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The alkyne aza-Prins cyclization of 3,5-diynyl amides and various aldehydes was developed using TfOH with/without (Me2AlO)2SO2. This method, which could be applied to homopropargyl amides, provides TfO-substituted pyrrolidines with E-selectivities and exclusive regioselectivities. This work represents a first example of the aza-Prins cyclization with the introduction of TfO groups. [ABSTRACT FROM AUTHOR]

Recent years have seen the development of a satellite communication system called a high-throughput satellite (HTS), which enables large-capacity communication to cope with various communication demands. Current HTSs have a fixed allocation of communication resources and cannot flexibly change this allocation during operation. Thus, effectively allocating communication resources for communication demands with a bias is not possible. Therefore, technology is being developed to add flexibility to satellite communication systems, but there is no system analysis model available to quantitatively evaluate the flexibility performance. In this study, we constructed a system analysis model to quantitatively evaluate the flexibility of a satellite communication system and used it to analyze a satellite communication system equipped with a digital channelizer. [ABSTRACT FROM AUTHOR]

To clarify the neuroprotective property of ceruloplasmin and the pathogenesis of aceruloplasminemia, we generated ceruloplasmin-deficient ( CP) mice on the C57BL/10 genetic background and further treated them with a mitochondrial complex I inhibitor, rotenone. There was no iron accumulation in the brains of CP mice at least up to 60 weeks of age. Without rotenone treatment, CP mice showed slight motor dysfunction compared with CP mice, but there were no detectable differences in the levels of oxidative stress markers between these two groups. A low dose of rotenone did not affect the mitochondrial complex I activity in our mice, however, it caused a significant change in motor behavior, neuropathology, or the levels of oxidative stress markers in CP mice, but not in CP mice. Our data support that ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity, probably through its antioxidant properties independently of its function of iron metabolism. [ABSTRACT FROM AUTHOR]

This report concerns a patient with systemic lupus erythematosus (SLE) who died of acute respiratory distress syndrome (ARDS) 1 day after the onset of pulmonary symptoms. Autopsy demonstrated severe hemophagocytosis in the bone marrow and histopathology indicating a marked increase in vascular permeability in both lungs and kidneys. In this patient, active SLE and associated hemophagocytic syndrome may have induced an increase in the production of inflammatory cytokines, which immediately induced ARDS. Since fatal ARDS can occur as a life-threatening complication of SLE, careful observation is necessary, particularly when there are clinical findings suggestive of associated hemophagocytic syndrome. [ABSTRACT FROM AUTHOR]

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin (Cp) gene. The neuropathological hallmark of this disease is intracellular iron overload, which is thought to lead to neuronal cell death through increased oxidative stress. We evaluated and characterized protein oxidation in the brain of a patient with this disease. The protein carbonyl content in the cerebral cortex of the patient was elevated compared to controls. Furthermore, peptide mass fingerprinting and partial amino acid sequencing identified glial fibrillary acidic protein (GFAP) as the major carbonylated protein in the cerebral cortex of the patient. In conjunction with the facts that Cp mainly localizes to astrocytes in the central nervous system and that astrocytes are loaded with much more iron than neurons in the cerebral cortex, our findings indicate that Cp deficiency may primarily damage astrocytes. We speculate that the dysfunction of astrocytes may be causatively related to neuronal cell loss in aceruloplasminemia. [ABSTRACT FROM AUTHOR]

Most molecular catalysts have been developed employing polar functional groups as catalytic sites. However, the use of non‐polar functional groups for catalysis has received less attention due to their modest molecular interactions while the bioorthogonal reactivity of non‐polar alkenes as substrates is frequently used in click chemistry. In this study, we conducted mechanistic studies on the catalysis of trans‐cyclooctene (TCO) derivatives with the strained olefin as the catalytic site using kinetic and computational analyses to aid the design of more active olefin catalysts. The analysis reveals the significant role of the benzyl substituents in accelerating the generation of bromonium species through dispersion interaction in the rate‐determining step. Guided by the mechanistic insights, we developed bifunctional TCO catalysts bearing a functionalized benzyl group, taking advantage of the remarkable substituent effects. Experimental studies confirmed the theoretical model and revealed that TCO with a para‐hydroxybenzyl group provided excellent catalytic activity. Furthermore, inclusion of the functionalized benzyl groups allowed more readily available and robust cis‐cyclooctenes to be used as active catalysts, expanding the practical utility of the olefin catalysts. By using a photochemically labile masking group on the para‐hydroxybenzyl substituent, the first light‐gated bromination catalyst was developed, enabling spatiotemporal control of the transformation. [ABSTRACT FROM AUTHOR]

Abstract: Ceruloplasmin (Cp) is the strongest ferroxidase in human plasma. Hereditary deficiency of this protein, named aceruloplasminemia, is an interesting model to elucidate the pathogenesis and pathophysiology of neurodegeneration induced by oxidative stress. Enhanced oxidative stress due to excessive iron accumulation is observed in the brains of aceruloplasminemia patients. Rotenone, a selective mitochondrial complex I inhibitor, induces neurodegeneration mimicking Parkinson’s disease. We investigated the influence of Cp deficiency upon neurodegeneration using rotenone-treated, Cp-deficient mouse brains. Immunohistochemical examination showed that acrolein, one of the products of lipid peroxides, and ubiquitin were more markedly immunoreacted in the brains of rotenone-treated, Cp-deficient mice than in rotenone-untreated, Cp-deficient or rotenone-treated, wild-type mice. These molecules were localized in neuronal cells. These results suggested that rotenone-induced lipid peroxidation and accumulation of ubiquitin immunoreactivity were enhanced in the absence of Cp. Therefore, Cp may protect neuronal cells from oxidative stress-induced neurodegeneration. [Copyright &y& Elsevier]

Objective: To investigate the prescription patterns for patients aged 6–17 years with headaches in the REZULT database. Methods: We cross-sectionally investigated (Study 1) the pattern of prescription and the proportion of triptan overprescription (≥30 tablets/90 d of triptans) among patients diagnosed with headaches in 2020. Next, we longitudinally studied patients (Study 2) for more than two years from the initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. Results: In Study 1, headache diagnoses were assigned to 62,568 of 543,628 (11.51%) patients, and 1524 of 62,568 (2.44%) patients received acute medication. Single nonsteroidal anti-inflammatory drugs and triptans were prescribed to 620/624 (99.36%) and 5/624 (0.80%) of patients aged 6–11 years, respectively, and 827/900 (91.89%) and 91/900 (10.11%) of patients aged 12–17 years, respectively. Triptan overprescription was observed in 11/96 (11.46%) patients, and 5/11 (45.45%) of those patients received prophylactic medication. In Study 2, 80,756/845,470 (9.55%) patients aged 6–17 years were diagnosed with headaches that persisted for at least two years. Over two years, 44/80,756 (0.05%) patients were overprescribed triptans, and 3408/80,756 (4.22%) patients were prescribed prophylaxis on at least one occasion. Conclusions: Based on real-world data, the appropriate use of prophylactic treatment is still problematic. Overprescription of triptans was observed, although the number of patients was small. [ABSTRACT FROM AUTHOR]

Recent studies using several knockout models have shown that autocrine insulin (and/or IGF-1) regulates growth and some functions of pancreatic β cells through activation of insulin receptor (IR)→insulin receptor substrate (IRS) proteins→Class IA phosphoinositide 3-kinase (PI3K). Class IA PI3K is composed of a catalytic subunit (p110) and a regulatory subunit (p85), which occurs in multiple isoforms. Among them, p85α and β are two major isoforms. P85α is derived from the Pik3rl gene that also encodes two shorter isoforms, p55α and p50α, while p85β is derived from the Pik3r2. To identify the role of Class IA P13K in β cells, we have generated β cell specific Pik3rl gene knockout (βPik3rlKO) mice using Cre-LoxP system, since the whole body Pik3rl KO mice die within 1 week after birth. To gain more insight in the PI3K pathway of β cells, we ablated the genes of two major regulatory subunits, p85α and p85β, of PI3K by crossing mice lacking Pik3rl in β cells with Pik3r2 null mice, for creating β cells-specific double knockout mice (βDKO mice). βPik3r1KO mice grew normally and were indistinguishable from control RIP-Cre transgenic mice. There was an 80% reduction of the regulatory subunits in isolated islets from βPik3rlKO mice, while p85β still remained. βPik3rlKO mice displayed modestly elevated fed glucose concentrations at 4 months of age and older, whereas fasting glucose levels were normal and they never developed diabetes during entire life. However, βPik3rlKO mice exhibited glucose intolerance and markedly suppressed glucose stimulated insulin secretion (GSIS) in vivo at 2 months and older. GSIS was also impaired using isolated islets from βPik3rlKO mice especially at lower concentrations of glucose, suggesting the existence of a defect in glucose sensing. Moreover, islet size of βPik3rlKO mouse was decreased by 30% compared to that of RIP-Cre mouse. Until a few months of age that we have observed for, βDKO mice also grew normally. However, βDKO mice showed more prominent glucose intolerance than βPik3rlKO mice due to a declined insulin secretion. Despite this, βDKO mice did not develop diabetes at this stage presumably because Pik3r2 null background is more sensitive to insulin than wild-type, as we have previously shown. These data suggest that Class IA PI3K is required for age-dependent islet growth and normal insulin secretion, and that decreased Class IA PI3K activity causes postprandial hyperglycemia. This may also provide a novel therapeutic approach for diabetes. [ABSTRACT FROM AUTHOR]

The article focuses on a medical report which discusses hypothalamic involvement in nonparaneoplastic, nonherpetic limbic encephalitis. Hypothermia is a life-threatening state that can be caused by several different mechanisms, such as extended exposure to a cold environment, drug overdose, sepsis, and endocrine disturbance. Here, the article report a nonherpetic nonparaneoplastic limbic encephalitis patient with a severe episodic hypothermia attack. Episodic hypothermia in this patient was thought to be due to the direct association of the central thermoregulatory center by encephalitis.

Although a wide variety of chiral organocatalysts have been developed for asymmetric transformations, effective chiral dialkyl sulfide organocatalysts remain relatively rare and under‐developed, despite the potential utility of dialkyl sulfide catalysts. Herein, we report the development of chiral bifunctional dialkyl sulfide catalysts possessing a urea moiety for regio‐, diastereo‐, and enantioselective bromolactonization. The importance of the bifunctional design of chiral sulfide catalysts was clearly demonstrated in the present work. The roles of both the sulfide and urea moieties of the catalyst were clarified based on the results of experimental and theoretical investigation. Chiral bifunctional dialkyl sulfide catalysts bearing a urea moiety were designed for enantioselective bromolactonization. The roles of both sulfide and urea moieties on the catalyst are discussed and clarified based on the results of both experimental and theoretical investigation. [ABSTRACT FROM AUTHOR]

Adiponectin has been reported to suppress gluconeogenesis in liver through downregulating PEPCK and G6Pase, and also shown to be involved in lipid regulation; activating PPARαleads to an increase in fatty acid oxidation while suppression of SREBP1c decreases fatty acid synthesis in liver. These actions are supposed to contribute to the insulin sensitizing effects of adiponectin. The glucose lowering action of adiponectin has been believed to be mainly mediated by AMPK activation, which is known to suppress key gluconeognic enzymes in liver. However, induction of a dominant negative mutant of AMPK only partially attenuated the glucose lowering action of adiponectin, suggesting the existence of some other regulatory mechanisms. This prompted us to investigate the direct crosstalk between adiponectin signaling and insulin signaling as one of the candidate mechanisms. Here we show adiponectin increases hepatic IRS-2 protein, which is one of the main downstream molecules of insulin receptor and plays essential roles in glucose and lipid metabolism in liver. In the liver of db/db mice, the up-regulation of IRS-2 protein induced by adiponectin led to enhanced p85 recruitment to IRS-2 and Akt phosphorylation caused by insulin. Interestingly, the mRNA of IRS-2 showed a sharp and transient upregulation 2hrs after adiponectin administration. During this time course, plasma insulin concentration did not change, nor the CREB phosphorylation in the liver of adiponectin-treated mice. Moreover, the suppression of SREBP1c by adiponectin took place 4 to 8hrs after adiponectin administration. Thus, the up-regulation of IRS-2 expression by adiponectin is likely to be independent of insulin, CREB or SREBP1c action. Moreover, we have recently reported that the expression of adiponectin receptors is negatively regulated by insulin signaling via FOXO-1 exclusion from nucleus, and accordingly, fasting leads to up-regulation of AdipoRs. On the other hand, the serum concentration of adiponectin and the expression of adiponectin in adipose tissues are also elevated in the fasted state. Taken together, it is assumed that the adiponectin action is enhanced by fasting, while refeeding or hyperinsulinemic condition suppresses it. These data suggest that adiponectin signaling contributes to the upregulation of IRS-2 during fasting in liver, which may be one of the mechanisms whereby adiponectin exerts its insulin sensitizing effect in liver and contributes to the maintenance of systemic insulin sensitivity. [ABSTRACT FROM AUTHOR]

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, lowgrade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class lB phosphoinositide-3 kinase (PI3K7) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of Pi3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking pilOy (Pik3cg-1-), the catalytic subunit of PI3Ky, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg' mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of Pi3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that Pi3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that Pi3K&#x03B3 can be a therapeutic target for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Adiponectin, one of the insulin-sensitizing adipokines, has been shown to activate fatty acid oxidation in liver and skeletal muscle, thus maintaining insulin sensitivity. However, the precise roles of adiponectin in fatty acid synthesis are poorly understood. Here we show that adiponectin administration acutely suppresses expression of sterol regulatory element-binding protein (SREBP) 1c, the master regulator which controls and upregulates the enzymes involved in fatty acid synthesis, in the liver of +Leprdb /+Leprdb (db/db) mouse as well as in cultured hepatocytes. We also show that adiponectin suppresses SREBP1c by AdipoR1, one of the functional receptors for adiponetin, and furthermore that suppressing either AMP-activated protein kinase (AMPK) via its upstream kinase LKB1 deletion cancels the negative effect of adiponectin on SREBP1c expression. These data show that adiponectin suppresses SREBP1c through the AdipoR1/LKB1/AMPK pathway, and suggest a possible role for adiponectin in the regulation of hepatic fatty acid synthesis. [Copyright &y& Elsevier]

This report concerns two patients with severe protein losing enteropathy and refractory diarrhea due to AA amyloidosis who were successfully treated with corticosteroid and octreotide. In these patients, biopsied tissues from the gastrointestinal (GI) tract showed extensive deposition of AA amyloid, which was caused by rheumatoid arthritis in one case and was of unidentified etiology in the other. Both patients manifested severe diarrhea unresponsive to conventional treatment with hypoproteinemia, and protein leakage from the small intestine to the ascending colon was confirmed by 99m Tc-diethylene triamine pentaacetic acid human serum albumin (HSA-D) scintigraphy. Soon after starting a long-acting somatostatin analogue, octreotide, with co-administration of oral prednisolone, their general status improved in parallel with a rapid decrease in the volume of watery diarrhea and an increase in serum levels of albumin and IgG. Also on 99m Tc-HSA-D scintigraphy protein leakage from the GI tract was apparently decreased in both patients. Combination therapy with a somatostatin analogue and corticosteroid may be effective for protein losing enteropathy with intractable diarrhea ascribable to GI amyloidosis. Because of the lack of specific therapies in this serious clinical situation, the described therapy should actively be considered as a therapeutic option not only in AA amyloidosis, but also in other types of systemic amyloidosis. [ABSTRACT FROM AUTHOR]

Hashimoto''s encephalopathy (HE) is thought to be caused by disorders of immune mechanisms. Although immunologically mediated central nervous system vasculitis or unidentified anti-neuronal autoantibodies have been suspected of causing HE, its pathogenesis is still unclear. For the study presented here, two patients with typical clinical and laboratory/electrophysiological findings of HE were analyzed to clarify the role of anti-neuronal autoantibodies in the pathogenesis of HE. The autopsied brain of one of the patients was histopathologically examined. For Western blotting analysis and immunohistochemistry, serum and purified immunoglobulin G obtained from the other patient were used. Autopsy revealed no evidence of central nervous system vasculitis or other abnormal findings in the brain. The patient''s serum contained an anti-neuronal autoantibody that immunohistochemically labeled neurons of mouse and human cerebral cortices and reacted with the 36-kDa antigenic protein present in a soluble fraction obtained from human cerebral cortex. Our results indicate that anti-neuronal autoantibodies may be associated with the pathogenesis of HE. [Copyright &y& Elsevier]

Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the ceruloplasmin (CP) gene, and is characterized by a unique combination of neurovisceral iron overload and iron deficiency anemia. We generated CP-deficient (CP−/−) mice to investigate the functional involvement of CP in iron metabolism. The mice showed a marked iron overload in the liver and mild iron deficiency anemia. We examined the expression of iron-metabolism genes in the duodenum and liver using TaqMan RT-PCR. The divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), and hephaestin (HEPH) genes were not up-regulated in the duodenum from CP−/− mice. These data suggest that the mechanism of hepatic iron overload in aceruloplasminemia is quite different from that in hemochromatoses and atransferrinemia. In the liver, CP−/− mice showed no increase of gene expression for DMT1 and transferrin receptors (TFR and TFR2), indicating that none of the known pathways of iron uptake is activated in hepatocytes of CP−/− mice. This result supports the hypothesis that CP mainly acts to release iron from cells in the liver. [Copyright &y& Elsevier]

We report a young female patient with Henoch–Schönlein purpura (HSP) nephritis complicated by reversible posterior leukoencephalopathy syndrome (RPLS). The patient suddenly showed generalized seizures and cortical blindness with severe hypertension due to renal insufficiency approximately 1 year after cessation of corticosteroid treatment for HSP nephritis. Magnetic resonance imaging (MRI) demonstrated bilateral abnormal signals mainly in the cerebellum and white matter of the occipital lobe. Clinical symptoms quickly improved in conjunction with disappearance of abnormal signals on brain MRI after starting control of hypertension and continuous hemodiafiltration with steroid pulse therapy and plasmapheresis. RPLS may be caused by vasculitis and also by hemodynamic change due to severe hypertension in HSP, particularly in patients with nephropathy. In such cases intensive treatment should be performed as soon as possible to avoid neurological sequelae. [ABSTRACT FROM AUTHOR]

Abstract: We report a patient with Isaacs’ syndrome associated with myasthenia gravis and pleural recurrence of thymoma, who showed severe limb pain attributed to hyperexcitability of sensory nerves. Myokymia and severe pain were successfully treated with cytoreductive surgery and intraoperative hyperthermic intrathoracic perfusion chemotherapy, but neither pharmacotherapy nor plasma exchange showed obvious clinical effects. Pleural thymoma in our patient may have caused Isaacs’ syndrome, probably by unconfirmed humoral immune mechanisms. Cytoreductive treatment for recurrent thymoma should be actively considered as a potent therapeutic option in refractory patients with disabling neuromyotonia symptoms. [Copyright &y& Elsevier]

The article presents a case report of a 79 year old man who complained of progressive weakness of extremities and was admitted to hospital. Neurological and electromyographical examinations revealed that he was suffering from sensorimotor polyneuropathy. His cerebrospinal fluid contained 2 cells/mm2 with a slightly elevated protein level. On admission, he was drowsy but easily irritated, could not maintain concentration. An examination of his cerebrospinal fluid showed no malignant cells and normal cell count with normal concentrations of protein and glucose. Magnetic resonance imaging showed moderate atrophy of bilateral temporal lobes. Electroencephalography was abnormal with diffuse appearance of slow irregular waves.

Numerous studies have demonstrated that adiponectin plays a crucial role in the protection from diabetes and atherosclerosis. Recently, we have identified AdipoR1 and AdipoR2 as the major receptors for adiponectin, although the precise mechanism whereby adiponectin improves insulin sensitivity through these receptors has not been fully elucidated. In the present study, we have extensively analyzed the changes in the levels of proteins in liver, the major site of adiponeetin effects, by overexpressing each receptor. B6 male mice were treated with the adenovirus encoding LacZ, AdipoR1 or AdipoR2 (n=4, each group). The mice overexpressing AdipoR1 or AdipoR2 in the liver showed significantly lower insulin concentrations with comparable glucose levels compared to the control mice, indicating that these mice are more sensitive to insulin. The livers were removed 7 days after the adenovirus injection and were extracted followed by a proteomics analysis. Spots whose intensity was altered (either increased or decreased more than 1.5 fold) by AdipoR1 or AdipoR2 overexpression compared to LacZ control were applied to mass spectrometry. Total 84 proteins were altered in expression by overexpressing AdipoR1, while 146 proteins were modulated by overexpressing AdipoR2. Interestingly, most of the enzymes in the glycolytic pathway and the TCA cycle were up-regulated by AdipoR1 overexpression, whereas these trends were not observed by AdipoR2 overexpression. Moreover, AdipoR1 overexpression prominently increased catalase expression and decreased SOD1 and SOD2 expression, suggesting that the increased catalase suppresses oxidative stress, leading to reductions in SOD1 and SOD2. This up-regulation of catalase by AdipoR1 was also confirmed in the primary hepatocytes overespressing AdipoR1, suggesting that AdipoR1-mediated signal directly modulates catalase expression. The enhanced glucose catabolism increases NADH production necessarily accompanied by the increased electron leak, leading to oxidative stress. These data suggest the fine mechanism of the effects by adiponectin that adiponectin coordinately enhances glucose catabolism by up-regulating the regulatory enzymes expression and the protection machinery for the oxidative stress against the increased NADH production through AdipoR1. Thus, the subjects with hyperadiponectinemia have better glucose utilization without increasing oxidative stress, leading to protection of diabetes and atherosclerosis. [ABSTRACT FROM AUTHOR]