RESUMO
Peripheral tolerance mechanisms exist to prevent autoimmune destruction by self-reactive T cells that escape thymic deletion. Dominant tolerance imposed by CD4+Foxp3+ T regulatory cells can actively control autoaggressive T cell responses. Tolerance mechanisms that act endogenous to the T cell also exist. These mechanisms include T cell inactivation (anergy) and deletion. A major difference between anergic T cells and T cells undergoing peripheral deletion is the capacity of the latter to still signal through MAPKs upon TCR stimulation, suggesting these signals may be required for T deletion. In this study, we used several different models of CD8 T cell deletion to investigate the contribution of MAPK activation. Using chemical inhibitors, we established that inhibition of p38, but not ERK or JNK, rescue T cells from undergoing peripheral deletion both in vitro and in vivo. Using T cell-specific murine lines genetically altered in expression of p38α, and mice in which p38α was deleted only in CD11c-expressing cells, we surprisingly found that CD8 T cell-intrinsic p38α activation was not responsible for increased survival, but rather that inhibition of p38α in the Ag-presenting dendritic cells prevented CD8 T cell deletion.
Assuntos
Linfócitos T CD8-Positivos/fisiologia , Deleção Clonal , Células Dendríticas/imunologia , Tolerância Periférica , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antígeno CD11c/metabolismo , Linhagem Celular , Apresentação Cruzada , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Geosynchronous orbit (GSO) is the ideal orbit for communication, navigation, meteorology and other satellites, but the space of GSO is limited, and there are still a large number of space debris threatening the safety of spacecraft. Therefore, real-time detection of GSO debris is necessary to avoid collision accidents. Because radar is limited by transmitting power and operating distance, it is difficult to detect GSO debris, so photoelectric detection becomes the mainstream way to detect GSO debris. This paper presents an adaptive real-time detection algorithm for GSO debris in the charge coupled device (CCD) images. The main work is as follows: An image adaptive fast registration algorithm and an enhanced dilation difference algorithm are proposed. Combining with mathematical morphology, threshold segmentation and global nearest neighbor (GNN) multi-target tracking algorithm, the functions of image background suppression, registration, suspected target extraction and multi-target tracking are realized. The processing results of a large number of measured data show that the algorithm can detect dim geostationary earth orbit (GEO) and non-GEO debris in GSO belt stably and efficiently, and the processing speed meets the real-time requirements, with strong adaptive ability, and has high practical application value.
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In the NOD mouse model of type 1 diabetes, insulin-dependent diabetes (Idd) loci control the development of insulitis and diabetes. Independently, protective alleles of Idd3/Il2 or Idd5 are able to partially protect congenic NOD mice from insulitis and diabetes, and to partially tolerize islet-specific CD8(+) T cells. However, when the two regions are combined, mice are almost completely protected, strongly suggesting the existence of genetic interactions between the two loci. Idd5 contains at least three protective subregions/causative gene candidates, Idd5.1/Ctla4, Idd5.2/Slc11a1, and Idd5.3/Acadl, yet it is unknown which of them interacts with Idd3/Il2. Through the use of a series of novel congenic strains containing the Idd3/Il2 region and different combinations of Idd5 subregion(s), we defined these genetic interactions. The combination of Idd3/Il2 and Idd5.3/Acadl was able to provide nearly complete protection from type 1 diabetes, but all three Idd5 subregions were required to protect from insulitis and fully restore self-tolerance. By backcrossing a Slc11a1 knockout allele onto the NOD genetic background, we have demonstrated that Slc11a1 is responsible for the diabetes protection resulting from Idd5.2. We also used Slc11a1 knockout-SCID and Idd5.2-SCID mice to show that both loss-of-function alleles provide protection from insulitis when expressed on the SCID host alone. These results lend further support to the hypothesis that Slc11a1 is Idd5.2.
Assuntos
Diabetes Mellitus Tipo 1/genética , Epistasia Genética , Locos de Características Quantitativas , Alelos , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Feminino , Predisposição Genética para Doença , Glucose-6-Fosfatase/imunologia , Tolerância Imunológica/genética , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas/imunologiaRESUMO
To investigate the mechanical properties of graphene (G) and calcium silicate hydrate (C-S-H) composites in different directions, molecular dynamics (MD) simulations and experiments were used, and the effects of temperature, loading rate, and graphene defects were also investigated. The experimental results show that the addition of graphene can improve the flexural, compressive, and tensile strength of the composite. The results of molecular dynamics simulation show that the addition of graphene in x and z directions can enhance the tensile strength of G/C-S-H in three directions, while the addition of graphene in y direction can reduce the tensile strength of G/C-S-H. At the same time, the tensile strength of G/C-S-H decreases with the increase in temperature and increases with the increase in loading rate. Meanwhile, the mechanical properties of G/C-S-H can be improved using a certain concentration of monatomic vacancy defects, diatomic vacancy defects, and S-W defects.
RESUMO
In this study, cellulose composite films (CCFs) were fabricated through controllable dissolution and regeneration process of cellulose with the addition of polyvinyl alcohol (PVA). The competition of hydrogen bond site between cellulose and PVA led to partial dissolution of cellulose and maintained morphology of micron fibers with width range from 14.55 to 16.16 µm, which served as in-situ visible light scatterers. With this unique micron structure, the obtained CCF exhibited high transparency up to 90.5 % at 550 nm and ultrahigh haze up to 96 %. Interestingly, CCF could be used as hazy and flexible substrate, such as scattering lamp covers for indoor light management, anti-glare screen protectors and anti-reflection layers of solar cell devices. Among them, the efficiency of the solar cell device could be improved by 10.38 % with the help of a low-cost, excellent-performance CCF.
RESUMO
Polypropylene film is the most important organic dielectric in capacitor technology; however, applications such as power electronic devices require more miniaturized capacitors and thinner dielectric films. The commercial biaxially oriented polypropylene film is losing the advantage of its high breakdown strength as it becomes thinner. This work carefully studies the breakdown strength of the film between 1 and 5 microns. The breakdown strength drops rapidly and hardly ensures that the capacitor reaches a volumetric energy density of 2 J/cm3. Differential scanning calorimetry, X-ray, and SEM analyses showed that this phenomenon has nothing to do with the crystallographic orientation and crystallinity of the film but is closely related to the non-uniform fibers and many voids produced by overstretching the film. Measures must be taken to avoid their premature breakdown due to high local electric fields. An improvement below 5 microns will maintain a high energy density and the important application of polypropylene films in capacitors. Without destroying the physical properties of commercial films, this work employs the ALD oxide coating scheme to augment the dielectric strength of a BOPP in the thickness range below 5 µm, especially its high temperature performance. Therefore, the problem of the reduction in dielectric strength and energy density caused by BOPP thinning can be alleviated.
RESUMO
ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are a family of 19 secreted zinc metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM) during development, morphogenesis, tissue repair, and remodeling. ADAMTS18 is a poorly characterized member of the ADAMTS family. Previously, ADAMTS18 was found to participate in the development of female reproductive tract in mice. However, whether ADAMTS18 also plays a role in the development of male reproductive system remains unclear. In this study, Adamts18 mRNA was found to be highly expressed in the basal cells of the developing preputial gland. Male Adamts18 knockout (Adamts18-/-) mice exhibit abnormal preputial gland morphogenesis, including reduced size and sharp outline. Histological analyses of preputial gland from 2-week-old male Adamts18-/- mice showed significant atrophy of the whole gland. Preputial glands from 7 months and older Adamts18-/- mice appeared macroscopic swelling on their surface. Histologically, preputial gland swelling is characterized by tissue fibrosis and thicker keratinized squamous cell layer. Preputial gland lesions in age-matched male Adamts18+/+ mice were barely detected. ADAMTS18 deficiency does not lead to significant changes in morphogenesis of prostate and testis in male mice. These results indicate that ADAMTS18 is required for normal morphogenesis and homeostasis of the preputial gland in male mice.
Assuntos
Proteínas ADAMTS/metabolismo , Fibrose/patologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Doenças dos Genitais Masculinos/patologia , Genitália Masculina/anormalidades , Proteínas ADAMTS/genética , Animais , Técnicas de Cultura Embrionária , Fibrose/metabolismo , Doenças dos Genitais Masculinos/metabolismo , Genitália Masculina/metabolismo , Homeostase , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , TranscriptomaRESUMO
The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) enzymes are secreted metalloproteinases with major roles in development, morphogenesis, and tissue repair via the assembly and degradation of extracellular matrix (ECM). In this study, we investigated the role of ADAMTS18 in the development of the reproductive tract in female mice by phenotyping Adamts18 knockout (Adamts18-/-) mice. The results showed that Adamst18 mRNAs were abundantly expressed in vaginal epithelial cells and muscularis cells of the developing vagina. At the time of vaginal opening (5 weeks of age), about 41 % of Adamts18-/- females showed enlarged protrusions in the upper and middle parts of the vagina, reduced vaginal length, and simultaneously exhibited vaginal atresia. 6% Adamts18-/- females exhibited vaginal septum. Histological analyses revealed that the paired Mullerian ducts in â¼33 % female Adamts18-/- embryos failed to fuse at embryonic day 15.5 (E15.5) resulting in the formation of two vaginal cavities. Results of TUNEL assay and immunohistochemistry for caspase-3 showed that the number of apoptotic cells in the terminal portion of the vagina of 5-week-old Adamts18-/- females with vaginal atresia was significantly decreased. Adamts18-/- females also showed a significant decrease in serum estradiol E2 compared to age-matched Adamts18+/+ females. Results of qRT-PCR showed that the expression level of the anti-apoptosis gene Bcl-2 was significantly increased and that of the apoptosis-related gene Epha1 was decreased in the vagina of 5-week-old Adamts18-/- females. These results suggest that ADAMTS18 regulates vaginal opening through influencing the fusion of Mullerian ducts and apoptosis of vaginal cells in mice.
Assuntos
Proteínas ADAMTS/metabolismo , Células Epiteliais/fisiologia , Ductos Paramesonéfricos/crescimento & desenvolvimento , Vagina/fisiologia , Proteínas ADAMTS/genética , Animais , Apoptose , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Knockout , Maturidade Sexual/fisiologia , Técnicas de Cultura de Tecidos , Vagina/citologiaRESUMO
ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18-deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis.
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A nanoscale rotating system that consists of a double-walled carbon nanotube (DWCNT) and graphene and is driven by a defect in the graphene is proposed, and its rotating dynamics and driving mechanism are investigated through molecular dynamics simulations. A potential energy difference caused by the presence of the vacancy defect on the graphene substrate causes the outer tube in the DWCNT to stably rotate in a specific direction. The rotational speed of the outer tubem initially increases before reaching a stable speed. This phenomenon indicates that the driving torque is a difference between the sides of the outer tube in the van der Waals potential; this difference in potential is caused by the presence of the defect in the graphene. In addition, the effects of the system temperature, the radius and chiral vectors of the DWCNT, and the location of the defect in the graphene are investigated. The theoretical work reported here should provide a reference for the design of motion systems based on carbon nanotubes and graphene and their applications.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Yupingfeng Powder (YPF), a Chinese medical formula, is used traditionally for allergic diseases and characterized by reducing allergy relapse. In the present study, we attempted to investigate the effect of YPF on the immunity of mice and the possible mechanisms. MATERIALS AND METHODS: An immunosuppressive mice model induced by Dexamethasone (Dex) was used. Blood samples, spleen and thymus were collected. Then, hematology parameters and organ weight were measured; Phenotypic analyses (CD4+/CD8+) of lymphocytes were performed using a flow cytometer; Phagocytosis of peritoneal macrophages were evaluated by particle tracers; Spleen lymphocytes were isolated, whose proliferation and apoptosis were assessed. NK cells' cytotoxicity was determined using the LDH release assay. RESULTS: YPF could ameliorate weight loss and improve low thymus and spleen coefficients caused by Dex. Treatment with YPF made decreased lymphocytic activity of Dex-treated mice back to normal and inhibited Dex-induced apoptosis of lymphocytes. YPF increased the Dex caused low proportion of CD4+/CD8+, and upregulated Dex-reduced NK cells' activity. CONCLUSION: The series of experiments demonstrated that YPF could exert immune regulation and enhance immunity of immunosuppressive mice through adjusting nonspecific and cellular immunity. The results would provide a basis for clinical application of YPF.
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Dexametasona/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Terapia de Imunossupressão/métodos , Imunossupressores/toxicidade , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pós , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
Achieving local tumour control is paramount for cure in head and neck and prostate cancers. With the transition to precision radiotherapy (RT) techniques, survival rates have improved in the majority of these cancers, but a substantial proportion of 30-40% still relapse following primary treatment. Recent large-scale molecular profiling studies have revealed unique biological events that could explain for tumour aggression and resistance to therapies, redefining the molecular taxonomy of head and neck and prostate cancers. Here, we reviewed the key findings from these studies, highlighting those relevant for clinical stratification. We also proposed novel combinatorial clinicomolecular models to identify subsets of patients with aggressive localised tumours and limited metastases, and to inform on the optimal management of these patients using molecular targeted agents, immunotherapy, and RT.
Assuntos
Genômica/métodos , Neoplasias de Cabeça e Pescoço/radioterapia , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Neoplasias da Próstata/radioterapia , Radiocirurgia/métodos , Humanos , Imunoterapia , Masculino , Recidiva Local de Neoplasia , Radioterapia (Especialidade) , Estudos RetrospectivosRESUMO
Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Inibidores da Colinesterase/efeitos adversos , Memantina/efeitos adversos , Receptores de N-Metil-D-Aspartato/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Humanos , Memantina/uso terapêuticoRESUMO
An allelic variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), PTPN22(R620W), is strongly associated with type 1 diabetes (T1D) in humans and increases the risk of T1D by two- to fourfold. The NOD mouse is a spontaneous T1D model that shares with humans many genetic pathways contributing to T1D. We hypothesized that the introduction of the murine orthologous Ptpn22(R619W) mutation to the NOD genome would enhance the spontaneous development of T1D. We microinjected CRISPR-Cas9 and a homology-directed repair template into NOD single-cell zygotes to introduce the Ptpn22(R619W) mutation to its endogenous locus. The resulting Ptpn22(R619W) mice showed increased insulin autoantibodies and earlier onset and higher penetrance of T1D. This is the first report demonstrating enhanced T1D in a mouse modeling human PTPN22(R620W) and the utility of CRISPR-Cas9 for direct genetic alternation of NOD mice.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Alelos , Animais , Western Blotting , Sistemas CRISPR-Cas/genética , Feminino , Predisposição Genética para Doença/genética , Genoma/genética , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Hepatitis B virus (HBV) infection, a global public health problem, is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. There are more than 350 million HBV carriers in the world and up to one million die annually due to hepatitis B associated liver disease. So far no optimal treatment is available for patients with chronic hepatitis B. In the paper we investigated the efficacy of intramuscular matrine in the treatment of chronic hepatitis B. METHODS: One hundred and twenty patients with chronic hepatitis B were randomly divided into matrine treatment group (n=60) and control group (n=60). The patients of the matrine group were given intramuscularly with matrine (an alkaloid extracted from a traditional Chinese herb Radix Sophorae Flavescentis by Guangzhou Ming Xing Pharmaceutical Factory, Guangzhou, China) of 100 mg daily for 90 days in addition to conventional liver-protective drugs including glucurone, inosine, compound vitamin B and caryophyllin. The control group received conventional liver-protective drugs alone. Clinical manifestations and laboratory parameters including liver biochemistry and serum hepatitis B virus markers were monitored before and after treatment in the two groups. RESULTS: Significant differences were seen between the two groups in terms of improvement of clinical symptoms and signs, recovery of liver functions, and serum conversion from hepatitis Be antigen to HBe antibody and from positive to negative serum HBV DNA (P<0.05-0.01). The result of the matrine group was more marked than that of the control group. Serious side-effects were not observed except mild pain at the site of injection of matrine in a few patients. CONCLUSION: These results indicate that intramuscular matrine may be an economical, efficacious, safe drug for the treatment of chronic hepatitis B.