and organizational factors? Meanwhile, organizations on either side of the market act as critical forces to enhance or challenge a market's capacity to survive (Fligstein and Dauter, 2007; King and Pearce, 2011); given this, how do the organizational participation decisions matter for the institutionalization of a new, morally convicted market as a whole? This dissertation studies organizations as customers, by looking at factors that facilitate or impede their purchasing decisions in morally contested markets. I examine firms' differing decisions toward participation in one such market, the carbon credit trade, across several countries displaying varying cultural attitudes. I study these choices at the nascent, unstable stage, before the carbon market has become institutionalized as a viable solution strategy responding to global environmental challenges. I argue that firms construct the proper scope of commercial activity via channels including managers' individual mental accounting as well as social norms and law, and that all channels can be understood as culturally dependent. Building upon cross-national qualitative comparative work of morally contested markets (Zelizer, 1979), I empirically link market participation patterns to dissimilarities originated from the various national institutional environments surrounding firms (Healy, 2006). I look at organizational structural and strategic factors that affect firms' participation in morally contested markets, in order to understand how cultural norms matter for firms' choices. The prevailing norms and values in the country where a firm operates may be deemed to matter, either because of a firm's reputational concerns vis-à-vis its customers; or because of firm internal rationales, e.g. the top management also shares those values, or the firm wants to appeal to current or potential employees who share those values. By looking at whether cultural values matter more for firms that are more retail oriented, or are more inclined to retain employees, or have a chief executive officer with educational background in economics, I disentangle the internal and external mechanisms. The empirical context for understanding the organizational and institutional dynamism of morally contested markets is the carbon market. By facilitating the exchange of carbon credits, the carbon market authorizes an entity to achieve greenhouse gas reduction goals by exchanging part of its obligation with another party, which is believed to both lower the costs of mitigation and increase the efficiency of emission reductions (Sandor, Walsh and Marques, 2002; Stern, 2006). Since its debut in 2005, however, the idea of carbon trading has been much contested, based on claims that the environment is a sacred good and that providing a market for pollution allows the wealthy to evade their responsibilities (Caney and Hepburn, 2011). The carbon market, then, offers a fitting setting for my study in three ways: First, the market prompts firms to make a distinct choice, between efficiency and norm. Firms reducing their carbon outputs choose either to trade on-market, which is a more efficient solution but violates the cultural notion of a "non-tradeable" environment, or to reduce in-house, which is perceived as a less tainted way of emission abatement, yet a more costly one. Second, the carbon market purports to respond to the issues of global warming and climate change, which has become increasingly recognized as a global priority. Examining the carbon market can elucidate how organizations across nations differ their choices on carbon trading, based on the given organization's headquartered country values and norms. Third, this carbon market allows for directly examining the values effect, by offering a relatively clean-cut measure for the efficiency gains that the market mechanism would provide. My results suggest evidence of a strong cultural norm effect that can indicate whether firms are likely, or not likely, to engage in the carbon credit market. Firms located in countries where people more frequently voice skepticism toward market mechanisms in environmental policy are less likely to engage in the carbon credit market. The channel is specific to cultural norms about environmental-economic trade-offs and not to norms about environmental concerns in general. Moreover, by looking at firm-level factors such as consumer orientation, CEO educational background, and sector-level factors such as unemployment rate, I highlight the mechanisms through which cultural values are demonstrated. The result suggests that for firms' choices, cultural values and norms do matter, for reasons based in rationales that are both internal and external. Beyond illuminating such a values effect that influences the choices firms make, this work reveals the nuanced ways in which values-based beliefs impact corporate behavior by examining the interplay between cultural norms and countervailing sources of legitimacy, namely, regulatory forces as well as other firms' decisions or experiences. The results suggest that while firms regulated to reduce emissions have a higher rate of carbon market participation, the rate difference between regulated and unregulated firms is evidently larger in countries where the idea of using the market to deal with environment problems is perceived as less acceptable. In the meantime, there is little to no evidence that similar or connected organizations' decisions toward participation in the contested market engenders a positive spillover that reinforces the values effect. Both results hint at the unique properties of the values effect as it tends to separates "good" firms from "bad" firms, according with the extent to which corporate behaviors conform to the moral ideals. My investigation of the carbon market among European firms contributes to the institutional literature by highlighting the importance of specific national institutions in particular organizational domains (Vasudeva, Spencer and Teegen, 2012) as well as interrelatedness between institutional theory and strategic perspectives in the context of firm market participation decisions (Oliver, 1991). By assessing the effect of national cultural values in legitimating these nascent markets while taking into account the opportunity cost of not using the market, my dissertation sheds light on some of the conditions that determine when and how much concerns about legitimacy, controlling for efficiency, loom large in market behaviors, as well as which organizational and institutional mechanisms are involved. This dissertation also contributes a new framework for thinking about morally contested markets in responding to the relative lack of studies on what happens before the institutions become institutionalized (Fligstein and Dauber, 1989), by connecting and extending literature on institutionalization. One of institutional theory's main ideas is that the legitimacy of practices within an organizational field rises with the level of their diffusion in the field (DiMaggio and Powell, 1983; Tolbert and Zucker, 1983). By studying the values effect in the nascent stage of institutional development, my dissertation reveals a necessary but often understated condition for extant explanations of institutional shifts (Schneiberg and Soule, 2005), that is, for the instrumental and normative rationality of an institutional project to occupy the same domain which implies the capacity to reinforce each other. In cases where the rationale of economic efficiency is separated from normative rationality by strict moral codes, these moral challenges not only impede buy-in, but also prevent the enactment of the diffusion processes as well as shifts in cultural framings and thus halted the dynamism that usually underlies the spread of practices and social changes. Identifying whether a market institution is embedded within the right social environment helps to shed light on the divergent institutional trajectory that new markets follow. This research has implications for corporate reputation management. A key aspect of corporate social responsibility is dialogue with and responsibilities to diverse stakeholders that project conflicting demands and raise difficulties for companies seeking to meet those demands. The case of the carbon market poses challenges and interesting trade-off for companies intending to pioneer in innovative but controversial CSR instruments. This paper also aims to arrive at implications for the design of the carbon market and policy making. Many observers take the view that the answer to invigorating the carbon market lies in identifying ways to increase demand or reduce supply of carbon credits. What I show and suggest is that, the dissolution of moral restrictions on the carbon market can be seen as one of the most important processes among attempts to institutionalize this currently quasi-taboo market, and should be part of the on-going policy debate.

Task scheduling is a key issue which must be solved in grid computing study, and a better scheduling scheme can greatly improve the efficiency of grid computing. Based on the analysis of disadvantages of adaptive genetic algorithm, the paper introduced a new local convergence criterion and its corresponding improved mutation operation. Combining with neighborhood search in mathematics task scheduling in grid was then performed. Simulation showed that this algorithm could greatly improve the performance of grid tasks scheduling.

This paper reviews the knowledge contributions of previous studies in the area of marriages and family life. The endeavor was to examine the extent of the knowledge contributions on this study area and to highlight possible research direction in line with the marriage and family life satisfaction. The review was done chronologically based on empirical and critical reviews of marriage patterns and family life. The review of empirical studies of marriage patterns and family life studies was done in two aspects: studies in Sri Lankan context and foreign context. According to the review it seemed that there is a research gap in the area of studying marriage patterns and their effects on family life satisfaction. In Sri Lankan context no any study could be found, on marriage and its effects on family life satisfaction. Because of this rationale, the review considered marriage as a major study phenomenon, which has a significant influence on the family life satisfaction and endeavored to provide a base for an empirical study on marriage and family life satisfaction in Sri Lankan context. Keywords: Marriage patterns; Family life satisfaction; Marital Quality; Cohabitation DOI: 10.4038/suslj.v8i1.1847 Sabaramuwa University Journal Vol. 8(1); December 2008, pp 1-17

The resistance-temperature properties of the complex conductive silicone rubber were studied.The change of the resistance of the conductive silicone rubber during the process of rising temperature was analyzed,and the influences of the content of conductive fillers on the resistance-temperature properties of the complex conductive silicone were studied in detail.The specific resistivity changes at different annealing temperatures and the resistance relaxation time with pulling force were measured,and the influence of thermal treatment and content of conductive fillers on the mechanism of the resistance properties was also analyzed.