Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

Abdominal obesity exhibits distinct effect on inflammatory and anti-inflammatory proteins in apparently healthy Japanese men

<p>Abstract</p> <p>Background</p> <p>Since visceral fat tissue is known to release various inflammatory and anti-inflammatory cytokines, abdominal obesity may play a key role in the inflammation associated with metabolic syndrome (MetS). However, few studies have determined precise relationships of abdominal obesity with inflammatory markers in MetS. To clarify the importance of abdominal obesity in sub-clinical inflammation, we examined the changes of inflammatory markers in clustering of MetS components with or without abdominal obesity.</p> <p>Methods</p> <p>Subjects consisted of 326 apparently healthy Japanese men (age: 30 to 59 years) who underwent health examination in the Osaka University Health Care Center. MetS components were assessed and serum levels of high sensitive C-reactive protein (hs-CRP), interleukin (IL)-6 and adiponectin were examined in all subjects.</p> <p>Results</p> <p>Subjects with abdominal obesity (waist circumference ≥ 85 cm) showed higher serum hs-CRP and IL-6 levels and a lower adiponectin level than those without abdominal obesity. Serum levels of hs-CRP and IL-6 significantly increased in association with clustering of MetS components in the subjects with abdominal obesity, but not in those without abdominal obesity. On the other hand, serum adiponectin level exhibited a little change with clustering of MetS components in the subjects with abdominal obesity. Significant negative correlation between adiponectin and hs-CRP was observed in the subjects with abdominal obesity, however this correlation was not detected in obese subjects defined by body mass index ≥ 25.</p> <p>Conclusion</p> <p>Inflammatory status is not exaggerated by clustering of MetS components in the subjects without abdominal obesity. Abdominal obesity may exhibit distinct effect on inflammatory and anti-inflammatory proteins and modulate inflammatory network in MetS.</p

Measuring the Complexity of Consciousness

The quest for a scientific description of consciousness has given rise to new theoretical and empirical paradigms for the investigation of phenomenological contents as well as clinical disorders of consciousness. An outstanding challenge in the field is to develop measures that uniquely quantify global brain states tied to consciousness. In particular, information-theoretic complexity measures such as integrated information have recently been proposed as measures of conscious awareness. This suggests a new framework to quantitatively classify states of consciousness. However, it has proven increasingly difficult to apply these complexity measures to realistic brain networks. In part, this is due to high computational costs incurred when implementing these measures on realistically large network dimensions. Nonetheless, complexity measures for quantifying states of consciousness are important for assisting clinical diagnosis and therapy. This article is meant to serve as a lookup table of measures of consciousness, with particular emphasis on clinical applicability of these measures. We consider both, principle-based complexity measures as well as empirical measures tested on patients. We address challenges facing these measures with regard to realistic brain networks, and where necessary, suggest possible resolutions.Comment: 9 page

Experience in Optimising Fertility Outcomes in Men with Congenital Adrenal Hyperplasia due to 21 Hydroxylase Deficiency.

OBJECTIVE: Men with congenital adrenal hyperplasia (CAH) have impaired fertility. We aimed to assess fertility outcomes and the importance of hypogonadotropic hypogonadism, testicular failure and the presence of testicular adrenal rest tumours (TART). DESIGN: Retrospective analysis of men attending an adult CAH clinic in a tertiary centre. PATIENTS: Fifty men with CAH due to 21 hydroxylase deficiency were identified of whom 35 were salt-wasting and 15 were non-salt-wasting. MEASUREMENTS: Review of fertility history and parameters including luteinising hormone (LH), follicle stimulating hormone (FSH), androstenedione, 17-hydroxyprogesterone (17-OHP), semen analysis and the presence of testicular adrenal rest tissue (TART) on ultrasound. RESULTS: TART were detected by ultrasound in 21 (47%) and their presence was associated with an elevated FSH (p=0.01). Severe oligospermia was present in 11/23 (48%), and this was associated with an elevated FSH (p=0.02), suppressed LH (p5 x 10(6) per ml. Of those that desired fertility, 10/17 (59%) required treatment intensification, and 4 underwent in vitro fertilisation. Intensification resulted in a rise in median LH (0.6 to 4.3 IU/L; p=0.01). Live birth rate was 15/17 (88%) with a median (range) time to conception of 8(0-38) months. CONCLUSIONS: Suppressed LH is a marker for subfertility and is often reversible. Testicular failure is closely associated with TART formation. If TART are detected, sperm cryopreservation should be offered given the risk of progression to irreversible testicular failure. Male fertility in CAH can be improved by intensified treatment and assisted reproductive technology. This article is protected by copyright. All rights reserved

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A–geminin–Cdt1 axis therefore represents a critical regulator of proper DNA replication

A New Insight into the Development of Novel Anti-Cancer Drugs that Improve the Expression of Mitochondrial Function-Associated Genes

Recent analyses of the whole genome sequencing data enable us to predict cancer incidence for healthy people at present. In addition, metabolome analyses rediscovered that “cancer is a metabolic disease”. Importantly, it has been suggested that mitochondrial dysfunction might precede the metabolic change. In this chapter, we would discuss if “cancer is a transcriptional disease”. Analyzing 5′-upstream non-protein-encoding regions of the human mitochondrial function-associated genes, we speculate that mitochondrial functions could be recovered or improved at a transcriptional level. In the near future, novel chemo-/gene-therapies might be applied to treat cancer patient converting cancerous cells into normal differentiated cells

Methodological advances in imaging intravital axonal transport.

Axonal transport is the active process whereby neurons transport cargoes such as organelles and proteins anterogradely from the cell body to the axon terminal and retrogradely in the opposite direction. Bi-directional transport in axons is absolutely essential for the functioning and survival of neurons and appears to be negatively impacted by both aging and diseases of the nervous system, such as Alzheimer's disease and amyotrophic lateral sclerosis. The movement of individual cargoes along axons has been studied in vitro in live neurons and tissue explants for a number of years; however, it is currently unclear as to whether these systems faithfully and consistently replicate the in vivo situation. A number of intravital techniques originally developed for studying diverse biological events have recently been adapted to monitor axonal transport in real-time in a range of live organisms and are providing novel insight into this dynamic process. Here, we highlight these methodological advances in intravital imaging of axonal transport, outlining key strengths and limitations while discussing findings, possible improvements, and outstanding questions

Effect of cyclodextrins on the thermal epimerization of tea catechins

金沢大学理工研究域物質化学系The epimerization reaction of tea catechins was investigated at pH 5.5 and 120°C in the absence/presence of cyclodextrins (CDs). In the absence of CDs, a considerable quantity (∼20%) of products originating from reactions other than the epimerization ("other products") was formed during the epimerization of gallated catechins. In the case of (-)-EGCg, addition of β-CD to the reaction solution reduced the quantity of these other products to just a few percent, but other CDs with different cavity sizes had little effect. Generally, the addition of β-CD increased the ratio of non-epi type catechins, that is, [non-epi type catechin] / ([epi type catechin]+[non-epi type catechin]). Molecular orbital (MO) calculations using the PM3 method suggested that non-epi type catechins are more thermodynamically stable than their epi-type counterparts, moving the equilibrium position in favor of non-epi type catechins in the epimerization process