The oligopeptide ABC transporter OppA4 negatively regulates the virulence factor OspC production of the Lyme disease pathogen

Borrelia burgdorferi sensu lato, the agent of Lyme disease, exists in nature through a complex enzootic life cycle that involves both ticks and mammals. The B. burgdorferi genome encodes five Oligopeptide ABC transporters (Opp) that are predicted to be involve in transport of various nutrients. Previously, it was reported that OppA5 is important for the optimal production of OspC, a major virulence factor of B. burgdorferi. In this study, possible role of another Oligopeptide ABC transporter, OppA4 in ospC expression was investigated by construction of an oppA4 deletion mutant and the complemented strain. Inactivation of oppA4 resulted an increased production of OspC, suggesting that OppA4 has a negative impact on ospC expression. Expression of ospC is controlled by Rrp2-RpoN-RpoS, the central pathway essential for mammal infection. We showed that increased ospC expression in the oppA4 mutant was due to an increased rpoS expression. We then further investigated how OppA4 negatively regulates this pathway. Two regulators, BosR and BadR, are known to positively and negatively, respectively, regulate the Rrp2-RpoN-RpoS pathway. We found that deletion of oppA4 resulted in an increased level of BosR. Previous reports showed that bosR is mainly regulated at the post-transcriptional level by other factors. However, OppA4 appears to negatively regulate bosR expression at the transcriptional level. The finding of OppA4 involved in regulation of the Rrp2-RpoN-RpoS pathway further reinforces the importance of nutritional virulence to the enzootic cycle of B. burgdorferi

Borrelia burgdorferi elongation factor EF-Tu is an immunogenic protein during Lyme borreliosis

Borrelia burgdorferi, the etiological agent of Lyme disease, does not produce lipopolysaccharide but expresses a large number of lipoproteins on its cell surface. These outer membrane lipoproteins are highly immunogenic and have been used for serodiagnosis of Lyme disease. Recent studies have shown that highly conserved cytosolic proteins such as enolase and elongation factor Tu (EF-Tu) unexpectedly localized on the surface of bacteria including B. burgdorferi, and surface-localized enolase has shown to contribute to the enzootic cycle of B. burgdorferi. In this study, we studied the immunogenicity, surface localization, and function of B. burgdorferi EF-Tu. We found that EF-Tu is highly immunogenic in mice, and EF-Tu antibodies were readily detected in Lyme disease patients. On the other hand, active immunization studies showed that EF-Tu antibodies did not protect mice from infection when challenged with B. burgdorferi via either needle inoculation or tick bites. Borrelial mouse-tick cycle studies showed that EF-Tu antibodies also did not block B. burgdorferi migration and survival in ticks. Consistent with these findings, we found that EF-Tu primarily localizes in the protoplasmic cylinder of spirochetes and is not on the surface of B. burgdorferi. Taken together, our studies suggest that B. burgdorferi EF-Tu is not surfaced exposed, but it is highly immunogenic and is a potential serodiagnostic marker for Lyme borreliosis

The Alignment between Satellites and Central Galaxies: Theory vs. Observations

Recent studies have shown that the distribution of satellite galaxies is preferentially aligned with the major axis of their central galaxy. The strength of this alignment has been found to depend strongly on the colours of the satellite and central galaxies, and only weakly on the mass of the halo in which the galaxies reside. In this paper we study whether these alignment signals, and their dependence on galaxy and halo properties, can be reproduced in a hierarchical structure formation model of a $\Lambda$CDM concordance cosmology. To that extent we use a large $N$-body simulation which we populate with galaxies following a semi-analytical model for galaxy formation. We find that if the orientation of the central galaxy is perfectly aligned with that of its dark matter halo, then the predicted central-satellite alignment signal is much stronger than observed. If, however, the minor axis of a central galaxy is perfectly aligned with the angular momentum vector of its dark matter halo, we can accurately reproduce the observed alignment strength as function of halo mass and galaxy color. Although this suggests that the orientation of central galaxies is governed by the angular momentum of their dark matter haloes, we emphasize that any other scenario in which the minor axes of central galaxy and halo are misaligned by $\sim 40^{\circ}$ (on average) will match the data equally well. Finally, we show that dependence of the alignment strength on the color of the central galaxy is most likely an artefact due to interlopers in the group catalogue. The dependence on the color of the satellite galaxies, on the other hand, is real and owes to the fact that red satellites are associated with subhaloes that were more massive at their time of accretion.Comment: 13 Pages, 10 Figures, one figure replaced. added in discussion about comparison with others results, Updated version to match accepted version to MNRA

Acetyl-Phosphate Is Not a Global Regulatory Bridge between Virulence and Central Metabolism in Borrelia burgdorferi

In B. burgdorferi, the Rrp2-RpoN-RpoS signaling cascade is a distinctive system that coordinates the expression of virulence factors required for successful transition between its arthropod vector and mammalian hosts. Rrp2 (BB0763), an RpoN specific response regulator, is essential to activate this regulatory pathway. Previous investigations have attempted to identify the phosphate donor of Rrp2, including the cognate histidine kinase, Hk2 (BB0764), non-cognate histidine kinases such as Hk1, CheA1, and CheA2, and small molecular weight P-donors such as carbamoyl-phosphate and acetyl-phosphate (AcP). In a report by Xu et al., exogenous sodium acetate led to increased expression of RpoS and OspC and it was hypothesized this effect was due to increased levels of AcP via the enzyme AckA (BB0622). Genome analyses identified only one pathway that could generate AcP in B. burgdorferi: the acetate/mevalonate pathway that synthesizes the lipid, undecaprenyl phosphate (C55-P, lipid I), which is essential for cell wall biogenesis. To assess the role of AcP in Rrp2-dependent regulation of RpoS and OspC, we used a unique selection strategy to generate mutants that lacked ackA (bb0622: acetate to AcP) or pta (bb0589: AcP to acetyl-CoA). These mutants have an absolute requirement for mevalonate and demonstrate that ackA and pta are required for cell viability. When the ΔackA or Δpta mutant was exposed to conditions (i.e., increased temperature or cell density) that up-regulate the expression of RpoS and OspC, normal induction of those proteins was observed. In addition, adding 20mM acetate or 20mM benzoate to the growth media of B. burgdorferi strain B31 ΔackA induced the expression of RpoS and OspC. These data suggest that AcP (generated by AckA) is not directly involved in modulating the Rrp2-RpoN-RpoS regulatory pathway and that exogenous acetate or benzoate are triggering an acid stress response in B. burgdorferi

Investigation of ospC Expression Variation among Borrelia burgdorferi Strains

Outer surface protein C (OspC) is the most studied major virulence factor of Borrelia burgdorferi, the causative agent of Lyme disease. The level of OspC varies dramatically among B. burgdorferi strains when cultured in vitro, but little is known about what causes such variation. It has been proposed that the difference in endogenous plasmid contents among strains contribute to variation in OspC phenotype, as B. burgdorferi contains more than 21 endogenous linear (lp) and circular plasmids (cp), and some of which are prone to be lost. In this study, we analyzed several clones isolated from B. burgdorferi strain 297, one of the most commonly used strains for studying ospC expression. By taking advantage of recently published plasmid sequence of strain 297, we developed a multiplex PCR method specifically for rapid plasmid profiling of B. burgdorferi strain 297. We found that some commonly used 297 clones that were thought having a complete plasmid profile, actually lacked some endogenous plasmids. Importantly, the result showed that the difference in plasmid profiles did not contribute to the ospC expression variation among the clones. Furthermore, we found that B. burgdorferi clones expressed different levels of BosR, which in turn led to different levels of RpoS and subsequently, resulted in OspC level variation among B. burgdorferi strains

Renyi’s entropy based multilevel thresholding using a novel meta-heuristics algorithm

Multi-level image thresholding is the most direct and effective method for image segmentation, which is a key step for image analysis and computer vision, however, as the number of threshold values increases, exhaustive search does not work efficiently and effectively and evolutionary algorithms often fall into a local optimal solution. In the paper, a meta-heuristics algorithm based on the breeding mechanism of Chinese hybrid rice is proposed to seek the optimal multi-level thresholds for image segmentation and Renyi’s entropy is utilized as the fitness function. Experiments have been run on four scanning electron microscope images of cement and four standard images, moreover, it is compared with other six classical and novel evolutionary algorithms: genetic algorithm, particle swarm optimization algorithm, differential evolution algorithm, ant lion optimization algorithm, whale optimization algorithm, and salp swarm algorithm. Meanwhile, some indicators, including the average fitness values, standard deviation, peak signal to noise ratio, and structural similarity index are used as evaluation criteria in the experiments. The experimental results show that the proposed method prevails over the other algorithms involved in the paper on most indicators and it can segment cement scanning electron microscope image effectively

Combinatorial proofs on the joint distribution of descents and inverse descents

Let $A_{n,i,j}$ be the number of permutations on $[n]$ with $i-1$ descents and $j-1$ inverse descents. Carlitz, Roselle and Scoville in 1966 first revealed some combinatorial and arithmetic properties of $A_{n,i,j}$, which contain a recurrence of $A_{n,i,j}$. Using the idea of balls in boxes, Petersen gave a combinatorial interpretation for the generating function of $A_{n,i,j}$, and obtained the same recurrence of $A_{n,i,j}$ from its generating function. Subsequently, Petersen asked whether there is a visual way to understand this recurrence. In this paper, after observing the internal structures of permutation grids, we present a combinatorial proof of the recurrence of $A_{n,i,j}$. Let $I_{n,k}$ and $J_{n,k}$ count the number of involutions and fixed-point free involutions on $[n]$ with $k$ descents, respectively. With the help of generating functions, Guo and Zeng derived two recurrences of $I_{n,k}$ and $J_{2n,k}$ that play an essential role in the proof of their unimodal properties. Unexpectedly, the constructive approach to the recurrence of $A_{n,i,j}$ is found to fuel the combinatorial interpretations of these two recurrences of $I_{n,k}$ and $J_{2n,k}$