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Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50–81] vs. 122 [89–209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications. [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP) is an extracellular signaling molecule that mainly affects the pathophysiological situation in the body and can be sensed by purinergic receptors, including ionotropic P2X7. Neuronal stem cells (NSCs) remain in adult neuronal tissues and can contribute to physiological processes via activation by evoked pathophysiological situations. In this study, we revealed that human-induced pluripotent stem cell-derived NSCs (iNSCs) have ATP-sensing ability primarily via the purinergic and ionotropic receptor P2X7. Next, to develop a machine learning (ML)-based screening system for food-derived neuronal effective substances and their effective doses, we collected ATP-triggered calcium responses of iNSCs pretreated with several substances and doses. Finally, we discovered that ML was performed using composite images, each containing nine waveform images, to achieve a better ML model (MLM) with higher precision. Our MLM can correctly sort subtle unidentified changes in waveforms produced by pretreated iNSCs with each substance and/or dose into the positive group, with common mRNA expression changes belonging to the gene ontology signatures. [ABSTRACT FROM AUTHOR]

CD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2. [ABSTRACT FROM AUTHOR]

Cionin is a homolog of vertebrate cholecystokinin/gastrin that has been identified in the ascidian Ciona intestinalis type A. The phylogenetic position of ascidians as the closest living relatives of vertebrates suggests that cionin can provide clues to the evolution of endocrine/neuroendocrine systems throughout chordates. Here, we show the biological role of cionin in the regulation of ovulation. In situ hybridization demonstrated that the mRNA of the cionin receptor, Cior2, was expressed specifically in the inner follicular cells of pre-ovulatory follicles in the Ciona ovary. Cionin was found to significantly stimulate ovulation after 24-h incubation. Transcriptome and subsequent Real-time PCR analyses confirmed that the expression levels of receptor tyrosine kinase (RTK) signaling genes and a matrix metalloproteinase (MMP) gene were significantly elevated in the cionin-treated follicles. Of particular interest is that an RTK inhibitor and MMP inhibitor markedly suppressed the stimulatory effect of cionin on ovulation. Furthermore, inhibition of RTK signaling reduced the MMP gene expression in the cionin-treated follicles. These results provide evidence that cionin induces ovulation by stimulating MMP gene expression via the RTK signaling pathway. This is the first report on the endogenous roles of cionin and the induction of ovulation by cholecystokinin/gastrin family peptides in an organism. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) often occurs in pediatric patients who received allogeneic hematopoietic cell transplantation (HCT). We evaluated the risk and effect of HCT-related AKI in pediatric patients. Methods: We retrospectively studied the survival and renal outcome of 69 children 100 days and 1-year posttransplant in our institution in 2004–2016. Stage-3 AKI developed in 34 patients (49%) until 100 days posttransplant. Results: The 100-day overall survival (OS) rates of patients with stage-3 AKI were lower than those without it (76.5% vs. 94.3%, P = 0.035). The 1-year OS rates did not differ markedly between 21 post-100-day survivors with stage-3 AKI and 29 without it (80.8% vs. 87.9%, P = 0.444). The causes of 19 deaths included the relapse of underlying disease or graft failure (n = 11), treatment-related events (4), and second HCT-related events (4). Underlying disease of malignancy (crude hazard ratio (HR) 5.7; 95% confidence interval (CI), 2.20 to 14.96), > 1000 ng/mL ferritinemia (crude HR 4.29; 95% CI, 2.11 to 8.71), stem cell source of peripheral (crude HR 2.96; 95% CI, 1.22 to 7.20) or cord blood (crude HR 2.29; 95% CI, 1.03 to 5.06), and myeloablative regimen (crude HR 2.56; 95% CI, 1.24 to 5.26), were identified as risk factors for stage-3 AKI until 100 days posttransplant. Hyperferritinemia alone was significant (adjusted HR 5.52; 95% CI, 2.21 to 13.76) on multivariable analyses. Conclusions: Hyperferritinemia was associated with stage-3 AKI and early mortality posttransplant. Pretransplant iron control may protect the kidney of pediatric HCT survivors. [ABSTRACT FROM AUTHOR]

Aim: Falls are a significant problem for older people, but are few studies of the risk of falling in residents of nursing homes in Japan. We aimed to investigate the risk factors for falls and the association of medication use and falls in nursing home residents in Japan. Methods: This case–control study reviewed the records of residents of who were ≥ 65 years of age and had fallen in 2012 and an age-, sex-, and facility-matched control group selected from 58 nursing homes in Japan. The odds ratios of potential risk factors and current medications were determined by conditional logistic regression. Results: A total of 1832 residents (916 cases and 916 controls) were included. Falls were significantly associated with an inability to walk without assistance or stand up without assistance, need for toileting assistance, visual impairment, insomnia, and dementia. Current prescription of antithrombotic, nonsteroidal anti-inflammatory, or antiparkinson drugs, muscle relaxants, antiepileptics, antipsychotics, antidepressants, opioids, selective serotonin reuptake inhibitors, and memantine was also associated with increased risk of falling. Conclusions: Many medications were associated with falls in nursing homes residents in Japan. To prevent these falls, caregivers should provide adequate care, and healthcare professionals should consider switching or dose reduction for these medications. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) occurs in neonates with disseminated infection of herpes simplex virus (HSV). Little has been reported on the control of rapid HLH progression. We studied the cytokine profile and genetic basis of two index cases with divergent outcomes after early treatment of type 2 HSV infection. One survivor had fever and elevated serum levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ at diagnosis. The other neonate had no fever or TNF-α production, but significant IL-6 or IFN responses during the treatment course, and died 19 days after birth. Among 16 reported cases of neonatal HSV-HLH including index cases, eight deceased neonates experienced significantly less fever at presentation (p = 0.028), lower platelet counts (p = 0.019), and lower ratios of soluble IL-2 receptor (sIL-2R) to ferritin levels (p = 0.044) than eight survivors. The 100-day overall survival rates were significantly higher in patients with fever (p = 0.004), > 100 × 109/L of platelet counts (p = 0.035) or > 20 of sIL-2R/ferritin ratio at diagnosis (p = 0.004). The first febrile and cytokine responses to HSV infection predict the early outcome of neonatal HSV-HLH. [ABSTRACT FROM AUTHOR]

The digestive system is responsible for nutrient intake and defense against pathogenic microbes. Thus, identification of regulatory factors for digestive functions and immune systems is a key step to the verification of the life cycle, homeostasis, survival strategy and evolutionary aspects of an organism. Over the past decade, there have been increasing reports on neuropeptides, their receptors, variable region-containing chitin-binding proteins (VCBPs) and Toll-like receptors (TLRs) in the ascidian, Ciona intestinalis. Mass spectrometry-based peptidomes and genome database-searching detected not only Ciona orthologs or prototypes of vertebrate peptides and their receptors, including cholecystokinin, gonadotropin-releasing hormones, tachykinin, calcitonin and vasopressin but also Ciona-specific neuropeptides including Ci-LFs and Ci-YFVs. The species-specific regulation of GnRHergic signaling including unique signaling control via heterodimerization among multiple GnRH receptors has also been revealed. These findings shed light on the remarkable significance of ascidians in investigations of the evolution and diversification of the peptidergic systems in chordates. In the defensive systems of C. intestinalis, VCBPs and TLRs have been shown to play major roles in the recognition of exogenous microbes in the innate immune system. These findings indicate both common and species-specific functions of the innate immunity-related molecules between C. intestinalis and vertebrates. In this review article, we present recent advances in molecular and functional features and evolutionary aspects of major neuropeptides, their receptors, VCBPs and TLRs in C. intestinalis. [ABSTRACT FROM AUTHOR]

Objective: The age-related effects of fasting on lipolysis, the production of ketone bodies, and plasma insulin levels were studied in male 3-, 8-, and 32-week-old Sprague-Dawley rats. Methods: The rats were divided into fasting and control groups. The 3-, 8- and 32-week-old rats tolerated fasting for 2, 5, and 12 days, respectively. Results: Fasting markedly reduced the weights of perirenal and periepididymal white adipose tissues in rats in the three age groups. The mean rates of reduction in both these adipose tissue weights during fasting periods were higher in the order of 3 > 8 > 32-week-old rats. Fasting transiently increased plasma free fatty acid (FFA), total ketone body, β-hydroxybutyrate, and acetoacetate concentrations in the rats in the three age groups. However, plasma FFA, total ketone body, β-hydroxybutyrate, and acetoacetate concentrations in the 3-week-old rats reached maximal peak within 2 days after the onset of fasting, although these concentrations in the 8- and 32-week-old rats took more than 2 days to reach the maximal peak. By contrast, the augmentation of plasma FFA, total ketone body, β-hydroxybutyrate, and acetoacetate concentrations in the rats in the three age groups had declined at the end of each experimental period. Thus, the capacity for fat mobilization was associated with tolerance to fasting. Plasma insulin concentrations in the rats in the three age groups were dramatically reduced during fasting periods, although basal levels of insulin were higher in the order of 32 > 8 > 3 week-old rats. Conclusion: These results suggest that differences in fat metabolism patterns among rats in the three age groups during prolonged fasting were partly reflected the metabolic turnover rates, plasma insulin levels, and amounts of fat storage. [ABSTRACT FROM AUTHOR]

Glucocorticoids are known to increase the density and mRNA levels of β-adrenoceptors (β-AR) via the glucocorticoid receptor (GR) in many tissues. However, the effects of these changes in the skeletal and cardiac muscles remain relatively unknown. We have investigated the effects of dexamethasone on the expression of the β1-, β2-, and β3-AR mRNAs and GR mRNA in fast-twitch fiber-rich extensor digitorum longus (EDL), slow-twitch fiber-rich soleus (SOL), and left ventricle (LV) muscles by real-time quantitative RT-PCR. Male rats were divided into a dexamethasone group and control group. The weight, RNA concentration, and total RNA content of EDL muscle were 0.76-, 0.85-, and 0.65-fold lower, respectively, in the dexamethasone group than in the control group. The weight, RNA concentration, and total RNA content of SOL muscle were 0.92-, 0.87-, and 0.81-fold lower, respectively, in the dexamethasone group than in the control group; these differences were significant. However, the weight/body weight and total RNA content/body weight of LV muscle were 1.38- and 1.39-fold higher, respectively, in the dexamethasone group than in the control group, respectively; these differences were also significant. Dexamethasone significantly decreased GR mRNA expression in EDL muscle without changing the expression of the β1-, β2-, and β3-AR mRNAs. However, dexamethasone significantly decreased the expressions of β2-AR and GR mRNAs in SOL muscle and significantly increased β1-AR mRNA expression in LV muscle—without changing GR mRNA expression. These results suggest that the effects of dexamethasone on the expression of β1- and β2-AR mRNAs and muscle mass depend on the muscle contractile and/or constructive types. [ABSTRACT FROM AUTHOR]

Pyrethrum (Tanacetum cinerariifolium), which is a perennial Asteraceae plant with white daisy-like flowers, is the original source of mosquito coils and is known for the biosynthesis of the pyrethrin class of natural insecticides. However, the molecular basis of the production of pyrethrins by T. cinerariifolium has yet to be fully elucidated. Here, we present the 7.1-Gb draft genome of T. cinerariifolium, consisting of 2,016,451 scaffolds and 60,080 genes predicted with high confidence. Notably, analyses of transposable elements (TEs) indicated that TEs occupy 33.84% of the genome sequence. Furthermore, TEs of the sire and oryco clades were found to be enriched in the T. cinerariifolium-specific evolutionary lineage, occupying a total of 13% of the genome sequence, a proportion approximately 8-fold higher than that in other plants. InterProScan analysis demonstrated that biodefense-related toxic proteins (e.g., ribosome inactivating proteins), signal transduction-related proteins (e.g., histidine kinases), and metabolic enzymes (e.g., lipoxygenases, acyl-CoA dehydrogenases/oxygenases, and P450s) are also highly enriched in the T. cinerariifolium genome. Molecular phylogenetic analysis detected a variety of enzymes with genus-specific multiplication, including both common enzymes and others that appear to be specific to pyrethrin biosynthesis. Together, these data identify possible novel components of the pyrethrin biosynthesis pathway and provide new insights into the unique genomic features of T. cinerariifolium. [ABSTRACT FROM AUTHOR]