Positive selection in glycolysis among Australasian stick insects

Background: The glycolytic pathway is central to cellular energy production. Selection on individual enzymes within glycolysis, particularly phosphoglucose isomerase (Pgi), has been associated with metabolic performance in numerous organisms. Nonetheless, how whole energy-producing pathways evolve to allow organisms to thrive in different environments and adopt new lifestyles remains little explored. The Lanceocercata radiation of Australasian stick insects includes transitions from tropical to temperate climates, lowland to alpine habitats, and winged to wingless forms. This permits a broad investigation to determine which steps within glycolysis and what sites within enzymes are the targets of positive selection. To address these questions we obtained transcript sequences from seven core glycolysis enzymes, including two Pgi paralogues, from 29 Lanceocercata species. Results: Using maximum likelihood methods a signature of positive selection was inferred in two core glycolysis enzymes. Pgi and Glyceraldehyde 3-phosphate dehydrogenase (Gaphd) genes both encode enzymes linking glycolysis to the pentose phosphate pathway. Positive selection among Pgi paralogues and orthologues predominately targets amino acids with residues exposed to the protein’s surface, where changes in physical properties may alter enzyme performance. Conclusion: Our results suggest that, for Lancerocercata stick insects, adaptation to new stressful lifestyles requires a balance between maintaining cellular energy production, efficiently exploiting different energy storage pools and compensating for stress-induced oxidative damag

SapB and the rodlins are required for development of Streptomyces coelicolor in high osmolarity media

Streptomyces coelicolor produces spore-forming aerial hyphae after a period of vegetative growth. These aerial structures are decorated with a hydrophobic coating of rodlets consisting of chaplins and rodlins. Here, we show that rodlins and the surface-active peptide SapB are essential for development during growth in a medium with high osmolarity. To this end, both vegetative and aerial hyphae secrete SapB, whereas rodlins are only secreted by the spore-forming aerial hyphae.

The effect of tibial slope on the biomechanics of cruciate-retaining total knee arthroplasty:A musculoskeletal simulation study

Introduction/Aim: More posterior tibial slope (PTS) can prevent flexion gap tightness in cruciate-retaining Total Knee Arthroplasty (TKA) and help achieving better knee function. However, the influence of PTS on knee function during activities of daily living (ADLs) is scarcely documented. The aim of this study was to investigate the effect of PTS and surgical referencing technique on tibiofemoral joint (TFJ) kinematics, quadriceps force, and patellofemoral joint (PFJ) force during ADLs. Materials and Methods: We used a previously validated musculoskeletal model of cruciate-retaining TKA [1] to simulate a squat activity. A baseline case with the original post-operative PTS (0°) was simulated, plus four PTS cases (-3°, +3°, +6°, +9°) obtained using anterior tibial cortex-referencing (ACR, Fig. 1a) technique and four using centre of tibial plateau-referencing (CPR, Fig. 1b) technique. Results: More PTS with ACR technique caused a larger and more anterior excursion of the TFJ contact point on the lateral side, and more posterior, on the medial side, in extension (Fig. 2). More PTS with the CPR technique caused the contact point in extension to shift gradually more posterior on both medial and lateral sides, and in flexion to shift gradually more posterior mainly on the lateral side. The peak quadriceps force decreased on average by 1.7 and 1.2 % BW for every degree of more PTS, with the ACR and CPR techniques, respectively. The peak PFJ contact force decreased more importantly with more PTS with the CPR technique rather than with the ACR technique (-3.9 vs. -1.5 % BW/degree more PTS, Fig. 3). Discussion: The ACR technique loosens the TFJ, thus leading to more unstable TFJ kinematics and anterior shift on the lateral side. More PTS also reduces the quadriceps force to squat. More PTS with the CPR technique resulted in stable and more posterior TFJ kinematics, and a greater reduction of the PFJ contact force, due to preservation of patellar height. Conclusions: TFJ stability should be maximally preserved to improve knee function. More PTS with the ACR technique has severe consequences on knee kinematics and function, whilst CPR technique results in more effective reduction of quadriceps and PFJ forces, while preserving TFJ stability. References: [1] Marra MA, Vanheule V, Fluit R, et al. A Subject-Specific Musculoskeletal Modeling Framework to Predict In Vivo Mechanics of Total Knee Arthroplasty. ASME. J Biomech Eng. 2015;137(2):020904-020904-1

The effect of flexion of the femoral component in TKA:A musculoskeletal simulation study

Introduction/Aim: More flexion of the femoral component (FFC) is a surgical option to better restore the femur anatomy in the sagittal plane in Total Knee Arthroplasty (TKA), and to prevent notching of the anterior femoral cortex. However, its true effects on the patellofemoral joint (PFJ) during activities of daily living (ADLs) remain unknown. We studied the effect of FFC on quadriceps and PFJ forces during ADLs. We hypothesised that more FFC has advantages for the knee extensor mechanism. Materials and Methods: A previous validated musculoskeletal model of cruciate-retaining TKA was used (Fig. 1) to simulate a rising-from-a-chair activity [1]. We simulated a baseline case with the original post-operative FFC (0°). We then increased the FFC by 3°, 6°, 9°, by referencing the posterior femoral condyles (Fig. 2) and repeated the simulation. Quadriceps forces, PFJ ligament forces and PFJ contact forces were calculated. Results: Peak quadriceps force decreased by 48 N (6.5 %BW), on average, for every 3° of FFC at 90° flexion (Fig. 3a). The peak PFJ contact force decreased by 64 N (8.7 %BW), on average, for every 3° of FFC at 90° flexion. Conversely, peak medial and lateral PFJ ligament forces increased by 23 N and 25 N, respectively, on average, for every 3° more FFC (Fig. 3c-d). Discussion: FFC moderately affects the PFJ mechanics. Reduced PFJ contact force with more FFC is explained by reduced quadriceps force. More FFC, thus, benefits the knee extensor mechanism, due to increased quadriceps moment arm. More FFC over-tightens both medial and lateral PFJ ligaments, due to a wider PFJ gap, although the effect on ligament forces is not dramatic. Conclusions: More FFC reduces the quadriceps and PFJ force to rise from and sit on a chair. This surgical option can potentially help preventing anterior femoral notching, while at the same time provide a better knee function. References: [1] Marra MA, Vanheule V, Fluit R, et al. A Subject-Specific Musculoskeletal Modeling Framework to Predict In Vivo Mechanics of Total Knee Arthroplasty. ASME. J Biomech Eng. 2015;137(2):020904-020904-1

The effect of posterior tibial slope on simulated laxity tests in cruciate-retaining total knee arthroplasty

Introduction/Aim: More posterior tibial slope (PTS) can potentially prevent flexion gap tightness in Total Knee Arthroplasty (TKA). However, the effects of more PTS on knee laxity remain unclear. The aim of this study was to investigate the effect of PTS on the anterior-posterior (AP) and varus-valgus (VV) laxity in TKA. We hypothesised that the effects also depend on whether an anterior tibial cortex-referencing (ACR) technique or a centre of tibial plateau-referencing (CPR) technique is used. Materials and Methods: A previous validated musculoskeletal model of cruciate-retaining TKA was configured to simulate AP and VV laxity tests [1]. First the model was simulated without any external loads applied, with the knee spanning a 0-90° flexion range of motion (ROM). Subsequently, anterior and posterior loads of 70 N were applied alternately to the proximal tibia, and the resulting AP tibial displacement recorded throughout the knee ROM. Similarly, varus and valgus loads of 15 Nm were applied alternately to the tibia, and the resulting knee VV rotation recorded. The simulations were repeated with -3°, +3°, +6°, +9° of PTS both with the ACR and CPR techniques (Fig. 1). Laxity were calculated as the unloaded case curves minus the loaded case curves. Results: More PTS with the ACR technique increased dramatically the anterior, varus and valgus laxities, throughout the knee flexion ROM. The anterior laxity was maximal (23 mm) at 60° of knee flexion in the +9° ACR case. Conversely, variations of PTS with the CPR technique hardly affected the AP and VV laxities. Discussion: More PTS with the ACR technique compromises the overall knee stability, throughout the knee flexion-extension ROM and, most interestingly, also in extension. This is due to an increase of the flexion gap. In contrast, the CPR technique preserves the translational and rotational laxities of the knee, throughout the ROM. CPR could be achieved by pre-planning the PTS and by accurately executing the tibial cut or by using inserts with built-in PTS. Conclusions: More PTS with the ACR technique has large effects on knee stability and laxity, therefore surgeons should avoid increasing PTS using the ACR technique and, instead, reference the tibial cut height and slope from the posterior one third of the tibia. References: [1] Marra MA, Vanheule V, Fluit R, et al. A Subject-Specific Musculoskeletal Modeling Framework to Predict In Vivo Mechanics of Total Knee Arthroplasty. ASME. J Biomech Eng. 2015;137(2):020904-020904-1

Projected impact of dengue vaccination in Yucatán, Mexico

Dengue vaccines will soon provide a new tool for reducing dengue disease, but the effectiveness of widespread vaccination campaigns has not yet been determined. We developed an agent-based dengue model representing movement of and transmission dynamics among people and mosquitoes in Yucatán, Mexico, and simulated various vaccine scenarios to evaluate effectiveness under those conditions. This model includes detailed spatial representation of the Yucatán population, including the location and movement of 1.8 million people between 375,000 households and 100,000 workplaces and schools. Where possible, we designed the model to use data sources with international coverage, to simplify re-parameterization for other regions. The simulation and analysis integrate 35 years of mild and severe case data (including dengue serotype when available), results of a seroprevalence survey, satellite imagery, and climatological, census, and economic data. To fit model parameters that are not directly informed by available data, such as disease reporting rates and dengue transmission parameters, we developed a parameter estimation toolkit called AbcSmc, which we have made publicly available. After fitting the simulation model to dengue case data, we forecasted transmission and assessed the relative effectiveness of several vaccination strategies over a 20 year period. Vaccine efficacy is based on phase III trial results for the Sanofi-Pasteur vaccine, Dengvaxia. We consider routine vaccination of 2, 9, or 16 year-olds, with and without a one-time catch-up campaign to age 30. Because the durability of Dengvaxia is not yet established, we consider hypothetical vaccines that confer either durable or waning immunity, and we evaluate the use of booster doses to counter waning. We find that plausible vaccination scenarios with a durable vaccine reduce annual dengue incidence by as much as 80% within five years. However, if vaccine efficacy wanes after administration, we find that there can be years with larger epidemics than would occur without any vaccination, and that vaccine booster doses are necessary to prevent this outcome

Variable loss of functional activities of androgen receptor mutants in patients with androgen insensitivity syndrome

Androgen receptor (AR) mutations in androgen insensitivity syndrome (AIS) are associated with a variety of clinical phenotypes. The aim of the present study was to compare the molecular properties and potential pathogenic nature of 8 novel and 3 recurrent AR variants with a broad variety of functional assays. Eleven AR variants (p.Cys177Gly, p.Arg609Met, p.Asp691del, p.Leu701Phe, p.Leu723Phe, p.Ser741Tyr, p.Ala766Ser, p.Arg775Leu, p.Phe814Cys, p.Lys913X, p.Ile915Thr) were analyzed for hormone binding, transcriptional activation, cofactor binding, translocation to the nucleus, nuclear dynamics, and structural conformation. Ligand-binding domain variants with low to intermediate transcriptional activation displayed aberrant Kd values for hormone binding and decreased nuclear translocation. Transcriptional activation data, FxxFF-like peptide binding and DNA binding correlated well for all variants, except for p.Arg609Met, p.Leu723Phe and p.Arg775Leu, which displayed a relatively higher peptide binding activity. Variants p.Cys177Gly, p.Asp691del, p.Ala766Ser, p.Phe814Cys, and p.Ile915Thr had intermediate or wild type values in all assays and showed a predominantly nuclear localization in living cells. All transcriptionally inactive variants (p.Arg609Met, p.Leu701Phe, p.Ser741Tyr, p.Arg775Leu, p.Lys913X) were unable to bind to DNA and were associated with complete AIS. Three variants (p.Asp691del, p.Arg775Leu, p.Ile915Thr) still displayed significant functional activities in in vitro assays, although the clinical phenotype was associated with complete AIS. The data show that molecular phenotyping based on 5 different functional assays matched in most (70%) but not all cases. Copyrigh

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Recent Advances in Understanding Particle Acceleration Processes in Solar Flares

We review basic theoretical concepts in particle acceleration, with particular emphasis on processes likely to occur in regions of magnetic reconnection. Several new developments are discussed, including detailed studies of reconnection in three-dimensional magnetic field configurations (e.g., current sheets, collapsing traps, separatrix regions) and stochastic acceleration in a turbulent environment. Fluid, test-particle, and particle-in-cell approaches are used and results compared. While these studies show considerable promise in accounting for the various observational manifestations of solar flares, they are limited by a number of factors, mostly relating to available computational power. Not the least of these issues is the need to explicitly incorporate the electrodynamic feedback of the accelerated particles themselves on the environment in which they are accelerated. A brief prognosis for future advancement is offered.Comment: This is a chapter in a monograph on the physics of solar flares, inspired by RHESSI observations. The individual articles are to appear in Space Science Reviews (2011

Coronal Dimmings and the Early Phase of a CME Observed with STEREO and Hinode/EIS

We investigate the early phase of the 13 February 2009 coronal mass ejection (CME). Observations with the twin STEREO spacecraft in quadrature allow us to compare for the first time in one and the same event the temporal evolution of coronal EUV dimmings, observed simultaneously on-disk and above the limb. We find that these dimmings are synchronized and appear during the impulsive acceleration phase of the CME, with the highest EUV intensity drop occurring a few minutes after the maximum CME acceleration. During the propagation phase two confined, bipolar dimming regions, appearing near the footpoints of a pre-flare sigmoid structure, show an apparent migration away from the site of the CME-associated flare. Additionally, they rotate around the 'center' of the flare site, i.e., the configuration of the dimmings exhibits the same 'sheared-to-potential' evolution as the postflare loops. We conclude that the motion pattern of the twin dimmings reflects not only the eruption of the flux rope, but also the ensuing stretching of the overlying arcade. Finally, we find that: (1) the global-scale dimmings, expanding from the source region of the eruption, propagate with a speed similar to that of the leaving CME front; (2) the mass loss occurs mainly during the period of strongest CME acceleration. Two hours after the eruption Hinode/EIS observations show no substantial plasma outflow, originating from the 'open' field twin dimming regions.Comment: accepted for publication in Solar Physic