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This article examines the folkloric protest and popular political culture during the anti‐Corn Law agitation. It offers a new analysis of the role of customary demonstration based on moral economy in supporting free importation of foreign corn. It examines previously unstudied bread processions during the 1841 general election and effigy burnings of Sir Robert Peel that occurred simultaneously against his minor revision of the Corn Laws in 1842. It argues that the practice of these traditional protests offered a basis on which plebeians understood the emerging idea of Free Trade. While the protesters and more moderate reformers represented by the Anti‐Corn Law League shared a common cause of Corn Law repeal, there was a potential conflict over respectability. Moreover, Chartists could appropriate this popular custom for promoting the People's Charter rather than Free Trade. This article contributes to understanding the relationship between popular custom and radical politics in the wider context of the emergence of Free Trade Britain in the early Victorian period. [ABSTRACT FROM AUTHOR]

The outcomes of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) who are not treated are unclear. This study aimed to clarify these outcomes and identify the factors related to them. We retrospectively evaluated various clinical features including laboratory data and involved organs at diagnosis in 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single center in Japan. We compared the clinical features of the 27 untreated patients with those of the 80 patients treated with glucocorticoid. The patient outcomes were investigated, and logistic regression analysis was performed to identify factors related to them. The patients comprised 73 men and 34 women (median age 67 years). The untreated patients had significantly lower IgG4-RD responder index (9 vs. 12) and fewer affected organs (1 vs. 3) than did those treated with glucocorticoid. Of these 27 patients, 8 experienced deterioration of IgG4-RD after the diagnosis. In the age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017–1.402) was the only significant factor related to disease deterioration in untreated patients with IgG4-RD, whereas not serum IgG4 levels (per 100 mg/dL, odds ratio 0.995, 95% confidence interval 0.921–1.075) but history of allergy (OR 3.134, 95% confidence interval 1.094–8.977, P = 0.033) related to deterioration in patients who underwent treatment. Serum IgG4 levels may be a useful predictor of unfavorable outcomes in untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index. [ABSTRACT FROM AUTHOR]

Systemic salt loading has been reported to facilitate operant heat-escape/cold-seeking behavior. In the present study, we hypothesized that the median preoptic nucleus (MnPO) would be involved in this mechanism. Rats were divided into two groups (n = 6 each): one group had the MnPO lesion with ibotenic acid (4.0 μg) and the other was the vehicle control. After subcutaneous injection (10 ml/kg) of either isotonic- (154 mM) or hypertonic-saline (2,500 mM), each rat was placed in a behavior box, where the ambient temperature was changed to 26°C, 35°C, and 40°C every 1 h. The position of a rat in the box and the body core temperature (Tcore) were monitored. A rat could trigger 0°C air for 45 s in the 35°C and 40°C heat when moved in a specific area in the box (operant behavior). In the control group, counts of the operant behavior were greater (P < 0.05) in the hypertonic- than in the isotonic-saline injection (17 ± 2 and 10 ± 2 at 35°C, 24 ± 2 and 18 ± 1 at 40°C). Tcore remained unchanged throughout the exposure, although the level was lower (P < 0.05) in the hypertonic- than in the isotonic-saline trial (36.6 ± 0.2°C and 37.4 ± 0.1°C at 26°C and 36.9 ± 0.2°C and 37.4 ± 0.1°C at 40°C, respectively). However, in the MnPO-lesion group, counts of the behavior were similar between the hypertonic- and isotonic-saline injection trials (10 ± 2 and 8 ± 1 at 35°C, and 17 ± 1 and 16 ± 1 at 40°C, respectively). Tcore increased (P < 0.05) in the heat in both trials (36.8 ± 0.1°C and 37.4 ± 0.1°C at 26°C and 37.4 ± 0.2°C and 37.8 ± 0.2°C at 40°C in the hypertonic- and isotonic-saline injection trials, respectively). These results may suggest that, at least in part, the MnPO is involved in the facilitation of heat-escape/cold-seeking behavior during osmotic stimulation. [ABSTRACT FROM AUTHOR]

Connective tissue growth factor (CTGF) is a pro-fibrogenic molecule involved in several human fibrotic disorders. CTGF overexpression in the liver, through upregulation of CTGF mRNA in hepatic stellate cells (HSCs), is reported to correlate with the degree of fibrosis. Although alcohol is a major cause of hepatic fibrosis, the role of CTGF in alcoholic hepatic fibrogenesis, has been poorly understood. Oxidative stress, mediated by ethanol-inducible Cytochrome P-4502E1(CYP2E1), has been implicated as a crucial factor in alcoholic hepatic fibrogenesis. Therefore, we investigated the contribution of CYP2E1-mediated ethanol oxidation to CTGF mRNA expression by using a well-established HepG2 cell line constitutively expressing CYP2E1 (E9 cells). CTGF mRNA quantitation by a real-time reverse polymerase chain reaction (RT-PCR) showed a significant increase in CTGF mRNA levels in ethanol-treated E9 cells. Phorbol myristate acetate (PMA), which enhances CYP2E1 expression, increased CTGF mRNA levels. This increase was diminished after co-incubation with 4-methylpyrazole (4MP), a CYP2E1 inhibitor, or an antioxidant, N-acetylcysteine. We visualized the state of oxidative stress only in ethanol-treated E9 cells by a newly-established anti-acrolein-modified antibody. In conclusion, our study has first identified a possible role of CYP2E1-mediated ethanol oxidation in CTGF gene upregulation, suggesting a considerable role of CTGF in alcoholic hepatic fiberogenesis. [Copyright &y& Elsevier]

Aim: Recently, substantial studies have been accumulated to indicate the important role of gut microbiota in diabetic kidney disease (DKD). The abnormal change of bacterial‐derived products could imply specific injuries or play beneficial or harmful roles in DKD progression. In this study, we examined the presence and contribution of the Klebsiella oxytoca gene in the circulation of patients with DKD. Method: We enrolled a total of 16 healthy participants, 17 patients with DKD, 5 patients with DKD requiring haemodialysis (HD), and 7 patients with CKD without diabetes. Bacterial‐derived DNA (16S rDNA and a specific K. oxytoca gene) in the blood was detected using droplet digital PCR, then investigated the relationship with clinical characteristics. Results: We identified an increase in K. oxytoca genes in the blood of DKD patients. Interestingly, blood K. oxytoca copies and K. oxytoca/ 16S DNA ratio correlated with higher blood creatinine and BUN levels together with lower eGFR in DKD patients. K. oxytoca levels were also associated with higher neutrophil percentage, lower lymphocyte frequency, and increased neutrophil‐to‐lymphocyte ratio. Conclusion: Collectively, the presence of the K. oxytoca gene in the circulation could serve as a biomarker reflecting reduced renal function in DKD patients. [ABSTRACT FROM AUTHOR]

Objectives Reportedly, patients with LN and low-level proteinuria have favourable short-term renal outcomes. We aimed to clarify the long-term renal outcomes and overall survival of these patients, and the significance of renal biopsy in the early phase with low-level proteinuria. Methods We included 144 Japanese patients with biopsy-proven LN from 10 hospitals. Low-level proteinuria was defined by a urine protein:creatinine ratio (UPCR) of ≤1 g/gCr based on previous reports. The outcomes were end-stage renal disease (ESRD) and death. Results Compared with patients with high-level proteinuria (UPCR >1 g/gCr), those with low-level proteinuria [ n  = 67 (46.5%)] had significantly improved renal function at the time of renal biopsy, and low activity index and chronicity index while the frequency of class III/IV was similar (79.1% vs 84.4%, P  = 0.409). In patients with low-level proteinuria, CYC usage was less, and the incidences of ESRD (3.0% vs 13.0%, P  = 0.036) and death (3.0% vs 16.9%, P  = 0.006) during the total observation period (median, 72 months) were low. Kaplan–Meier analysis showed significant differences in the incidence of ESRD and death between the groups. Multivariate Cox regression analysis revealed that the significant risk factors for ESRD were high chronicity index and hypertension, whereas those for death were increased age and high-level proteinuria. Conclusion Patients with LN and low-level proteinuria had favourable long-term renal and life outcomes. As these patients have substantial active pathological lesions, renal biopsy in the early phase with low-level proteinuria could enable early diagnosis and treatment and thus improve prognosis. [ABSTRACT FROM AUTHOR]

We present a multiple emission line study of ∼1300 H α emitters (HAEs) at z ∼ 2.3 in the ZFOURGE survey. In contrast to the traditional spectroscopic method, our sample is selected based on the flux excess in the ZFOURGE K s broadband data relative to the best-fit stellar continuum. Using the same method, we also extract the strong diagnostic emission lines for these individual HAEs: [O iii ] λ λ 4959, 5007 and [O ii ] λ λ 3726, 3729. Our measurements demonstrate good consistency with those obtained from spectroscopic surveys. We investigate the relationship between the equivalent widths (EWs) of these emission lines and various galaxy properties, including stellar mass, stellar age, star formation rate, specific star formation rate, and ionization state (O32). We have identified a discrepancy between HAEs at z ∼ 2.3 and typical local star-forming galaxies observed in the Sloan Digital Sky Survey, suggesting the evolution of lower gas-phase metallicity (Z) and higher ionization parameters (U) with redshift. Notably, we have observed a significant number of low-mass HAEs exhibiting exceptionally high EW[O iii ]. Their galaxy properties are comparable to those of extreme objects, such as extreme O3 emitters and Ly α emitters at z ≃ 2–3. Considering that these characteristics may indicate potential strong Lyman continuum leakage, higher-redshift analogs of the low-mass HAEs could be significant contributors to the cosmic reionization. Further investigations of this particular population are required to gain a clearer understanding of galaxy evolution and cosmic reionization. [ABSTRACT FROM AUTHOR]

We have developed a near-infrared camera called ANIR (Atacama Near-InfraRed camera) for the University of Tokyo Atacama Observatory 1.0 m telescope (miniTAO) installed at the summit of Cerro Chajnantor (5640 m above sea level) in the north of Chile. The camera provides a field of view of 5${^{\prime}_{.}}$1 × 5${^{\prime}_{.}}$1 with a spatial resolution of 0${^{\prime\prime}_{.}}$298 pixel−1 in the wavelength range of 0.95 to 2.4 μm, using Offner relay optics and a PACE HAWAII-2 focal plane array. Taking advantage of the dry site, the camera is capable of narrow-band imaging observations at the hydrogen Paschen-α (Paα, λ = 1.8751 μm in air) wavelength ground-based observations of which have been quite difficult due to deep atmospheric absorption, mainly from water vapor. We have been successfully obtaining Paα images of Galactic objects and nearby galaxies since the first-light observation in 2009 with ANIR. The throughputs at the narrow-band filters (N1875, N191) including the atmospheric absorption show larger dispersion (∼ 10%) than those at broad-band filters (a few percent), indicating that they are affected by temporal fluctuations in precipitable water vapor (PWV) above the site. We evaluate the PWV content via the atmospheric transmittance at the narrow-band filters, and deduce that the median and the dispersion of the distribution of the PWV are 0.40 ± 0.30 and 0.37 ± 0.21 mm, for the N1875 and N191 data respectively, which are remarkably smaller (49% ± 38% for N1875 and 59% ± 26% for N191) than radiometry measurements at the base of Cerro Chajnantor (an altitude of 5100 m). The decrease in PWV can be explained by the altitude of the site when we assume that the vertical distribution of the water vapor is approximated at an exponential profile with scale heights within 0.3–1.9 km (previously observed values at night). We thus conclude that miniTAO/ANIR at the summit of Cerro Chajnantor indeed provides us an excellent capability for a ground-based Paα observation. [ABSTRACT FROM PUBLISHER]

Chronic ethanol consumption results in the proliferation of the membranes of the smooth endoplasmic reticulum. Although these microsomal changes can be interpreted as adaptive alterations secondary to induction of the membranes after chronic ethanol ingestion, some injurious consequences may ensue. Accelerated ethanol metabolism results in enhanced production of acetaldehyde and exacerbation of its various toxic manifestations including enhanced lipid peroxidation. The latter may also be promoted more directly through enhanced free radical formation by the induced microsomes and cytochrome P4502E1 (CYP2E1). Ethanol-inducible CYP2E1 is of interest because of its ability to metabolize and activate many toxicologically important substrates including ethanol, CCl4, acetaminophen, and N-nitrosodimethylamine, to more toxic products. Major interest in CYP2E1 reflects the ability of this enzyme to oxidize ethanol, to generate reactive products from ethanol oxidation (e.g. acetaldehyde and 1-hydroxyethyl radical), to activate various agents including CCl4 and acetaminophen into reactive products, and to generate reactive oxygen species. There is considerable interest in the role of ethanol-induced oxidative stress and generation of reactive oxygen species in the mechanisms by which ethanol becomes hepatotoxic. To understand the basic effects and actions of CYP2E1, an approach has been established to utilize the cell lines that constitutively express human CYP2E1. This review article briefly describes a role of microsomal enzymes in the development of alcoholic liver injury as well as the usefulness of this cell line to further clarify the mechanisms of CYP2E1-related hepatotoxicity. [ABSTRACT FROM AUTHOR]

The criptochrome genes (Cry1 and Cry2) are involved in the molecular mechanism that controls the circadian clock, and mice lacking these genes (Cry1-/-/Cry2-/-) are behaviorally arrhythmic. It has been speculated that the circadian clock modulates the characteristics of thermoregulation, resulting in body temperature (Tb) rhythm. However, there is no direct evidence proving this speculation. We show here that Tb and heat production in Cry1-/-/Cry2-/- mice are arrhythmic under constant darkness. In contrast, both rhythms occur under a light-dark cycle and/or periodical food restriction linked with spontaneous activity and/or eating, although they are not robust as those in wild-type mice. The relationship between heat production and Tb in Cry1-/-/Cry2-/- mice is linear and identical under any conditions, indicating that their Tb rhythm is determined by heat production rhythm associated with activity and eating. However, Tb in wild-type mice is maintained at a relatively higher level in the active phase than the inactive phase regardless of the heat production level. These results indicate that the thermoregulatory responses are modulated according to the circadian phase, and the Cry genes are involved in this mechanism. [ABSTRACT FROM AUTHOR]

We surveyed the neural substrata for behavioral thermoregulation with immunohistochemical analysis of the expression of Fos protein in the rat brain. We used an operant system in which a rat exposed to heat (40°C) could get cold air (0°C) for 30 s when it moved into the reward area. Rats moved in and out of the reward area of the system periodically and thus maintained their body temperature at a normal level. In the rats performing heat escape behavior (active group), strong Fos immunoreactivity (Fos-IR) was found in the median preoptic nucleus (MnPO), parastrial nucleus (PS), and dorsomedial hypothalamus (DMH) compared with the controls. Another group of rats (passive group) were given the same temperature changes, regardless of the rat's movement, as those obtained by rats of the active group. Fos-IR in the MnPO was also seen in this group. The present results suggest that the PS and DMH play an important role in the genesis of thermoregulatory behavior, whereas the MnPO may be important for detecting changes in ambient and/or body temperatures. [ABSTRACT FROM AUTHOR]

Studies increased heat-escape/cold-seeking behavior following hypertonic saline injection in rats. Changes in body weight, blood volume and plasma osmolality before and after hypertonic saline injections; Reduction in body water levels following thermally-induced dehydration; Occurrence of autonomic and behavioral regulatory adjustments in response to dehydration.

The formation of massive stars in dense and cold molecular clouds is a fundamental problem in star formation. In this work, we studied three compact massive star-forming regions, M8E, RAFGL 6366S, and IRAS 18317−0513, to investigate the environment of massive star formation, specifically the possibility of a local feedback process. Our new mid-infrared observations using miniTAO/MAX38 at 31 and 37 μm resolved individual objects in each region and allowed us to obtain their individual luminosities and masses. Together with existence/absence of ultra-compact H  ii regions, it is suggested that less-massive objects are more evolved than the more-massive objects in two out of the three regions. Because the objects that are more massive evolve faster, those that are less massive form earlier. This formation trend of local mass-sequential star was first suggested in 0.1 pc-scale massive star-forming regions. Therefore, feedback, such as outflows, jets, or radiative heating, from previously formed lower-mass young stellar objects might affect the environment of parental clouds and lead to next-generation massive young stellar objects. [ABSTRACT FROM AUTHOR]

Reduced glucose uptake into the skeletal muscle is an important pathophysiological abnormality in type 2 diabetes, and is caused by impaired translocation of glucose transporter 4 (GLUT4) to the skeletal muscle cell surface. Here, we show a xanthene derivative, DS20060511, induces GLUT4 translocation to the skeletal muscle cell surface, thereby stimulating glucose uptake into the tissue. DS20060511 induced GLUT4 translocation and stimulated glucose uptake into differentiated L6-myotubes and into the skeletal muscles in mice. These effects were completely abolished in GLUT4 knockout mice. Induction of GLUT4 translocation by DS20060511 was independent of the insulin signaling pathways including IRS1-Akt-AS160 phosphorylation and IRS1-Rac1-actin polymerization, eNOS pathway, and AMPK pathway. Acute and chronic DS20060511 treatment attenuated the glucose intolerance in obese diabetic mice. Taken together, DS20060511 acts as a skeletal muscle-specific GLUT4 translocation enhancer to facilitate glucose uptake. Further studies of DS20060511 may pave the way for the development of novel antidiabetic medicines. Furuzono et al. identify DS20060511, a skeletal muscle cell-specific GLUT4 translocation enhancer. They find that DS20060511 have remarkable effects on lowering blood glucose and enhancing skeletal muscle glucose uptake via GLUT4, highlighting its potential as antidiabetic medicine. [ABSTRACT FROM AUTHOR]

The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na+ and K+ channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes. [ABSTRACT FROM AUTHOR]

Galaxies change their properties as they assemble into clusters. In order to understand the physics behind that, we need to go back in time and observe directly what is occurring in galaxies as they fall into a cluster. We have conducted a narrowband and J-band imaging survey on a cluster CL1604-D at z = 0.923 using a new infrared instrument SWIMS installed at the Subaru Telescope. The narrowband filter, NB1261, matches to Hα emission from the cluster at z = 0.923. Combined with a wide range of existing data from various surveys, we have investigated galaxy properties in and around this cluster in great detail. We have identified 27 Hα emitters associated with the cluster. They have significant overlap with MIPS sources and are located exclusively in the star-forming regime on the rest-frame UVJ diagram. We have identified two groups of galaxies near the cluster in the 2D spatial distribution and the phase-space diagram, which are likely to be in-falling to the cluster main body. We have compared various physical properties of star-forming galaxies, such as specific star formation rates (burstiness) and morphologies (merger) as a function of environment, cluster center, older group, younger group, and the field. As a result, a global picture has emerged on how the galaxy properties are altered as they assemble into a denser region. This includes the occurrence of mergers, enhancement of star formation activity, excursion to the dusty starburst phase, and eventual quenching to a passive phase. [ABSTRACT FROM AUTHOR]

Highlights from the article: That star-forming galaxies with classical bulges have compact star-forming regions con- Key words: HII regions - galaxies: interactions - galaxies: star formation - galaxies: starburst - infrared: Thus selected 20 non-irregular galaxies out of 38 galaxies A Seyfert 1 galaxy whose concentrated Pa emission may HII regions, galaxies: interactions, galaxies: star formation, galaxies: starburst, infrared: galaxies.

We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b , which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db / db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus. [ABSTRACT FROM AUTHOR]

Abstract Imaging observations of faint meteors were carried out on April 11 and 14, 2016 with a wide-field CMOS mosaic camera, Tomo-e PM, mounted on the 105-cm Schmidt telescope at Kiso Observatory, the University of Tokyo. Tomo-e PM, which is a prototype model of Tomo-e Gozen, can monitor a sky of ∼ 1.98 deg 2 at 2 Hz. The numbers of detected meteors are 1514 and 706 on April 11 and 14, respectively. The detected meteors are attributed to sporadic meteors. Their absolute magnitudes range from + 4 to + 10 mag in the V -band, corresponding to about 8.3 × 10 − 2 to 3.3 × 10 − 4 g in mass. The present magnitude distributions we obtained are well explained by a single power-law luminosity function with a slope parameter r = 3.1 ± 0.4 and a meteor rate log 10 N 0 = − 5.5 ± 0.5. The results demonstrate a high performance of telescopic observations with a wide-field video camera to constrain the luminosity function of faint meteors. The performance of Tomo-e Gozenis about two times higher than that of Tomo-e PM. A survey with Tomo-e Gozenwill provide a more robust measurement of the luminosity function. Highlights • More than 2000 faint meteors were recorded in two days with a newly-developed wide-field CMOS mosaic camera, Tomo-e PM. • The visual magnitudes of the detected meteors range from +4 to +10 mag. • The present magnitude distribution is consistent with a power-law function with a slope parameter r = 3.1 ± 0.4 and a meteor rate log 10 N 0 = −5.5 ± 0.5. • Tomo-e Gozen, a successor to Tomo-e PM, will provide a practical tool to investigate the luminosity function of faint meteors. [ABSTRACT FROM AUTHOR]

In order to investigate populations of massive stars in massive star clusters, we have constructed a near-infrared image set: narrow bands of 1.87 and 2.07 $$\mu$$ m and the K s standard band with miniTAO, a 1-m infrared telescope at Atacama. First, we observed the well-known three massive star clusters near the Galactic Centre. Colour–colour diagrams made from the set of images show clear excess in 1.87 μm for WN-type Wolf–Rayet stars, luminous blue variables and Ofpe stars, and also clear excess in 2.07 μm for WC-type Wolf–Rayet stars. Our detection in 1.87 μm agrees well with the 1.87-μm detection with the Hubble Space Telescope by Dong et al. The 1.87-μm excess of WN stars seems to have a clear correlation to the K s magnitude. The correlation suggests that the 1.87-μm excess originates in recombination line emission of H and He, and the K s magnitude includes free–free radiation. Moreover, the K s magnitude of WN-late stars, excluding the component of the free–free emission, seems to have nearly a common K s magnitude. However, the colour–colour diagrams also enable us to find the extinction for each star and thus to draw extinction maps. Furthermore, almost all Mira variables reported by Matsunaga et al. are detected in our images. By using the extinction maps, several tens of extremely red sources except for Mira variables are detected. These are considered to be possibly low-temperature (T < 1000 K) objects. [ABSTRACT FROM AUTHOR]

Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states. [ABSTRACT FROM AUTHOR]

Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential. [ABSTRACT FROM AUTHOR]

Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion. [ABSTRACT FROM AUTHOR]

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile. [ABSTRACT FROM AUTHOR]

Abstract: The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s. [Copyright &y& Elsevier]

In response to increased core temperature, mammals initiate evaporative cooling responses (e.g. sweating, punting). These responses result in dehydration and plasma hypertonicity if the fluid losses are not replaced. The aim of the present study was to determine whether osmoreceptors in the lamina terminalis (LT) may exert an inhibitory influence on evaporative thermoregulatory cooling responses. We studied the effect of infusions of either hypertonic 1.65M NaCl or 3M sorbitol in 0.15M NaCl at 1.6 ml/min for 10 min into a carotid artery, on the rate of punting of 4 conscious sheep exposed to an ambient temperature of 39°C for 1,-2 hours. Both intracarotid (IC) 1.65M NaCl or 3M sorbitol caused rapid and large reduction in punting (127 ± 18 to 65 ± 15 and 110 ± 15 to 76 ± 24 breaths/rain respectively) that reversed immediately infusions ended. Control IC infusion of isotonic saline did not inhibit panting during heat exposure. In 3 sheep in which the osmoregulatory region of the lamina term±nails had been ablated, IC infusion of 1.65M NaCl or 3M sorbitol did not reduce punting. Drinking in response to IC hypertonic saline was also abolished in these 3 sheep with LT lesions. We propose that osmoreceptors in the region of the lamina terminal±s, probably located in the organum vaseulosum laminae term±nails and/or subfornical organ, may exert inhibitory osmoregulatory influences on evaporative cooling mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID50 =0.6mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC50 (mouse)=2nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10mg/kg). [ABSTRACT FROM AUTHOR]

Abstract: Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis. [Copyright &y& Elsevier]

Abstract: Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd). [Copyright &y& Elsevier]

Abstract: The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC50 in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration. [Copyright &y& Elsevier]

Alcohol has been known to be associated with an increased risk of cancer. We investigated the characteristics of hepatocellular carcinoma (HCC) in heavy drinkers with negative serum markers for viral hepatitis (non-B, non-C) to determine whether ethanol enhances the development of HCC in Japanese patients with or without serum markers for viral hepatitis. Among the 432 HCC cases seen at our hospital between 1995 and 2000, 26 patients had negative serum markers (non-B, non-C) and were heavy drinkers. The mean patient age at the time of HCC diagnosis was 64.2±7.6 years. The mean total ethanol intake was 1617±796 kg. Most of the patients also had liver cirrhosis (LC), although the frequency was significantly higher in non-B, non-C, heavy drinkers HCC cases than in non-B, non-C, non-alcoholic HCC cases. Among the hepatitis C virus (HCV)-positive cases, the mean age at the time of HCC diagnosis was lower in heavy drinkers; this trend was not seen in HBV-positive cases. In HCC cases with heavy drinking, a high frequency of gastrointestinal (oropharynx, esophagus, stomach, colon and anal) cancers was seen. As for the aldehyde dehydrogenase-2 (ALDH2) genotype, the frequency of normal homozygotes was 87.5% in heavy drinkers with HCC and the frequency of heterozygotes was 12.5%; the frequency of heterozygotes was 58.3% in alcoholics with esophageal cancer. More than half of the non-B, non-C, heavy drinkers HCC cases had a normal range of serum alpha-fetoprotein (AFP) levels. These results indicate that heavy drinking enhances HCV-related hepatocarcinogenesis. Whether or not ethanol is directly involved in hepatocarcinogenesis remains controversial, but LC may progress HCC in heavy drinkers even if their serum markers for HBV (including tissue) or HCV are negative. Therefore, close observation, including radiographic examinations, is recommended for non-B, non-C, heavy drinkers with LC. In HCV-positive cases, abstinence or a reduction in daily ethanol intake is recommended. [Copyright &y& Elsevier]

To investigate the mechanism involved in the reduction of body core temperature (T[sub core]) during fasting in rats, which is selective in the light phase, we measured T[sub core], surface temperature, and oxygen consumption rate in fed control animals and in fasted animals on day 3 of fasting and day 4 of recovery at an ambient temperature (T[sub a]) of 23°C by biotelemetry, infrared thermography, and indirect calorimetry, respectively. On the fasting day, 1) T[sub core] in the light phase decreased (P < 0.05) from the control; however, T[sub core] in the dark phase was unchanged, 2) tail temperature fell from the control (P < 0.05, from 30.7 ± 0.1 to 23.9 ± 0.1°C in the dark phase and from 29.4 ± 0.1 to 25.2 ± 0.2°C in the light phase), 3) oxygen consumption rate decreased from the control (P < 0.05, from 24.37 ± 1.06 to 16.24 ± 0.69 ml·min[sup -1]·kg body wt[sup -0.75] in the dark phase and from 18.91 ± 0.64 to 14.00 ± 0.41 ml·min[sup -1]·kg body wt[sup -0.75] in the light phase). All these values returned to the control levels on the recovery day. The results suggest that, in the fasting condition, T[sub core] in the dark phase was maintained by suppression of the heat loss mechanism, despite the reduction of metabolic heat production. In contrast, the response was weakened in the light phase, decreasing T[sub core] greatly. Moreover, the change in the regulation of tail blood flow was a likely mechanism to suppress heat loss. [ABSTRACT FROM AUTHOR]

Using a prototype of the Tomo-e Gozen wide-field CMOS mosaic camera, we acquire wide-field optical images at a cadence of |$2\:$| Hz and search them for transient sources of duration 1.5 to |$11.5\:$| s. Over the course of eight nights, our survey encompasses the equivalent of roughly two days on one square degree, to a fluence equivalent to a limiting magnitude of about |$V = 15.6$| in a 1-s exposure. After examining by-eye the candidates identified by a software pipeline, we find no sources which meet all our criteria. We compute upper limits to the rate of optical transients consistent with our survey, and compare those to the rates expected and observed for representative sources of ephemeral optical light. [ABSTRACT FROM AUTHOR]

Impaired insulin signaling in brain leads to both metabolic and behavioral abnormalities. To understand the role of insulin on gene expression in the brain, we performed hyperinsulinemic-euglycemic clamps using physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes by RNA Seq. In response to peripheral insulin, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P < 0.01). Other regions showed different responses with 205 genes significantly regulated by ≥ 50% in hippocampus and 131 regulated in nucleus accumbens. Insulin upregulated the pathway for very long chain fatty acyl-CoA synthesis in all three regions, but most insulin responsive genes were region specific. Thus, in hypothalamus, insulin modulated metabolism by suppressing the glycolysis and pentose phosphate pathway, while increasing expression of genes in the pyruvate dehydrogenase complex and cholesterol biosynthesis. Conversely, mice with streptozotocin diabetes displayed decreased expression of genes involved in the regulation of pyruvate dehydrogenase complex, very long-chain fatty acyl-CoA and cholesterol biosynthesis in hypothalamus, all of which were normalized by exogenous insulin. In addition, insulin regulated many genes in the hypothalamus involved in neurotransmission, including enhancing the expression of multiple GABA-A receptor subunits and suppressing many neuropeptides. Based on the transcriptional signature, changes in gene expression by insulin involve neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. In summary, peripherally administered insulin rapidly and potently regulates expression of genes involved in neurotransmission, neuromodulation and brain metabolism, especially in the hypothalamus. This helps reroute substrate carbons to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling. Disclosure: W. Cai: None. T.M. Batista: None. R. Garcia Martin: None. A. Ramirez: None. M. Konishi: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam. [ABSTRACT FROM AUTHOR]