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Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete pro-inflammatory factors, affect surrounding somatic cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the age-related changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4+ T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4+ T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas Cd8α, NK receptors, and Granzymes were upregulated in aging IEL CD4+ T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids in vitro than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8αα+CD4+ T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4+ T cells showed that two unique subsets are increased that are distinct from the systemic CD4+ T cells. Subset 1 has a pro-inflammatory component, with expression of IFNγ and upregulation of NFkB signaling pathways. Subset 2 does not express IFNγ, but upregulates inhibitory molecules and nIEL markers. Expression of granzymes and Cd8a was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research.

Abstract The elastic wave caused by the input at the wallhead spreads throughout the plane of the wall, and thus, inspecting the soundness of underground walls using a pile integrity test (PIT) is a challenging task. This paper presents a feasible method for evaluating the soundness of underground walls via a PIT. In particular, by applying a low‐pass filter to the reflected wave recorded at the wall head, the wave components reflected from the wall ends and cracks are effectively separated from the components reflected from the wall sides. Hence, through the proposed strategy, the wave can be clearly identified for soundness evaluation.

Background: Veno-venous extracorporeal membrane oxygenation is an established therapy for patients with refractory acute respiratory distress syndrome (ARDS). One complication related to the use of veno-venous extracorporeal membrane oxygenation is thrombosis despite proper anticoagulation. We report the diagnosis and management of a clot-obstruction in a single site cannula placed through the internal jugular vein, guided by transesophageal echocardiography. Case report: A 39 year-old male developed acute respiratory distress syndrome and hemodynamic instability after an episode of pulmonary aspiration in the ICU. Eight hours after placement of a single site veno-venous extracorporeal membrane oxygenation, suddenly the perfusionist noticed a reduction in flow. TEE showed a thrombus-like mass obstructing the inflow port in SVC and inflow at IVC was intact. After unsuccessful attempts to reposition the cannula, the team decided to insert additional femoral inflow cannula through the IVC. The single site catheter was then pulled out until its tip was positioned in the right atrium and all three ports of the catheter were switched to the infusion ports. After this, flows and oxygenation improved significantly. Unfortunately, despite all of the efforts, the patient died 2 days later. Discussion: The diagnosis of veno-venous extracorporeal membrane oxygenation cannula obstruction is based on reduced inflow rates, hemodynamic instability and poor oxygenation of blood. TEE allows evaluation of the flows inside the cannula and in this case, an obstruction was found. The management presented points to the fact that in a situation of catheter obstruction caused by a clot, there is a feasible alternative to assure minimal interruption of the hemodynamic support offered by the veno-venous extracorporeal membrane oxygenation. Resumo: Justificativa: A oxigenação por membrana extracorpórea veno-venosa é terapia estabelecida para pacientes com a síndrome do desconforto respiratório agudo. Uma complicação relacionada ao uso da oxigenação por membrana extracorpórea veno-venosa é trombose apesar de anti-coagulação adequada. Relatamos o diagnóstico e conduta em obstrução por coágulo em cânula de acesso único inserida pela veia jugular interna, guiada por ecocardiografia transesofageana. Relato de caso: Paciente do sexo masculino de 39 anos desenvolveu síndrome do desconforto respiratório agudo e instabilidade hemodinâmica após episódio de aspiração pulmonar na UTI. Oito horas após a instalação de oxigenação por membrana extracorpórea veno-venosa de acesso único, o perfusionista notou repentina redução no fluxo. A ETE revelou massa semelhante a um trombo obstruindo o portal de fluxo de entrada na VCS e o fluxo de saída na VCI estava intacto. Após tentativas sem sucesso para reposicionar a cânula, a equipe decidiu inserir cânula de entrada de fluxo adicional pela VCI. O catéter de acesso único foi então puxado até que sua ponta se posicionasse no átrio direito e todos os três portais do catéter fossem transferidos para os portais de infusão. A seguir, os fluxos e oxigenação melhoraram significativamente. Infelizmente, apesar dos esforços, o paciente foi a óbito 2 dias depois. Discussão: O diagnóstico de obstrução de cânula da oxigenação por membrana extracorpórea veno-venosa se baseia em velocidades reduzidas de entrada de fluxo, instabilidade hemodinâmica e oxigenação pobre do sangue. A ETE permite a avaliação dos fluxos dentro da cânula, e nesse caso foi encontrada obstrução. A técnica apresentada aponta para o fato de que em situação de obstrução de catéter causada por coágulo, existe alternativa factível para garantir interrrupção mínima do suporte hemodinâmico oferecido pela oxigenação por membrana extracorpórea veno-venosa.

Abstract This study addresses the development of a seismic‐isolated foundation embedded with improved soil to reduce the response of a superstructure. The material properties of the new improved composite soil are investigated by performing laboratory tests. Subsequently, the response behaviors of test model structures are discussed considering various contact conditions at the bottom of the foundation and different improved backfill soils around the foundation by conducting shaking table tests. Furthermore, the results of the analysis are obtained using a three‐dimensional nonlinear finite element method to clarify the effect of contact conditions at the bottom of the foundation and that of the improved compound soil on the seismic response of a building. Based on these results, an effective method to reduce the response of a building is to decrease the frictional resistance of the foundation bottom in order to reduce the input motion and make it non‐resonant. In addition, the response can be reduced by absorbing the seismic vibration energy in the improved composite soil embedded around the foundation. Furthermore, it is expected that the improved composite soil along with its toughness will result in the suppression of the excessive deformation of the foundation due to the effect of embedding.

Summary: ATOH1 is a master transcription factor for the secretory lineage differentiation of intestinal epithelial cells (IECs). However, the comprehensive contribution of ATOH1+ secretory lineage IECs to the homeostasis, repair, and tumorigenesis of the intestinal epithelium remains uncertain. Through our ATOH1+ cell-lineage tracing, we show here that a definite number of ATOH1+ IECs retain stem cell properties and can form ATOH1+IEC-derived clonal ribbons (ATOH1+ICRs) under completely homeostatic conditions. Interestingly, colonic ATOH1+ IECs appeared to exhibit their stem cell function more frequently compared with those of the small intestine. Consistently, the formation of ATOH1+ICRs was significantly enhanced upon dextran sodium sulfate colitis-induced mucosal damage. In addition, colonic ATOH1+ IECs acquired tumor stem cell-like properties in the azoxymethane-DSS tumor model. Our results reveal an unexpected contribution of colonic ATOH1+ IECs to maintaining the stem cell population under both homeostatic and pathologic conditions and further illustrate the high plasticity of the crypt-intrinsic stem cell hierarchy.

The data on the immunohistochemical analysis of conditional Notch ligand knockout mice is presented. Targeted deletion of Jag1, Dll1, Dll4, or Dll1 plus Dll4 in Lgr5+ve cells was induced by a Cre-mediated gene recombination, and differentiation or proliferation of the intestinal epithelial cells was examined by immunohistochemistry. These data are the extension of the data presented and discussed in the paper entitled “Indispensable role of non-canonical Notch signaling in the proliferation of Apc-deficient intestinal tumors“ (Nakata et al., Submitted for publication) [1].

Reports have suggested that the two Notch ligands, Dll1 and Dll4, are indispensable to maintain the homeostasis of the intestinal epithelium. However, within the intestinal epithelium, the precise distribution of the cells that express those ligands at the protein level remains largely unknown. Here, we show a series of immunohistochemical analysis through which we successfully identified mice intestinal epithelial cells (IECs) that endogenously express Dll1 or Dll4. Results showed that Dll1-positive (Dll1+ve) IECs reside exclusively within the crypt, whereas Dll4-positive (Dll4+ve) IECs can locate both in the crypt and in the villus of the small intestine. Also in the colon, Dll1+ve IECs resided at the lower part of the crypt, whereas Dll4+ve IECs resided at both upper and lower part of the crypt, including the surface epithelium. Both Dll1+ve and Dll4+ve IECs were ATOH1-positive, but Hes1-negative cells, and located adjacent to Hes1-positive cells within the crypts. A sub-population of both Dll1+ve and Dll4+ve IECs appeared to co-express Muc2, but rarely co-expressed other secretory lineage markers. However, as compared to Dll1+ve IECs, Dll4+ve IECs included larger number of Muc2-postive IECs, suggesting that Dll4 is more preferentially expressed by goblet cells. Also, we identified that Dll4 is expressed in the Paneth cells of the small intestine, whereas Dll1 and Dll4 is expressed in the c-kit-positive IECs of the colon, indicating that Dll1+ve and Dll4+ve IECs may contribute to constitute the intestinal stem cell niche. Compared to the normal colon, analysis of DSS-colitis showed that number of Dll1+ve IECs significantly decrease in the elongated crypts of the inflamed colonic mucosa. In sharp contrast, number of Dll4+ve IECs showed a significant increase in those crypts, which was accompanied by the increase in number of Hes1-positive IECs. Those Dll4+ve IECs were mostly found adjacent to the Hes1-positive IECs, suggesting that Dll4 may act as a major Notch ligand in the crypts of the inflamed colonic mucosa. Our results illustrate distinct expression patterns of Dll1 and Dll4 within the intestinal epithelium, and suggest that these two ligands may have different roles in normal and inflamed mucosa.

Intestinal epithelial cells (IECs) regulate the absorption and secretion of anions, such as HCO3(-) or Cl(-). Bestrophin genes represent a newly identified group of calcium-activated Cl(-) channels (CaCCs). Studies have suggested that, among the four human bestrophin-family genes, bestrophin-2 (BEST2) and bestrophin-4 (BEST4) might be expressed within the intestinal tissue. Consistently, a study showed that BEST2 is expressed by human colonic goblet cells. However, their precise expression pattern along the gastrointestinal tract, or the lineage specificity of the cells expressing these genes, remains largely unknown. Here, we show that BEST2 and BEST4 are expressed in vivo, each in a distinct, lineage-specific manner, in human IECs. While BEST2 was expressed exclusively in colonic goblet cells, BEST4 was expressed in the absorptive cells of both the small intestine and the colon. In addition, we found that BEST2 expression is significantly down-regulated in the active lesions of ulcerative colitis, where goblet cells were depleted, suggesting that BEST2 expression is restricted to goblet cells under both normal and pathologic conditions. Consistently, the induction of goblet cell differentiation by a Notch inhibitor, LY411575, significantly up-regulated the expression of not BEST4 but BEST2 in MUC2-positive HT-29 cells. Conversely, the induction of absorptive cell differentiation up-regulated the expression of BEST4 in villin-positive Caco-2 cells. In addition, we found that the up- or down-regulation of Notch activity leads to the preferential expression of either BEST4 or BEST2, respectively, in LS174T cells. These results collectively confirmed that BEST2 and BEST4 could be added to the lineage-specific genes of humans IECs due to their abilities to clearly identify goblet cells of colonic origin and a distinct subset of absorptive cells, respectively.

Abstract Background: Veno-venous extracorporeal membrane oxygenation is an established therapy for patients with refractory acute respiratory distress syndrome (ARDS). One complication related to the use of veno-venous extracorporeal membrane oxygenation is thrombosis despite proper anticoagulation. We report the diagnosis and management of a clot-obstruction in a single site cannula placed through the internal jugular vein, guided by transesophageal echocardiography. Case report: A 39 year-old male developed acute respiratory distress syndrome and hemodynamic instability after an episode of pulmonary aspiration in the ICU. Eight hours after placement of a single site veno-venous extracorporeal membrane oxygenation, suddenly the perfusionist noticed a reduction in flow. TEE showed a thrombus-like mass obstructing the inflow port in SVC and inflow at IVC was intact. After unsuccessful attempts to reposition the cannula, the team decided to insert additional femoral inflow cannula through the IVC. The single site catheter was then pulled out until its tip was positioned in the right atrium and all three ports of the catheter were switched to the infusion ports. After this, flows and oxygenation improved significantly. Unfortunately, despite all of the efforts, the patient died 2 days later. Discussion: The diagnosis of veno-venous extracorporeal membrane oxygenation cannula obstruction is based on reduced inflow rates, hemodynamic instability and poor oxygenation of blood. TEE allows evaluation of the flows inside the cannula and in this case, an obstruction was found. The management presented points to the fact that in a situation of catheter obstruction caused by a clot, there is a feasible alternative to assure minimal interruption of the hemodynamic support offered by the veno-venous extracorporeal membrane oxygenation.

Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete proinflammatory factors, affect surrounding somatic cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the agerelated changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4+ T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4+ T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas Cd8a, NK receptors, and Granzymes were upregulated in aging IEL CD4+ T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids in vitro than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8aa+CD4+ T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4+ T cells showed that two unique subsets are increased that are distinct from the systemic CD4+ T cells. Subset 1 has a pro-inflammatory component, with expression of IFNg and upregulation of NFkB signaling pathways. Subset 2 does not express IFNg, but upregulates inhibitory molecules and nIEL markers. Expression of granzymes and Cd8a was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research. [ABSTRACT FROM AUTHOR]