Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: Synthesis, biological evaluation, and molecular modeling in the homology model

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compoundsthe bisulfate salt of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (−)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(−)-3-(4-chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.

Significant effects of Pgi genotype and body reserves on lifespan in the Glanville fritillary butterfly

Individuals with a particular variant of the gene phosphoglucose isomerase (Pgi ) have been shown to have superior dispersal capacity and fecundity in the Glanville fritillary butterfly (Melitaea cinxia), raising questions about the mechanisms that maintain polymorphism in this gene in the field. Here, we investigate how variation in the Pgi genotype affects female and male life history under controlled conditions. The most striking effect is the longer lifespan of genotypes with high dispersal capacity, especially in nonreproducing females. Butterflies use body reserves for somatic maintenance and reproduction, but
different resources (in thorax versus abdomen) are used under dissimilar conditions, with some interactions with the Pgi genotype. These results indicate life-history trade-offs that involve resource allocation and genotype!environment interactions, and these trade-offs are likely to contribute to the maintenance of Pgi polymorphism in the natural populations.

Compressible axially symmetric laminar boundary layer flow in the stagnation region of a blunt body in the presence of magnetic field

In this paper, the steady laminar viscous hypersonic flow of an electrically conducting fluid in the region of the stagnation point of an insulating blunt body in the presence of a radial magnetic field is studied by similarity solution approach, taking into account the variation of the product of density and viscosity across the boundary layer. The two coupled non-linear ordinary differential equations are solved simultaneously using Runge-Kutta-Gill method. It has been found that the effect of the variation of the product of density and viscosity on skin friction coefficient and Nusselt number is appreciable. The skin friction coefficient increases but Nusselt number decreases as the magnetic field or the total enthalpy at the wall increases

The Physical Strenuousness of Work is Slightly Associated with an Upward Trend in the Body Mass Index

This paper explores the relationship between the physical strenuousness of work and the body mass index in Finland, using individual microdata over the period 1972-2002. The data contain self-reported information about the physical strenuousness of a respondent’s current occupation. Our estimates show that the changes in the physical strenuousness of work can explain around 8% at most of the definite increase in BMI observed over the period. The main reason for this appears to be that the quantitative magnitude of the effect of the physical strenuousness of work on BMI is rather moderate. Hence, according to the point estimates, BMI is only around 1.5% lower when one’s current occupation is physically very demanding and involves lifting and carrying heavy objects compared with sedentary job (reference group of the estimations), other things being equal. Accordingly, the changes in eating habits and the amount of physical activity during leisure time must be the most important contributors to the upward trend in BMI in industrialised countries, but not the changes in the labour market structure.

Electrochemical aspects of leaching of ocean nodules in the presence and absence of microorganisms

instead of using chemical-reducing agents to facilitate the reduction and dissolution of manganese and iron oxide in the ocean nodule, electrochemical reduction based on two approaches, namely, cathodic polarization and galvanic interaction, can also be considered as attractive alternatives. Galvanic leaching of ocean nodules in the presence of pyrite and pyrolusite for complete recovery of Cu, Ni and Co has been discussed. The key for successful and efficient dissolution of copper, nickel and cobalt from ocean nodules depends on prior reduction of the manganese and ferric oxides with which the above valuable nonferrous metals are interlocked. Polarization studies using a slurry electrode system indicated that maximum dissolution of iron and manganese due to electrochemical reduction occurred at negative DC potentials of -600 mV (SCE) and -1400 mV (SCE). The present work is also relevant to galvanic bioleaching of ocean nodules using autotrophic microorganisms, such as Thiobacillus ferrooxidans and T thiooxidans, which resulted in significant dissolution of copper, nickel and cobalt at the expense of microbiologically generated acids. Various electrochemical and biochemical mechanisms are outlined and the electroleaching and galvanic processes so developed are shown to yield almost complete dissolution of all metal values. (C) 2002 Elsevier Science B.V. All rights reserved.

Many-Body Localization in the Presence of a Single-Particle Mobility Edge

In one dimension, noninteracting particles can undergo a localization-delocalization transition in a quasiperiodic potential. Recent studies have suggested that this transition transforms into a many-body localization (MBL) transition upon the introduction of interactions. It has also been shown that mobility edges can appear in the single particle spectrum for certain types of quasiperiodic potentials. Here, we investigate the effect of interactions in two models with such mobility edges. Employing the technique of exact diagonalization for finite-sized systems, we calculate the level spacing distribution, time evolution of entanglement entropy, optical conductivity, and return probability to detect MBL. We find that MBL does indeed occur in one of the two models we study, but the entanglement appears to grow faster than logarithmically with time unlike in other MBL systems.

Spread of Salmonella enterica in the body during systemic infection: unravelling host and pathogen determinants.

Salmonella enterica causes a range of life-threatening diseases in humans and animals worldwide. Current treatments for S. enterica infections are not sufficiently effective, and there is a need to develop new vaccines and therapeutics. An understanding of how S. enterica spreads in tissues has very important implications for targeting bacteria with vaccine-induced immune responses and antimicrobial drugs. Development of new control strategies would benefit from a more sophisticated evaluation of bacterial location, spatiotemporal patterns of spread and distribution in the tissues, and sites of microbial persistence. We review here recent studies of S. enterica serovar Typhimurium (S. Typhimurium) infections in mice, an established model of systemic typhoid fever in humans, which suggest that continuous bacterial spread to new infection foci and host phagocytes is an essential trait in the virulence of S. enterica during systemic infections. We further highlight how infections within host tissues are truly heterogeneous processes despite the fact that they are caused by the expansion of a genetically homogeneous microbial population. We conclude by discussing how understanding the within-host quantitative, spatial and temporal dynamics of S. enterica infections might aid the development of novel targeted preventative measures and drug regimens.

Odontocete Stranding Patterns in the Main Hawaiian Islands 1937–2002): how do they compare with live animal surveys?

In this study we (1) synthesized 65 yr of odontocete stranding data around the main Hawaiian Islands (1937–2002); (2) analyzed stranding patterns and trends over time; and (3) compared occurrence patterns based on sightings of live animals with stranding data and evaluated the compatibility of these data sets. From 1937 to 2002, 202 odontocete strandings were recorded by the National Marine Fisheries Service, Pacific Islands Regional Office. Strandings increased through time due to increased reporting effort and occurred throughout the year. The four most common of 16 species reported were Kogia spp. (18%), spinner dolphins (Stenella longirostris) (15%), striped dolphins (Stenella coeruleoalba) (11%), and sperm whales (Physeter macrocephalus) (10%). The highest proportion of strandings was recorded on O‘ahu (48%), followed by Maui/La¯na‘i (24%), Kaua‘i (12%), Hawai‘i (11%), and Moloka‘i (5%). Comparison with four previously published live animal survey studies suggests that stranding records are a good indicator of species composition and yield reasonable data on the frequency of occurrence of species in the region they cover.

GABAergic and Cortical and Subcortical Glutamatergic Axon Terminals Contain CB1 Cannabinoid Receptors in the Ventromedial Nucleus of the Hypothalamus

Background: Type-1 cannabinoid receptors (CB1R) are enriched in the hypothalamus, particularly in the ventromedial hypothalamic nucleus (VMH) that participates in homeostatic and behavioral functions including food intake. Although CB1R activation modulates excitatory and inhibitory synaptic transmission in the brain, CB1R contribution to the molecular architecture of the excitatory and inhibitory synaptic terminals in the VMH is not known. Therefore, the aim of this study was to investigate the precise subcellular distribution of CB1R in the VMH to better understand the modulation exerted by the endocannabinoid system on the complex brain circuitries converging into this nucleus. Methodology/Principal Findings: Light and electron microscopy techniques were used to analyze CB1R distribution in the VMH of CB1R-WT, CB1R-KO and conditional mutant mice bearing a selective deletion of CB1R in cortical glutamatergic (Glu-CB1R-KO) or GABAergic neurons (GABA-CB1R-KO). At light microscopy, CB1R immunolabeling was observed in the VMH of CB1R-WT and Glu-CB1R-KO animals, being remarkably reduced in GABA-CB1R-KO mice. In the electron microscope, CB1R appeared in membranes of both glutamatergic and GABAergic terminals/preterminals. There was no significant difference in the percentage of CB1R immunopositive profiles and CB1R density in terminals making asymmetric or symmetric synapses in CB1R-WT mice. Furthermore, the proportion of CB1R immunopositive terminals/preterminals in CB1R-WT and Glu-CB1R-KO mice was reduced in GABA-CB1R-KO mutants. CB1R density was similar in all animal conditions. Finally, the percentage of CB1R labeled boutons making asymmetric synapses slightly decreased in Glu-CB1R-KO mutants relative to CB1R-WT mice, indicating that CB1R was distributed in cortical and subcortical excitatory synaptic terminals. Conclusions/Significance: Our anatomical results support the idea that the VMH is a relevant hub candidate in the endocannabinoid-mediated modulation of the excitatory and inhibitory neurotransmission of cortical and subcortical pathways regulating essential hypothalamic functions for the individual's survival such as the feeding behavior.

Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

The EC (entorhinal cortex) is fundamental for cognitive and mnesic functions. Thus damage to this area appears as a key element in the progression of AD (Alzheimer's disease), resulting in memory deficits arising from neuronal and synaptic alterations as well as glial malfunction. In this paper, we have performed an in-depth analysis of astroglial morphology in the EC by measuring the surface and volume of the GFAP (glial fibrillary acidic protein) profiles in a triple transgenic mouse model of AD [3xTg-AD (triple transgenic mice of AD)]. We found significant reduction in both the surface and volume of GFAP-labelled profiles in 3xTg-AD animals from very early ages (1 month) when compared with non-Tg (non-transgenic) controls (48 and 54%, reduction respectively), which was sustained for up to 12 months (33 and 45% reduction respectively). The appearance of Lambda beta (amyloid beta-peptide) depositions at 12 months of age did not trigger astroglial hypertrophy; nor did it result in the close association of astrocytes with senile plaques. Our results suggest that the AD progressive cognitive deterioration can be associated with an early reduction of astrocytic arborization and shrinkage of the astroglial domain, which may affect synaptic connectivity within the EC and between the EC and other brain regions. In addition, the EC seems to be particularly vulnerable to AD pathology because of the absence of evident astrogliosis in response to A beta accumulation. Thus we can consider that targeting astroglial atrophy may represent a therapeutic strategy which might slow down the progression of AD.

The interplay of localization and interactions in quantum many-body systems

Disorder and interactions both play crucial roles in quantum transport. Decades ago, Mott showed that electron-electron interactions can lead to insulating behavior in materials that conventional band theory predicts to be conducting. Soon thereafter, Anderson demonstrated that disorder can localize a quantum particle through the wave interference phenomenon of Anderson localization. Although interactions and disorder both separately induce insulating behavior, the interplay of these two ingredients is subtle and often leads to surprising behavior at the periphery of our current understanding. Modern experiments probe these phenomena in a variety of contexts (e.g. disordered superconductors, cold atoms, photonic waveguides, etc.); thus, theoretical and numerical advancements are urgently needed. In this thesis, we report progress on understanding two contexts in which the interplay of disorder and interactions is especially important.

The first is the so-called “dirty” or random boson problem. In the past decade, a strong-disorder renormalization group (SDRG) treatment by Altman, Kafri, Polkovnikov, and Refael has raised the possibility of a new unstable fixed point governing the superfluid-insulator transition in the one-dimensional dirty boson problem. This new critical behavior may take over from the weak-disorder criticality of Giamarchi and Schulz when disorder is sufficiently strong. We analytically determine the scaling of the superfluid susceptibility at the strong-disorder fixed point and connect our analysis to recent Monte Carlo simulations by Hrahsheh and Vojta. We then shift our attention to two dimensions and use a numerical implementation of the SDRG to locate the fixed point governing the superfluid-insulator transition there. We identify several universal properties of this transition, which are fully independent of the microscopic features of the disorder.

The second focus of this thesis is the interplay of localization and interactions in systems with high energy density (i.e., far from the usual low energy limit of condensed matter physics). Recent theoretical and numerical work indicates that localization can survive in this regime, provided that interactions are sufficiently weak. Stronger interactions can destroy localization, leading to a so-called many-body localization transition. This dynamical phase transition is relevant to questions of thermalization in isolated quantum systems: it separates a many-body localized phase, in which localization prevents transport and thermalization, from a conducting (“ergodic”) phase in which the usual assumptions of quantum statistical mechanics hold. Here, we present evidence that many-body localization also occurs in quasiperiodic systems that lack true disorder.

The head-body weight and head-body length relationship of Synodontis schall (Bloch and Schneider 1801) in Asa Lake, Ilorin, Nigeria

A total of 710 specimens of Synodontis schall were analyzed for the head body weight and head body length relationship. The head constituted 40% of the total body weight and 30% of the total body length. The mean head weight for male and female computed was 23.90g and 29.13g respectively. Head weight in both male and female was significantly different (P<0.01) while the head length for the combined sexes showed no significant difference (P>0.05). Fat accumulation in the body tissue was prominent in the females than males usually before the breeding season. The significance of the cephalo-nuchal shield in the bony head of Synodontis species compared with some other catfishes in the lake was also discussed

Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain

Background: An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Methods: Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Results: Each cytokine evaluated (Interferon-gamma (IFN-gamma), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-alpha and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-kappa B)p65 levels were not different between the groups. Interleukin-1beta (IL-1 beta) and IL-6 levels were beneath detection limits. Conclusions: The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.

Offshore Migratory Corridors and Aerial Photogrammetric Body Length Comparisons of Southbound Gray Whales, Eschrichtius robustus, in the Southern California Bight, 1988–1990

Through most of their annual migration, gray whales, Eschrichtius robustus, remain within 10 km of shore, but in the Southern California Bight many individuals migrate much farther from shore. This paper summarizes aerial survey and photogrammetric efforts to determine body lengths and temporal and spatial distributions of migratory gray whales in the southern portion of the Southern California Bight. Aerial surveys were flown along 13 east–west transects between lat. 32°35′N and 33°30′N during the southbound gray whale migratory seasons of 1988–90 in the Southern California Bight. Photogrammetry was used to obtain body length estimates of animals during some of the surveys. A total of 1,878 whales in 675 groups were sighted along 25,440 km of transect distance flown and 217 body lengths were measured. Using position and heading data, three major migratory pathways or corridors in the southern portion of the bight are defined. Those migrating offshore were split almost evenly between two corridors along the west sides of Santa Catalina and San Clemente Islands. These corridors converge on the mainland coast between San Diego and the United States–Mexico border. No whales larger than 11.5 m were photographed within 30 km of the mainland coast, suggesting that smaller, and presumably younger, whales use the coastal migratory corridor through the California Bight.