3d interaction homology: The structurally known rotamers of tyrosine derive from a surprisingly limited set of information‐rich hydropathic interaction environments described by maps

Sidechain rotamer libraries are obtained through exhaustive statistical analysis of existing crystallographic structures of proteins and have been applied in multiple aspects of structural biology, for example, crystallography of relatively low‐resolution structures, in homology model building and in biomolecular NMR. Little is known, however, about the driving forces that lead to the preference or suitability of one rotamer over another. Construction of 3D hydropathic interaction maps for nearly 30,000 tyrosines reveals the environment around each, in terms of hydrophobic (π–π stacking, etc.) and polar (hydrogen bonding, etc.) interactions. After partitioning the tyrosines into backbone‐dependent (?, ψ) bins, a map similarity metric based on the correlation coefficient was applied to each map‐map pair to build matrices suitable for clustering with k‐means. The first bin (?200° ≤ ? < –155°; ?205° ≤ ψ < –160°), representing 631 tyrosines, reduced to 14 unique hydropathic environments, with most diversity arising from favorable hydrophobic interactions with many different residue partner types. Polar interactions for tyrosine include surprisingly ubiquitous hydrogen bonding with the phenolic OH and a handful of unique environments surrounding the tyrosine backbone. The memberships of all but one of the 14 environments are dominated (>50%) by a single χ₁/χ₂ rotamer. The last environment has weak or no interactions with the tyrosine ring and its χ₁/χ₂ rotamer is indeterminate, which is consistent with it being composed of mostly surface residues. Each tyrosine residue attempts to fulfill its hydropathic valence and thus, structural water molecules are seen in a variety of roles throughout protein structure. Proteins 2015; 83:1118–1136. © 2015 Wiley Periodicals, Inc.     

Insect life history and the evolution of bacterial mutualism

Bacterial symbiosis has played a fundamental role in the evolution of eukaryotes. However, we still know little about how cooperative relationships with bacteria originate, and why they form in some host species but not others. Facultative symbionts that are beneficial, but not essential, provide unique insights into these processes. We use data from over a hundred aphid species to test if host life history is associated with the presence of facultative symbionts. We find that aphid species that have mutualistic associations with ants that protect them from natural enemies are less likely to carry symbionts that provide similar benefits. We also find one symbiont species occurs more frequently in unrelated aphid species that specialise on certain plant genera. In addition, aphid species that attack multiple plants often carry different symbiont complements. Our findings provide evidence of the ecological conditions that facilitate stable, mutually beneficial relationships between microbes and eukaryotic hosts.     

Current perspectives on biosimilars

In this work, an overview of the biosimilars market, pipeline and industry targets is discussed. Biosimilars typically have a shorter timeline for approval (8 years) compared to 12 years for innovator drugs and the development cost can be 10–20% of the innovator drug. The biosimilar pipeline is reviewed as well as the quality management system (QMS) that is needed to generate traceable, trackable data sets. One difference between developing a biosimilar compared to an originator is that a broader analytical foundation is required for biosimilars and advances made in developing analytical similarity to characterize these products are discussed. An example is presented on the decisions and considerations explored in the development of a biosimilar and includes identification of the best process parameters and methods based on cost, time, and titer. Finally factors to consider in the manufacture of a biosimilar and approaches used to achieve the target-directed development of a biosimilar are discussed.

     

Cost-Effectiveness of Coronary Artery Calcium Testing for Coronary Heart and Cardiovascular Disease Risk Prediction to Guide Statin Allocation: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background

The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated.

Objective

To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines.

Methods

We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC≥1 and CAC≥100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a “treat all” strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas.

Results

We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC≥1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC≥100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use.

Conclusion

Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients'' risks of CVD.     

Cued to Act on Impulse: More Impulsive Choice and Risky Decision Making by Women Susceptible to Overeating after Exposure to Food Stimuli

There is increasing evidence that individual differences in tendency to overeat relate to impulsivity, possibly by increasing reactivity to food-related cues in the environment. This study tested whether acute exposure to food cues enhanced impulsive and risky responses in women classified on tendency to overeat, indexed by scores on the three factor eating questionnaire disinhibition (TFEQ-D), restraint (TFEQ-R) and hunger scales. Ninety six healthy women completed two measures of impulsive responding (delayed discounting, DDT and a Go No-Go, GNG, task) and a measure of risky decision making (the balloon analogue risk task, BART) as well as questionnaire measures of impulsive behaviour either after looking at a series of pictures of food or visually matched controls. Impulsivity (DDT) and risk-taking (BART) were both positively associated with TFEQ-D scores, but in both cases this effect was exacerbated by prior exposure to food cues. No effects of restraint were found. TFEQ-D scores were also related to more commission errors on the GNG, while restrained women were slower on the GNG, but neither effect was modified by cue exposure. Overall these data suggest that exposure to food cues act to enhance general impulsive responding in women at risk of overeating and tentatively suggest an important interaction between tendency for impulsive decision making and food cues that may help explain a key underlying risk factor for overeating.     

Regional differences in WT-1 and Tcf21 expression during ventricular development: implications for myocardial compaction

Background

Morphological and functional differences of the right and left ventricle are apparent in the adult human heart. A differential contribution of cardiac fibroblasts and smooth muscle cells (populations of epicardium-derived cells) to each ventricle may account for part of the morphological-functional disparity. Here we studied the relation between epicardial derivatives and the development of compact ventricular myocardium.

Results

Wildtype and Wt1^CreERT2/+ reporter mice were used to study WT-1 expressing cells, and Tcf21^lacZ/+ reporter mice and PDGFRα^-/-;Tcf21^LacZ/+ mice to study the formation of the cardiac fibroblast population. After covering the heart, intramyocardial WT-1+ cells were first observed at the inner curvature, the right ventricular postero-lateral wall and left ventricular apical wall. Later, WT-1+ cells were present in the walls of both ventricles, but significantly more pronounced in the left ventricle. Tcf21-^LacZ + cells followed the same distribution pattern as WT-1+ cells but at later stages, indicating a timing difference between these cell populations. Within the right ventricle, WT-1+ and Tcf21-lacZ+ cell distribution was more pronounced in the posterior inlet part. A gradual increase in myocardial wall thickness was observed early in the left ventricle and at later stages in the right ventricle. PDGFRα^-/-;Tcf21^LacZ/+ mice showed deficient epicardium, diminished number of Tcf21-^LacZ + cells and reduced ventricular compaction.

Conclusions

During normal heart development, spatio-temporal differences in contribution of WT-1 and Tcf21-^LacZ + cells to right versus left ventricular myocardium occur parallel to myocardial thickening. These findings may relate to lateralized differences in ventricular (patho)morphology in humans.     

The dynamics of coupled populations subject to control

The dynamics of coupled populations have mostly been studied in the context of metapopulation viability with application to, for example, species at risk. However, when considering pests and pathogens, eradication, not persistence, is often the end goal. Humans may intervene to control nuisance populations, resulting in reciprocal interactions between the human and natural systems that can lead to unexpected dynamics. The incidence of these human-natural couplings has been increasing, hastening the need to better understand the emergent properties of such systems in order to predict and manage outbreaks of pests and pathogens. For example, the success of the growing aquaculture industry depends on our ability to manage pathogens and maintain a healthy environment for farmed and wild fish. We developed a model for the dynamics of connected populations subject to control, motivated by sea louse parasites that can disperse among salmon farms. The model includes exponential population growth with a forced decline when populations reach a threshold, representing control interventions. Coupling two populations with equal growth rates resulted in phase locking or synchrony in their dynamics. Populations with different growth rates had different periods of oscillation, leading to quasiperiodic dynamics when coupled. Adding small amounts of stochasticity destabilized quasiperiodic cycles to chaos, while stochasticity was damped for periodic or stable dynamics. Our analysis suggests that strict treatment thresholds, although well intended, can complicate parasite dynamics and hinder control efforts. Synchronizing populations via coordinated management among farms leads to more effective control that is required less frequently. Our model is simple and generally applicable to other systems where dispersal affects the management of pests and pathogens.     

Exome sequencing identifies a nonsense mutation in <Emphasis Type="Italic">Fam46a</Emphasis> associated with bone abnormalities in a new mouse model for skeletal dysplasia

We performed exome sequencing for mutation discovery of an ENU (N-ethyl-N-nitrosourea)-derived mouse model characterized by significant elevated plasma alkaline phosphatase (ALP) activities in female and male mutant mice, originally named BAP014 (bone screen alkaline phosphatase #14). We identified a novel loss-of-function mutation within the Fam46a (family with sequence similarity 46, member A) gene (NM_001160378.1:c.469G>T, NP_001153850.1:p.Glu157*). Heterozygous mice of this mouse line (renamed Fam46a ^E157*Mhda) had significantly high ALP activities and apparently no other differences in morphology compared to wild-type mice. In contrast, homozygous Fam46a ^E157*Mhda mice showed severe morphological and skeletal abnormalities including short stature along with limb, rib, pelvis, and skull deformities with minimal trabecular bone and reduced cortical bone thickness in long bones. ALP activities of homozygous mutants were almost two-fold higher than in heterozygous mice. Fam46a is weakly expressed in most adult and embryonic tissues with a strong expression in mineralized tissues as calvaria and femur. The FAM46A protein is computationally predicted as a new member of the superfamily of nucleotidyltransferase fold proteins, but little is known about its function. Fam46a ^E157*Mhda mice are the first mouse model for a mutation within the Fam46a gene.     

Timing of spring migration in birds: long-term trends, North Atlantic Oscillation and the significance of different migration routes

We studied long-term trends and the yearly variation in mean spring passage time in 36 passerine bird species trapped at Ottenby Bird Observatory in south-eastern Sweden. Between the years 1952–2002, data were available for 22–45 years depending on species. Most long-distance migrant species passed progressively earlier over the study period (range: 2.5 days earlier to 0.7 days later per 10 years, with an average of 0.9 days earlier per 10 years). The annual variation in timing of migration in most species, regardless of migration distance, correlated negatively with the winter index of the North Atlantic Oscillation (NAO), a large-scale climate phenomenon influencing the climate in the North Atlantic region. Birds passed earlier after mild and humid winters, corresponding to the high phase of the NAO. This corroborates the pattern found at a nearby migration site with a comparable dataset (Helgoland, 600 km WSW of Ottenby). However, short/medium-distance migrant species at Ottenby, in contrast to the situation at Helgoland, have shown no general trend of earlier passage in recent years. This was probably a consequence of the shorter study period at Ottenby, which included only the last 22–32 years (41 years at Helgoland), when the NAO showed no significant trend. At the species-specific level, the long-term trends in passage time were similar at the two sites, and there was some congruence to the extent that a given species was affected by NAO. Long-distance migrants wintering south and south-east of the breeding grounds showed some of the strongest changes in long-term trends (passing progressively earlier) at Ottenby, and for some of these species passage time varied negatively with NAO. Obviously, and contrary to previous suggestions, variations in NAO also influence birds migrating through eastern Europe, although the direct or indirect mechanisms through which this is achieved are unknown.