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Purpose The present study investigated potential access vessels in patients receiving hemodialysis who underwent surgical aortic valve replacement and determined which approaches were most suitable for performing transcatheter aortic valve implantation. Methods Consecutive patients undergoing hemodialysis with aortic valve stenosis who underwent surgical aortic valve replacement were included. Preoperative computed tomography data were analyzed to assess the vessel diameter and calcification. Simulations were conducted to determine the feasibility of inserting the 14-F eSheath of Sapien 3 via transfemoral, trans-cervical , trans-subclavian, and direct aorta approaches. Results A total of 72 patients were included in this study. The access route was characterized by severe calcification of the common iliac artery. The transfemoral approach was feasible in 77.8% of the cases, but the rate decreased to 33% when the calculations were based on the maximum sheath extension diameter. The trans-cervical, trans-subclavian, and direct aortic approaches were suitable for many patients. Lower extremity artery disease was identified as a risk factor for the unsuitability of the transfemoral approach. Conclusions Common iliac artery calcification in patients undergoing hemodialysis restricts the use of the transfemoral approach. Therefore, some patients require alternative approaches.

Macroautophagy is a highly conserved system that degrades various materials inside the cell ranging from proteins to organelles. Atg5 is a protein essential for the formation of autophagosomes, which sequester materials by double membrane and degrade them after fusion with lysosomes. MIN6 cells derived from mouse pancreatic β cells retain the ability to secrete insulin in response to a change in glucose concentration from low to high. We knocked out the Atg5 gene in MIN6 cells and identified an abnormality in the endoplasmic reticulum (ER) under normal culture conditions using electron microscopy. The ER was slightly enlarged and the ER membrane was ruptured at some places adjacent to inclusion body-like structures. Numerous granule-like structures were accumulated in the lumen of the ER, some of which appeared to have leaked into the cytoplasm. These abnormalities caused ER stress, resulting in activation of all three pathways (IRE1, PERK, and ATF6) of the unfolded protein response but no induction of apoptosis. We also observed the activation of alternative autophagy/Golgi membrane-associated degradation in Atg5-KO MIN6 cells, but this was insufficient for the removal of a majority of these granule-like structures from the ER. Thus, macroautophagy but not activation of the unfolded protein response or Golgi membrane-associated degradation is essential for the homeostasis of the ER in MIN6 cells.Key words: autophagy, endoplasmic reticulum, unfolded protein response, proinsulin, Golgi membrane-associated degradation.

Newly synthesized proteins destined for the secretory pathway are folded and assembled in the endoplasmic reticulum (ER) and then transported to the Golgi apparatus via COPII vesicles, which are normally 60–90 nm. COPII vesicles must accordingly be enlarged to accommodate proteins larger than 90 nm, such as long-chain collagen. Key molecules involved in this enlargement are Tango1 and Tango1-like (Tali), which are transmembrane proteins in the ER encoded by the MIA3 and MIA2 genes, respectively. Interestingly, two splicing variants are expressed from each of these two genes: Tango1L and Tango1S from the MIA3 gene, and Tali and cTAGE5 from the MIA2 gene. Here, we constructed Tango1L-knockout (KO), Tango1S-KO, Tali-KO, and cTAGE5-KO separately in medaka fish, a vertebrate model organism, and characterized them. Results showed that only Tango1L-KO conferred a lethal phenotype to medaka fish. Only Tango1L-KO medaka fish exhibited a shorter tail than wild-type (WT) fish and showed the defects in the export of type II collagen from the ER, contrary to the previous reports analyzing Tango1-KO or Tali-KO mice and the results of knockdown experiments in human cultured cells. Medaka fish may employ a simpler system than mammals for the export of large molecules from the ER.Key words: intracellular transport, COPII vesicles, enlargement, endoplasmic reticulum, Golgi apparatus

A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membrane twice. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above.

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca 2+ -binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b −/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca 2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b −/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca 2+ -modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b −/− and Calr + /− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca 2+ homeostasis.

Background Ischemic cardiomyopathy, characterized by coronary artery atherosclerosis, impairs the myocardial tissue. Coronary artery bypass grafting (CABG) is commonly used to revascularize affected areas and improve patient survival rates; however, it can fail to enhance cardiac function. Impaired capillary blood flow may obstruct functional recovery, prompting interest in treatments, such as angiogenic factor administration. Adipose-derived stem cells (ADSCs), which are known for immune evasion, have shown the potential to construct capillary networks and improve myocardial function. This clinical trial aimed to evaluate the safety and efficacy of ADSC spray therapy combined with CABG. Methods This single-center, randomized, double-blind study involved patients with ischemic cardiomyopathy who were scheduled for CABG and who had a left ventricular ejection fraction ≤ 40%. The participants were randomized to receive CABG as well as ADSC spray therapy or placebo. The primary endpoints were safety, changes in late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) volumes, and feasibility. The secondary endpoints included left ventricular function, exercise tolerance, and heart failure symptoms. Results Seven patients were enrolled; of them, six were randomized to receive ADSC therapy (n = 3) or placebo (n = 3). The procedure was successfully completed with minimal adverse events. One patient in the ADSC group developed pleural effusion that was resolved with drainage. The LGE-MRI volumes decreased in the ADSC group but remained unchanged in the placebo group. Improvements in left ventricular function and exercise tolerance were noted in the ADSC group, with heart failure symptoms improving to New York Heart Association class I. In contrast, the placebo group showed no significant changes, with one patient experiencing worsening symptoms. Conclusions ADSC spray therapy combined with CABG demonstrated safety and efficacy at enhancing cardiac function. ADSC likely contributes to capillary network reconstruction, thereby augmenting the benefits of CABG. Future phase II and III trials are warranted to confirm its therapeutic efficacy and long-term outcomes. This novel approach represents a significant advancement in the treatment of ischemic cardiomyopathy and offers a viable strategy for improving myocardial function and patient prognosis. Trial registration This study was registered with the Japan Registry of Clinical Trials (jRCT2053190103) and ClinicalTrials.gov (NCT04695522) Graphical Abstract

Bacterial cellulose nanofiber (BCNF) with high thermal stability produced by an ecofriendly process has emerged as a promising solution to realize safe and sustainable materials in the large-scale battery. However, an understanding of the actual thermal behavior of the BCNF in the full-cell battery has been lacking, and the yield is still limited for commercialization. Here, we report the entire process of BCNF production and battery manufacture. We systematically constructed a strain with the highest yield (31.5%) by increasing metabolic flux and improved safety by introducing a Lewis base to overcome thermochemical degradation in the battery. This report will open ways of exploiting the BCNF as a “single-layer” separator, a good alternative to the existing chemical-derived one, and thus can greatly contribute to solving the environmental and safety issues.

Objective We evaluated the blood flow within the downstream aortic false lumen after frozen elephant trunk repair for acute aortic dissection and identified hemodynamic predictors of false lumen expansion and negative false lumen remodeling using four-dimensional flow magnetic resonance imaging. Methods Thirty-one patients (Stanford type A, n  = 28; Stanford type B, n  = 3) with patent false lumen who underwent frozen elephant trunk procedures for acute aortic dissection were included in this observational study. Each patient underwent computed tomography during the follow-up period and four-dimensional flow magnetic resonance imaging within 3 postoperative months. The false lumen volumetric expansion rate was calculated using computed tomography data. The direction and the rate of flow in the lower descending aortic false lumen were analyzed. Negative false lumen remodeling was defined as a volumetric increase of > 10% from the baseline volume. Results Negative false lumen remodeling had developed in 6 of the 31 patients during the observation period. Most of the false lumen flows were biphasic during systole. The range between peak and nadir flow rates was associated with the false lumen volumetric expansion rate ( β coefficient = 6.77; p  < 0.01, R 2  = 0.43). Conclusions The range between peak and nadir flow rates may serve as a hemodynamic predictor of negative false lumen remodeling, enabling further treatment for patients at risk of expansion in the downstream aorta.

The purpose of this article is to clarify all of the uniformly relatively Ding stable toric Fano threefolds and fourfolds as well as unstable ones. The key player in our classification result is the Mabuchi constants, which can be calculated by combinatorial data of the associated moment polytopes due to the work of Yao (Int Math Res Not IMRN 2022(24):19790–19853, 2022). In this article, we give the list of uniform relative Ding stability of all toric Fano manifolds in dimension up to four with the values of the Mabuchi constants. As an application of our main theorem, we clarify the difference between relative K -stability and relative Ding stability by considering some specific toric Fano manifolds. In the proof, we used Bott tower structure of relatively Ding unstable toric Fano manifolds.

The world's first clinical cardiac xenotransplantation, using a genetically engineered pig heart with 10 gene modifications, prolonged the life of a 57-year-old man with no other life-saving options, by 60 days. It is foreseeable that xenotransplantation will be introduced in clinical practice in the United States. However, little clinical or regulatory progress has been made in the field of xenotransplantation in Japan in recent years. Japan seems to be heading toward a \"device lag\", and the over-importation of medical devices and technology in the medical field is becoming problematic. In this review, we discuss the concept of pig-heart xenotransplantation, including the pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental heart overgrowth, as well as genetic modification strategies in pigs to prevent or minimize these problems. Moreover, we summarize the necessity for and current status of xenotransplantation worldwide, and future prospects in Japan, with the aim of initiating xenotransplantation in Japan using genetically modified pigs without a global delay. It is imperative that this study prompts the initiation of preclinical xenotransplantation research using non-human primates and leads to clinical studies.