Exact phase diagram of quasispecies model with mutation rate modifier

We consider an infinite asexual population with a mutator allele which can elevate mutation rates. With probability $f$, a transition from nonmutator to mutator state occurs but the reverse transition is forbidden. We find that at $f=0$, the population is in the state with minimum mutation rate and at $f=f_c$, a phase transition occurs between a mixed phase with both nonmutators and mutators and a pure mutator phase. We calculate the critical probability $f_c$ and the total mutator fraction $Q$ in the mixed phase exactly. Our predictions for $Q$ are in agreement with those seen in microbial populations in static environments.Comment: Revised versio

Point Interaction in two and three dimensional Riemannian Manifolds

We present a non-perturbative renormalization of the bound state problem of n bosons interacting with finitely many Dirac delta interactions on two and three dimensional Riemannian manifolds using the heat kernel. We formulate the problem in terms of a new operator called the principal or characteristic operator. In order to investigate the problem in more detail, we then restrict the problem to one particle sector. The lower bound of the ground state energy is found for general class of manifolds, e.g., for compact and Cartan-Hadamard manifolds. The estimate of the bound state energies in the tunneling regime is calculated by perturbation theory. Non-degeneracy and uniqueness of the ground state is proven by Perron-Frobenius theorem. Moreover, the pointwise bounds on the wave function is given and all these results are consistent with the one given in standard quantum mechanics. Renormalization procedure does not lead to any radical change in these cases. Finally, renormalization group equations are derived and the beta-function is exactly calculated. This work is a natural continuation of our previous work based on a novel approach to the renormalization of point interactions, developed by S. G. Rajeev.Comment: 43 page

A translocation motif in relaxase TrwC specifically affects recruitment by its conjugative type IV secretion system

Type IV secretion system (T4SS) substrates are recruited through a translocation signal that is poorly defined for conjugative relaxases. The relaxase TrwC of plasmid R388 is translocated by its cognate conjugative T4SS, and it can also be translocated by the VirB/D4 T4SS of Bartonella henselae, causing DNA transfer to human cells. In this work, we constructed a series of TrwC variants and assayed them for DNA transfer to bacteria and human cells to compare recruitment requirements by both T4SSs. Comparison with other reported relaxase translocation signals allowed us to determine two putative translocation sequence (TS) motifs, TS1 and TS2. Mutations affecting TS1 drastically affected conjugation frequencies, while mutations affecting either motif had only a mild effect on DNA transfer rates through the VirB/D4 T4SS of B. henselae. These results indicate that a single substrate can be recruited by two different T4SSs through different signals. The C terminus affected DNA transfer rates through both T4SSs tested, but no specific sequence requirement was detected. The addition of a Bartonella intracellular delivery (BID) domain, the translocation signal for the Bartonella VirB/D4 T4SS, increased DNA transfer up to 4% of infected human cells, providing an excellent tool for DNA delivery to specific cell types. We show that the R388 coupling protein TrwB is also required for this high-efficiency TrwC-BID translocation. Other elements apart from the coupling protein may also be involved in substrate recognition by T4SSs

The Legionella effector WipB is a translocated Ser/Thr phosphatase that targets the host lysosomal nutrient sensing machinery

Legionella pneumophila infects human alveolar macrophages and is responsible for Legionnaire’s disease, a severe form of pneumonia. L. pneumophila encodes more than 300 putative effectors, which are translocated into the host cell via the Dot/Icm type IV secretion system. These effectors highjack the host’s cellular processes to allow bacterial intracellular growth and replication. Here we adopted a multidisciplinary approach to investigate WipB, a Dot/Icm effector of unknown function. The crystal structure of the N-terminal domain at 1.7 Å resolution comprising residues 25 to 344 revealed that WipB harbours a Ser/Thr phosphatase domain related to the eukaryotic phospho-protein phosphatase (PPP) family. The C-terminal domain (residues 365–524) is sufficient to pilot the effector to acidified LAMP1-positive lysosomal compartments, where WipB interacts with the v-ATPase and the associated LAMTOR1 phosphoprotein, key components of the lysosomal nutrient sensing (LYNUS) apparatus that controls the mammalian target of rapamycin (mTORC1) kinase complex at the lysosomal surface. We propose that WipB is a lysosome-targeted phosphatase that modulates cellular nutrient sensing and the control of energy metabolism during Legionella infection

Spatial abundance and clustering of Culicoides (Diptera: Ceratopogonidae) on a local scale

BACKGROUND: Biting midges, Culicoides, of the Obsoletus group and the Pulicaris group have been involved in recent outbreaks of bluetongue virus and the former was also involved in the Schmallenberg virus outbreak in northern Europe. METHODS: For the first time, here we investigate the local abundance pattern of these two species groups in the field by intensive sampling with a grid of light traps on 16 catch nights. Neighboring trap catches can be spatially dependent on each other, hence we developed a conditional autoregressive (CAR) model framework to test a number of spatial and non-spatial covariates expected to affect Culicoides abundance. RESULTS: The distance to sheep penned in the corner of the study field significantly increased the abundance level up to 200 meters away from the sheep. Spatial clustering was found to be significant but could not be explained by any known factors, and cluster locations shifted between catch nights. No significant temporal autocorrelation was detected. CAR models for both species groups identified a significant positive impact of humidity and significant negative impacts of precipitation and wind turbulence. Temperature was also found to be significant with a peak at just below 16 degrees Celcius. Surprisingly, there was a significant positive impact of wind speed. The CAR model for the Pulicaris group also identified a significant attraction to the smaller groups of sheep placed in the field. Furthermore, a large number of spatial covariates which were incorrectly found to be significant in ordinary regression models were not significant in the CAR models. The 95% C.I. on the prediction estimates ranged from 20.4% to 304.8%, underlining the difficulties of predicting the abundance of Culicoides. CONCLUSIONS: We found that significant spatial clusters of Culicoides moved around in a dynamic pattern varying between catch nights. This conforms with the modeling but was not explained by any of the tested covariates. The mean abundance within these clusters was up to 11 times higher for the Obsoletus group and 4 times higher for the Pulicaris group compared to the rest of the field

Quantifying Dispersal of European Culicoides (Diptera: Ceratopogonidae) Vectors between Farms Using a Novel Mark-Release-Recapture Technique

Studying the dispersal of small flying insects such as Culicoides constitutes a great challenge due to huge population sizes and lack of a method to efficiently mark and objectively detect many specimens at a time. We here describe a novel mark-release-recapture method for Culicoides in the field using fluorescein isothiocyanate (FITC) as marking agent without anaesthesia. Using a plate scanner, this detection technique can be used to analyse thousands of individual Culicoides specimens per day at a reasonable cost. We marked and released an estimated 853 specimens of the Pulicaris group and 607 specimens of the Obsoletus group on a cattle farm in Denmark. An estimated 9,090 (8,918-9,260) Obsoletus group specimens and 14,272 (14,194-14,448) Pulicaris group specimens were captured in the surroundings and subsequently analysed. Two (0.3%) Obsoletus group specimens and 28 (4.6%) Pulicaris group specimens were recaptured. The two recaptured Obsoletus group specimens were caught at the release point on the night following release. Eight (29%) of the recaptured Pulicaris group specimens were caught at a pig farm 1,750 m upwind from the release point. Five of these were recaptured on the night following release and the three other were recaptured on the second night after release. This is the first time that movement of Culicoides vectors between farms in Europe has been directly quantified. The findings suggest an extensive and rapid exchange of disease vectors between farms. Rapid movement of vectors between neighboring farms may explain the the high rate of spatial spread of Schmallenberg and bluetongue virus (BTV) in northern Europe

Platelet-activating factor levels of serum and gingival crevicular fluid in nonsmoking patients with periodontitis and/or coronary heart disease

The purpose of the present study was to investigate systemic and local levels of platelet-activating factor (PAF), a potent proinflammatory mediator implicated in cardiovascular pathophysiology in adult nonsmoking patients with periodontitis with or without coronary heart disease (CHD). Eighty-seven volunteers, 25 periodontitis patients, 19 periodontitis with CHD patients, 19 CHD patients, and 24 healthy controls were included, and periodontal conditions were assessed. Gingival crevicular fluid (GCF) and venous blood were collected, and PAF levels were measured by enzyme-linked immunosorbent assay. PAF levels in serum (303.3 ± 204 pg/ml) and in GCF (26.3 ± 6 pg/μl) of the periodontitis group with CHD, the periodontitis group (serum, 302.4 ± 241 pg/ml and GCF, 26.3 ± 8 pg/μl) and the CHD group (serum, 284.7 ± 192 pg/ml and GCF, 20.8 ± 6 pg/μl) were significantly higher than the healthy control group (serum, 65.4 ± 35 pg/ml and GCF, 7.7 ± 3 pg/μl; p < 0.05). In summary, the present study could demonstrate that in patients with periodontitis, the inflammatory mediator PAF is released into serum at least in the same range as for patients with coronary heart disease. However, no additive effects were seen when both conditions were present

Molecular and functional characterization of polymorphisms in the secreted phospholipase A2 group X gene: relevance to coronary artery disease

Among secreted phospholipases A2 (sPLA2s), human group X sPLA2 (hGX sPLA2) is emerging as a novel attractive therapeutic target due to its implication in inflammatory diseases. To elucidate whether hGX sPLA2 plays a causative role in coronary artery disease (CAD), we screened the human PLA2G10 gene to identify polymorphisms and possible associations with CAD end-points in a prospective study, AtheroGene. We identified eight polymorphisms, among which, one non-synonymous polymorphism R38C in the propeptide region of the sPLA2. The T-512C polymorphism located in the 5′ untranslated region was associated with a decreased risk of recurrent cardiovascular events during follow-up. The functional analysis of the R38C polymorphism showed that it leads to a profound change in expression and activity of hGX sPLA2, although there was no detectable impact on CAD risk. Due to the potential role of hGX sPLA2 in inflammatory processes, these polymorphisms should be investigated in other inflammatory diseases

Type IV Secretion-Dependent Activation of Host MAP Kinases Induces an Increased Proinflammatory Cytokine Response to Legionella pneumophila

The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized secretion systems or pore-forming toxins of bacterial pathogens. The host signaling pathways that respond to bacterial secretion systems remain poorly understood. Infection with the pathogen Legionella pneumophila, which utilizes a type IV secretion system (T4SS), induced an increased proinflammatory cytokine response compared to avirulent bacteria in which the T4SS was inactivated. This enhanced response involved NF-κB activation by TLR signaling as well as Nod1 and Nod2 detection of type IV secretion. Furthermore, a TLR- and RIP2-independent pathway leading to p38 and SAPK/JNK MAPK activation was found to play an equally important role in the host response to virulent L. pneumophila. Activation of this MAPK pathway was T4SS-dependent and coordinated with TLR signaling to mount a robust proinflammatory cytokine response to virulent L. pneumophila. These findings define a previously uncharacterized host response to bacterial type IV secretion that activates MAPK signaling and demonstrate that coincident detection of multiple bacterial components enables immune discrimination between virulent and avirulent bacteria