RESUMO
Memory B cells (Bmem cells) are the basis of long-lasting humoral immunity. They respond to re-encountered antigens by rapidly producing specific antibodies and forming germinal centers (GCs), a recall response that has been known for decades but remains poorly understood. We found that the receptor for the cytokine IL-9 (IL-9R) was induced selectively on Bmem cells after primary immunization and that IL-9R-deficient mice exhibited a normal primary antibody response but impaired recall antibody responses, with attenuated population expansion and plasma-cell differentiation of Bmem cells. In contrast, there was augmented GC formation, possibly due to defective downregulation of the ligand for the co-stimulatory receptor ICOS on Bmem cells. A fraction of Bmem cells produced IL-9. These findings indicate that IL-9R signaling in Bmem cells regulates humoral recall responses.
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Linfócitos B/imunologia , Centro Germinativo/fisiologia , Interleucina-9/metabolismo , Plasmócitos/imunologia , Receptores de Interleucina-9/genética , Animais , Diferenciação Celular , Células Cultivadas , Imunidade Humoral , Imunização Secundária , Região Variável de Imunoglobulina/genética , Memória Imunológica , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-9/metabolismo , Transdução de SinaisRESUMO
The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.
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Epiderme , Imunidade Inata , Dermatopatias Bacterianas , Animais , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Relógios Circadianos/imunologia , Epiderme/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Queratinócitos/imunologia , Mamíferos , Camundongos , Dermatopatias Bacterianas/imunologia , Dermatopatias Bacterianas/metabolismo , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologiaRESUMO
The evolutionary forces arising from differential dispersal are known as "spatial sorting," distinguishing them from natural selection arising from differential survival or differential reproductive success. Spatial sorting is often considered to be transient, because it is offset by the return of dispersers in many cases. However, in riverine systems, spatial sorting by downstream dispersal can be cumulative in habitats upstream of migration barriers such as weirs or falls, which can block the return of the dispersers. Terraced rice paddies are often found on steep mountain slopes in Japan and often incorporate small streams with numerous migration barriers. This study investigated the morphological features of fat minnow, Rhynchocypris oxycephalus jouyi (Cyprinidae), inhabiting above-barrier habitats of the small streams flowing through flood-prone terraced rice paddies and examined their function via a mark-recapture experiment. Although this study did not reveal a consistent pattern across all local populations, some above-barrier populations were characterised by individuals with a thinner caudal peduncle, thinner body, and longer ventral caudal fin lobes than those in neighbouring mainstream populations. A mark-recapture experiment during flooding showed that a thinner caudal peduncle and deeper body helped fat minnow avoid downstream dispersal and ascend a small step, and suggested that a longer ventral caudal fin lobe was important for ascending. These results suggest that the caudal morphologies of some above-barrier populations avoid or reduce the risk of downstream dispersal, supporting the idea that spatial sorting shapes functional traits, enhancing the spatial persistence of individuals in upstream habitats.
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SIGNIFICANCE STATEMENT: Nuclear translocation of dendrin is observed in injured podocytes, but the mechanism and its consequence are unknown. In nephropathy mouse models, dendrin ablation attenuates proteinuria, podocyte loss, and glomerulosclerosis. The nuclear translocation of dendrin promotes c-Jun N -terminal kinase phosphorylation in podocytes, altering focal adhesion and enhancing cell detachment-induced apoptosis. We identified mediation of dendrin nuclear translocation by nuclear localization signal 1 (NLS1) sequence and adaptor protein importin- α . Inhibition of importin- α prevents nuclear translocation of dendrin, decreases podocyte loss, and attenuates glomerulosclerosis in nephropathy models. Thus, inhibiting importin- α -mediated nuclear translocation of dendrin is a potential strategy to halt podocyte loss and glomerulosclerosis. BACKGROUND: Nuclear translocation of dendrin is observed in the glomeruli in numerous human renal diseases, but the mechanism remains unknown. This study investigated that mechanism and its consequence in podocytes. METHODS: The effect of dendrin deficiency was studied in adriamycin (ADR) nephropathy model and membrane-associated guanylate kinase inverted 2 ( MAGI2 ) podocyte-specific knockout ( MAGI2 podKO) mice. The mechanism and the effect of nuclear translocation of dendrin were studied in podocytes overexpressing full-length dendrin and nuclear localization signal 1-deleted dendrin. Ivermectin was used to inhibit importin- α . RESULTS: Dendrin ablation reduced albuminuria, podocyte loss, and glomerulosclerosis in ADR-induced nephropathy and MAGI2 podKO mice. Dendrin deficiency also prolonged the lifespan of MAGI2 podKO mice. Nuclear dendrin promoted c-Jun N -terminal kinase phosphorylation that subsequently altered focal adhesion, reducing cell attachment and enhancing apoptosis in cultured podocytes. Classical bipartite nuclear localization signal sequence and importin- α mediate nuclear translocation of dendrin. The inhibition of importin- α / ß reduced dendrin nuclear translocation and apoptosis in vitro as well as albuminuria, podocyte loss, and glomerulosclerosis in ADR-induced nephropathy and MAGI2 podKO mice. Importin- α 3 colocalized with nuclear dendrin in the glomeruli of FSGS and IgA nephropathy patients. CONCLUSIONS: Nuclear translocation of dendrin promotes cell detachment-induced apoptosis in podocytes. Therefore, inhibiting importin- α -mediated dendrin nuclear translocation is a potential strategy to prevent podocyte loss and glomerulosclerosis.
Assuntos
Glomerulonefrite por IGA , Glomerulosclerose Segmentar e Focal , Podócitos , Humanos , Camundongos , Animais , Podócitos/metabolismo , Albuminúria/metabolismo , alfa Carioferinas/metabolismo , Sinais de Localização Nuclear/metabolismo , Doxorrubicina/metabolismo , Glomerulonefrite por IGA/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismoRESUMO
In many organisms, including fishes, downstream dispersal is often phenotype-dependent. Phenotype-dependent downstream dispersal can generate evolutionary pressure via spatial sorting, which non-randomly removes phenotypes enhancing downstream dispersal from upstream populations. Spatial sorting due to downstream dispersal could accumulate in fish populations in above-barrier habitats to which dispersed individuals cannot return, resulting in functional traits that reduce downstream dispersal. This evolutionary mechanism may be more important in smaller above-barrier habitats where downstream emigration occurs over shorter dispersal distances. This study observed the dispersal behavior of fat minnow Rhynchocypris oxycephalus jouyi juveniles in an experimental tank to examine whether juveniles from small above-barrier habitats show more behaviors favorable for reducing downstream dispersal than those from large above-barrier habitats. Juveniles from small above-barrier habitats avoided downstream dispersal for longer durations than those from large above-barrier habitats, but there was no difference in the frequency of ascending attempts. These results support the notion that behavioral traits of juveniles in small above-barrier populations have been refined by spatial sorting to reduce downstream dispersal. The finding that interpopulation variation in dispersal behavior occurred only for certain dispersal directions implies that the behavioral consequences of habitat fragmentation are more complex than previously assumed.
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Natriuretic peptides exert not only blood-lowering but also kidney-protective effects through guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. Signaling through GC-A has been shown to protect podocytes from aldosterone-induced glomerular injury, and a p38 mitogen-activated protein kinase (MAPK) inhibitor reduced glomerular injury in aldosterone-infused podocyte-specific GC-A knockout mice. To explore the role of p38 MAPK in podocytes, we constructed podocyte-specific p38 MAPK and GC-A double knockout mice (pod-double knockout mice). Unexpectedly, aldosterone-infused and high salt-fed (B-ALDO)-treated pod-double knockout mice resulted in elevated serum creatinine, massive albuminuria, macrophage infiltration, foot process effacement, nephrin and podocin reduction, and additionally, intra-capillary fibrin thrombi, indicating endothelial injury. Microarray analysis showed increased plasminogen activator inhibitor-1 (PAI-1) in glomeruli of B-ALDO-treated pod-double knockout mice. In B-ALDO-treated pod-double knockout mice, PAI-1 increased in podocytes, and treatment with PAI-1 neutralizing antibody ameliorated intra-capillary thrombus formation. In vitro, deletion of p38 MAPK by the CRISPR/Cas9 system and knockdown of GC-A in human cultured podocytes upregulated PAI-1 and transforming growth factor- ß1 (TGF-ß1). When p38 MAPK knockout podocytes, transfected with a small interfering RNA to suppress GC-A, were co-cultured with glomerular endothelial cells in a transwell system, the expression of TGF-ß1 was increased in glomerular endothelial cells. PAI-1 inhibition ameliorated both podocyte and endothelial injury in the transwell system signifying elevated PAI-1 in podocytes is a factor disrupting normal podocyte-endothelial crosstalk. Thus, our results indicate that genetic dual deletion of p38 MAPK and GC-A in podocytes accelerates both podocyte and endothelial injuries, suggesting these two molecules play indispensable roles in podocyte function.
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Podócitos , Trombose , Animais , Humanos , Camundongos , Aldosterona/farmacologia , Aldosterona/metabolismo , Células Endoteliais/metabolismo , Guanilato Ciclase/metabolismo , Guanilato Ciclase/farmacologia , Camundongos Knockout , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Podócitos/metabolismo , Trombose/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteína Quinase 14 Ativada por MitógenoRESUMO
One of the most common causes of discontinued peritoneal dialysis is impaired peritoneal function. However, its molecular mechanisms remain unclear. Previously, by microarray analysis of mouse peritoneum, we showed that MMP (matrix metalloproteinase)-10 expression is significantly increased in mice with peritoneal fibrosis, but its function remains unknown. Chlorhexidine gluconate (CG) was intraperitoneally injected to wild-type and MMP-10 knockout mice to induce fibrosis to elucidate the role of MMP-10 on peritoneal injury. We also examined function of peritoneal macrophages and mesothelial cells obtained from wild-type and MMP-10 knockout mice, MMP-10-overexpressing macrophage-like RAW 264.7 cells and MeT-5A mesothelial cells, investigated MMP-10 expression on peritoneal biopsy specimens, and the association between serum proMMP-10 and peritoneal solute transfer rates determined by peritoneal equilibration test on patients. MMP-10 was expressed in cells positive for WT1, a mesothelial marker, and for MAC-2, a macrophage marker, in the thickened peritoneum of both mice and patients. Serum proMMP-10 levels were well correlated with peritoneal solute transfer rates. Peritoneal fibrosis, inflammation, and high peritoneal solute transfer rates induced by CG were all ameliorated by MMP-10 deletion, with reduction of CD31-positive vessels and VEGF-A-positive cells. Expression of inflammatory mediators and phosphorylation of NFκΒ subunit p65 at S536 were suppressed in both MMP-10 knockout macrophages and mesothelial cells in response to lipopolysaccharide stimulation. Overexpression of MMP-10 in RAW 264.7 and MeT-5A cells upregulated pro-inflammatory cytokines with phosphorylation of NFκΒ subunit p65. Thus, our results suggest that inflammatory responses induced by MMP-10 are mediated through the NFκΒ pathway, and that systemic deletion of MMP-10 ameliorates peritoneal inflammation and fibrosis caused by NFκΒ activation of peritoneal macrophages and mesothelial cells.
Assuntos
Metaloproteinase 10 da Matriz , Fibrose Peritoneal , Peritonite , Animais , Humanos , Camundongos , Inflamação/metabolismo , Metaloproteinase 10 da Matriz/genética , Metaloproteinase 10 da Matriz/metabolismo , Camundongos Knockout , Subunidade p50 de NF-kappa B/metabolismo , Fibrose Peritoneal/genética , Peritônio/patologia , Peritonite/etiologia , Fatores de Transcrição/metabolismoRESUMO
The clinical importance of Mycobacterium abscessus species (MABS) infections has been increasing. However, the standard treatment regimens recommended in the current guidelines often result in unfavorable outcomes. Therefore, we investigated the in vitro activity of omadacycline (OMC), a novel tetracycline, against MABS to explore its potential as a novel therapeutic option. The drug susceptibilities of 40 Mycobacterium abscessus subsp. abscessus (Mab) clinical strains obtained from the sputum of 40 patients from January 2005 to May 2014 were investigated. The MIC results for OMC, amikacin (AMK), clarithromycin (CLR), clofazimine (CLO), imipenem (IPM), rifabutin (RFB), and tedizolid (TZD) alone and their combined effects (with OMC) were examined using the checkerboard method. Additionally, we studied the differences in the effectiveness of the antibiotic combinations based on the colony morphotype of Mab. The MIC50 and MIC90 of OMC alone were 2 and 4 µg/mL, respectively. The combinations of OMC with AMK, CLR, CLO, IPM, RFB, and TZD showed synergy against 17.5%, 75.8%, 25.0%, 21.1%, 76.9%, and 34.4% of the strains, respectively. Additionally, OMC combined with CLO (47.1% versus 9.5%, P = 0.023) or TZD (60.0% versus 12.5%, P = 0.009) showed significantly higher synergy against strains with rough morphotypes than those with smooth morphotypes. In conclusion, the checkerboard analyses revealed that the synergistic effects of OMC were observed most frequently with RFB, followed by CLR, TZD, CLO, IPM, and AMK. Furthermore, OMC tended to be more effective against rough-morphotype Mab strains.
Assuntos
Anti-Infecciosos , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Mycobacterium , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Amicacina/farmacologia , Amicacina/uso terapêutico , Anti-Infecciosos/farmacologia , Rifabutina/farmacologia , Tetraciclinas/farmacologia , Tetraciclinas/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified. METHODS: Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 µg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid. RESULTS: The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2, and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR. CONCLUSION: In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Masculino , Camundongos , Animais , Aldosterona , Fluxo Plasmático Renal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Rim , Valsartana/farmacologia , Valsartana/uso terapêutico , Compostos de Bifenilo/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Peptídeos Natriuréticos/farmacologia , FibroseRESUMO
BACKGROUND AND OBJECTIVES: Hertwig's epithelial root sheath (HERS) plays a role in root dentin formation. It produces the epithelial rests of Malassez (ERM) for the induction of periodontal tissue development during root formation. Although ERM is thought to be caused by epithelial-mesenchymal transition (EMT), the mechanism by which HERS is maintained as epithelium is unknown. Here, we aimed to elucidate the molecular mechanisms regulating the relationship between HERS maintenance and ERM development. METHODS: To understand the relationship between HERS and ERM development during root formation, we observed the developing molar root using cytokeratin14 (CK14) Cre/tdTomato mice via stereomicroscopy. The relationship between semaphorin and transforming growth factor (TGF) signaling in the maintenance of HERS and ERM development was examined using CK14cre/R26-tdTomato mice and a HERS cell line. RESULTS: tdTomato-positive cells were observed on HERS and the migrating cells from HERS. The migrating cells showed reduced E-cadherin expression. In contrast, HERS cells expressed semaphorin receptors and active RhoA. Semaphorin signaling was associated with RhoA activation and cell-cell adhesion, while TGF-ß induced decreased E-cadherin and active RhoA expression, and consequently enhanced cell migration. CONCLUSION: HERS induces root formation by controlling epithelial maintenance and EMT through the opposing effects of semaphorin and TGF-ß signaling.
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Transição Epitelial-Mesenquimal , Fator de Crescimento Transformador beta , Feminino , Camundongos , Animais , Fator de Crescimento Transformador beta/farmacologia , Células Epiteliais , Raiz Dentária/fisiologia , Caderinas/metabolismoRESUMO
Nephrotoxicity is one of the most important complications in cancer patients. In particular, acute kidney injury (AKI) is known to be associated with discontinuing effective oncological treatments, longer hospitalizations, increased costs, and a higher risk of death. In addition to acute kidney injury, clinical signs associated with nephrotoxicity during treatment with anticancer agents include chronic kidney disease, proteinuria, hypertension, electrolyte abnormalities, and other characteristic manifestations. Many of these signs are caused both by cancer treatment as well as by cancer itself. Therefore, it is important to carefully recognize whether the underlying causes of renal impairment in cancer patients are cancer-related, treatment-related, or both. This review describes the epidemiology and pathophysiology of anticancer agent-induced acute kidney injury, proteinuria, hypertension, and other characteristic manifestations.
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Injúria Renal Aguda , Antineoplásicos , Hipertensão , Neoplasias , Humanos , Nefrologistas , Antineoplásicos/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Proteinúria/induzido quimicamente , Neoplasias/tratamento farmacológico , Neoplasias/complicaçõesRESUMO
The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft-Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology's GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.
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Antineoplásicos , Insuficiência Renal Crônica , Humanos , Taxa de Filtração Glomerular , Rim , Testes de Função Renal , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Antineoplásicos/efeitos adversos , CreatininaRESUMO
Osteogenesis imperfecta (OI) is an inherited disease characterized by bone fragility due to impaired type I collagen. Although orthopedic management is improving, other complications are poorly understood. We describe three patients with OI with unruptured intracranial aneurysm (IA) detected by magnetic resonance angiography (MRA) screening of 14 patients. Case 1 was a 73-year-old woman with type 1 OI with blue sclera, vertebral compression fractures, and impaired hearing. Lumbar spine bone mineral density (BMD) was preserved (young adult mean (YAM): 86%). MRA revealed an IA in the right internal carotid artery. Case 2 was a 43-year-old man with type 4 OI and leg-length discrepancy due to left femoral neck fracture. Lumbar spine BMD was decreased (YAM: 61%). MRA showed an IA in the left anterior cerebral artery. Case 3 was a 35-year-old woman with type 3 OI with blue sclera, dentinogenesis imperfecta, deformity of the long bones, and severe scoliosis. She had undergone spine surgery and needed wheelchair assistance. The YAM of the femoral neck BMD was 71%. MRA indicated an IA in the right posterior communicating artery. The prevalence of IA in our series of patients with OI was 21%, which is higher than the reported prevalence of unruptured IA in the Japanese general population (2.2%), suggesting that IA may be a complication of OI. Our literature review revealed no cases of OI with unruptured IA, but 11 cases of OI with subarachnoid hemorrhage. IA seems unrelated to OI type, sex, or age. We recommend MRA of adults with OI.
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Fraturas por Compressão , Aneurisma Intracraniano , Osteogênese Imperfeita , Fraturas da Coluna Vertebral , Masculino , Feminino , Adulto Jovem , Humanos , Idoso , Adulto , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/patologia , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico por imagem , Fraturas da Coluna Vertebral/complicações , Colágeno Tipo I , Densidade ÓsseaRESUMO
BACKGROUND: The COVID-19 pandemic has affected every aspect of our lives, including the decision to become pregnant. Existing literature suggests that infertility and the decision to delay childbearing at a younger age are associated with a lower level of well-being and regrets when women start to desire a baby. Thus, the decision to delay childbearing due to the pandemic could negatively affect the well-being of women. This study focuses on how pregnancy decisions affect the well-being of women during the COVID-19 pandemic. METHODS: From the Japan COVID-19 and Society Internet Survey, a nationally representative web-based survey, 768 observations of married women aged 18 to 50 years who had the intention of getting pregnant during the pre-pandemic period (conducted in 2020 and 2021) were used. Loneliness, severe psychological distress, and suicidal ideation were used as well-being indicators. For pooled data, a generalised estimated equation (GEE) model was used to estimate how pregnancy decision related to well-being indicators. For a sub-analysis, the sample was divided by the survey year and a Poisson regression model was used. RESULTS: The GEE analysis showed an association between delaying childbearing and severe psychological distress, with the prevalence ratio (PR) being 2.06 [95% CI (1.40-3.03)]. Furthermore, loneliness and suicidal ideation that occurred after the beginning of the pandemic were significantly related to the decision to delay childbearing-1.55 [95% CI (1.03,2.34)] and 2.55 [95% CI (1.45-4.51)], respectively. Moreover, these PRs were larger for 2021 compared to 2020. CONCLUSION: During the COVID-19 pandemic, approximately one-fifth of married women who had childbearing intentions before the pandemic decided to postpone pregnancy. They exhibited a deteriorated mental health state. Furthermore, the negative associations were larger in 2021 compared to 2020. Loneliness has negative consequences for both mental and physical health, as well as elevated severe psychological distress and suicidal ideation among those who decided to postpone pregnancy. Therefore, the current results should not be overlooked by society.
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COVID-19 , Angústia Psicológica , Lactente , Gravidez , Feminino , Humanos , Ideação Suicida , Solidão , Pandemias , COVID-19/epidemiologia , Análise de DadosRESUMO
BACKGROUND: In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathologic processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. METHODS: To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. RESULTS: MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, LPS administration accelerated kidney injury in the murine diabetic kidney disease model. CONCLUSIONS: Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Translocação Bacteriana , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Interleucina-17 , Rim/metabolismo , Camundongos , Camundongos KnockoutRESUMO
We performed a retrospective cohort study using medical records of 374 pediatric patients who visited a university dental clinic specializing in dysphagia rehabilitation in Japan between 2019 and 2020 to clarify the usefulness of telemedicine among disabled children receiving feeding therapy. The primary outcome was the feeding developmental stage confirmed at the final evaluation. Propensity score matching was performed between individuals in two treatment groups (in-person and telemedicine) before the final analysis using patients' age, sex, primary disease, gross motor function, and feeding developmental stage as covariates. A total of 36 patients were enrolled in each of the in-person and telemedicine groups. The initial evaluation for the propensity score matched population using the χ2 test showed no significant difference between the two groups in any parameter. The feeding developmental stage evaluated at the final evaluation using the Wilcoxon signed-rank test significantly improved compared with the stage at the initial evaluation in both groups (in-parson group, p = 0.007; telemedicine group, p = 0.013). The difference in level achieved at the final evaluation revealed that the most common level was "unchanged," followed by "improvement by one level" in both groups, indicating that there was no significant difference in the efficacy of feeding therapy between the two groups (p = 0.314). Our results show that telemedicine can achieve the same therapeutic outcomes as in-person therapy to improve feeding function in children with disabilities when receiving feeding therapy.
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Transtornos de Deglutição , Crianças com Deficiência , Telemedicina , Humanos , Criança , Estudos Retrospectivos , Transtornos de Deglutição/reabilitação , JapãoRESUMO
Japan has faced a decline in fertility since the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to investigate the rate of pregnancy postponement and its contributing factors, with a particular focus on economic- and COVID-19 infection-related indicators. This study used data from 768 observations of married women aged 18 to 50 years with pregnancy intentions. The data were obtained from two rounds of a large web-based survey conducted by the Japan COVID-19 and Society Internet Survey (JACSIS) in 2020 and 2021. A generalised estimating equation (GEE) model was employed, as well as Poisson regression models for sub-sample analysis divided by year to estimate the year differential magnitude of the contributing factors' impacts. Approximately 20% of married women with childbearing intentions postponed their childbearing. The analyses revealed that declining income and anxiety about future household finances were significantly related to delayed childbearing, while fear of COVID-19 and infection rate were not. Additionally, the adverse effects of unfavourable economic conditions were stronger in 2021. Notably, age did not influence the decision of pregnancy postponement. Older women postponed pregnancy just as much as younger women. In conclusion, this study confirmed that the COVID-19 pandemic, particularly its related adverse economic conditions, contributed to Japan's current baby bust. Considering that advanced maternal age is already common in Japan, this decreased fertility may result in the long-term negative consequence of further population decline.
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COVID-19 , Pandemias , Animais , Gravidez , Feminino , Humanos , Idoso , Japão , Fertilidade , Dinâmica PopulacionalRESUMO
Downstream displacement, the passive downstream dispersal of riverine organisms, can generate evolutionary pressures that selectively remove susceptible individuals from upstream habitats. These evolutionary pressures may accumulate over time in fish populations situated upstream of a tall check dam that displaced fish are unable to swim over and can be diluted by the homing of displaced individuals in the absence of such barriers. Here, we conducted interpopulation comparisons between above-dam and unrestricted open-stream populations of the juvenile white-spotted charr Salvelinus leucomaenis to test the hypothesis that above-dam juveniles possess more advantageous traits that reduce downstream displacement than open-stream juveniles. We focused on sedentary behaviour and body depth, both of which are known to affect downstream displacement. Interpopulation comparisons revealed that juveniles from above-dam populations were consistently more sedentary than those from open-stream populations. On the other hand, there were no systematic differences in body depth between above-dam and open-stream populations. These results are consistent with the evolution of behaviours in above-dam populations that inhibit downstream displacement. However, several other factors could explain the results obtained and further studies will be needed to confirm the presence of behavioural evolution in our study system.
Assuntos
Ecossistema , Truta , Animais , FenótipoRESUMO
PURPOSE: Aiming at complete excision of cholesteatoma during trympanomastoidectomy and therefore reducing the risk of recurrence, intraoperative imaging techniques are required to assist the visualization of cholesteatoma residue. Galectin-7 has been demonstrated to be a biomarker for cholesteatoma matrix and used for intraoperatively identifying the excision margins. METHODS: A galectin-7-targeted DNA-aptamer library was generated for labeling the cholesteatoma matrix using cell-systematic evolution of ligands by an exponential enrichment technique. The binding characteristics of the identified aptamers were analyzed, and structure optimization of the identified aptamers was carried out both in silico and in vitro. FINDINGS: A fluorophore-labeled structure-optimized DNA fragment was commercially synthesized as a non-invasive aptamer-based probe for intraoperative lesion detection. Using galectin-7-aptamer-guided molecular imaging, the excision margins of cholesteatoma matrix and surrounding normal tissue were successfully achieved within 15-20 min. CONCLUSIONS: Galectin-7-targeted aptamers could benefit molecular imaging-guided surgical treatment, which would enable clinicians to not only intraoperatively detect the locations of cholesteatoma matrix in the middle ear, but also assess the postoperative response of the expression profile to therapy. It is highly expected that further efforts for rational design and development should be directed towards the development of clinically translatable aptamer-based imaging agents.
Assuntos
Aptâmeros de Nucleotídeos , Colesteatoma , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Biomarcadores , Galectinas/genética , Humanos , Margens de Excisão , Técnica de Seleção de Aptâmeros/métodosRESUMO
BACKGROUND: The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood. METHODS: To investigate the role of the UPS in podocytes, mice were generated that had deletion of Rpt3 (Rpt3pdKO), which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function. RESULTS: Rpt3pdKO mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of Rpt3pdKO mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an in vitro study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the Rpt3pdKO mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of Rpt3pdKO mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of Rpt3pdKO mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes. CONCLUSIONS: Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.