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Liver injury is a common cause of drug approval withdrawal during drug development, pre-clinical research, and clinical treatment. If not properly treated, patients with severe liver injury can suffer from acute liver failure or even death. Thus, utilization of the convenient in vitro hepatotoxicity assessment model for early detection of drug-induced hepatotoxicity is vital for drug development and safe personalized medication. Biomaterials (e.g., hydrogels, nanofibers, decellularized liver matrix) and bioengineering technologies (e.g., microarrays, micropatterns, 3D printing, and microfluidics) have been applied for in vitro hepatotoxicity assessment models. This review summarizes the structure and functions of the liver as well as the components of in vitro hepatotoxicity assessment models. In addition, it highlights the latest advances in developing hepatotoxicity models with the ultimate goal of further clinical translation.

Square-circle hybrid section (SCHS) tubes under axial loading which combine the advantage of square tubes and circular tubes are investigated. Firstly, effective finite element models of SCHS tubes...

Based on the theoretical crashworthiness model of variable thickness rectangular section tubes, this article simplified the super-folding element to analyze the energy absorption characteristics of...

Background: Crystal-storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of nonneoplastic histiocytes containing intracytoplasmic crystallized immunoglobulins. Although CSH can occur in a variety of organs, including the bone marrow, lungs, lymph nodes, liver, spleen, and kidney, gastric CSH is very rare. Case presentation: We present a 69-year-old man with localized gastric CSH, presenting as positive fecal occult blood for 2 days. Gastroscopy showed that there was a piece of irregular whitish focus in the big bend of gastric antrum, which was soft and elastic. Histologically, the biopsied gastric mucosa showed chronic inflammation, mild activity with erosion, and a large number of eosinophilic mononuclear cells containing fibrillary crystalloid inclusion in the lamina propria. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1 and Igk, which revealed that the cells were histiocytes harboring kappa light chain-restricted immunoglobulin crystals. Electron microscopic examination showed that a large number of high electron density particles were found in the cytoplasm of cells, with the crystal structure, different sizes and shapes.Conclusion: Since this entity is rare and unfamiliar, difficulties in diagnosis may arise. We present a case of localized CSH associated with just such an incidental gastric lesion and reviewed the related literature, in order to improve our understanding of it and avoid misdiagnosis.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is composed of at least four molecular subgroups with distinct clinical characteristics. The sonic hedgehog (SHH) subgroup exhibits the most abundant tumor-associated microglia/macrophages (TAMs) infiltration. SHH-MB patients treated by anti-SHH drugs showed high drug resistance. However, the comprehensive role of TAMs in SHH-MB remains enigma. The aim of this study is to explore the mechanism of TAM activation/polarization in SHH-MB and discover a potential immunotherapeutic target to reduce drug resistance. We first analyzed expression profiles of immuno-microenvironment (IME) in four subgroups of 48 MB tumors using NanoString PanCancer IO360 panel and found TAMs were the major component of IME in SHH-MBs. We further distinguished M1/M2-like TAMs in tumors and found M2-like macrophages, rather than microglia, were enriched in SHH-MBs. In transgenic SHH-MB mice, these TAMs had close relationship with tumor progression. Polarization of the TAMs could be induced by MB-derived exosomes in vitro. We then screened SHH MB-derived exosomal miRNAs and their target genes using RNA sequencing and luciferase assay to clarify their roles in regulating TAM polarization. We found down-regulated let-7i-5p and miR-221-3p can induce M2-like polarization of TAMs via upregulating peroxisome proliferator activated receptor gamma (PPARγ). Finally, we demonstrated the PPARγ antagonist efficiently improved the antitumor activity of SMO inhibitor in vivo, which may be related to inhibition of M2-like TAMs. Our findings suggest a potential therapeutic strategy for SHH-MB by targeting tumor-supportive M2-like TAMs to enhance the therapeutic effect of SMO inhibitors.

Background GNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases. Results The absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family. Conclusions These rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.

Background & Aims C-C motif chemokine receptor 2 (CCR2) has been recognized as a promising target for the treatment of liver fibrosis. PC3-secreted microprotein (PSMP)/microseminoprotein (MSMP) is a novel chemotactic cytokine and its receptor is CCR2. In the present study we investigated the expression and role of PSMP in liver fibrosis/cirrhosis. Methods PSMP expression was studied in patients with fibrosis/cirrhosis and in 3 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl4), bile-duct ligation, or a 5-diethoxycarbonyl-1,4-dihydrocollidine diet. The role of PSMP was evaluated in Psmp-/- mice and after treatment with a PSMP antibody in wild-type mice. The direct effects of PSMP on macrophages and hepatic stellate cells were studied in vitro. Results In this study, we found that PSMP was highly expressed in fibrotic/cirrhotic tissues from patients with different etiologies of liver disease and in the 3 experimental mouse models of fibrosis. Damage-associated molecular pattern molecules HMGB-1 and IL-33 induced hepatocytes to produce PSMP. PSMP deficiency resulted in a marked amelioration of hepatic injury and fibrosis. In CCl4-induced hepatic injury, the infiltration of macrophages and CCR2+ monocytes into the liver was significantly decreased in Psmp-/- mice. Consistent with the decreased levels of intrahepatic macrophages, proinflammatory cytokines were significantly reduced. Moreover, adeno-associated virus-8 vectors successfully overexpressing human PSMP in Psmp-/- mouse livers could reverse the attenuation of liver injury and fibrosis induced by CCl4 in a CCR2-dependent manner. Treatment with a specific PSMP-neutralizing antibody, 3D5, prevented liver injury and fibrosis induced by CCl4 in mice. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of LX-2 cells. Conclusion PSMP enhances liver fibrosis through its receptor, CCR2. PSMP is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis. Lay summary Our present study identifies the essential role of the protein PSMP for the development and progression of liver fibrosis in humans and mice. PSMP promotes liver fibrosis through inflammatory macrophage infiltration, polarization and production of proinflammatory cytokines, as well as direct activation of hepatic stellate cells via its receptor CCR2. A PSMP antibody can significantly reduce liver fibrosis development in vivo. These findings indicate that PSMP is a potential therapeutic target and its antibody is a potential therapeutic agent for the treatment of liver fibrosis.

Background: Alzheimer's disease (AD) currently lacks a cure. Because substantial neuronal damage usually occurs before AD is advanced enough for diagnosis, the best hope for disease-modifying AD therapies likely relies on early intervention or even prevention, and targeting multiple pathways implicated in early AD pathogenesis rather than focusing exclusively on excessive production of β-amyloid (Aβ) species. Methods: Coniferaldehyde (CFA), a food flavoring and agonist of NF-E2-related factor 2 (Nrf2), was selected by multimodal in vitro screening, followed by investigation of several downstream effects potentially involved. Furthermore, in the APP/PS1 AD mouse model, the therapeutic effects of CFA (0.2 mmol kg-1d-1) were tested beginning at 3 months of age. Behavioral phenotypes related to learning and memory capacity, brain pathology and biochemistry, including Aβ transport, were assessed at different time intervals. Results: CFA promoted neuron viability and showed potent neuroprotective effects, especially on mitochondrial structure and functions. In addition, CFA greatly enhanced the brain clearance of Aβ in both free and extracellular vesicle (EV)-contained Aβ forms. In the APP/PS1 mouse model, CFA effectively abolished brain Aβ deposits and reduced the level of toxic soluble Aβ peptides, thus eliminating AD-like pathological changes in the hippocampus and cerebral cortex and preserving learning and memory capacity of the mice. Conclusion: The experimental evidence overall indicated that Nrf2 activation may contribute to the potent anti-AD effects of CFA. With an excellent safety profile, further clinical investigation of coniferaldehyde might bring hope for AD prevention/therapy.

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is aberrantly expressed in multiple myeloma (MM) patients, however, its role remains largely unknown. The present study aimed to investigate the effect of NY-ESO-1 knockdown on MM impact and provide evidence for targeting treatment of MM. Human MM U266 cells were infected with lentivirus-based small hairpin RNA-targeting NY-ESO-1 (LV-shNY-ESO-1). Cellular proliferation, colony-forming, migration, and invasion assays were employed. The expressions of cell cycle and epithelial-mesenchymal transition (EMT)-related molecules, MM growth, and mouse osteolytic lesions were evaluated. The results showed that the LV-shNY-ESO-1-U266 cells had a lower expression of NY-ESO-1 and a higher expressions of p21 and E-cadherin, and a weaker abilities of colony formation, drug-resistant to adriamycin, migration, and invasion than those of the control cells. Importantly, the knockdown of NY-ESO-1 inhibited significantly the U266 cell-induced MM growth and osteolytic lesions along with increasing the expressions of E-cadherin, p21, and p53 in mice challenged with LV-shNY-ESO-1-U266 cells. Collectively, our findings demonstrate that knockdown of NY-ESO-1 suppressed the U266 cell-induced MM growth and osteolytic lesions by inhibition of the MMs cell cycle and EMT. The NY-ESO-1 knockdown may be considered for future clinical trials in MM.

Hybrid square tubes wrapping fiber reinforced polymer (FRP) around metallic tubes are excellent structures for both collision energy absorption and lightweight. This paper deals with axial crushing theory of hybrid square tubes wrapped with antisymmetric angle-ply. The energy dissipation mechanism of hybrid square tubes is analyzed based on deformation of metallic square tubes. Considering the effects of stacking sequences of FRP on the crashworthiness and energy absorption, theoretical expressions of the membrane force and fully plastic bending moments per unit length of hybrid squares tube are derived. Then, the expression of mean crushing force of hybrid square tubes wrapped with antisymmetric angle-ply is established. Theoretical predictions compare well with the results of three groups of experiments and forty simulation models. The theoretical calculation presented in this paper can predict the behavior of hybrid square tubes during the conceptual design.

Jun Dou,1,* Luoyang Li,1,* Mei Guo,1,* Feng Mei,1 Danfeng Zheng,1 Hui Xu,1 Rui Xue,1 Xueyang Bao,1 Fengshu Zhao,1 Yu Zhang2 1Department of Pathogenic Biology and Immunology, Medical College, Southeast University, Nanjing, 210009, People’s Republic of China; 2State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun DouDepartment of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, 210009, People’s Republic of ChinaEmail njdoujun@seu.edu.cnYu ZhangSchool of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of ChinaEmail zhangyu@seu.edu.cnBackground and Aim: Acute myeloid leukemia (AML), initiated and maintained by leukemia stem cells (LSCs), is often relapsed or refractory to therapy. The present study aimed at assessing the effects of nanozyme-like Fe3O4 nanoparticles (IONPs) combined with cytosine arabinoside (Ara-C) on LSCs in vitro and in vivo.Methods: The CD34+CD38–LSCs, isolated from human AML cell line KG1a by a magnetic activated cell sorting method, were treated with Ara-C, IONPs, and Ara-C+ IONPs respectively in vitro. The cellular proliferation, apoptosis, reactive oxygen species (ROS), and the related molecular expression levels in LSCs were analyzed using flow cytometry, RT-qPCR, and Western blot. The nonobese diabetic/severe combined immune deficiency mice were transplanted with LSCs or non-LSCs via tail vein, and then the mice were treated with Ara-C, IONPs and IONPs plus Ara-C, respectively. The therapeutic effects on the AML bearing mice were further evaluated.Results: LSCs indicated stronger cellular proliferation, more clone formation, and more robust resistance to Ara-C than non-LSCs. Compared with LSCs treated with Ara-C alone, LSCs treated with IONPs plus Ara-C showed a significant increase in apoptosis and ROS levels that might be regulated by nanozyme-like IONPs via improving the expression of pro-oxidation molecule gp91-phox but decreasing the expression of antioxidation molecule superoxide dismutase 1. The in vivo results suggested that, compared with the AML bearing mice treated with Ara-C alone, the mice treated with IONPs plus Ara-C markedly reduced the abnormal leukocyte numbers in peripheral blood and bone marrow and significantly extended the survival of AML bearing mice.Conclusion: IONPs combined with Ara-C showed the effectiveness on reducing AML burden in the mice engrafted with LSCs and extending mouse survival by increasing LSC’s ROS level to induce LSC apoptosis. Our findings suggest that targeting LSCs could control the AML relapse by using IONPs plus Ara-C.Keywords: acute myeloid leukemia, leukemia stem cells, Fe3O4 nanoparticles, cytosine arabinoside, reactive oxygen species

This study aimed to present evidence that miR-7 inhibited the metastasis of breast cancer stem cells (BCSCs) and elucidated the mechanisms that have remained unknown. The samples collected from miR-7 agomir-treated, BCSC-driven tumors were subjected to a protein array to analyze the protein expression profiles. A dual-luciferase reporter and chromatin immunoprecipitation-PCR were used to validate and evaluate the molecular expressions of interest in the collected breast cancer tissues and cell lines. miR-7 overexpression affecting metastasis of BCSCs was further evaluated in mice. The endothelial cell-selective adhesion molecule (ESAM) was highly expressed in breast cancer tissues and in BCSC-driven xenografts. Results of the dual-luciferase reporter and chromatin immunoprecipitation-PCR indicated that the miR-7 mimic reduced RELA expression by directly targeting the 3′ UTR of RELA to inhibit ESAM expression in MDA-MB-231 cells. Moreover, the expression levels of RELA, CD44, and ESAM were significantly decreased in lentivirus (Lenti)-miR-7-BCSC-driven xenografts compared with the control xenografts, accompanied with an increase in E-cadherin and a decrease in vimentin expression, as well as reduction in tumor growth and metastasis to lungs. Our data demonstrated that miR-7 overexpression reduced the metastasis of BCSCs via inhibiting ESAM, suggesting that ESAM could be a potential target for breast cancer therapy., Graphical Abstract, BCSCs are “seed cells” of distant metastasis. ESAM is highly expressed in breast cancer tissues, and its expression is reduced in miR-7-treated BCSC-driven tumor. miR-7 overexpression decreases the BCSC metastasis by inhibiting ESAM, which could be a therapeutic target for breast cancer therapy.

FAM19A1 is a member of the family with sequence similarity 19 with unknown function. FAM19A1 mRNA expression is restricted to the CNS. Here, we report that FAM19A1 is a classic secretory protein, and expression levels correlate with brain development, increasing from embryonic d 12.5, peaking between postnatal d (P)1 and P7 and decreasing at wk 8. The adult hippocampus is a region of FAM19A1 high expression. Recombinant FAM19A1 suppressed the proliferation and self-renewal of neural stem cells (NSCs) and altered the lineage progression of NSCs with promoted neuron differentiation and suppressed astrocyte differentiation. Although GPCR 1 (GPR1) has been reported to be expressed in the CNS, its functions in the brain remain unclear. We identified GPR1 to be a functional receptor for FAM19A1. FAM19A1 interacted with GPR1 via the N-terminal domain (GPR1-ND), and its NSC modulatory functions required the Rho-associated protein kinase (ROCK) /ERK1/2 and ROCK/signal transducer and activator of transcription 3 signaling pathways. GPR1-ND that selectively bound to FAM19A1 neutralized the effects of FAM19A1 on NSC functions. Taken together, our results show, for the first time to our knowledge, that FAM19A1 is a novel regulatory factor of the proliferation and differentiation of NSCs, and identified a novel mechanism by which GPCR mediates the effects of FAM19A1 on NSC functions that may be important for brain development and neurogenesis. Additional exploration of the functions of FAM19A1 and GPR1 in the CNS may broaden the range of therapeutic options available for major brain disorders.-Zheng, C., Chen, D., Zhang, Y., Bai, Y., Huang, S., Zheng, D., Liang, W., She, S., Peng, X., Wang, P., Mo, X., Song, Q., Lv, P., Huang, J., Ye, R. D., Wang, Y. FAM19A1 is a new ligand for GPR1 that modulates neural stem-cell proliferation and differentiation.

This paper investigates energy absorption performance of multi-cell tubes considering the influence of axial constrain in bending process Firstly, three-point-bending tests and fully clamped bending tests were conducted. Experimental results showed that the energy absorption of tubes increased to 2.5–3 times if the end of the tube is constrained. Based on the FE model verified by experiments, the effect of rib direction and rib number is investigated under fully clamped condition. Results show that the multi-cell tubes with rib parallel to the load direction (MT-Y0Zn) have better energy absorption performance than that with rib perpendicular to the load direction (MT-YnZ0), especially in the frontal part of bending process. Meanwhile, following with the increase of rib number, specific energy absorption (SEA) of MT-Y0Zn increases gradually, while SEA of MT-YnZ0 remains almost unchanged. Considering the fact that MT-Y0Zn shows better energy absorption performance, theoretical model of MT-Y0Zn is established and highly consistent with FE model. Finally, the influence of thickness and cross-section size is discussed. SEA increases with increase of cross-section and remains unchanged with increase of thickness as predicted by theory. However, when cross-section exceeds 80 mm or thickness is smaller than 1 mm, local denting caused by shear force decreased SEA significantly.

Variable thickness hybrid square (VTHS) tubes which had variable thickness of CFRP to achieve the variation of axial crushing performance are proposed. To study the crushing characteristics and relative advantages of the VTHS, pure aluminum tube, uniform hybrid square tube and VTHS were manufactured firstly, and their axial crushing tests were conducted. Experimental results showed that, compared with uniform hybrid square tube, VTHS had lower initial peak crushing force. Finite element models were established and verified to explore the effect of parameters of the tubes on axial crushing performance further. Numerical results showed that the crushing force can be controlled by varying the thickness of CFRP. Compared with uniform thickness hybrid square tube, VTHS had an improvement of 24.5% in specific energy absorption and increase was greater for the VTHS with thinner metal. Effects of the mean thickness, thickness difference, and number of segments of CFRP on the energy absorption performance were studied. Finally, a theoretical model to predict the mean crushing force was proposed and its accuracy was verified by tests. Results demonstrate that theory can be used to obtain the mean crushing force of each segment of VTHS accurately.

Additional file 4: Table S1. Clinical specimen data. Table S2. The primers used for q-PCR. Table S3. The microRNA mimic and siRNA sequences. Table S4. The primers used in the dual-luciferase reporter assay. Table S5. The primers for ChIP-PCR.

Compared with the excellent energy absorption performance under axial loading, thin-walled tubes are vulnerable to unstable global bending under oblique loading. To improve the energy absorption performance of tubes under oblique loads, a novel designed tube with hybrid cross section is studied in this paper by adding ribs at the bottom end of the tube. Quasi-static compression experiments of square (single-cell) tube, single-double hybrid tube, double-cell tube under three oblique loads were performed to verify the finite element model. Based on the verified finite element model, the energy absorption performance was compared between the single cell tube (SCT), double cell tube (DCT) and single-double hybrid tube (SDHT) under seven oblique loads. Results showed that the SDHT has the best energy absorption performance. The influence of the height, direction and number of the ribs on the energy absorption performance of the hybrid cross section tubes is also discussed in this paper. The hybrid cross-section tubes could get the best energy absorption performance when the direction and height of the ribs were appropriate. And the energy absorption performance could be further improved by increasing the number of the ribs to compose the multi-cell hybrid cross section tube. The results also showed that the multi-cell hybrid cross section tube is more stable than the traditional multi cell tube under oblique loads. This will promote the application of multi-cell tubes in vehicles.

Metal/composite hybrid square tubes that combine the advantages of low-density of composite with low-cost of metal provide a potential energy absorption device for automobiles. The axial crushing performance of CFRP/aluminum hybrid square tubes wrapped with single angle-ply and antisymmetric angle-ply was studied by experimental and numerical methods. Results show that for tubes wrapped with single angle-ply [0]4 or [45]4, crack propagation occurred and the CFRP separated from aluminum, which resulted in worse energy absorption capacity than pure aluminum tube. A stable symmetric deformation was observed in hybrid square tubes wrapped with antisymmetric angle-ply. The specific energy absorption (SEA) for those tubes was improved 11% and they showed better energy absorption performance compared to pure aluminum tube. Then, the effect of thickness of tubes, including hybrid square tubes with identical aluminum and hybrid square tubes with identical mass, on the energy absorption capacity was further investigated by simulation. It was found that only when the number of CFRP layer reaches a certain value, hybrid square tubes perform better than pure aluminum tube with identical mass in energy absorption. Moreover, influence of mass of the tube, and substituting aluminum alloy with CFRP on the energy absorption of hybrid square tubes with identical aluminum and different number of CFRP layers was studied.

Monocytes/macrophages have been found to be an important component of colitis. However, the key chemokine that initiates the CCR2+ monocytes migration from circulation to colitis tissue remains to be undiscovered. PC3-secreted microprotein (PSMP) is a novel chemokine whose receptor is CCR2. The physiological and pathological functions of PSMP have not yet been reported. In this study, PSMP was found to be expressed in colitis and colonic tumor tissues from patients and significantly up-regulated in mouse DSS-induced colitis tissues. PSMP overexpression in the colon aggravated the DSS-induced colitis and the anti-PSMP neutralizing antibody mollified the colitis by reducing macrophage infiltration and inhibiting the expression of IL-6, TNF-α and CCL2. Furthermore, we demonstrated that lipopolysaccharide and muramyl dipeptide induced PSMP expression in the colonic epithelial cells. PSMP was up-regulated in the initial stage prior to IL-6, TNF-α and CCL2 up-regulated expression in DSS colitis and promoted the M1 macrophages to produce CCL2. PSMP chemo-attracted Ly6Chi monocytes in a CCR2 dependent manner via in situ chemotaxis and adoptive transfer assays. Our data identify PSMP as a key molecule in ulcerative colitis, which provides a novel mechanism of monocyte/macrophage migration that affects gut innate immunity and makes PSMP a potential target for controlling colitis.

Background The development of an hourglass-like constriction in the nerve is rare, and its origin is unknown. Its clinical manifestations are not well documented, and the treatment protocol has not been established. Objective To identify the cause, presentation, and possible treatment for patients with nerve palsies secondary to an hourglass-like constriction in the affected nerves. Methods Patients presenting with peripheral nerve palsy caused by an hourglass-like constriction of nerves were retrospectively investigated in 2 hand centers. The patients' presentation and neurological findings were reviewed, and the immunohistochemistry of excised specimens was studied. Results Forty-two patients who presented with 47 nerve palsies were examined. Forty-one patients experienced a sudden onset of pain in the upper limb, followed by flaccid paralysis in the affected muscles. Ten patients had multiple nerve involvement. Surgical exploration found 1 or more hourglass-like constrictions in the nerve. The treatments included internal neurolysis, neurorrhaphy, and nerve grafting. Thirty-one of 42 patients (36 nerves) were followed up for a mean of 48 months (range, 8-157 months). Fifteen of 16 nerves treated by neurolysis, 10 of 13 nerves treated by neurorrhaphy, and 4 of 7 nerves treated by nerve grafting had good recovery. CD8-positive T-lymphocyte infiltration was observed in all the excised specimens. Conclusion The clinical presentation of patients with hourglass-like constrictions in their nerves is similar to that of patients with neuralgic amyotrophy. Histochemical analysis suggests that the pathogenesis may be immunological in origin. The role of surgery in this condition is uncertain.

The paper addresses the design of anti-windup control for flexible satellite attitude system with actuator saturation. First, a linear observer-based controller is designed to stabilize the satellite attitude system and realizes flexible vibration suppression without considering saturation. According to the difference between the controller output and the saturated actuator output, an anti-windup method which utilizes the dynamics of the observer is proposed for dropping off the saturated effect. It is shown that the resulting closed-loop system of flexible satellite obtained from the controller plus the anti-windup gains can be described as a linear system with the dead-zone nonlinearity. Finally the generalized inequality sector conditions are used to obtain stability conditions based on quadratic Lyapunov function. The simulation results show that the scheme is feasible.

In this study, we aimed to explore the correlation between solute carrier family 38 member 4 (SLC38A4) and system A activity in human placentas from pregnancies with abnormal fetal birth weight. We collected placentas from consenting women immediately after their full-term babies were born, with normal, low birth weight or macrosomia, and used real-time PCR and Western blot analysis to detect the levels of SLC38A4 mRNA and protein [also known as sodium-coupled neutral amino acid transport protein 4 (SNAT4)]. Isotope incorporation assay was applied to measure system A activity in the placentas. Compared to the normal birth weight (NBW) group, placentas from the fetal macrosomia (FM) group had significantly increased levels of SLC38A4 mRNA and SNAT4 (both were increased by almost 2-fold; P

The family with sequence similarity 3 (FAM3) gene family is a cytokine-like gene family with four members FAM3A, FAM3B, FAM3C and FAM3D. In this study, we found that FAM3D strongly chemoattracted human peripheral blood neutrophils and monocytes. To identify the FAM3D receptor, we used chemotaxis, receptor internalization, Ca(2+) flux and radioligand-binding assays in FAM3D-stimulated HEK293 cells that transiently expressed formyl peptide receptor (FPR)1 or FPR2 to show that FAM3D was a high affinity ligand of these receptors, both of which were highly expressed on the surface of neutrophils, and monocytes and macrophages. After being injected into the mouse peritoneal cavity, FAM3D chemoattracted CD11b+ Ly6G+ neutrophils in a short time. In response to FAM3D stimulation, phosphorylated ERK1/2 and phosphorylated p38 MAPK family proteins were upregulated in the mouse neutrophils, and this increase was inhibited upon treatment with an inhibitor of FPR1 or FPR2. FAM3D has been reported to be constitutively expressed in the gastrointestinal tract. We found that FAM3D expression increased significantly during colitis induced by dextran sulfate sodium. Taken together, we propose that FAM3D plays a role in gastrointestinal homeostasis and inflammation through its receptors FPR1 and FPR2.

Introduction Alzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. Methods Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)–derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects. Results The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau. Conclusions Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

Chemokines plays a crucial role in the migration of leukocytes, which are involved in immune and inflammatory reactions with their receptors. To find novel chemotactic cytokines, we carried out genome-wide bioinformatics analysis and PBMC chemoattractant platform screen. Seven novel potential chemotactic cytokines were picked up, one of them was PC3-secreted microprotein (PSMP). The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, lymphocytes and THP-1 cells. CCR2 was identified as a high-affinity receptor for PSMP by in vitro chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays. Furthermore, we found that PSMP was extensively expressed at low levels in normal human tissues, but was significantly up-regulated in intestinal biopsies from patients with inflammatory bowel disease and mouse DSS-induced colitic tissue in the early stage prior to IL-6, TNF-α and CCL2 up-regulation. Moreover, the results showed that PSMP triggered inflammatory Ly6ChiCCR2+ monocyte migration from the circulation into the lamina propria in a CCR2-dependent manner and promoted the progression of inflammation. A PSMP neutralizing monoclonal antibody significantly mollified inflammation in a mouse DSS colitis model. Taken together, our study provides the first evidence that PSMP is a novel chemotactic cytokines whose receptor is CCR2 and PSMP plays a vital and irreplaceable role in triggering and promoting DSS colitis. Our finding not only reveals the function and regulating mechanism of PSMP, but also provides a promising therapeutic strategy for treating inflammatory bowel disease.