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Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies. Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses. Here the authors show that autophosphorylation at Ser166 is required for RIPK1-mediated cell death and inflammation in mouse models of inflammatory pathologies, making Ser166 phosphorylation a possible biomarker for RIPK1-mediated inflammatory diseases.

Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi–Goutières syndrome and bilateral striatal necrosis 1 – 3 . The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA 4 , 5 . Hemizygous ADAR1 mutations in the Zα domain cause type I IFN-mediated pathologies in humans 2 , 3 and mice 6 – 8 ; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation. Here we show that Z-DNA-binding protein 1 (ZBP1), the only other protein in mammals known to harbour Zα domains 9 , promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain ( Adar1 mZα /– mice). Adar1 mZα /– mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1 mZα /– mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by ADAR1 mutations. ADAR1 prevents Z-RNA-dependent activation of pathogenic type I interferon responses by ZBP1, whose activity may contribute to pathology in type I interferonopathies with ADAR1 mutations.

In Japan, there is a huge number of short- and medium-span bridges in service, and it is becoming a major social concern how these bridges can be maintained in good condition during their whole lifetime. In this paper, we propose a method for assessing the condition of existing short-span (10–20 m span length) reinforced concrete bridges based on data obtained by monitoring public bus vibrations. This paper describes the details of not only a prototype monitoring system using information technology and sensors, which is capable of providing more accurate knowledge about bridge performance than traditional ways, but also a few specific examples of bridge condition assessment using public bus vibrations measured when driving on bridges, based on the data from the system.

Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

Purpose To explore factors associated with metastasis and prognosis in T1a renal cell carcinoma (RCC). Methods We retrospectively reviewed 451 cases of sporadic T1aRCC among 1,060 patients admitted to the Department of Urology at Hamamatsu University Hospital and affiliated hospitals between 1978 and 2007. Clinicopathological factors were analyzed for metastatic and prognostic risks. Results We identified 32 RCC patients with metastatic disease, 22 with synchronous and 10 with metachronous metastatic RCC. Patients with metastatic disease had a significantly higher incidence of symptomatic cancer, as well as greater tumor size, C-reactive protein (CRP) level, sarcomatoid component ratio, histological grade 3 and microvascular invasion than those without metastasis. Among the 32 patients with metastasis, there is no significant difference in clinicopathological factors. The most common site of metastasis was bone. Among patients with metastatic T1aRCC, findings at diagnosis of a symptomatic cancer, CRP level of 0.4 mg/dL or more, tumor size of 3.0 cm or greater, histological grade 3, a sarcomatoid component and microvascular invasion appeared to be significant and independent risk factors. Significant independent risk factors with metachronous metastatic RCC were a symptomatic cancer and a sarcomatoid component at diagnosis. A CRP level of 0.4 mg/dL or more was also an independent prognostic factor for overall survival. Conclusion RCC patients with findings at diagnosis of a symptomatic cancer, a sarcomatoid component and CRP level of 0.4 mg/dL or more require intensive follow-up.

Cryptococcus neoformans ( Cn ) is a fungal pathogen responsible for cryptococcal meningitis, which accounts for 15% of AIDS-related deaths. Recent studies have shown that the absence of sterol β-glucosidase (EGCrP2, also known as Sgl1) in Cn significantly attenuates its virulence in a mouse infection model. However, the mechanisms underlying this virulence attenuation remain unclear. In this study, we observed a significant increase in dead cells after 3 days of culture of SGL1 -deficient Cn ( sgl1 Δ, KO) at 37°C, compared with wild-type (WT) and SGL1 -reconstituted Cn ( sgl1 Δ:: SGL1 , RE). qPCR analysis of WT, KO, and RE strains indicated that autophagy-related genes ( ATG s) were significantly downregulated in KO strain. Atg8-dependent GFP translocation to the vacuole was significantly delayed in KO strain under starvation conditions. This autophagy dysfunction was identified as the primary cause of the increased cell death observed in KO strain under nitrogen starvation conditions at 37°C. EGCrP2/Sgl1 is predominantly localized in the vacuoles of Cn , and its deletion results in the accumulation of not only ergosterol β-glucoside (EG), as previously reported, but also acylated EGs (AEGs). AEGs were much more potent than EG in activating the C-type lectin receptor Mincle in mice, rats, and humans. AEGs were released from KO strain via extracellular vesicles (EVs). Chemically synthesized 18:1-EG and EVs derived from KO strain, but not WT or RE strains, enhanced cytokine production in murine and human dendritic cells. AEG-dependent cytokine production was markedly reduced in dendritic cells from Mincle-deficient mice, and the number of KO strain in lung tissue from Mincle-deficient mice was substantially higher than wild-type mice on day 3 after infection. Intranasal administration of acylated sitosterol β-glucoside increased Mincle expression and cytokine production and reduced the Cn burden in lung tissue of Cn -infected mice. These findings suggest that autophagy dysfunction in KO strain and the host innate immune response via the AEG-dependent Mincle activation are critical in reducing Cn virulence in mice.

Cryptococcus neoformans (Cn) is a fungal pathogen responsible for cryptococcal meningitis, which accounts for 15% of AIDS-related deaths. Recent studies have shown that the absence of sterol [beta]-glucosidase (EGCrP2, also known as Sgl1) in Cn significantly attenuates its virulence in a mouse infection model. However, the mechanisms underlying this virulence attenuation remain unclear. In this study, we observed a significant increase in dead cells after 3 days of culture of SGL1-deficient Cn (sgl1[DELTA], KO) at 37°C, compared with wild-type (WT) and SGL1-reconstituted Cn (sgl1[DELTA]::SGL1, RE). qPCR analysis of WT, KO, and RE strains indicated that autophagy-related genes (ATGs) were significantly downregulated in KO strain. Atg8-dependent GFP translocation to the vacuole was significantly delayed in KO strain under starvation conditions. This autophagy dysfunction was identified as the primary cause of the increased cell death observed in KO strain under nitrogen starvation conditions at 37°C. EGCrP2/Sgl1 is predominantly localized in the vacuoles of Cn, and its deletion results in the accumulation of not only ergosterol [beta]-glucoside (EG), as previously reported, but also acylated EGs (AEGs). AEGs were much more potent than EG in activating the C-type lectin receptor Mincle in mice, rats, and humans. AEGs were released from KO strain via extracellular vesicles (EVs). Chemically synthesized 18:1-EG and EVs derived from KO strain, but not WT or RE strains, enhanced cytokine production in murine and human dendritic cells. AEG-dependent cytokine production was markedly reduced in dendritic cells from Mincle-deficient mice, and the number of KO strain in lung tissue from Mincle-deficient mice was substantially higher than wild-type mice on day 3 after infection. Intranasal administration of acylated sitosterol [beta]-glucoside increased Mincle expression and cytokine production and reduced the Cn burden in lung tissue of Cn-infected mice. These findings suggest that autophagy dysfunction in KO strain and the host innate immune response via the AEG-dependent Mincle activation are critical in reducing Cn virulence in mice.

Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 x Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

INTRODUCTION: Situs inversus totalis (SIT) is a rare congenital condition characterized by mirror-image transposition of the thoracic and abdominal viscera. Herein, we report a rare case of laparoscopic common bile duct exploration with choledochotomy and stone extraction in a patient with SIT and a history of total gastrectomy with Roux-en-Y (R-Y) reconstruction.CASE PRESENTATION: A 70-year-old woman with SIT and a history of total gastrectomy with R-Y reconstruction presented with recurrent cholangitis caused by choledocholithiasis. Conservative therapy led to temporary improvement, but symptoms recurred after 2 months. Percutaneous transhepatic gallbladder drainage was followed by laparoscopic cholecystectomy and laparoscopic common bile duct exploration (LCBDE) one week later. Dense adhesions along the midline and right upper quadrant prevented standard port placement, so all maneuvers were confined to the left abdomen. A 3-cm umbilical minilaparotomy accommodated a Lap Protector with two 5-mm working ports, and additional 5-mm ports were inserted in the left lower abdomen for the camera, in the left upper abdomen for the assistant, and above the choledochotomy site for choledochoscope access. CT confirmed complete SIT and an 18-mm common bile duct (CBD) stone with upstream dilation. Endoscopic retrograde cholangiopancreatography was impossible because the long Roux limb and adhesions limited endoscopic access. Choledochotomy was aided by traction sutures; the impacted stone was fragmented intraductally and retrieved with basket forceps. The CBD was closed primarily without drainage. The postoperative course was uneventful, and the patient was discharged on day 8. No complications occurred during the 4-week follow-up.CONCLUSIONS: This case emphasizes the technical challenges of laparoscopic biliary surgery in patients with situs inversus and a history of R-Y reconstruction. The key points include individualized port placement, surgeon positioning, traction, and secure primary closure. LCBDE is feasible in patients with SIT and prior R-Y reconstruction if surgical strategies are individualized based on anatomical variation and surgical history.