Performance comparison of two-point linkage methods using microsatellite markers flanking known disease locations

The Genetic Analysis Workshop 14 simulated data presents an interesting, challenging, and plausible example of a complex disease interaction in a dataset. This paper summarizes the ease of detection for each of the simulated Kofendrerd Personality Disorder (KPD) genes across all of the replicates for five standard linkage statistics. Using the KPD affection status, we have analyzed the microsatellite markers flanking each of the disease genes, plus an additional 2 markers that were not linked to any of the disease loci. All markers were analyzed using the following two-point linkage methods: 1) a MMLS, which is a standard admixture LOD score maximized over theta, alpha, and mode of inheritance, 2) a MLS calculated by GENEHUNTER, 3) the Kong and Cox LOD score as computed by MERLIN, 4) a MOD score (standard heterogeneity LOD maximized over theta, alpha, and a grid of genetic model parameters), and 5) the PPL, a Bayesian statistic that directly measures the strength of evidence for linkage to a marker. All of the major loci (D1-D4) were detectable with varying probabilities in the different populations. However, the modifier genes (D5 and D6) were difficult to detect, with similar distributions under the null and alternative across populations and statistics. The pooling of the four datasets in each replicate (n = 350 pedigrees) greatly improved the chance of detecting the major genes using all five methods, but failed to increase the chance to detect D5 and D6.     

A new intrinsic thermal parameter for enzymes reveals true temperature optima

Two established thermal properties of enzymes are the Arrhenius activation energy and thermal stability. Arising from anomalies found in the variation of enzyme activity with temperature, a comparison has been made of experimental data for the activity and stability properties of five different enzymes with theoretical models. The results provide evidence for a new and fundamental third thermal parameter of enzymes, T(eq), arising from a subsecond timescale-reversible temperature-dependent equilibrium between the active enzyme and an inactive (or less active) form. Thus, at temperatures above its optimum, the decrease in enzyme activity arising from the temperature-dependent shift in this equilibrium is up to two orders of magnitude greater than what occurs through thermal denaturation. This parameter has important implications for our understanding of the connection between catalytic activity and thermostability and of the effect of temperature on enzyme reactions within the cell. Unlike the Arrhenius activation energy, which is unaffected by the source ("evolved") temperature of the enzyme, and enzyme stability, which is not necessarily related to activity, T(eq) is central to the physiological adaptation of an enzyme to its environmental temperature and links the molecular, physiological, and environmental aspects of the adaptation of life to temperature in a way that has not been described previously. We may therefore expect the effect of evolution on T(eq) with respect to enzyme temperature/activity effects to be more important than on thermal stability. T(eq) is also an important parameter to consider when engineering enzymes to modify their thermal properties by both rational design and by directed enzyme evolution.     

A homolog of Albino3/OxaI is essential for thylakoid biogenesis in the cyanobacterium Synechocystis sp. PCC6803

YidC/OxaI play essential roles in the insertion of a wide range of membrane proteins in Eschericha coli and mitochondria, respectively. In contrast, the chloroplast thylakoid homolog Albino3 (Alb3) facilitates the insertion of only a specialized subset of proteins, and the vast majority insert into thylakoids by a pathway that is so far unique to chloroplasts. In this study, we have analyzed the role of Alb3 in the cyanobacterium Synechocystis sp. PCC6803, which contains internal thylakoids that are similar in some respects to those of chloroplasts. The single alb3 gene (slr1471) was disrupted by the introduction of an antibiotic cassette, and photoautotrophic growth resulted in the generation of a merodiploid species (but not full segregation), indicating an essential role for Alb3 in maintaining the photosynthetic apparatus. Thylakoid organization is lost under these conditions, and the levels of photosynthetic pigments fall to approximately 40% of wild-type levels. Photosynthetic electron transport and oxygen evolution are reduced by a similar extent. Growth on glucose relieves the selective pressure to maintain photosynthetic competence, and under these conditions, the cells become completely bleached, again indicating that Alb3 is essential for thylakoid biogenesis. Full segregation could not be achieved under any growth regime, strongly suggesting that the slr1471 open reading frame is essential for cell viability.     

Oncostatin M suppresses EGF-mediated protein tyrosine phosphorylation in breast cancer cells

The effect of oncostatin M (OM) on epidermal growth factor (EGF)-mediated protein tyrosine phosphorylation in an infiltrating ductal breast carcinoma cell line, H3922, was investigated by Western blot analysis. Pretreatment of H3922 cells with OM for 72 h suppressed EGF-stimulated protein tyrosine phosphorylation signals by 77%. Interestingly, pretreatment with OM for 6 or 48 h had little effect on these signals. EGF-mediated tyrosine phosphorylation of EGF receptor (EGFR) was suppressed by 55% in 72-h OM pretreated H3922 cells. No reduction in EGFR protein expression was detected in these cells. Flow cytometric analysis verified that OM does not suppress EGFR expression. The effect of OM could not be attributed to induction of protein tyrosine phosphatases. An H3922 subclone cell line, designated H3922-8, was found to exhibit no proliferative response to treatment with EGF. However, EGF-mediated protein tyrosine phosphorylation was detected in these cells. Radioligand EGF binding studies comparing H3922 to H3922-8 cells indicated that the clonal cells apparently lack high affinity EGF receptors. The mechanism by which OM suppresses EGF-mediated tyrosine phosphorylation has not been completely characterized. However, the suppressive effect occurs regardless of whether the cells are acutely responsive (H3922) or virtually unresponsive (H3922-8) to EGF stimulation of cell growth.     

Linear enamel hypoplasia as an indicator of physiological stress in great apes: reviewing the evidence in light of enamel growth variation

Physiological stress, such as malnutrition or illness, can disrupt normal enamel growth, resulting in linear enamel hypoplasias (LEHs). Although ecological factors may contribute to LEH expression, other factors, such as surface abrasion and enamel growth variables, are also likely to be involved. Attention to these other factors is necessary before we can begin to understand what LEH might signify in terms of ecological sources of physiological stress in non-human primates. This study focuses on assessing the contribution of these other factors to variation in LEH expression within and across great ape taxa. Here, we present LEH data from unabraded crown regions in samples of seven great ape species. We analyze these data with respect to lateral enamel formation time and the angles that striae of Retzius make with the enamel surface, as these variables are expected to affect variation in LEH expression. We find that although the duration of enamel formation is associated with sex differences in LEH expression, it is not clearly related to taxonomic variation in LEH expression, and does not explain the low frequency of LEH in mountain gorillas found in this and a previous study. Our data on striae of Retzius angles suggest that these influence LEH expression along the tooth crown and may contribute to the consistently high frequencies of LEH seen in Pongo in this and previous studies. We suggest that future work aimed at understanding species variation in these angles is crucial to evaluating taxonomic patterns of LEH expression in great apes.     

Legumes mitigate ecological consequences of a topographic gradient in a northern Mongolian steppe

Topography should create spatial variation in water and nutrients and play an especially important role in the ecology of water-limited systems. We use stable isotopes to discern how plants respond both to ecological gradients associated with elevation and to neighboring legumes on a south-facing slope in the semi-arid, historically grazed steppe of northern Mongolia. Out of three target species, Potentilla acaulis, Potentilla sericea, and Festuca lenensis, when >30 cm from a legume, all showed a decrease in leaf δ¹⁵N with increasing elevation. This, together with measures of soil δ¹⁵N, suggests greater N processing at the moister, more productive, lower elevation, and more N fixation at the upper elevation, where cover of legumes and lichens and plant-available nitrate were greater. Total soil N was greater at the lower elevation, but not lichen biomass or root colonization by AMF. Leaf δ¹³C values for P. acaulis and F. lenensis are consistent with increasing water stress with elevation; δ¹³C values indicated the greatest intrinsic water use efficiency for P. sericea, which is more abundant at the upper elevation. Nearby legumes (<10 cm) moderate the effect of elevation on leaf δ¹⁵N, confirming legumes’ meaningful input of N, and affect leaf δ¹³C for two species, suggesting an influence on the efficiency of carbon fixation. Variation in leaf %N and %C as a function of elevation and proximity to a legume differs among species. Apparently, most N input is at upper elevations, pointing to the possible importance of grazers, in addition to hydrological processes, as transporters of N throughout this landscape.     

When correlation implies causation in multisensory integration

Inferring which signals have a common underlying cause, and hence should be integrated, represents a primary challenge for a perceptual system dealing with multiple sensory inputs [1-3]. This challenge is often referred to as the correspondence problem or causal inference. Previous research has demonstrated that spatiotemporal cues, along with prior knowledge, are exploited by the human brain to solve this problem [4-9]. Here we explore the role of correlation between the fine temporal structure of auditory and visual signals in causal inference. Specifically, we investigated whether correlated signals are inferred to originate from the same distal event and hence are integrated optimally [10]. In a localization task with visual, auditory, and combined audiovisual targets, the improvement in precision for combined relative to unimodal targets was statistically optimal only when audiovisual signals were correlated. This result demonstrates that humans use the similarity in the temporal structure of multisensory signals to solve the correspondence problem, hence inferring causation from correlation.     

Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model

Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications.     

Spatio-temporal updating in the left posterior parietal cortex

Adopting an unusual posture can sometimes give rise to paradoxical experiences. For example, the subjective ordering of successive unseen tactile stimuli delivered to the two arms can be affected when people cross them. A growing body of evidence now highlights the role played by the parietal cortex in spatio-temporal information processing when sensory stimuli are delivered to the body or when actions are executed; however, little is known about the neural basis of such paradoxical feelings resulting from such unusual limb positions. Here, we demonstrate increased fMRI activation in the left posterior parietal cortex when human participants adopted a crossed hands posture with their eyes closed. Furthermore, by assessing tactile temporal order judgments (TOJs) in the same individuals, we observed a positive association between activity in this area and the degree of reversal in TOJs resulting from crossing arms. The strongest positive association was observed in the left intraparietal sulcus. This result implies that the left posterior parietal cortex may be critically involved in monitoring limb position and in spatio-temporal binding when serial events are delivered to the limbs.