Linkage and Genome‐wide Association Analysis of Obesity‐related Phenotypes: Association of Weight With the MGAT1 Gene

As major risk‐factors for diabetes and cardiovascular diseases, the genetic contribution to obesity‐related traits has been of interest for decades. Recently, a limited number of common genetic variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome‐wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome‐wide level (nominal P < 1.6 × 10^?7, Bonferroni‐adjusted P < 0.05) one single‐nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 × 10^?8) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women.     

Novel wheel running blocks the preovulatory luteinizing hormone surge and advances the hamster circadian pacemaker

In rodents, the preovulatory luteinizing hormone (LH) surge is timed by a circadian rhythm. We recently reported that a phenobarbital-induced delay of the estrous cycle in Syrian hamsters is associated with an approximately 2-h phase advance in both the circadian locomotor activity rhythm and the timing of the LH surge. The following study tests the hypothesis that a >2-h nonpharmacological phase advance in the circadian pacemaker that delays the estrous cycle by a day will also phase advance the LH surge by approximately 2 h. Activity rhythms were continuously monitored in regularly cycling hamsters using running wheels or infrared detectors for about 10 days prior to jugular cannulation. The next day, on proestrus, hamsters were transferred to the laboratory for 1 of 3 treatments: transfer to a "new cage" (and wheel) from zeitgeber time (ZT) 4 to 8 (with ZT12 defined as time of lights-off), or exposure to a "novel wheel" at ZT5 or ZT1. All animals were then placed in constant dark (DD). Blood samples were obtained just before onset of DD and hourly for the next 6 h, on that day and the next day for determination of plasma LH concentrations. Running activity was monitored in DD for about 10 more days. Transfer to a novel wheel at either ZT5 or ZT1 delayed the LH surge to day 2 in most hamsters, whereas exposure to a new cage did not. Only the delayed LH surges were phase advanced at least 2.5 h on average in all 3 groups. However, wheel-running activity was similarly phase advanced in all 3 groups regardless of the timing of the LH surge; thus, the phase advances in circadian activity rhythms were not associated with the 1-day delay of the LH surge. Interestingly, the number of wheel revolutions was closely associated with the 1-day delay of LH surges following exposure to a novel wheel at either ZT1 or ZT5. These results suggest that the intensity of wheel running (or an associated stimulus) plays an important role in the circadian timing mechanism for the LH surge.     

Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity

We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.     

SPR-MS in functional proteomics

The mapping of protein networks and the establishment of thefunctional relationships between expressed proteins and theireffects on cellular processes represents a great challenge forfunctional or interaction proteomics. The combination of surfaceplasmon resonance (SPR)-based technology with mass spectrometry(MS) has created a unique analytical tool for functional proteomicsinvestigations. Proteins are affinity purified, quantified andcharacterised in terms of their interactions, while the massspectrometer identifies and structurally characterises the biomolecules.Recent developments have led to a closer integration of thesekey technologies, providing a combined approach which enablesidentification of proteins selected on the basis of their functionalbinding criteria. In addition to a historical overview of thisfield, some recent detailed examples of combined SPR-MS approacheswill be reviewed in a number of key application areas, includingligand fishing, peptide sequence and post-translational modificationanalysis by SPR-MS/MS and enzyme inhibitor screening.      

A multi-scale biogeographical analysis of Bambusa arnhemica, a bamboo from monsoonal northern Australia

Aims To identify the edaphic, environmental and historical factors influencing the patchy distribution of the semelparous bamboo Bambusa arnhemica F. Muell. at global, catchment and streambank scales. Location The entire range of B. arnhemica, a highly fire‐prone savanna matrix with generally infertile soils in the north‐west of the Northern Territory of Australia above the 1200 mm mean annual rainfall isohyet. Methods Distribution surveys were conducted by air, boat and on the ground. Plot data were collected throughout the range of the species. Results Bambusa arnhemica occurred predominantly in gallery forests on flood‐prone but nevertheless well‐drained and deep alluvial soils on sloping stream banks. It ranged widely along lentic watercourses from ephemeral headwater streams to the banks of major rivers and levees on the coastal floodplain. The species did not occur in savannas; savannas adjacent to B. arnhemica gallery forests were also flood‐prone and on deep alluvial soils, but were upslope on level ground. Bambusa arnhemica's infrequent non‐riparian occurrences were on a wide variety of substrates but generally on soils of moderate fertility and in coastal and/or rocky areas where at least partial topographic protection from fire is likely. Within and between catchments, the distribution of B. arnhemica was idiosyncratic, occurrence being almost always continuous downstream from highly variable ‘starting’ points to the poorly drained coastal floodplain. Main conclusions At local scales, B. arnhemica appears constrained by poor drainage and high fire‐frequencies. Enhanced soil fertility may increase its capacity to cope with fire. At the catchment and global scales, we propose that the distribution of B. arnhemica is the product of infrequent and as yet incomplete dispersal across and away from watercourses by seed that lacks specialized dispersal mechanisms, combined with passive dispersal along streams. From this we infer that B. arnhemica is neither a very recent, nor very ancient colonist from Asia. Bambusa arnhemica's circumscribed global distribution has no parallel amongst co‐occurring rain forest plants and may be the product of poor dispersal capacity and a substantial rock and floodplain barrier to the east. Limited dispersal capacity may be inextricably linked to local domination of space and the subsequent creation of regeneration space by parental death.     

Champion and Noteworthy Trees

Summary.  The University Botanic Garden, Cambridge boasts one of the finest tree collections in eastern England; an up‐to‐date account of noteworthy and champion trees in the Garden is provided, based in part on previous accounts dating from 1915 and 1984. The history and attributes of some of the finest specimens are given.     

Determinants of intra-annual population dynamics in a tropical soil arthropod

Studies on inter-annual dynamics of populations from temperate regions have shown that density dependence and climate effects are relatively common, albeit weak. Yet, for short-lived organisms, intra-annual variation may be at least as important. Furthermore, tropical species commonly experience temperatures close to their upper thermal limit and thus may be more likely to experience heat stress. Here, we used the soil mite Rostrozetes ovulum to investigate the drivers of intra-annual population dynamics in an Amazonian rain forest. We sampled 3,600 soil cores from 20 transects during 13 months, obtaining 180 mite counts. Next, we built a dynamic N-mixture model accounting for different detection probabilities between soil types. In a Bayesian framework, we used this model to estimate (a) the strength of density dependence and (b) per capita growth rates, which were then tested against environmental variables. We found that the intra-annual population dynamics of R. ovulum were weakly density dependent. Further, per capita growth rates increased with resource supply (litterfall) and decreased with maximum temperature over much of the observed thermal range, although these effects explained relatively little variance. Yet, the seasonal correlation between these factors created a trade-off, so that realized population growth was highest when neither resource supply nor thermal suitability was optimal. Overall, our results suggest that the mechanisms shaping soil animal population dynamics may be surprisingly similar across latitudes. Our model offers a starting point for analyses of soil animal counts when extraction from soil samples is imperfect.     

Spectroscopic characterization,DFT studies,molecular docking and cytotoxic evaluation of 4‐nitro‐indole‐3‐carboxaldehyde: A potent lung cancer agent

The 4‐nitro‐1H‐indole‐carboxaldehyde (NICA) molecule was characterized experimentally using FT‐IR, FT‐Raman and UV‐Vis spectra, and it was studied theoretically using DFT calculations. The optimized structure of the NICA molecule was determined by DFT calculations using B3LYP functional with cc‐pVTZ basis set. The electron localization function (ELF) and local orbital localizer (LOL) studies were performed to visualize the electron delocalization in the molecule. The experimental and theoretical wavenumbers of the title molecule were assigned using VEDA 4.0 program. The charge delocalization and stability of the title molecule were investigated using natural bond orbital (NBO) analysis. Frontier molecular orbitals (FMOs) and related molecular properties were calculated. UV‐Vis spectrum was calculated theoretically and validated experimentally. The reactive sites of the molecule were studied from the MEP surface and Fukui function analysis. The molecular docking analysis reveals that the NICA ligand shows better inhibitory activity against RAS, which causes lung cancer. The in vitro cytotoxic activity of the molecule against human lung cancer cell lines (A549) was determined by MTT assay. Thus, the NICA molecule can be used as a potential candidate for the development of the drug against lung cancer.     

Reduced Incidence of Cardiac Arrhythmias in Walkers and Runners

Purpose

Walking is purported to reduce the risk of atrial fibrillation by 48%, whereas jogging is purported to increase its risk by 53%, suggesting a strong anti-arrhythmic benefit of walking over running. The purpose of these analyses is to compare incident self-reported physician-diagnosed cardiac arrhythmia to baseline energy expenditure (metabolic equivalent hours per day, METhr/d) from walking, running and other exercise.

Methods

Proportional hazards analysis of 14,734 walkers and 32,073 runners.

Results

There were 1,060 incident cardiac arrhythmias (412 walkers, 648 runners) during 6.2 years of follow-up. The risk for incident cardiac arrhythmias declined 4.4% per baseline METhr/d walked by the walkers, or running in the runners (P = 0.0001). Specifically, the risk declined 14.2% (hazard ratio: 0.858) for 1.8 to 3.6 METhr/d, 26.5% for 3.6 to 5.4 METhr/d, and 31.7% for ≥5.4 METhr/d, relative to <1.8 METhr/d. The risk reduction per METhr/d was significantly greater for walking than running (P<0.01), but only because walkers were at 34% greater risk than runners who fell below contemporary physical activity guideline recommendations; otherwise the walkers and runners had similar risks for cardiac arrhythmias. Cardiac arrhythmias were unrelated to walking and running intensity, and unrelated to marathon participation and performance.

Conclusions

The risk for cardiac arrhythmias was similar in walkers and runners who expended comparable METhr/d during structured exercise. We found no significant risk increase for self-reported cardiac arrhythmias associated with running distance, exercise intensity, or marathon participation. Rhythm abnormalities were based on self-report, precluding definitive categorization of the nature of the rhythm disturbance. However, even if the runners’ arrhythmias include sinus bradycardia due to running itself, there was no increase in arrhythmias with greater running distance.