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Myxoid liposarcoma (MLPS) is a rare sarcoma, typically arising in deep soft tissues during the fourth to fifth decades of life. Histologically, MLPS is composed of uniform oval cells within a background of myxoid stroma and chicken-wire capillaries. Genetically, MLPS is characterized by the FUS/EWSR1::DDIT3 fusion gene, which generally results from balanced interchromosomal translocation and is detectable via DDIT3 break-apart fluorescence in situ hybridization (FISH). Here, we report an unusual intra-articular MLPS case, negative for DDIT3 break-apart FISH but positive for EWSR1::DDIT3. An 18-year-old female was referred to our hospital complaining of an intra-articular mass in the right knee joint. Histologically, the tumor was mainly composed of mature adipocytes, brown fat-like cells, and lipoblasts. Nanopore sequencing detected DNA rearrangements between EWSR1 and DDIT3 and clustered complex rearrangements involving multiple chromosomes, suggesting chromoplexy. Methylation classification using random forest, t-distributed stochastic neighbor embedding, and unsupervised hierarchical clustering correctly classified the tumor as MLPS. The copy number was almost flat. The TERT promoter C-124T was also detected. This report highlights, for the first time, the potential value of a fast and low-cost nanopore sequencer for diagnosing sarcomas.
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Dermatofibroma (DF) is a benign tumor that forms pedunculated lesions ranging in size from a few millimeters to 2 cm, usually affecting the extremities and trunks of young adults. Histopathologically, DF is characterized by the storiform proliferation of monomorphic fibroblast-like spindle cells. In addition to neoplastic cells, secondary elements such as foamy histiocytes, Touton-type giant cells, lymphoplasmacytes, and epidermal hyperplasia are characteristic histological features. Several histological variants, including atypical, cellular, aneurysmal, and lipidized variants, have been reported; cases with variant histologies are sometimes misdiagnosed as sarcomas. We present a case of metastasizing aneurysmal DF that was initially diagnosed as an angiosarcoma on biopsy. A 26-year-old woman was referred to our hospital with a gradually enlarging subcutaneous mass in her lower left leg. Positron emission tomography-computed tomography revealed high fluorodeoxyglucose uptake not only in the tumor but also in the left inguinal region. On biopsy, ERG and CD31-positive atypical spindle cells proliferated in slit-like spaces with extravasation, leading to the diagnosis of angiosarcoma. Histology of the wide-resection specimen was consistent with DF, and lymph node metastasis was also observed. Nanopore DNA sequencing detected CD63::PRKCD fusion and copy number gain, although CD63 was not included in the target region of adaptive sampling. This report highlights the importance of recognizing the unusual clinical, radiological, and pathological features of DF to avoid misdiagnosis, and the potential diagnostic utility of nanopore sequencer.
Assuntos
Hemangiossarcoma , Histiocitoma Fibroso Benigno , Sequenciamento por Nanoporos , Proteínas de Fusão Oncogênica , Adulto , Feminino , Humanos , Hemangiossarcoma/genética , Hemangiossarcoma/diagnóstico , Hemangiossarcoma/patologia , Histiocitoma Fibroso Benigno/genética , Histiocitoma Fibroso Benigno/diagnóstico , Histiocitoma Fibroso Benigno/patologia , Sequenciamento por Nanoporos/métodos , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/diagnóstico , Tetraspanina 30/genética , Tetraspanina 30/metabolismoRESUMO
To maintain fertility, male mice re-repress transposable elements (TEs) that were de-silenced in the early gonocytes before their differentiation into spermatogonia. However, the mechanism of TE silencing re-establishment remains unknown. Here, we found that the DNA-binding protein Morc1, in cooperation with the methyltransferase SetDB1, deposits the repressive histone mark H3K9me3 on a large fraction of activated TEs, leading to heterochromatin. Morc1 also triggers DNA methylation, but TEs targeted by Morc1-driven DNA methylation only slightly overlapped with those repressed by Morc1/SetDB1-dependent heterochromatin formation, suggesting that Morc1 silences TEs in two different manners. In contrast, TEs regulated by Morc1 and Miwi2, the nuclear PIWI-family protein, almost overlapped. Miwi2 binds to PIWI-interacting RNAs (piRNAs) that base-pair with TE mRNAs via sequence complementarity, while Morc1 DNA binding is not sequence specific, suggesting that Miwi2 selects its targets, and then, Morc1 acts to repress them with cofactors. A high-ordered mechanism of TE repression in gonocytes has been identified.
Assuntos
Heterocromatina , RNA de Interação com Piwi , Animais , Masculino , Camundongos , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Metilação de DNA , Elementos de DNA Transponíveis/genética , Drosophila melanogaster/genética , Heterocromatina/genética , Proteínas Nucleares/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
EWSR1::NFATC2 sarcoma, a rare round cell sarcoma constituting the majority of EWSR1::non-ETS sarcomas, has recently been defined in the latest WHO classification. To date, the cytological findings of EWSR1::NFATC2 sarcoma remain undocumented. We present the case of a 25-year-old man with a history of polyostotic fibrous dysplasia in the right leg, referred to our hospital with left thigh pain. Cytological findings included metachromasia, minimally pleomorphic round cells, and eosinophilic infiltration. There was no precursor fibrous dysplasia and the initial diagnosis was undifferentiated pleomorphic sarcoma. Following histologic review, we successfully performed immunocytochemistry and fluorescence in situ hybridization (FISH) on archival cytology specimens. The tumor cells were positive for NKX2-2, NKX3-1, and PAX7 and showed amplified 5' single signals of EWSR1 gene. Reverse transcriptase-polymerase chain reaction revealed an in-frame fusion of EWSR1 and NFATC2. This report describes the cytological features of EWSR1::NFATC2 sarcoma and highlights the diagnostic utility of archival cytology specimens.
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Citologia , Proteínas de Fusão Oncogênica , Sarcoma , Adulto , Humanos , Masculino , Diagnóstico Diferencial , Hibridização in Situ Fluorescente , Fatores de Transcrição NFATC/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma/diagnóstico , Sarcoma/genética , Fatores de Transcrição/genéticaRESUMO
The Dja2 knockout (Dja2-/- ) mice had respiratory distress, and >60% died within 2 days after birth. The surviving adult Dja2-/- mice were infertile and the lungs of Dja2-/- mice showed several abnormalities, including the processing defect of prosurfactant protein C in the alveolar epithelial type II cells and the accumulation of glycolipids in enlarged alveolar macrophages. The luminal pH of acidic organelles in Dja2-/- cells was shifted to pH 5.37-5.45. This deviated pH was immediately restored to control levels (pH 4.56-4.65) by the addition of a diuretic, ethyl isopropyl amiloride (EIPA). Although the role of DJA2 in maintaining the pH homeostasis of lysosome-related organelles is currently obscure, this rapid and remarkable pH resilience is best explained by an EIPA-sensitive proton efflux machinery that is disorganized and overactivated due to the loss of Dja2.
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Lisossomos , Prótons , Animais , Camundongos , Transporte Biológico , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Macrófagos Alveolares , Camundongos Endogâmicos C57BLRESUMO
Meiosis is differently regulated in males and females. In females, germ cells initiate meiosis within a limited time period in the fetal ovary and undergo a prolonged meiotic arrest until puberty. However, how meiosis initiation is coordinated with the cell cycle to coincide with S phase remains elusive. Here, we demonstrate that STRA8 binds to RB via the LXCXE motif. Mutation of the RB-binding site of STRA8 in female mice delays meiotic entry, which consequently delays progression of meiotic prophase and leads to precocious depletion of the oocyte pool. Single-cell RNA-sequencing analysis reveals that the STRA8-RB interaction is required for S phase entry and meiotic gene activation, ensuring precise timing of meiosis initiation in oocytes. Strikingly, the results suggest STRA8 could sequester RB from E2F during pre-meiotic G1/S transition. This study highlights the gene regulatory mechanisms underlying the female-specific mode of meiotic initiation in mice.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Meiose , Animais , Feminino , Masculino , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação da Expressão Gênica , Células Germinativas/metabolismo , Maturidade Sexual , Proteína do RetinoblastomaRESUMO
l-Ornithine (Orn) is a core amino acid responsible for ammonia detoxification in the body via the hepatic urea cycle. Clinical studies in Orn therapy have focused on interventions for hyperammonemia-associated diseases, such as hepatic encephalopathy (HE), a life-threatening neurological symptom affecting more than 80% of patients with liver cirrhosis. However, its low molecular weight (LMW) causes Orn to diffuse nonspecifically and be rapidly eliminated from the body after oral administration, resulting in unfavorable therapeutic efficacy. Hence, Orn is constantly supplied by intravenous infusion in many clinical settings; however, this treatment inevitably decreases patient compliance and limits its application in long-term management. To improve the performance of Orn, we designed self-assembling polyOrn-based nanoparticles for oral administration through ring-opening polymerization of Orn-N-carboxy anhydride initiated with amino-ended poly(ethylene glycol), followed by acylation of free amino groups in the main chain of the polyOrn segment. The obtained amphiphilic block copolymers, poly(ethylene glycol)-block-polyOrn(acyl) (PEG-block-POrn(acyl)), enabled the formation of stable nanoparticles (NanoOrn(acyl)) in aqueous media. We employed the isobutyryl (iBu) group for acyl derivatization in this study (NanoOrn(iBu)). In the healthy mice, daily oral administration of NanoOrn(iBu) for one week did not induce any abnormalities. In the mice exhibiting acetaminophen (APAP)-induced acute liver injury, oral pretreatment with NanoOrn(iBu) effectively reduced systemic ammonia and transaminases levels compared to the LMW Orn and untreated groups. The results suggest that the application of NanoOrn(iBu) is of significant clinical value with the feasibility of oral delivery and improvement in APAP-induced hepatic pathogenesis. STATEMENT OF SIGNIFICANCE: Liver injury is often accompanied by hyperammonemia, a life-threatening condition characterized by elevated blood ammonia levels. Current clinical treatments for reducing ammonia typically entail the invasive approach of intravenous infusion, involving the administration of l-ornithine (Orn) or a combination of Orn and L-aspartate. This method is employed due to the poor pharmacokinetics associated with these compounds. In our pursuit of enhancing therapy, we have developed an orally administrable nanomedicine based on Orn-based self-assembling nanoparticle (NanoOrn(iBu)), which provides sustained Orn supply to the injured liver. Oral administration of NanoOrn(iBu) to healthy mice did not cause any toxic effects. In a mouse model of acetaminophen-induced acute liver injury, oral administration of NanoOrn(iBu) surpassed Orn in reducing systemic ammonia levels and liver damage, thereby establishing NanoOrn(iBu) as a safe and effective therapeutic option.
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Hiperamonemia , Camundongos , Animais , Hiperamonemia/induzido quimicamente , Hiperamonemia/complicações , Hiperamonemia/tratamento farmacológico , Ornitina/farmacologia , Ornitina/uso terapêutico , Ornitina/metabolismo , Acetaminofen/farmacologia , Polímeros/farmacologia , Amônia/metabolismo , Amônia/farmacologia , Nanomedicina , Fígado , Polietilenoglicóis/farmacologiaRESUMO
Self-renewal and differentiation are tightly controlled to maintain haematopoietic stem cell (HSC) homeostasis in the adult bone marrow1,2. During fetal development, expansion of HSCs (self-renewal) and production of differentiated haematopoietic cells (differentiation) are both required to sustain the haematopoietic system for body growth3,4. However, it remains unclear how these two seemingly opposing tasks are accomplished within the short embryonic period. Here we used in vivo genetic tracing in mice to analyse the formation of HSCs and progenitors from intra-arterial haematopoietic clusters, which contain HSC precursors and express the transcription factor hepatic leukaemia factor (HLF). Through kinetic study, we observed the simultaneous formation of HSCs and defined progenitors-previously regarded as descendants of HSCs5-from the HLF+ precursor population, followed by prompt formation of the hierarchical haematopoietic population structure in the fetal liver in an HSC-independent manner. The transcription factor EVI1 is heterogeneously expressed within the precursor population, with EVI1hi cells being predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs. By genetically manipulating EVI1 expression, we were able to alter HSC and progenitor output from precursors in vivo. Using fate tracking, we also demonstrated that fetal HSCs are slowly used to produce short-term HSCs at late gestation. These data suggest that fetal HSCs minimally contribute to the generation of progenitors and functional blood cells before birth. Stem cell-independent pathways during development thus offer a rational strategy for the rapid and simultaneous growth of tissues and stem cell pools.
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Linhagem da Célula , Feto , Células-Tronco Hematopoéticas , Fígado , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Medula Óssea , Diferenciação Celular , Autorrenovação Celular , Rastreamento de Células , Feminino , Feto/citologia , Células-Tronco Hematopoéticas/citologia , Fígado/citologia , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Camundongos , Gravidez , Fatores de Transcrição/metabolismoRESUMO
Meiotic prophase I is a prolonged G2 phase that ensures the completion of numerous meiosis-specific chromosome events. During meiotic prophase I, homologous chromosomes undergo synapsis to facilitate meiotic recombination yielding crossovers. It remains largely elusive how homolog synapsis is temporally maintained and destabilized during meiotic prophase I. Here we show that FBXO47 is the stabilizer of the synaptonemal complex during male meiotic prophase I. Disruption of FBXO47 shows severe impact on homologous chromosome synapsis, meiotic recombination, and XY body formation, leading to male infertility. Notably, in the absence of FBXO47, although once homologous chromosomes are synapsed, the synaptonemal complex is precociously disassembled before progressing beyond pachytene. Remarkably, Fbxo47 KO spermatocytes remain in an earlier stage of meiotic prophase I and lack crossovers, despite apparently exhibiting diplotene-like chromosome morphology. We propose that FBXO47 plays a crucial role in preventing the synaptonemal complex from premature disassembly during cell cycle progression of meiotic prophase I.
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The effects of the regular consumption of soy, barley, and green tea in a real-life setting are unclear. This longitudinal observational study showed the associations of their intake with cardiometabolic health when employees freely selected these foods in the workplace cafeteria of an industrial company in Japan. The consumption was objectively assessed by an electronic purchase system using integrated circuit chip-equipped tableware and personal identification cards. The associations between the cumulative number of servings of each food during the 12 weeks prior to a health examination and changes in cardiometabolic measurements were examined among Japanese male workers (n = 890). Higher total intake of soy products was associated with significant lower levels in low-density lipoprotein cholesterol. Higher total intake of rice with barley was marginally associated with lower levels in systolic blood pressure and glycated hemoglobin. These associations were attenuated after adjustment for the baseline values of the dependent variables. Serving soy and barley products in the workplace cafeteria possibly promotes real-life benefits to employees' cardiometabolic health.
Assuntos
Comportamento do Consumidor/estatística & dados numéricos , Dieta/estatística & dados numéricos , Alimento Funcional/estatística & dados numéricos , Adulto , Registros de Dieta , Dislipidemias/epidemiologia , Hordeum , Humanos , Hipertensão/epidemiologia , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Alimentos de Soja/estatística & dados numéricosRESUMO
The influence of excess salt intake on acute kidney injury (AKI) has not been examined precisely except for some clinical data, unlike in chronic kidney disease. Here, we addressed the influence of high salt (HS) on AKI and its underlying mechanisms in terms of the activity of circulating apoptosis inhibitor of macrophage (AIM, also called CD5L) protein, a facilitator of AKI repair. HS loading in mice subjected to ischemia/reperfusion (IR) resulted in high mortality with advanced renal tubular obstruction and marked exacerbation in biomarkers of proximal renal tubular damage. This AKI exacerbation appeared to be caused mainly by the reduced AIM dissociation from IgM pentamer in serum, as IgM-free AIM is indispensable for the removal of intratubular debris to facilitate AKI repair. Injection of recombinant AIM (rAIM) ameliorated the AKI induced by IR/HS, dramatically improving the tubular damage and mouse survival. The repair of lethal AKI by AIM was dependent on AIM/ kidney injury molecule-1 (KIM-1) axis, as rAIM injection was not effective in KIM-1 deficient mice. Our results demonstrate that the inhibition of AIM dissociation from IgM is an important reason for the exacerbation of AKI by HS, that AIM is a strong therapeutic tool for severe AKI.
Assuntos
Injúria Renal Aguda/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Receptores Depuradores/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Injúria Renal Aguda/patologia , Animais , Feminino , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Camundongos Endogâmicos ICR , Cloreto de Sódio na Dieta/metabolismoRESUMO
Powder electroluminescent (EL) devices with an electric field type excitation are surface light sources that are expected to have a wide range of practical applications, owing to their high environmental resistance; however, their low luminance has hindered their use. A clarification of the relationship between the properties of the film substrates and the electroluminescence is important to drastically improve light extraction efficiency. In this study, powder EL devices with different substrates of various levels of surface roughness and different optical transmittances were fabricated to quantitatively evaluate the relationships between the substrate properties and the device characteristics. A decrease in the surface roughness of the substrate caused a clear increase in both the current density and the luminance. The luminance was found to have a direct relationship with the optical transmittance of the substrates. The powder EL device, which was based on a cellulose nanofiber film and was the smoothest and most transparent substrate investigated, showed the highest luminance (641 cd/cm2) when 300 V was applied at 1 kHz.
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Niemann-Pick C1 Like 1 (NPC1L1) is known to be involved in the intestinal absorption of cholesterol. For evaluating the function of NPC1L1, cell lines such as Caco-2, Madin-Darby canine kidney (MDCK) II, and McA-RH7777 have been used in previous studies, but the detailed molecular mechanism of transport has not been elucidated. In this study, the characteristics of cholesterol transport via NPC1L1 were investigated using a Xenopus laevis oocyte expression system in addition to a conventional cell line with stable expression. The transport activity of cholesterol uptake was increased in NPC1L1-overexpressed MDCK cells compared with that in mock cells, but MDCK cells expressed endogenous NPC1L1 and had high cholesterol transport activity. On the other hand, cRNA-injected oocytes expressed NPC1L1 after culturing for 5-6 days. The transport activity of cholesterol uptake was increased in NPC1L1 cRNA-injected oocytes compared with that in water-injected oocytes. In addition, the uptake of cholesterol was decreased in the presence of ezetimibe, an NPC1L1 inhibitor, in cRNA-injected oocytes but not in control oocytes, indicating that endogenous NPC1L1 is not expressed in oocytes. Furthermore, cholesterol uptake was substantially decreased in NPC1L1 L216A cRNA-injected oocytes compared with that in NPC1L1 cRNA-injected oocytes, indicating that leucine at position 216 of NPC1L1 is important for cholesterol transport and that an oocyte expression system is useful for mutant analysis. These results indicate that the oocyte expression system is useful for evaluating the characteristics of NPC1L1-mediated cholesterol transport and may contribute to the elucidation of the detailed molecular mechanism of cholesterol transport via NPC1L1.
Assuntos
Colesterol/metabolismo , Proteínas de Membrana Transportadoras/biossíntese , Oócitos/metabolismo , Animais , Transporte Biológico Ativo , Células CACO-2 , Colesterol/genética , Cães , Humanos , Células Madin Darby de Rim Canino , Proteínas de Membrana Transportadoras/genética , Xenopus laevisRESUMO
A recently developed biopesticide made of safflower and cottonseed oils has excellent ovicidal activity against the hard-to-control spider mite Tetranychus urticae Koch (Acari: Tetranychidae). It has attracted attention as a sustainable treatment for controlling T. urticae because it has low potential for promoting resistance and little effect on the predatory mite Neoseiulus californicus (McGregor) (Acari: Phytoseiidae), which is an important natural enemy of spider mites. Here, we investigated the mechanism of its ovicidal activity against T. urticae. The oil droplets in the oil-in-water emulsion of the biopesticide strongly adhered to T. urticae eggs, seeped through the chorion being cut during hatching, and inhibited the embryonic rotational movement necessary for cutting and hatching. No adverse effect was observed on N. californicus eggs even in undiluted biopesticide. We conclude that this biopesticide and N. californicus can be used simultaneously in the integrated management of T. urticae in oily biopesticide-tolerant plant species.
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Vesicular monoamine transporter 2 (VMAT2) uptakes cytoplasmic monoamines into vesicles for storage. VMAT2 plays a role in modulating insulin release by regulating dopamine levels in the pancreas, although the exact mechanism remains elusive. We found that VMAT2 expression in ß-cells specifically increases under high blood glucose conditions. The islets isolated from ß-cell-specific Vmat2 knockout (ßVmat2KO) mice show elevated insulin secretion levels in response to glucose stimulation. Under prolonged high-fat diet feedings, the ßVmat2KO mice exhibit impaired glucose and insulin tolerance and progressive ß-cell dysfunction. Here we demonstrate VMAT2 uptake of dopamine to protect dopamine from degradation by monoamine oxidase, thereby safeguarding ß-cells from excess reactive oxygen species (ROS) exposure. In the context of high demand for insulin secretion, the absence of VMAT2 leads to elevated ROS in ß-cells, which accelerates ß-cell dedifferentiation and ß-cell loss. Therefore, VMAT2 controls the amount of dopamine in ß-cells, thereby protecting pancreatic ß-cells from excessive oxidative stress.
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Dieta Hiperlipídica , Gorduras na Dieta/efeitos adversos , Dopamina/metabolismo , Células Secretoras de Insulina/metabolismo , Obesidade/induzido quimicamente , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Glicemia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Espécies Reativas de Oxigênio , Proteínas Vesiculares de Transporte de Monoamina/genéticaRESUMO
FZR1/CDH1 is an activator of Anaphase promoting complex/Cyclosome (APC/C), best known for its role as E3 ubiquitin ligase that drives the cell cycle. APC/C activity is regulated by CDK-mediated phosphorylation of FZR1 during mitotic cell cycle. Although the critical role of FZR1 phosphorylation has been shown mainly in yeast and in vitro cell culture studies, its biological significance in mammalian tissues in vivo remained elusive. Here, we examined the in vivo role of FZR1 phosphorylation using a mouse model, in which non-phosphorylatable substitutions were introduced in the putative CDK-phosphorylation sites of FZR1. Although ablation of FZR1 phosphorylation did not show substantial consequences in mouse somatic tissues, it led to severe testicular defects resulting in male infertility. In the absence of FZR1 phosphorylation, male juvenile germ cells entered meiosis normally but failed to enter meiosis II or form differentiated spermatids. In aged testis, male mutant germ cells were overall abolished, showing Sertoli cell-only phenotype. In contrast, female mutants showed apparently normal progression of meiosis. The present study demonstrated that phosphorylation of FZR1 is required for temporal regulation of APC/C activity at meiosis II entry, and for maintenance of spermatogonia, which raised an insight into the sexual dimorphism of FZR1-regulation in germ cells.
Assuntos
Proteínas Cdh1/metabolismo , Meiose/fisiologia , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Animais , Proteínas Cdh1/fisiologia , Proteínas de Ciclo Celular/metabolismo , Técnicas de Introdução de Genes/métodos , Células Germinativas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Espermatogênese/fisiologia , Espermatogônias/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Malignant fibrous histiocytoma (MFH) of the spine is rare, with only a few dozen cases reported in the literature. A 60-year-old male was referred to us with symptoms of thoracic myelopathy. A solid tumor in the Th8 right costovertebral junction invading the spinal canal and compressing the spinal cord, and multiple bony metastases were discovered. Biopsy confirmed MFH. The thoracic spine tumor showed good response to irradiation followed by embolization and partial resection. The patient was followed until his death 22 months later. A good quality of life was sustained for more than 18 months. Despite a poor prognosis and an aggressive course of MFH of the spine, a good quality of life could be sustained for more than a year with palliative interventions.
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The mechanisms regulating meiotic initiation in mammals are enigmatic. It is known that retinoic acid (RA) signaling plays a pivotal role during meiotic initiation. STRA8, which is expressed in response to RA, is thought to be a key factor promoting meiotic initiation. However, the specific role of STRA8 in meiotic initiation has remained elusive. Here, we identified MEIOSIN as a germ-cell-specific factor that associates with STRA8. MEIOSIN, like STRA8, is expressed in response to RA and plays an essential role in meiotic initiation in both males and females. Functional analyses revealed that MEIOSIN acts as a transcription factor together with STRA8, and that both factors are critical for driving meiotic gene activation. Furthermore, temporally restricted expression of MEIOSIN leads to meiotic entry decision during spermatogenesis. The present study demonstrates that MEIOSIN, in collaboration with STRA8, plays a central role in regulating the mitosis to meiosis germ cell fate decision in mammals.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Ciclo Celular , Regulação da Expressão Gênica , Células Germinativas/fisiologia , Meiose , Mitose , Fatores de Transcrição/fisiologia , Animais , Diferenciação Celular , Feminino , Células Germinativas/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , EspermatogêneseRESUMO
Secondary inorganic aerosols, including sulfate, nitrate, and ammonium contribute to a large extent to the severe haze pollution events in China. Understanding their formation mechanisms is critical for designing effective mitigation strategies to control haze pollution, especially as the role of nitrate seemed to become more important recently, especially in some megacities. In the present study, simultaneous observations were conducted in two megacities (Chengdu and Chongqing) in Sichuan Basin of southwest China, one of the regions suffering from severe aerosol pollution. One typical long-lasting pollution event in Chengdu and Chongqing was captured during wintertime from December 25, 2016 to January 5, 2017. The campaign-average of hourly concentrations of PM2.5, sulfate, and nitrate, measured by an Aerosol Analyzer (ZSF) were 101⯱â¯73.8⯵g/m3, 15.9⯱â¯11.8⯵g/m3, and 24.9⯱â¯20.6⯵g/m3, respectively, in Chengdu, and were 87.7⯱â¯53.8⯵g/m3, 19.7⯱â¯13.5⯵g/m3, and 15.1⯱â¯10.1⯵g/m3, respectively, in Chongqing. Nitrate contributed substantially to PM2.5 pollution when PM2.5 was lower than 150⯵g/m3, largely due to the strong secondary transformation of NOX to nitrate during the occurrence of the pollution episode. Heterogeneous hydrolysis of N2O5 dominated nitrate formation during nighttime, while photochemical reactions and high-RH enhanced gas- to aqueous-phase dissolution of NH3 and HNO3 or cloud processes likely played important roles for nitrate formation during daytime. RH-dependent heterogeneous reactions contributed greatly to the formation of sulfate. NOX is confirmed to play an important role as an oxidant in accelerating the secondary transformation of SO2 to sulfate at high RH and low O3 levels under neutralization condition during heavy PM2.5 pollution episode. Results from this study identified the formation mechanism of nitrate, especially during the daytime, and addressed the importance of heterogeneous inorganic reactions in the formation of heavy aerosol pollution events.
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Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Nitratos/análise , Material Particulado/análise , Aerossóis , China , Cidades , Óxidos de Nitrogênio/análise , Estações do Ano , Sulfatos/análiseRESUMO
Although sequence variants in CD2-associated protein (CD2AP) have been identified in patients with focal segmental glomerulosclerosis (FSGS), definitive proof of causality in human disease is meager. By whole-exome sequencing, we identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease. When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure. These results provide conclusive evidence that homozygous mutation of CD2AP causes FSGS in humans.