Thinking Evolutionarily About Obesity

Obesity, diabetes, and metabolic syndrome are growing worldwide health concerns, yet their causes are not fully understood. Research into the etiology of the obesity epidemic is highly influenced by our understanding of the evolutionary roots of metabolic control. For half a century, the thrifty gene hypothesis, which argues that obesity is an evolutionary adaptation for surviving periods of famine, has dominated the thinking on this topic. Obesity researchers are often not aware that there is, in fact, limited evidence to support the thrifty gene hypothesis and that alternative hypotheses have been suggested. This review presents evidence for and against the thrifty gene hypothesis and introduces readers to additional hypotheses for the evolutionary origins of the obesity epidemic. Because these alternate hypotheses imply significantly different strategies for research and clinical management of obesity, their consideration is critical to halting the spread of this epidemic.     

Concanavalin A distorts the beta-GlcNAc-(1-->2)-Man linkage of beta- GlcNAc-(1-->2)-alpha-Man-(1-->3)-[beta-GlcNAc-(1-->2)-alpha-Man- (1-- >6)]-Man upon binding

Carbohydrate recognition by proteins is a key event in many biological processes. Concanavalin A is known to specifically recognize the pentasaccharide core (beta-GlcNAc-(1-->2)-alpha- Man-(1-->3)-[beta- GlcNAc-(1-->2)-alpha-Man-(1-->6)]-Man) of N-linked oligosaccharides with a Ka of 1.41 x 10(6 )M-1. We have determined the structure of concanavalin A bound to beta-GlcNAc-(1-->2)-alpha-Man-(1-->3)-[beta- GlcNAc-(1-->2)-alpha-Man- (1-->6)]-Man to 2.7A. In six of eight subunits there is clear density for all five sugar residues and a well ordered binding site. The pentasaccharide adopts the same conformation in all eight subunits. The binding site is a continuous extended cleft on the surface of the protein. Van der Waals interactions and hydrogen bonds anchor the carbohydrate to the protein. Both GlcNAc residues contact the protein. The GlcNAc on the 1-->6 arm of the pentasaccharide makes particularly extensive contacts and including two hydrogen bonds. The binding site of the 1-->3 arm GlcNAc is much less extensive. Oligosaccharide recognition by Con A occurs through specific protein carbohydrate interactions and does not require recruitment of adventitious water molecules. The beta-GlcNAc-(1-->2)-Man glycosidic linkage PSI torsion angle on the 1-->6 arm is rotated by over 50 degrees from that observed in solution. This rotation is coupled to disruption of interactions at the monosaccharide site. We suggest destabilization of the monosaccharide site and the conformational strain reduces the free energy liberated by additional interactions at the 1-->6 arm GlcNAc site.      

Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay

The activity and levels of the metazoan HIF (hypoxia-inducible factor) are regulated by its hydroxylation, catalysed by 2OG (2-oxoglutarate)- and Fe(II)-dependent dioxygenases. An oxygen consumption assay was developed and used to study the relationship between HIF hydroxylase activity and oxygen concentration for recombinant forms of two human HIF hydroxylases, PHD2 (prolyl hydroxylase domain-containing protein 2) and FIH (factor inhibiting HIF), and compared with two other 2OG-dependent dioxygenases. Although there are caveats on the absolute values, the apparent K(m) (oxygen) values for PHD2 and FIH were within the range observed for other 2OG oxygenases. Recombinant protein substrates were found to have lower apparent K(m) (oxygen) values compared with shorter synthetic peptides of HIF. The analyses also suggest that human PHD2 is selective for fragments of the C-terminal over the N-terminal oxygen-dependent degradation domain of HIF-1alpha. The present results, albeit obtained under non-physiological conditions, imply that the apparent K(m) (oxygen) values of the HIF hydroxylases enable them to act as oxygen sensors providing their in vivo capacity is appropriately matched to a hydroxylation-sensitive signalling pathway.     

Adenosine analogs bearing phosphate isosteres as human MDO1 ligands

The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5′-oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations.     

C1 Domain-targeted isophthalate derivatives induce cell elongation and cell cycle arrest in HeLa cells

Diacylglycerol (DAG)-mediated signaling pathways, such as those mediated by protein kinase C (PKC), are central in regulating cell proliferation and apoptosis. DAG-responsive C1 domains are therefore considered attractive drug targets. Our group has designed a novel class of compounds targeted to the DAG binding site within the C1 domain of PKC. We have previously shown that these 5-(hydroxymethyl)isophthalates modulate PKC activation in living cells. In this study we investigated their effects on HeLa human cervical cancer cell viability and proliferation by using standard cytotoxicity tests and an automated imaging platform with machine vision technology. Cellular effects and their mechanisms were further characterized with the most potent compound, HMI-1a3. Isophthalate derivatives with high affinity to the PKC C1 domain exhibited antiproliferative and non-necrotic cytotoxic effects on HeLa cells. The anti-proliferative effect was irreversible and accompanied by cell elongation. HMI-1a3 induced down-regulation of retinoblastoma protein and cyclins A, B1, D1, and E. Effects of isophthalates on cell morphology, cell proliferation and expression of cell cycle-related proteins were different from those induced by phorbol 12-myristate-13-acetate (PMA) or bryostatin 1, but correlated closely to binding affinities. Therefore, the results strongly indicate that the effect is C1 domain-mediated.     

Tobacco Stained Fingers and Its Association with Death and Hospital Admission: A Retrospective Cohort Study

Background

Among smokers, the presence of tobacco stains on fingers has recently been associated with a high prevalence of tobacco related conditions and alcohol abuse.

Objective

we aimed to explore tobacco stains as a marker of death and hospital readmission.

Method

Seventy-three smokers presenting tobacco-tar staining on their fingers and 70 control smokers were followed during a median of 5.5 years in a retrospective cohort study. We used the Kaplan-Meier survival analysis and the log-rank test to compare mortality and hospital readmission rates among smokers with and smokers without tobacco stains. Multivariable Cox models were used to adjust for confounding factors: age, gender, pack-year unit smoked, cancer, harmful alcohol use and diabetes. The number of hospital admissions was compared through a negative binomial regression and adjusted for the follow-up time, diabetes, and alcohol use.

Results

Forty-three patients with tobacco-stained fingers died compared to 26 control smokers (HR 1.6; 95%CI: 1.0 to 2.7; p 0.048). The association was not statistically significant after adjustment. Patients with tobacco-stained fingers needed a readmission earlier than smokers without stains (HR 2.1; 95%CI: 1.4 to 3.1; p<0.001), and more often (incidence rate ratio (IRR) 1.6; 95%CI: 1.1 to 2.1). Associations between stains and the first hospital readmission (HR 1.6; 95%CI: 1.0 to 2.5), and number of readmissions (IRR 1.5; 95%CI: 1.1 to 2.1) persisted after adjustment for confounding factors.

Conclusions

Compared to other smokers, those presenting tobacco-stained fingers have a high unadjusted mortality rate and need early and frequent hospital readmission even when controlling for confounders.     

Design and applicability of DNA arrays and DNA barcodes in biodiversity monitoring

Background  

The rapid and accurate identification of species is a critical component of large-scale biodiversity monitoring programs. DNA arrays (micro and macro) and DNA barcodes are two molecular approaches that have recently garnered much attention. Here, we compare these two platforms for identification of an important group, the mammals.     

Interaction between Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in Asthma

Retinoid acid receptor-related Orphan Receptor Alpha (RORA) was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs) in the vicinity of the asthma-associated SNP (rs11071559) and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1), has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children) and the European cross-sectional PARSIFAL study (1120 children). Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C) was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36–2.93, p = 0.0003 in BAMSE; and 1.61, 1.18–2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively), and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility.     

Tono Reservoir fishery contribution to poverty reduction among fishers in northern Ghana

Fishery characteristics and livelihood status of fishers at Tono Reservoir, Ghana, were investigated between January 2015 and June 2016. Data on fisher demography, fishing gears, fishing methods, perceptions of the state of fish stocks, management practices, income and consumption of fishers were obtained through structured interviews. Censuses of fishers and fishing gears were conducted through direct observation and counts. The population of fishers was 950 and the majority (74%) of the sampled respondents fell within the ages of 24–41 years. Gillnet, cast net, trap and hook and line were the four main gears utilised. Illegal methods of fishing observed included the use of mosquito nets (nets with mesh <1.0 cm) and the use of brewer’s waste (pito mash) as bait. Brycinus nurse, Synodontis spp., Parailia spiniserrata and Chrysichthys spp. were perceived to have disappeared from the reservoir. The fishers were unaware of the existence of any fisheries regulations, hence there was no adherence to management practices. Their daily income was derived mainly from fishing. The incidence of poverty among fishers was low (8%). The Tono Reservoir has a great potential for supporting livelihood if it is properly managed.