Domain size distributions can predict domain boundaries

MOTIVATION: The sizes of protein domains observed in the 3D-structure database follow a surprisingly narrow distribution. Structural domains are furthermore formed from a single-chain continuous segment in over 80% of instances. These observations imply that some choices of domain boundaries on an otherwise uncharacterized sequence are more likely than others, based solely on the size and segment number of predicted domains. This property might be used to guess the locations of protein domain boundaries. RESULTS: To test this possibility we enumerate putative domain boundaries and calculate their relative likelihood under a probability model that considers only the size and segment number of predicted domains. We ask, in a cross-validated test using sequences with known 3D structure, whether the most likely guesses agree with the observed domain structure. We find that domain boundary predictions are surprisingly successful for sequences up to 400 residues long and that guessing domain boundaries in this way can improve the sensitivity of threading analysis.     

Subject-specific finite element models can accurately predict strain levels in long bones

The prediction of the stress-state and fracture risk induced in bones by various loading conditions in individual patients using subject-specific finite element models still represents a challenge in orthopaedic biomechanics. The accuracy of the strain predictions reported in the literature is variable and generally not satisfactory. The aim of the present study was to evaluate if a proper choice of the density-elasticity relationship can lead to accurate strain predictions in the frame of an automatic subject-specific model generation strategy. To this aim, a combined numerical-experimental study was performed comparing finite element predicted strains with strain-gauges measurements obtained on eight cadaver proximal femurs, each instrumented with 15 rosettes mostly concentrated in the bone metaphyses, tested non-destructively in vitro under six different loading scenarios. Three different density-elasticity power relationships were selected from the literature and implemented in the finite element models derived from computed tomography data. The results of the present study confirm the great influence of the density-elasticity relationship used on the accuracy of numerical predictions. One of the tested constitutive laws provided a very good agreement (R(2)=0.91, RMSE lower than 10% of the maximum measured value) between numerical calculations and experimental measurements. The presented results show, in addition, that the adoption of a single density-elasticity relationship over the whole bone density range is adequate to obtain an accuracy that is already suitable for many applications.     

Primary productivity can affect mammalian body size frequency distributions

Frequency distributions of mammal body sizes in large‐scale assemblages have often been found to show a positive skew. In an attempt to explain this pattern, a model has been put forward which incorporates energetic constraints on fitness and thereby predicts optimal body sizes corresponding to the mode of the distribution. A key assumption of the model is that energy is unlimited. However, if energy is limited, the input of energy into a herbivorous mammal community should influence the shape of the frequency distribution. Thus, I propose that increases in primary productivity will decrease the variation of body size and increase the mean body size in a distribution. So, in low‐productivity environments we should see a predominance of small‐sized species, but with a great variation of body sizes due to limitations of resources (energy). I tested this hypothesis using the herbivorous mammal fauna (rodents, bats and marsupials) in seven biomes of Australia. Because herbivorous marsupials generally are fairly large‐bodied while rodents and bats are small‐sized and because marsupials also have a different mode of reproduction from placental mammals, the hypothesis was also tested on placental mammals and marsupials separately. There was no clear mode for the entire assemblage in any biome, but as primary productivity increased, the variation of body masses decreased and the mean body mass of the distribution increased. Body mass distributions of both placental mammals and marsupials displayed clear modes. Placental mammals also showed an increase in mean body mass. The variation in body mass of marsupials was highest for the intermediately productive biomes. Primary productivity does seem to have some effect on mammalian body mass in this case, but the results here need to be complemented with studies of other assemblages before any general conclusions can be drawn. It is also important to distinguish which taxa are affected in a heterogeneous assemblage like the Australian herbivorous mammal fauna.     

Cribriform plate of ethmoid, olfactory bulb and olfactory acuity in forty species of bats

Relationships between the cribriform plate of the ethmoid, the olfactory bulb, and olfactory acuity were explored using material from 13 of the 17 bat families. All megachiropteran cribriform plates were entirely perforated. In contrast, microchiropteran plates showed distinct perforated portions dorsally and nonperforated portions ventrally. The plates of frugivorous species had more foramina than those of insectivorous ones. Bats with mixed dietary habits were intermediate. Our data suggest that the Chilonycterinae were originally frugivorous, and have only secondarily reverted to an insectivorous diet. Trend analyses show that wherever dietary preference appears to favor a more acute sense of smell, bulb diameter tends to be larger. In general, frugivorous bats tend to have bulbs exceeding 2 mm in diameter; insectivorous bats tend to have bulb diameters of 2 mm or less. The number of foramina in the plates and total cribriform plate area tends to increase as a function of bulb area, but the plate area the foramina occupied increases as a function of bulb volume. The ratio of the size of the bulb to the size of the cerebral hemisphere does not predict olfactory acuity in bats.     

The number of functional olfactory receptor genes and the relative size of olfactory brain structures are poor predictors of olfactory discrimination performance with enantiomers

The ability of four squirrel monkeys and three pigtail macaques to distinguish between nine enantiomeric odor pairs sharing an isopropenyl group at the chiral center was investigated in terms of a conditioning paradigm. All animals from both species were able to discriminate between the optical isomers of limonene, carvone, dihydrocarvone, dihydrocarveole and dihydrocarvyl acetate, whereas they failed to distinguish between the (+)- and (-)-forms of perillaaldehyde and limonene oxide. The pigtail macaques, but not the squirrel monkeys, also discriminated between the antipodes of perillaalcohol and isopulegol. A comparison of the across-task patterns of discrimination performance shows a high degree of similarity among the two primate species and also between these nonhuman primates and human subjects tested in an earlier study on the same tasks. These findings suggest that between-species comparisons of the relative size of olfactory brain structures or of the number of functional olfactory receptor genes are poor predictors of olfactory discrimination performance with enantiomers.     

Scaling properties of cell and organelle size

How size is controlled is a fundamental question in biology. In this review, we discuss the use of scaling relationships-for example, power-laws of the form y∝x(α)-to provide a framework for comparison and interpretation of size measurements. Such analysis can illustrate the biological and physical principles underlying observed trends, as has been proposed for the allometric dependence of metabolic rate or limb structure on organism mass. Techniques for measuring size at smaller length-scales continue to improve, leading to more data on the control of size in cells and organelles. Size scaling of these structures is expected to influence growth patterns, functional capacity and intracellular transport. Furthermore, organelles such as the nucleus, mitochondria and endoplasmic reticulum show widely varying morphologies that affect their scaling properties. We provide brief summaries of these issues for individual organelles, and conclude with a discussion on how to apply this concept to better understand the mechanisms of size control in the cellular environment.     

The bioassay of mammalian olfactory signals

The bioassay of chemical signals in mammals presents a number of problems. Many of these difficulties are the result of the complexity of the behaviour which has to be analysed and of the odiferous output itself. Additionally, it is usual for the response to the odour to be affected by information from other sensory modalities, by experience and by the spatial and social context. This degree of variability and of flexibility which is characteristic of mammals also has the result that concepts such as ‘pheromone’, which were originally developed in simpler organisms, can be seriously misleading. Although valuable information can be gained by less direct methods, a bioassay is only likely to be successful in the identification of active substances if: 1. there is a clearly defined behavioural or physiological response to the odour, 2. the method of testing actually measures this response, 3. the situation used for testing is as close as possible to that in which the response naturally occurs, 4. in the case of a behavioural response, the recording technique is as detailed as possible so that ambiguous results are avoided, 5. an adequate test population is available to allow repeated testing, 6. considerable resources are available for chemical analysis. Although it is not easy to fulfil all of these requirements at one time, olfaction is of such importance in mammalian communication that the attempt to do so will always be valuable.     

Scaling of follicular sizes in mammalian ovaries

The scaling of ovarian follicle and oocyte sizes according to body weight ( M , ranging from 0005–500 kg) has been analysed using data obtained from 22 mammalian species in nine orders. The diameters of non-growing (primordial) follicles were correlated significantly with body weight, the relationship being described by the allometric formula y = 0028 M ^0.10. The mean size at which growing follicles began to accumulate extracellular fluid was approximately the same in all species, 0–3 mm diameter. Graafian follicle sizes varied allometrically with body weight as a result of differences in the volumes of follicular fluid rather than those of oocytes, which were relatively similar in eutherian mammals. The statistical significance of the correlation between Graafian and body sizes was increased when the dimensions for an ovulatory quota of follicles were combined because follicles in polyovulating species were disproportionately small. The total Graafian surface areas and volumes were then predicted from body weight by 58–4 M ^0.65 and 18–5 M ^1.06, respectively. Follicular dimensions in the three species of primates were significantly greater than predicted by the allometric relationship. The exponents of these relationships show that the total volume of a set of preovulatory follicles varies approximately isometrically with body weight and, therefore, with the presumptive hormone distribution volume ( M ^1.0). The hypoallometric relationship of follicular surface area demonstrates that, during the course of the evolution of body size, the surface area for secretion has not increased to match the dilution of hormones in the body pool.     

Baseline strength can influence the ability of salivary free testosterone to predict squat and sprinting performance

The objective of this study was to determine if salivary free testosterone can predict an athlete's performance during back squats and sprints over time and the influence baseline strength on this relationship. Ten weight-trained male athletes were divided into 2 groups based on their 1 repetition maximum (1RM) squats, good squatters (1RM > 2.0 × body weight, n = 5) and average squatters (1RM < 1.9 × body weight, n = 5). The good squatters were stronger than the average squatters (p < 0.05). Each subject was assessed for squat 1RM and 10-m sprint times on 10 separate occasions over a 40-day period. A saliva sample was collected before testing and assayed for free testosterone and cortisol. The pooled testosterone correlations were strong and significant in the good squatters (r = 0.92 for squats, r = -0.87 for sprints, p < 0.01), but not significant for the average squatters (r = 0.35 for squats, r = -0.18 for sprints). Cortisol showed no significant correlations with 1RM squat and 10-m sprint performance, and no differences were identified between the 2 squatting groups. In summary, these results suggest that free testosterone is a strong individual predictor of squat and sprinting performance in individuals with relatively high strength levels but a poor predictor in less strong individuals. This information can assist coaches, trainers, and performance scientists working with stronger weight-trained athletes, for example, the preworkout measurement of free testosterone could indicate likely training outcomes or a readiness to train at a certain intensity level, especially if real-time measurements are made. Our results also highlight the need to separate group and individual hormonal data during the repeated testing of athletes with variable strength levels.     

Ligand-selective activation of heterologously-expressed mammalian olfactory receptor

Mammalian olfactory receptors (ORs) appear to have the capacity to couple to multiple G protein-coupled signaling pathways in a ligand-dependent selective manner. To better understand the mechanisms and molecular range of such ligand selectivity, we expressed the mouse eugenol OR (mOR-EG) in HEK293T cells together with Gα15 to monitor activation of the phospholipase-C (PLC) signaling pathway and/or Gαolf to monitor activation of the adenylate cyclase (AC) signaling pathway, resulting in intracellular Ca²⁺ release and/or Ca²⁺ influx through a cyclic nucleotide-gated channel, respectively. PLC-dependent responses differed dynamically from AC-dependent responses, allowing them to be distinguished when Gα15 and Gαolf were co-expressed. The dynamic difference in readout was independent of the receptor, the heterologous expression system, and the ligand concentration. Of 17 reported mOR-EG ligands tested, including eugenol, its analogs, and structurally dissimilar compounds (mousse cristal, nootkatone, orivone), some equally activated both signaling pathways, some differentially activated both signaling pathways, and some had no noticeable effect even at 1–5 mM. Our findings argue that mOR-EG, when heterologously expressed, can couple to two different signaling pathways in a ligand selective manner. The challenge now is to determine the potential of mOR-EG, and perhaps other ORs, to activate multiple signaling pathways in a ligand selective manner in native ORNs.     

Modeling of mammalian olfactory receptors and docking of odorants

Olfactory receptors (ORs) belong to the superfamily of G protein-coupled receptors (GPCRs), the second largest class of genes after those related to immunity, and account for about 3 % of mammalian genomes. ORs are present in all multicellular organisms and represent more than half the GPCRs in mammalian species (e.g., the mouse OR repertoire contains >1,000 functional genes). ORs are mainly expressed in the olfactory epithelium where they detect odorant molecules, but they are also expressed in a number of other cells, such as sperm cells, although their functions in these cells remain mostly unknown. It has recently been reported that ORs are present in tumoral tissues where they are expressed at different levels than in healthy tissues. A specific OR is over-expressed in prostate cancer cells, and activation of this OR has been shown to inhibit the proliferation of these cells. Odorant stimulation of some of these receptors results in inhibition of cell proliferation. Even though their biological role has not yet been elucidated, these receptors might constitute new targets for diagnosis and therapeutics. It is important to understand the activation mechanism of these receptors at the molecular level, in particular to be able to predict which ligands are likely to activate a particular receptor (‘deorphanization’) or to design antagonists for a given receptor. In this review, we describe the in silico methodologies used to model the three-dimensional (3D) structure of ORs (in the more general framework of GPCR modeling) and to dock ligands into these 3D structures.     

Scaling of long bones in ruminants with respect to the scapula

The significance of the scapula for locomotion is becoming more and more established. Studies of locomotion in small and medium‐sized mammals show a considerable amplitude of the scapula and a large contribution to step length. Taking this into account, long bone studies of forelimb movement restricted to the ‘arm’ miss one important segment. A regression model (reduced major axis) was used for analysis of a sample of 77 species of ruminants. This sample was divided according to (1) phylogenetic relationships and (2) habitat. The proximal elements of the limbs, scapula and humerus in the anterior extremity, femur in the hindlimb, show a similar scaling in the different analyses. The changes to limb proportions in the different subsamples are caused by the variability of the distal segments. The anterior extremity scales with a higher coefficient than the hindlimb in all analyses. Concepts like elastic or geometric similarity are inadequate for long bone scaling when the full range of body size in the sample is used. Taking all analyses into account, the differences in limb proportions are due more to phylogenetic relationships than to habitat.     

Scaling effects in the fatigue strength of bones from different animals

The bones of vertebrates are all made from the same basic material, despite a huge variation in size from one species to another. This introduces a problem: large structures are more prone to fatigue failure (stress fracture) than smaller structures made of the same material. This implies that bones in larger animals cannot withstand as much stress in daily use as bones in smaller animals. In fact, this is not the case, because all bones experience approximately the same stresses and strains in use. This implies a variation in the underlying material: bone material in large animals must have superior fatigue properties to offset the disadvantages of size. This hypothesis is tested here by reference to fatigue data from the literature, taken from a range of animals from cows to mice. Fatigue strength was plotted as a function of stressed volume and modelled mathematically using a Weibull distribution. This shows a general tendency for fatigue strength to reduce as volume increases. But when the volume effect is taken into account, there remains a tendency for bones from smaller animals to have lower fatigue strength. This can be modelled by a simple variation in one of the parameters in the Weibull equation, which defines the intrinsic fatigue strength of the material. When extrapolated to the size of the whole bone for each animal, all bones were found to have the same fatigue strength. This resolves the anomaly and implies a complex system in which the underlying structure of bone varies with animal size in order to cancel out scaling effects.     

Impact of left and right nostril olfactory abilities on binasal olfactory performance

Four models were tested which from theoretical points of viewuse the combined inputs from each side of the nose to predictthe binasal olfactory ability. The best predictor was the modelwhich states that input from the better side accounts for thebinasal ability.     

Scaling of postcranial joint size in hominoid primates

The scaling of sixteen articular dimensions in the locomotor skeleton of hominoid primates is examined with special reference to a recently proposed model of geometric similarity. Seven species are included in the analysis (gorillas, common chimpanzees, bonobos, orang-utans, siamang, lar gibbons, and modern humans of European descent); all specimens are adult individuals of known body mass (N=87). No significant sexual dimorphism in the scaling of joint size was observed. Overal results are compatible with the biomechanical model predictions of isometry, and lend additional support to the suggestion that joint stresses are of the same order of magnitude in animals differing vastly in body size and locomotor adaptations. The hindlimb and lumbosacral joints of humans, however, are consistently much larger than expected for their body mass. Full-time bipedality obviously precludes the sharing of weight support and propulsion with the forelimbs, and this fundamental difference is accurately reflected in the relative joint size of humans.