Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 140
Filtrar
1.
Hered Cancer Clin Pract ; 19(1): 48, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34838098

RESUMO

BACKGROUND: RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. CASE PRESENTATION: A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. CONCLUSIONS: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

2.
Viruses ; 13(10)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34696508

RESUMO

HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites of the HIV-1 genome, dramatically alter the Vif expression level, resulting in variants with low or excessive Vif expression. In this study, we investigated how these HIV-1 variants with poor replication ability adapt and evolve under the pressure of APOBEC3 proteins. Adapted clones obtained through adaptation experiments exhibited an altered replication ability and Vif expression level compared to each parental clone. While various mutations were present throughout the viral genome, all replication-competent adapted clones with altered Vif expression levels were found to bear them within SA1D2prox, without exception. Indeed, the mutations identified within SA1D2prox were responsible for changes in the Vif expression levels and altered the splicing pattern. Moreover, for samples collected from HIV-1-infected patients, we showed that the nucleotide sequences of SA1D2prox can be chronologically changed and concomitantly affect the Vif expression levels. Taken together, these results demonstrated the importance of the SA1D2prox nucleotide sequence for modulating the Vif expression level during HIV-1 replication and adaptation.

3.
Microorganisms ; 9(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34683377

RESUMO

Microbial diversity in an apple orchard cultivated with natural farming practices for over 30 years was compared with conventionally farmed orchards to analyze differences in disease suppression. In this long-term naturally farmed orchard, major apple diseases were more severe than in conventional orchards but milder than in a short-term natural farming orchard. Among major fungal species in the phyllosphere, we found that Aureobasidium pullulans and Cryptococcus victoriae were significantly less abundant in long-term natural farming, while Cladosporium tenuissimum predominated. However, diversity of fungal species in the phyllosphere was not necessarily the main determinant in the disease suppression observed in natural farming; instead, the maintenance of a balanced, constant selection of fungal species under a suitable predominant species such as C. tenuissimum seemed to be the important factors. Analysis of bacteria in the phyllosphere revealed Pseudomonas graminis, a potential inducer of plant defenses, predominated in long-term natural farming in August. Rhizosphere metagenome analysis showed that Cordyceps and Arthrobotrys, fungal genera are known to include insect- or nematode-infecting species, were found only in long-term natural farming. Among soil bacteria, the genus Nitrospira was most abundant, and its level in long-term natural farming was more than double that in the conventionally farmed orchard.

4.
Sci Rep ; 11(1): 21110, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702961

RESUMO

Cryptococcus deneoformans is an opportunistic fungal pathogen that infects the lungs via airborne transmission and frequently causes fatal meningoencephalitis. Claudins (Cldns), a family of proteins with 27 members found in mammals, form the tight junctions within epithelial cell sheets. Cldn-4 and 18 are highly expressed in airway tissues, yet the roles of these claudins in respiratory infections have not been clarified. In the present study, we analyzed the roles of Cldn-4 and lung-specific Cldn-18 (luCldn-18) in host defense against C. deneoformans infection. luCldn-18-deficient mice exhibited increased susceptibility to pulmonary infection, while Cldn-4-deficient mice had normal fungal clearance. In luCldn-18-deficient mice, production of cytokines including IFN-γ was significantly decreased compared to wild-type mice, although infiltration of inflammatory cells including CD4+ T cells into the alveolar space was significantly increased. In addition, luCldn-18 deficiency led to high K+ ion concentrations in bronchoalveolar lavage fluids and also to alveolus acidification. The fungal replication was significantly enhanced both in acidic culture conditions and in the alveolar spaces of luCldn-18-deficient mice, compared with physiological pH conditions and those of wild-type mice, respectively. These results suggest that luCldn-18 may affect the clinical course of cryptococcal infection indirectly through dysregulation of the alveolar space microenvironment.

5.
ACS Omega ; 6(34): 21884-21891, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34497883

RESUMO

High-temperature superconductivity appears in cuprate materials that have been tuned in a way where the copper-oxygen bond configuration and coordination is in a state of minimal energy. In competition with the Jahn-Teller effect, which impedes the formation of infinitely connected CuO2 planes, the state of minimal energy persists for planar copper-oxygen bond length variations of up to 10%. We have synthesized the infinite-layer phases of CaCuO2 and SrCuO2 as single-crystalline films using molecular beam epitaxy and performed in-plane scanning transmission electron microscopy mapping. For the infinite-layer phase of CaCuO2 with a short Cu-O bond length, the CuO2 planes maintain their minimal energy by forming distinguished atomic stripes. In contrast, atomic stripe formation does not occur in the infinite-layer phase of SrCuO2, which has a larger Cu-O bond length. The polar field provided by the charge reservoir layer in cuprates with infinitely connected CuO2 planes holds the key over the emergence of superconductivity and is vital to maintain infinitely connected CuO2 planes themselves.

6.
Am J Case Rep ; 22: e932241, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34143765

RESUMO

BACKGROUND Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. CASE REPORT A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. CONCLUSIONS JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.


Assuntos
Adenocarcinoma , Laparoscopia , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Endoscopia do Sistema Digestório , Feminino , Gastrectomia , Células Germinativas , Humanos , Polipose Intestinal/congênito , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias , Proteína Smad4/genética , Estômago
7.
Oncogene ; 40(26): 4486-4502, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34117362

RESUMO

Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5'-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.

8.
Neuropathology ; 41(4): 266-272, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33942396

RESUMO

Immune-related adverse events (irAEs) commonly involve the gastrointestinal tract, endocrine glands, skin, and liver, and rarely the nervous system. The pathomechanism of irAEs in the nervous system is unclear, and so characterizing these severe toxic effects is a priority, even if irAEs are uncommon in the nervous system. Our patient presented subacute muscle weakness and dysesthesia with colitis as irAEs caused by pembrolizumab, one of the anti-programmed death-1 (PD-1) antibodies. Electromyography revealed abundant fibrillations and fasciculations of upper and lower extremities and severe reduction in motor unit potentials; however, antineutrophil cytoplasmic antibodies, rheumatoid factor, autoantibodies against Hu and Yo, and anti-ganglioside antibodies, such as GQ1b, were undetectable in the serum. Although he was treated with high-dose glucocorticoids, antibiotics, and a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, he developed colonic perforation. The total colorectal resection was performed, and the resected colon showed mucosal defect and perforation. He died of lung aspergillosis. Postmortem examination revealed CD8-positive lymphocyte infiltration around neurons of dorsal root ganglia. The sciatic nerve displayed the widening of myelin laminae and thinning of myelinated fibers but not a decrease in the density of myelinated nerve fibers. In the sural nerve, the density of myelinated fibers slightly decreased, and some fibers showed less densely myelinated laminae. Drug safety information, including previous randomized trials of anti-PD-1 and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies, showed that patients treated with anti-PD-1 antibodies appeared to have more frequent and severe peripheral neuropathies compared to those in patients who received anti-CTLA-4 antibodies (1.59% vs. 0.69%; Fisher exact test, P < 0.001; three severe events vs. zero severe events). The present results and drug safety information suggest that the pathomechanism of irAEs caused by anti-PD-1 antibodies is different from that by anti-CTLA-4 antibodies. The neurological irAEs might be clues to solving the pathomechanism of irAEs.

9.
Biomed Res ; 42(2): 53-66, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33840686

RESUMO

Antigen-presenting cells express pattern recognition receptors (PRRs), which sense pathogen-associated molecular patterns from microorganisms and lead to the induction of inflammatory responses. C-type lectin receptors (CLRs), the representative PRRs, bind to microbial polysaccharides, among which Dectin-2 and Mincle recognize mannose-containing polysaccharides. Because influenza virus (IFV) hemagglutinin (HA) is rich in mannose polysaccharides, Dectin-2 or Mincle may contribute to the recognition of HA. In this study, we addressed the possible involvement of Dectin-2 and Mincle in the viral recognition and the initiation of cytokine production. Interleukin (IL)-12p40 and IL-6 production by bone marrow-derived dendritic cells (BM-DCs) upon stimulation with HA was significantly reduced in Dectin-2 knockout (KO) mice compared to wild-type (WT) mice whereas there was no difference between WT mice and Mincle KO mice. BM-DCs that were treated with Syk inhibitor resulted in a significant reduction of cytokine production upon stimulation with HA. The treatment of BM-DCs with methyl-α-D-mannopyranoside (ManP) also led to a significant reduction in cytokine production by BM-DCs that were stimulated with HA, except for the A/H1N1pdm09 subtype. IL-12p40 and IL-6 synthesis by BM-DCs was completely diminished upon stimulation with HA treated with concanavalin A (ConA)-bound sepharose beads. Finally, GFP expression was detected in reporter cells that were transfected with the Dectin-2 gene, but not with the Mincle gene, when stimulated with HA derived from the A/H3N2 subtype. These data suggested that Dectin-2 may be a key molecule as the sensor for IFV to initiate the immune response and regulate the pathogenesis of IFV infection.

10.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920301

RESUMO

Chronic infections are considered one of the most severe problems in skin wounds, and bacteria are present in over 90% of chronic wounds. Pseudomonas aeruginosa is frequently isolated from chronic wounds and is thought to be a cause of delayed wound healing. Invariant natural killer T (iNKT) cells, unique lymphocytes with a potent regulatory ability in various inflammatory responses, accelerate the wound healing process. In the present study, we investigated the contribution of iNKT cells in the host defense against P. aeruginosa inoculation at the wound sites. We analyzed the re-epithelialization, bacterial load, accumulation of leukocytes, and production of cytokines and antimicrobial peptides. In iNKT cell-deficient (Jα18KO) mice, re-epithelialization was significantly decreased, and the number of live colonies was significantly increased, when compared with those in wild-type (WT) mice on day 7. IL-17A, and IL-22 production was significantly lower in Jα18KO mice than in WT mice on day 5. Furthermore, the administration of α-galactosylceramide (α-GalCer), a specific activator of iNKT cells, led to enhanced host protection, as shown by reduced bacterial load, and to increased production of IL-22, IL-23, and S100A9 compared that of with WT mice. These results suggest that iNKT cells promote P. aeruginosa clearance during skin wound healing.


Assuntos
Células T Matadoras Naturais/imunologia , Reepitelização/genética , Pele/imunologia , Cicatrização/genética , Animais , Calgranulina B/genética , Galactosilceramidas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon gama/genética , Interleucina-17/genética , Interleucina-23/genética , Interleucinas/genética , Leucócitos/imunologia , Leucócitos/microbiologia , Camundongos , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidade , Reepitelização/imunologia , Pele/microbiologia , Pele/patologia , Cicatrização/imunologia
11.
Toxicol Lett ; 342: 1-5, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33545305

RESUMO

Eye irritation predictions are very important in the development of cosmetics and pharmaceuticals. For animal protection, alternative tests are being developed to replace the Draize test, which involves the use of rabbits to test eye irritation. The Vitrigel-eye irritancy test (Vitrigel-EIT), is one such alternative. As a preliminary study, we evaluated if Hansen solubility parameter (HSP) values can be used to predict Vitrigel-EIT results. An Hansen sphere was created based on the HSP values and Vitrigel-EIT results from 61 substances. Substances inside and outside of the sphere were designated as dangerous and safe substances, respectively. The safety of each test substance was predicted by comparing the center point (Ro) of the sphere with the relative energy difference, i.e., the ratio of each test substance (Ra). The accuracy, false negativity, and false positivity of the "irritant" and "nonirritant" designations, as determined by the Vitrigel-EIT results and Hansen sphere, were 91.8% (56/61), 2.3% (1/43), and 22.2% (4/18), respectively. These results indicated that HSP values can be used to predict Vitrigel-EIT results with high reproducibility, and thus are useful for evaluating the safety of substances.


Assuntos
Alternativas aos Testes com Animais/métodos , Epitélio Corneano/efeitos dos fármacos , Irritantes/toxicidade , Humanos , Testes de Toxicidade/métodos
12.
Toxicol In Vitro ; 70: 105039, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33137446

RESUMO

Concerns regarding animal welfare have led to the need for alternatives to animal eye irritation tests. The reconstructed human cornea-like epithelium (RhCE) test is described in the OECD TG 492 as an alternative to animal eye irritation tests. However, the accuracy and labor investment of this method can be improved if the results can be predicted before the experiment. In this study, we evaluated whether Hansen solubility parameter (HSP) values can be used to predict the results of RhCE method using the LabCyte CORNEA-MODEL for 65 test substances. We found that HSP values can predict the RhCE method with high correlation (accuracy 84.6% (55/65), false-negative rate of 16.2% (7/43), and false-positive rate of 13.6% (3/22). These results indicate that HSP values can be used to predict the results RhCE method using LabCyte CORNEA-MODEL with high reproducibility, and thus are useful for evaluating the safety of substances.


Assuntos
Epitélio Corneano/efeitos dos fármacos , Irritantes/química , Irritantes/toxicidade , Testes de Toxicidade Aguda/métodos , Alternativas aos Testes com Animais , Sobrevivência Celular/efeitos dos fármacos , Humanos , Reprodutibilidade dos Testes , Solubilidade
13.
Case Rep Oncol ; 13(3): 1176-1184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173482

RESUMO

We report a case of long-standing ulcerative colitis with intramucosal well- and poorly differentiated adenocarcinomas detected over a 6-month duration. A Japanese man in his sixties with a 31-year history of ulcerative colitis had a 1.1-cm-sized intramucosal well-differentiated tubular adenocarcinoma in the rectum resected by endoscopic submucosal dissection. At the follow-up colonoscopy, a biopsy near the endoscopic submucosal dissection scar revealed poorly differentiated adenocarcinoma, and a total proctocolectomy was performed 6 months after the endoscopic submucosal dissection. The whole colorectal pathological exam showed 2 flat foci of intramucosal poorly differentiated adenocarcinoma, 4 and 2 mm in size each, near the endoscopic submucosal dissection scar in the rectum, and an increased number of Paneth cells, thickened muscularis mucosa, and widening of the distance between the gland base and muscularis mucosa in the transverse colon to the rectum. Adenocarcinomas were not found in areas where architecturally severe changes of the mucosa or the highest number of Paneth cells proliferation were detected. Multiple biopsies using magnifying narrow band imaging or crystal violet staining around the initial high-grade dysplasia or intramucosal adenocarcinoma were effective to find other lesions, such as poorly differentiated adenocarcinoma foci in the mucosa in a long-standing ulcerative colitis patient.

14.
Heliyon ; 6(9): e04792, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33015382

RESUMO

We measured the blood viscosity of 25 male and 25 female healthy people (total 50) using a compact-sized falling needle viscometer (Falling Needle Rheometer) capable of highly accurate measurements. Based on the analysis of the flow characteristics, most of the blood specific non-Newtonian fluid (Casson fluid) behavior was confirmed. Additionally, the blood from males has a higher apparent viscosity and Casson yield value than that from women. Furthermore, a new Herschel-Bulkley type model equation representing the relationship between the shear rate and apparent viscosity of human blood was proposed based on the measured blood flow characteristics. The proposed model improved the exponential term on the shear rate and added the constant term on the yield stress so that the measured value can be correlated with a high accuracy. Using the proposed model equation, the correlation accuracy of all of the measured human blood viscosities was better than in the Herschel-Bulkley model equation and Casson model in a wide range of shear rate regions. By incorporating numerical flow analysis (computational fluid dynamics), this model equation may contribute to analyses considering the non-Newtonian fluidity of human blood.

15.
Infect Immun ; 89(1)2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33020213

RESUMO

Streptococcus pneumoniae is a major causative bacterium of community-acquired pneumonia. Dendritic cell-associated C-type lectin-2 (dectin-2), one of the C-type lectin receptors (CLRs), was previously reported to play a pivotal role in host defense against pneumococcal infection through regulating phagocytosis by neutrophils while not being involved in neutrophil accumulation. In the present study, to elucidate the possible contribution of other CLRs to neutrophil accumulation, we examined the role of caspase recruitment domain-containing protein 9 (CARD9), a common adaptor molecule for signal transduction triggered by CLRs, in neutrophilic inflammatory response against pneumococcal infection. Wild-type (WT), CARD9 knockout (KO), and dectin-2 KO mice were infected intratracheally with pneumococcus, and the infected lungs were histopathologically analyzed to assess neutrophil accumulation at 24 h postinfection. Bronchoalveolar lavage fluids (BALFs) were collected at the same time point to count the neutrophils and assess the production of inflammatory cytokines and chemokines. Neutrophil accumulation was significantly decreased in CARD9 KO mice, but not in dectin-2 KO mice. Tumor necrosis factor alpha (TNF-α), keratinocyte-derived chemokine (KC), and macrophage inflammatory protein-2 (MIP-2) production in BALFs were also attenuated in CARD9 KO mice, but not in dectin-2 KO mice. Production of TNF-α and KC by alveolar macrophages stimulated with pneumococcal culture supernatants was significantly attenuated in CARD9 KO mice, but not in dectin-2 KO mice, compared to that in each group's respective control mice. In addition, pneumococcus-infected CARD9 KO mice showed larger bacterial burdens in the lungs than did WT mice. These data indicate that CARD9 is required for neutrophil migration after pneumococcal infection, as well as inflammatory cytokine and chemokine production by alveolar macrophages, and suggest that a CLR distinct from dectin-2 may be involved in this response.


Assuntos
Candidíase Mucocutânea Crônica/complicações , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Neutrófilos/imunologia , Pneumonia Pneumocócica/etiologia , Streptococcus pneumoniae , Animais , Biópsia , Quimiocinas/metabolismo , Citocinas/metabolismo , Suscetibilidade a Doenças , Imunoglobulina G/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Neutrófilos/metabolismo , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/patologia
16.
Nat Commun ; 11(1): 4969, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037206

RESUMO

Magnetic Weyl semimetals have novel transport phenomena related to pairs of Weyl nodes in the band structure. Although the existence of Weyl fermions is expected in various oxides, the evidence of Weyl fermions in oxide materials remains elusive. Here we show direct quantum transport evidence of Weyl fermions in an epitaxial 4d ferromagnetic oxide SrRuO3. We employ machine-learning-assisted molecular beam epitaxy to synthesize SrRuO3 films whose quality is sufficiently high to probe their intrinsic transport properties. Experimental observation of the five transport signatures of Weyl fermions-the linear positive magnetoresistance, chiral-anomaly-induced negative magnetoresistance, π phase shift in a quantum oscillation, light cyclotron mass, and high quantum mobility of about 10,000 cm2V-1s-1-combined with first-principles electronic structure calculations establishes SrRuO3 as a magnetic Weyl semimetal. We also clarify the disorder dependence of the transport of the Weyl fermions, which gives a clear guideline for accessing the topologically nontrivial transport phenomena.

17.
Infect Immun ; 88(11)2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-32868343

RESUMO

Cryptococcus deneoformans is an opportunistic fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired cell-mediated immune responses such as AIDS. Caspase-associated recruitment domain 9 (CARD9) plays a critical role in the host defense against cryptococcal infection, suggesting the involvement of one or more C-type lectin receptors (CLRs). In the present study, we analyzed the role of macrophage-inducible C-type lectin (Mincle), one of the CLRs, in the host defense against C. deneoformans infection. Mincle expression in the lungs of wild-type (WT) mice was increased in the early stage of cryptococcal infection in a CARD9-dependent manner. In Mincle gene-disrupted (Mincle KO) mice, the clearance of this fungus, pathological findings, Th1/Th2 response, and antimicrobial peptide production in the infected lungs were nearly comparable to those in WT mice. However, the production of interleukin-22 (IL-22), tumor necrosis factor alpha (TNF-α), and IL-6 and the expression of AhR were significantly decreased in the lungs of Mincle KO mice compared to those of WT mice. In in vitro experiments, TNF-α production by bone marrow-derived dendritic cells was significantly decreased in Mincle KO mice. In addition, the disrupted lysates of C. deneoformans, but not those of whole yeast cells, activated Mincle-triggered signaling in an assay with a nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Mincle may be involved in the production of Th22-related cytokines at the early stage of cryptococcal infection, although its role may be limited in the host defense against infection with C. deneoformans.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/imunologia , Lectinas Tipo C/imunologia , Proteínas de Membrana/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
BMC Med Genet ; 21(1): 141, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611331

RESUMO

BACKGROUND: Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes. CASE PRESENTATION: A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot's syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis. CONCLUSION: This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot's syndrome type 1.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/imunologia , Predisposição Genética para Doença , Neoplasias Hepáticas/secundário , Mutação/genética , Síndromes Neoplásicas Hereditárias/genética , Adulto , Sequência de Bases , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Linhagem
19.
J Immunol ; 205(3): 686-698, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32561568

RESUMO

IL-17A is a proinflammatory cytokine produced by many types of innate immune cells and Th17 cells and is involved in the elimination of extracellularly growing microorganisms, yet the role of this cytokine in the host defense against intracellularly growing microorganisms is not well known. Cryptococcus deneoformans is an opportunistic intracellular growth fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired immune responses. In the current study, we analyzed the role of IL-17A in the host defense against C. deneoformans infection. IL-17A was quickly produced by γδT cells at an innate immune phase in infected lungs. In IL-17A gene-disrupted mice, clearance of this fungal pathogen and the host immune response mediated by Th1 cells were significantly accelerated in infected lungs compared with wild-type mice. Similarly, killing of this fungus and production of inducible NO synthase and TNF-α were significantly enhanced in IL-17A gene-disrupted mice. In addition, elimination of this fungal pathogen, Th1 response, and expression of IL-12Rß2 and IFN-γ in NK and NKT cells were significantly suppressed by treatment with rIL-17A. The production of IL-12p40 and TNF-α from bone marrow-derived dendritic cells stimulated with C. deneoformans was significantly suppressed by rIL-17A. In addition, rIL-17A attenuated Th1 cell differentiation in splenocytes from transgenic mice highly expressing TCR for mannoprotein 98, a cryptococcal Ag, upon stimulation with recombinant mannoprotein 98. These data suggest that IL-17A may be involved in the negative regulation of the local host defense against C. deneoformans infection through suppression of the Th1 response.


Assuntos
Criptococose/imunologia , Cryptococcus/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Interleucina-17/imunologia , Células Th1/imunologia , Animais , Criptococose/genética , Cryptococcus/genética , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/imunologia
20.
Int Arch Allergy Immunol ; 181(9): 651-664, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32585675

RESUMO

INTRODUCTION: The enhanced type 2 helper (Th2) immune response is responsible for the pathogenesis of allergic asthma. To suppress the enhanced Th2 immune response, activation of the Th1 immune response has been an alternative strategy for anti-asthma therapy. In this context, effective Th1-inducing adjuvants that inhibit the development of allergic asthma but do not flare the side effects of the primary agent are required in clinical treatment and preventive medicine. OBJECTIVE: In this study, we aimed to determine the regulation of the Th2 type immune response in asthma by a novel immunostimulatory oligodeoxynucleotide (ODN) derived from Cryptococcus neoformans, termed ODN112, which contains a cytosine-guanine (CG) sequence but not canonical CpG motifs. METHODS: Using an ovalbumin-induced asthma mouse model, we assessed the effect of ODN112 on prototypical asthma-related features in the lung and on the Th1/Th2 profile in the lymph nodes and lung of mice treated with ODN112 during sensitization. RESULTS AND CONCLUSION: ODN112 treatment attenuated asthma features in mice. In the bronchial lymph nodes of the lungs and in the spleen, ODN112 increased interferon-γ production and attenuated Th2 recall responses. In dendritic cells (DCs) after allergen sensitization, ODN112 enhanced cluster of differentiation (CD) 40 and CD80 expression but did not alter CD86 expression. Interleukin-12p40 production from DCs was also increased in a Th2-polarizing condition. Our results suggest that ODN112 is a potential Th1-inducing adjuvant during Th2 cell differentiation in the sensitization phase.


Assuntos
Asma/tratamento farmacológico , Cryptococcus neoformans/metabolismo , Células Dendríticas/imunologia , Hipersensibilidade/tratamento farmacológico , Oligodesoxirribonucleotídeos/uso terapêutico , Células Th2/imunologia , Receptor Toll-Like 9/agonistas , Alérgenos/imunologia , Animais , Diferenciação Celular , Ilhas de CpG/genética , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/genética , Ovalbumina/imunologia , Equilíbrio Th1-Th2
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...