論文

IW And stars are a recently recognized subgroup of dwarf novae which are characterized by (often repetitive) slowly rising standstills terminated by brightening, but the exact mechanism for this variation is not yet identified. We have identified BO Cet, which had been considered as a novalike cataclysmic variable, as a new member of IW And stars based on the behavior in 2019-2020. In addition to this, the object showed dwarf nova-type outbursts in 2020-2021, and superhumps having a period 7.8% longer than the orbital one developed at least during one long outburst. This object has been confirmed as an SU UMa-type dwarf nova with an exceptionally long orbital period (0.1398 d). BO Cet is thus the first cataclysmic variable showing both SU UMa-type and IW And-type features. We obtained a mass ratio (q) of 0.31-0.34 from the superhumps in the growing phase (stage A superhumps). At this q, the radius of the 3:1 resonance, responsible for tidal instability and superhumps, and the tidal truncation radius are very similar. We interpret that in some occasions this object showed IW And-type variation when the disk size was not large enough, but that the radius of the 3:1 resonance could be reached as the result of thermal instability. We also discuss that there are SU UMa-type dwarf novae above q=0.30, which is above the previously considered limit (q~0.25) derived from numerical simulations and that this is possible since the radius of the 3:1 resonance is inside the tidal truncation radius. We constrained the mass of the white dwarf larger than 1.0Msol, which may be responsible for the IW And-type behavior and the observed strength of the He II emission. The exact reason, however, why this object is unique in that it shows both SU UMa-type and IW And-type features is still unsolved.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Although several cases of BP in end-stage renal disease patients receiving peritoneal dialysis (PD) or hemodialysis have been reported, the incidence of BP in these patients remains unknown. We recently experienced three PD patients diagnosed with BP. The skin injury was likely to be a trigger of BP in all the three PD patients. Nifedipine and icodextrin exposures were possible factors directly or indirectly affecting the onset of BP, because they were common in the three cases. We also report that the incidence of BP in PD patients was 3/478.3 person-years in a single-center 10-year study. This case series with a literature survey describes that the skin and tissue injuries are potential triggers responsible for the onset of BP in dialysis patients and that the incidence of BP in these patients seems to be much higher than that in the general population.

Aims/hypothesis: Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms. Methods: To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks. Results: WT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4+ T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT. Conclusions/interpretation: CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut–VAT–liver axis. Graphical abstract: [Figure not available: see fulltext.]

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

Background: The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment. Methods: Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats. Results: Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin. Conclusions: The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.

Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

Aldosterone is a biological ligand for mineralocorticoid receptor (MR) that elevates blood pressure by promoting sodium reabsorption in the kidneys. However, the molecular mechanisms of aldosterone-MR-mediated transcription and the role of this transcription in hypertension remain largely unknown. In this study, we aimed to identify novel MR coregulators and elucidate one of the molecular mechanisms of hypertension. We purified MR-interacting factors from HEK293F cells stably expressing FLAG-MR through a biochemical approach and identified the zinc finger protein castor homolog 1 isoform b (CASZ1b) as a candidate novel MR coregulator via liquid chromatography—tandem mass spectrometry analysis. The CASZ1 gene has been implicated in hypertension in genome-wide single-nucleotide polymorphism studies, but its role in the development of hypertension remains unclear. We found that CASZ1b colocalized with MR in the kidneys and interacted with MR in an aldosterone-dependent manner. In luciferase assays using HEK293F cells, overexpression of CASZ1b reduced aldosterone-dependent MR transcriptional activity by ~50%. In contrast, knockdown of CASZ1b via RNA interference increased the expression levels of the aldosterone-induced MR target genes epithelial Na+ channel-α (ENaCα) and serum/glucocorticoid regulated kinase 1 (SGK1) by approximately twofold and 2.3-fold, respectively. Upon aldosterone-MR binding, CASZ1b interacted with MR and formed a protein complex with nucleosome remodeling deacetylase (Mi-2/NuRD), a corepressor complex with chromatin remodeling and histone deacetylation activity, which suppressed ENaCα and SGK1. These findings reveal a critical role of CASZ1b in regulating MR-mediated transcriptional activity and provide new insights into the pathophysiology of hypertension.

Background: We investigated the changes in blood glucose fluctuation, gastric emptying, and vascular endothelial function by switching from an exenatide twice-daily formulation (BID) to a once-weekly formulation (QW) since the evaluation of postprandial glucose excursion and glycemic variability (GV) by continuous glucose monitoring (CGM) after switching was lacking. Methods: Twenty-nine patients with type 2 diabetes treated with exenatide BID were included in this study and switched to exenatide QW for 24 weeks. GV assessed by CGM, gastric emptying (by 13 C-acetate breath test) and vascular endothelial function (by reactive hyperemia - peripheral arterial tonometry) were evaluated at baseline and 24 weeks after switching. Results: HbA1c decreased significantly from the baseline to week 24, while postprandial glucose levels after breakfast and dinner significantly increased (both P <0.05). However, the increases in GV indices were modest and not statistically significant at week 24. Vascular endothelial function was also not significantly changed after switching (P >0.05). Gastric emptying was significantly accelerated at week 24 (Tmax 83.4 ± 12.1 min vs. 58.2 ± 16.4 min) (P <0.001) and correlated with increased postprandial glucose levels after breakfast and dinner (both P <0.05). Conclusions: Despite the increase in postprandial glucose associated with accelerated gastric emptying after switching from exenatide BID to QW, change in GV was modest and no significant deterioration in vascular endothelial function was observed after switching. These results support the superiority of treatment with exenatide QW over exenatide BID in clinical practice; however, attention should be paid to the monitoring and management of postprandial glucose levels when selecting exenatide QW. Trial registration: Clinical trial registry number; UMIN000016390 and jRCTs031180320. Approval date of Registry and the Registration: December 12, 2014.

To push gate performance to levels beyond the thresholds for quantum error correction, it is important to characterize the error sources occurring on quantum gates. However, the characterization of non-Markovian error poses a challenge to current quantum process tomography techniques. Fast Bayesian Tomography (FBT) is a self-consistent gate set tomography protocol that can be bootstrapped from earlier characterization knowledge and be updated in real-time with arbitrary gate sequences. Here we demonstrate how FBT allows for the characterization of key non-Markovian error processes. We introduce two experimental protocols for FBT to diagnose the non-Markovian behavior of two-qubit systems on silicon quantum dots. To increase the efficiency and scalability of the experiment-analysis loop, we develop an online FBT software stack. To reduce experiment cost and analysis time, we also introduce a native readout method and warm boot strategy. Our results demonstrate that FBT is a useful tool for probing non-Markovian errors that can be detrimental to the ultimate realization of fault-tolerant operation on quantum computing.

Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

OBJECTIVES: Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS: Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS: At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION: Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.