Quantitative Values from Synthetic MRI Correlate with Breast Cancer Subtypes

The purpose of this study is to correlate quantitative T1, T2, and proton density (PD) values with breast cancer subtypes. Twenty-eight breast cancer patients underwent MRI of the breast including synthetic MRI. T1, T2, and PD values were correlated with Ki-67 and were compared between ER-positive and ER-negative cancers, and between Luminal A and Luminal B cancers. The effectiveness of T1, T2, and PD in differentiating the ER-negative from the ER-positive group and Luminal A from Luminal B cancers was evaluated using receiver operating characteristic analysis. Mean T2 relaxation of ER-negative cancers was significantly higher than that of ER-positive cancers (p < 0.05). The T1, T2, and PD values exhibited a strong positive correlation with Ki-67 (Pearson’s r = 0.75, 0.69, and 0.60 respectively; p < 0.001). Among ER-positive cancers, T1, T2, and PD values of Luminal A cancers were significantly lower than those of Luminal B cancers (p < 0.05). The area under the curve (AUC) of T2 for discriminating ER-negative from ER-positive cancers was 0.87 (95% CI: 0.69–0.97). The AUC of T1 for discriminating Luminal A from Luminal B cancers was 0.83 (95% CI: 0.61–0.95). In conclusion, quantitative values derived from synthetic MRI show potential for subtyping of invasive breast cancers

Expressions of the cytochrome P450 monooxygenase gene Cyp4g1 and its homolog in the prothoracic glands of the fruit fly Drosophila melanogaster (Diptera: Drosophilidae) and the silkworm Bombyx mori (Lepidoptera: Bombycidae)

Here we describe the expression profiles of the cytochrome P450 monooxygenase gene Cyp4g1 in the fruit fly, Drosophila melanogaster Meigen, and its homolog in the silkworm, Bombyx mori L. We identified Cyp4g1 by a microarray analysis to examine the expression levels of 86 predicted D. melanogaster P450 genes in the ring gland that contains the prothoracic gland (PG), an endocrine organ responsible for synthesizing ecdysteroids. B. mori Cyp4g25 is a closely related homolog of D. melanogaster Cyp4g1 and is also expressed in the PG. A developmental expression pattern of Cyp4g25 in the PG is positively correlated with a fluctuation in hemolymph ecdysteroid titer in the late stage of the final instar. Moreover, the expression of Cyp4g25 in cultured PGs is significantly induced by the addition of prothoracicotropic hormone (PTTH), a neuropeptide hormone that stimulates the synthesis and release of ecdysone. We propose that Cyp4g1 and Cyp4g25 are the candidates that play a role in regulating PG function and control ecdysteroid production and/or metabolism during insect development

Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy

Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. During neurotransmitter exocytosis, SNARE proteins on a synaptic vesicle and the target membrane form a complex, resulting in neurotransmitter release. N-ethylmaleimide-sensitive factor (NSF), a homohexameric ATPase, disassembles the complex, allowing individual SNARE proteins to be recycled. Recently, the association between pathogenic NSF variants and developmental and epileptic encephalopathy (DEE) was reported; however, the molecular pathomechanism of NSF-related DEE remains unclear. Here, three patients with de novo heterozygous NSF variants were presented, of which two were associated with DEE and one with a very mild phenotype. One of the DEE patients also had hypocalcemia from parathyroid hormone deficiency and neuromuscular junction impairment. Using PC12 cells, a neurosecretion model, we show that NSF with DEE-associated variants impaired the recycling of vesicular membrane proteins and vesicle enlargement in response to exocytotic stimulation. In addition, DEE-associated variants caused neurodegenerative change and defective autophagy through overactivation of the mTOR pathway. Treatment with rapamycin, an mTOR inhibitor, or overexpression of wild-type NSF ameliorated these phenotypes. Furthermore, neurons differentiated from patient-derived induced pluripotent stem cells showed neurite degeneration, which was also alleviated by rapamycin treatment or gene correction using genome editing. Protein structure analysis of NSF revealed that DEE-associated variants might disrupt the transmission of the conformational change of NSF monomers and consequently halt the rotation of ATP hydrolysis, indicating a dominant negative mechanism. In conclusion, this study elucidates the pathomechanism underlying NSF-related DEE and identifies a potential therapeutic approach

Precocious Metamorphosis in the Juvenile Hormone–Deficient Mutant of the Silkworm, Bombyx mori

Insect molting and metamorphosis are intricately governed by two hormones, ecdysteroids and juvenile hormones (JHs). JHs prevent precocious metamorphosis and allow the larva to undergo multiple rounds of molting until it attains the proper size for metamorphosis. In the silkworm, Bombyx mori, several “moltinism” mutations have been identified that exhibit variations in the number of larval molts; however, none of them have been characterized molecularly. Here we report the identification and characterization of the gene responsible for the dimolting (mod) mutant that undergoes precocious metamorphosis with fewer larval–larval molts. We show that the mod mutation results in complete loss of JHs in the larval hemolymph and that the mutant phenotype can be rescued by topical application of a JH analog. We performed positional cloning of mod and found a null mutation in the cytochrome P450 gene CYP15C1 in the mod allele. We also demonstrated that CYP15C1 is specifically expressed in the corpus allatum, an endocrine organ that synthesizes and secretes JHs. Furthermore, a biochemical experiment showed that CYP15C1 epoxidizes farnesoic acid to JH acid in a highly stereospecific manner. Precocious metamorphosis of mod larvae was rescued when the wild-type allele of CYP15C1 was expressed in transgenic mod larvae using the GAL4/UAS system. Our data therefore reveal that CYP15C1 is the gene responsible for the mod mutation and is essential for JH biosynthesis. Remarkably, precocious larval–pupal transition in mod larvae does not occur in the first or second instar, suggesting that authentic epoxidized JHs are not essential in very young larvae of B. mori. Our identification of a JH–deficient mutant in this model insect will lead to a greater understanding of the molecular basis of the hormonal control of development and metamorphosis

京丹後地区早期高齢者健診（活き生き長寿研究）における認知症スクリーニング

京都府立医科大学付属北部医療センター神経内科京都府立医科大学院医学研究科神経内科Department of Neurology, North medical center, Kyoto prefectural university of medicineDepartment of Neurology, Kyoto Prefectural University of Medicine GraduateSchool of Medical Science京都丹後地区の認知機能健診事業「活き生き長寿研究」にて、効率よく認知機能低下を拾い上げるべく独自の認知症スクリーニング（original Dementia Rating：oDR）を用いた。認知症の疑いありの被験者には二次検診で正規版の臨床認知症評価Clinical Dementia Rating-Japan（CDR-J）との比較検証を行なったところ、oDR によるスクリーニングの陽性反応適中度は38 %という結果であった。われわれの健診に用いたoDR は、大規模集団の中で認知機能低下の疑いのある被験者を大まかにスクリーニングするには適しているものの、偽陽性を拾い上げている可能性があり、二次検診の再評価で認知機能低下被験者をさらにふるい分ける必要があると考えた

Annexin XI may be involved in Ca2+- or GTP-γS-induced insulin secretion in the pancreatic β-cell

AbstractThe aim of this study was to investigate possible involvement of annexin XI in the insulin secretory machinery. In fluorescence immunocytochemistry, annexin XI was found in the cytoplasm of pancreatic endocrine cells and a pancreatic β-cell line, MIN6, in a granular pattern. MIN6 cells also possessed weak and diffused annexin XI immunoreactivity in the cytoplasm. Immunoelectron microscopy revealed annexin XI in the insulin granules. Insulin secretion from streptolysin-O-permeabilized MIN6 cells was inhibited by anti-annexin XI antibody, when the release was stimulated by either Ca2+ or GTP-γS, but not by a protein kinase C-activating phorbol ester. Inhibition of insulin release by anti-annexin XI antibody was reproduced in permeabilized rat islets. These findings suggest that annexin XI may be involved in the regulation of insulin secretion from the pancreatic β-cells