Genetic races associated with the genera and sections of host species in the holoparasitic plant Cytinus (Cytinaceae) in the Western Mediterranean basin

* Speciation via race formation is an important evolutionary process in parasites, producing changes that favour their development on particular host species. Here, the holoparasitic plant Cytinus, which has diverse host species in the family Cistaceae, has been used to study the occurrence of such races. * Amplified fragment length polymorphism (AFLP) analyses were performed on 174 individuals of 22 populations parasitizing 10 Cistaceae species in the Western Mediterranean basin. * Neighbour-joining, multivariate ordination analyses, and individual-based Bayesian analyses, clustered Cytinus populations into five well-characterized genetic races that, overall, agreed with the taxonomic sections of their hosts. In the AMOVA, among-races differences accounted for almost 50% of the genetic variation. The isolation-by-distance model was not supported by a Mantel test among Cytinus populations (r = 0.012; P = 0.456). All races showed low within-population genetic diversity, probably as a result of restricted pollen flow aggravated by flowering asynchrony, restricted seed dispersion, or stochastic processes. * The genetic differentiation among the five races of Cytinus is congruent with the view that these races are well-characterized lineages that have evolved independently as a result of selective pressures imposed by their hosts. This pattern, with genetically distinctive groups associated with the infrageneric sections of the host species, has not been reported previously for parasitic angiosperms.     

Identification of novel proteins associated with both alpha-synuclein and DJ-1

The molecular mechanisms leading to neurodegeneration in Parkinson disease (PD) remain elusive, although many lines of evidence have indicated that alpha-synuclein and DJ-1, two critical proteins in PD pathogenesis, interact with each other functionally. The investigation on whether alpha-synuclein directly interacts with DJ-1 has been controversial. In the current study, we analyzed proteins associated with alpha-synuclein and/or DJ-1 with a robust proteomics technique called stable isotope labeling by amino acids in cell culture (SILAC) in dopaminergic MES cells exposed to rotenone versus controls. We identified 324 and 306 proteins in the alpha-synuclein- and DJ-1-associated protein complexes, respectively. Among alpha-synuclein-associated proteins, 141 proteins displayed significant changes in the relative abundance (increase or decrease) after rotenone treatment; among DJ-1-associated proteins, 119 proteins displayed significant changes in the relative abundance after rotenone treatment. Although no direct interaction was observed between alpha-synuclein and DJ-1, whether analyzed by affinity purification followed by mass spectrometry or subsequent direct co-immunoprecipitation, 144 proteins were seen in association with both alpha-synuclein and DJ-1. Of those, 114 proteins displayed significant changes in the relative abundance in the complexes associated with alpha-synuclein, DJ-1, or both after rotenone treatment. A subset of these proteins (mortalin, nucleolin, grp94, calnexin, and clathrin) was further validated for their association with both alpha-synuclein and DJ-1 using confocal microscopy, Western blot, and/or immunoprecipitation. Thus, we not only confirmed that there was no direct interaction between alpha-synuclein and DJ-1 but also, for the first time, report these five novel proteins to be associating with both alpha-synuclein and DJ-1. Further characterization of these docking proteins will likely shed more light on the mechanisms by which DJ-1 modulates the function of alpha-synuclein, and vice versa, in the setting of PD.     

Seroprevalence of Merkel Cell Polyomavirus in the General Rural Population of Anyang,China

Background

Despite the probably causal link between Merkel cell polyomavirus (MCPyV) infection and Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy, little is known about the seroepidemiology of MCPyV among healthy adults in China.

Methods

Serum antibodies against MCPyV were evaluated by multiplex serology in a population-based study of 5548 adults (including 1587 heterosexual couples) aged 25–65 years who were enrolled from rural Anyang, China in 2007–2009. Univariate and multivariate logistic regression analyses were performed to assess the risk factors for the seropositivity of MCPyV.

Results

The seroprevalence for MCPyV was 61.0%. MCPyV seropositivity was significantly higher in males than in females (64.5% vs. 57.7%, P<0.001), and for both genders, showed a trend of increase with age (Male: P _trend<0.001; Female: P _trend<0.001). Furthermore, among antibody positives, antibody levels of MCPyV increased with advancing age (P _trend = 0.017). MCPyV seropositivity of one spouse was significantly associated with that of the other partner (Adjusted OR = 1.32, 95% CI: 1.07–1.62). However, there was no association between sexual behaviors and the seropositivity of MCPyV.

Conclusions

High seroprevalence of MCPyV was observed in healthy Chinese individuals. Serological evidence suggests that nonsexual horizontal spread of MCPyV can occur among family members, and further research in this regard is needed.     

"Similarity trap" in protein-protein interactions could be carcinogenic: simulations of p53 core domain complexed with 53BP1 and BRCA1 BRCT domains

Similar binding sites often imply similar protein-protein interactions and similar functions; however, similar binding sites may also constitute traps for nonfunctional associations. How are similar sites distinguished to prevent misassociations? BRCT domains from breast cancer-susceptibility gene product BRCA1 and protein 53BP1 have similar structures yet different binding behaviors with p53 core domain. 53BP1-BRCT domain forms a stable complex with p53. In contrast, BRCA1-p53 interaction is weak or other mechanisms operate. To delineate the difference, we designed 13 BRCA1-BRCT mutants and computationally investigated the structural and stability changes compared to the experimental p53-53BP1 structure. Interestingly, of the 13, the 2 mutations that are cancerous and involve nonconserved residues are those that enforced p53 core domain binding with BRCA1-BRCT in a way similar to p53-53BP1 binding. Hence, falling into the "similarity trap" may disrupt normal BRCA1 and p53 functions. Our results illustrate how this trap is avoided in the native state.     

Probable blind spot in the International Diabetes Federation definition of metabolic syndrome

Objectives: The International Diabetes Federation (IDF) proposed a novel definition of the metabolic syndrome (MS) in 2005, which designated central obesity as mandatory. The new National Cholesterol Education Program (NCEP) version, announced by the American Heart Association and National Heart Lung and Blood Institute in October 2005, did not favor any of the five components. We set out to compare the cardiovascular profiles of patients cross‐defined by these two definitions to shed light on the differential meanings of the two. Research Methods and Procedures: We analyzed data from 2608 non‐institutionalized adults (≥19 years old) in the National Nutrition and Health Survey in Taiwan, who had complete data for the five MS defining components. Both definitions adopted lower cut‐points for fasting glucose and race‐specific cut‐points for waist circumference. Results: Under the IDF's and new NCEP's definitions, the MS prevalence was 6.2% and 11.6% in men and 12.6% and 16.5% in women, respectively. Although the two definitions had high agreement, IDF failed to pick up ～4% to 5% of people with more than three MS component disorders but a waist circumference less than the cut‐point. Subjects whose physical conditions only satisfied NCEP's definition had similar or worse metabolic profiles than those whose conditions satisfied both IDF's definition and the new NCEP's definition. Discussion: The IDF definition would fail to identify a portion of people who have more than three MS component disorders but a small waistline. Further research and discussion are needed on whether and how to implement the IDF's definition.     

B-cell epitope prediction for peptide-based vaccine design: towards a paradigm of biological outcomes for global health

Global health must address a rapidly evolving burden of disease, hence the urgent need for versatile generic technologies exemplified by peptide-based vaccines. B-cell epitope prediction is crucial for designing such vaccines; yet this approach has thus far been largely unsuccessful, prompting further inquiry into the underlying reasons for its apparent inadequacy. Two major obstacles to the development of B-cell epitope prediction for peptide-based vaccine design are (1) the prevailing binary classification paradigm, which mandates the problematic dichotomization of continuous outcome variables, and (2) failure to explicitly model biological consequences of immunization that are relevant to practical considerations of safety and efficacy. The first obstacle is eliminated by redefining the predictive task as quantitative estimation of empirically observable biological effects of antibody-antigen binding, such that prediction is benchmarked using measures of correlation between continuous rather than dichotomous variables; but this alternative approach by itself fails to address the second obstacle even if benchmark data are selected to exclusively reflect functionally relevant cross-reactivity of antipeptide antibodies with protein antigens (as evidenced by antibody-modulated protein biological activity), particularly where only antibody-antigen binding is actually predicted as a surrogate for its biological effects. To overcome the second obstacle, the prerequisite is deliberate effort to predict, a priori, biological outcomes that are of immediate practical significance from the perspective of vaccination. This demands a much broader and deeper systems view of immunobiology than has hitherto been invoked for B-cell epitope prediction. Such a view would facilitate comprehension of many crucial yet largely neglected aspects of the vaccine-design problem. Of these, immunodominance among B-cell epitopes is a central unifying theme that subsumes immune phenomena of tolerance, imprinting and refocusing; but it is meaningful for vaccine design only in the light of disease-specific pathophysiology, which for infectious processes is complicated by host-pathogen coevolution. To better support peptide-based vaccine design, B-cell epitope prediction would entail individualized quantitative estimation of biological outcomes relevant to safety and efficacy. Passive-immunization experiments could serve as an important initial proving ground for B-cell epitope prediction en route to vaccine-design applications, by restricting biological complexity to render epitope-prediction problems more computationally tractable.      

Sanguinarine Decreases Cell Stiffness and Traction Force and Inhibits the Reactivity of Airway Smooth Muscle Cells in Culture

Airway hyperresponsiveness (AHR) is the cardinal character of asthma, which involves the biomechanical properties such as cell stiffness and traction force of airway smooth muscle cells (ASMCs). Therefore, these biomechanical properties comprise logical targets of therapy. β2-adrenergic agonist is currently the mainstream drug to target ASMCs in clinical practice for treating asthma. However, this drug is known for side effects such as desensitization and non-responsiveness in some patients. Therefore, it is desirable to search for new drug agents to be alternative of β2-adrenergic agonist. In this context, sanguinarine, a natural product derived from plants such as bloodroots, that has been reported to relax gut smooth muscle emerges as a potential candidate. So far, it is unknown whether sanguinarine can regulate the biomechanical properties of ASMCs and reactivity of ASMCs to irritants. Thus, we tested the hypothesis that sanguinarine reduce the contractile potentials of ASMCs in culture. To do so, the primary cultured rat ASMCs were first treated with different concentration of sanguinarine. Then, cell stiffness, traction force, fiber distribution, and calcium signaling of the ASMCs were evaluated by optical magnetic twisting cytometry, Fourier transform traction microscopy, atomic force microscopy, and Fluo-4/AM based fluorescence confocal scanning microscopy, respectively. The results indicated that sanguinarine (0.05 and 0.5 μmol/L) significantly decreased cell stiffness and traction force, inhibited reactivity of ASMCs to histamine, and disrupted the fiber structures in ASMCs in dose-dependent manner. These findings establish that sanguinarine can indeed change the biomechanical properties of ASMCs and may be used to treat AHR in asthma.     

Strength of density feedback in census data increases from slow to fast life histories

Life-history theory predicts an increasing rate of population growth among species arranged along a continuum from slow to fast life histories. We examine the effects of this continuum on density-feedback strength estimated using long-term census data from >700 vertebrates, invertebrates, and plants. Four life-history traits (Age at first reproduction, Body size, Fertility, Longevity) were related statistically to Gompertz strength of density feedback using generalized linear mixed-effects models and multi-model inference. Life-history traits alone explained 10 to 30% of the variation in strength across species (after controlling for time-series length and phylogenetic nonindependence). Effect sizes were largest for body size in mammals and longevity in birds, and density feedback was consistently stronger for smaller-bodied and shorter-lived species. Overcompensatory density feedback (strength <-1) occurred in 20% of species, predominantly at the fast end of the life-history continuum, implying relatively high population variability. These results support the idea that life history leaves an evolutionary signal in long-term population trends as inferred from census data. Where there is a lack of detailed demographic data, broad life-history information can inform management and conservation decisions about rebound capacity from low numbers, and propensity to fluctuate, of arrays of species in areas planned for development, harvesting, protection, and population recovery.     

F-Box Only Protein 31 (FBXO31) Negatively Regulates p38 Mitogen-activated Protein Kinase (MAPK) Signaling by Mediating Lysine 48-linked Ubiquitination and Degradation of Mitogen-activated Protein Kinase Kinase 6 (MKK6)

The p38 MAPK signal transduction pathway plays an important role in inflammatory and stress responses. MAPKK6 (MKK6), a dual specificity protein kinase, is a p38 activator. Activation of the MKK6-p38 pathway is kept in check by multiple layers of regulations, including autoinhibition, dimerization, scaffold proteins, and Lys-63-linked polyubiquitination. However, the mechanisms underlying deactivation of MKK6-p38, which is crucial for maintaining the magnitude and duration of signal transduction, are not well understood. Lys-48-linked ubiquitination, which marks substrates for proteasomal degradation, is an important negative posttranslational regulatory machinery for signal pathway transduction. Here we report that the accumulation of F-box only protein 31 (FBXO31), a component of Skp1·Cul1·F-box protein E3 ligase, negatively regulated p38 activation in cancer cells upon genotoxic stresses. Our results show that FBXO31 binds to MKK6 and mediates its Lys-48-linked polyubiquitination and degradation, thereby functioning as a negative regulator of MKK6-p38 signaling and protecting cells from stress-induced cell apoptosis. Taken together, our findings uncover a new mechanism of deactivation of MKK6-p38 and substantiate a novel regulatory role of FBXO31 in stress response.