Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2

The hepatitis B virus (HBV) core Ag (HBcAg) serves as the structural subunit of the highly immunogenic capsid shell. HBcAg harbors a unique arginine-rich C terminus that was implicated in immune responses induced by the capsid. In this study, we examined the capacity of the HBV capsid to induce proinflammatory and regulatory cytokines in human THP-1 macrophages and the possible underlying mechanism. Full-length HBc capsids, but not HBc-144 capsids lacking the arginine-rich domain of HBcAg, efficiently bound differentiated THP-1 macrophages and strongly induced TNF-alpha, IL-6, and IL-12p40. Capsid binding to macrophages and cytokine induction were independent of the RNA associated with the arginine-rich domain. Soluble heparin and heparan sulfate but not chondroitin sulfates greatly diminished cytokine induction through inhibition of capsid binding to THP-1 macrophages. Furthermore, serine phosphorylation in the arginine-rich domain modulates capsid binding to macrophages and the cytokine response. Induction of cytokines by the capsid involved activation of NF-kappaB, ERK-1/2, and p38 MAPK and did not require endosomal acidification. Finally, NF-kappaB activation by the capsid in HEK 293 cells specifically required expression of TLR2 and was compromised by soluble heparin. Thus, cytokine induction by the HBV capsid in macrophages is facilitated by interaction of its arginine-rich domain with membrane heparan sulfate and involves signaling through TLR2.     

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug’s permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone’s absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K_1∶1 = 2311 M⁻¹), all experimental models showed that the drug’s permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone’s permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.     

Sister species diverge in modality‐specific courtship signal form and function

Understanding the relative importance of different sources of selection (e.g., the environment, social/sexual selection) on the divergence or convergence of reproductive communication can shed light on the origin, maintenance, or even disappearance of species boundaries. Using a multistep approach, we tested the hypothesis that two presumed sister species of wolf spider with overlapping ranges and microhabitat use, yet differing degrees of sexual dimorphism, have diverged in their reliance on modality‐specific courtship signaling. We predicted that male Schizocosa crassipalpata (no ornamentation) rely predominantly on diet‐dependent vibratory signaling for mating success. In contrast, we predicted that male S. bilineata (black foreleg brushes) rely on diet‐dependent visual signaling. We first tested and corroborated the sister‐species relationship between S. crassipalpata and S. bilineata using phylogenomic scale data. Next, we tested for species‐specific, diet‐dependent vibratory and visual signaling by manipulating subadult diet and subsequently quantifying adult morphology and mature male courtship signals. As predicted, vibratory signal form was diet‐dependent in S. crassipalpata, while visual ornamentation (brush area) was diet‐dependent in S. bilineata. We then compared the species‐specific reliance on vibratory and visual signaling by recording mating across artificially manipulated signaling environments (presence/absence of each modality in a 2 × 2 full factorial design). In accordance with our diet dependence results for S. crassipalpata, the presence of vibratory signaling was important for mating success. In contrast, the light and vibratory environment interacted to influence mating success in S. bilineata, with vibratory signaling being important only in the absence of light. We found no differences in overall activity patterns. Given that these species overlap in much of their range and microhabitat use, we suggest that competition for signaling space may have led to the divergence and differential use of sensory modalities between these sister species.     

Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency

In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.     

Modelling transmission of vector-borne pathogens shows complex dynamics when vector feeding sites are limited

The relationship between species richness and the prevalence of vector-borne disease has been widely studied with a range of outcomes. Increasing the number of host species for a pathogen may decrease infection prevalence (dilution effect), increase it (amplification), or have no effect. We derive a general model, and a specific implementation, which show that when the number of vector feeding sites on each host is limiting, the effects on pathogen dynamics of host population size are more complex than previously thought. The model examines vector-borne disease in the presence of different host species that are either competent or incompetent (i.e. that cannot transmit the pathogen to vectors) as reservoirs for the pathogen. With a single host species present, the basic reproduction ratio R(0) is a non-monotonic function of the population size of host individuals (H), i.e. a value [Formula: see text] exists that maximises R(0). Surprisingly, if [Formula: see text] a reduction in host population size may actually increase R(0). Extending this model to a two-host species system, incompetent individuals from the second host species can alter the value of [Formula: see text] which may reverse the effect on pathogen prevalence of host population reduction. We argue that when vector-feeding sites on hosts are limiting, the net effect of increasing host diversity might not be correctly predicted using simple frequency-dependent epidemiological models.     

Modelling evolutionarily stable strategies in oviposition site selection, with varying risks of predation and intraspecific competition

Many ovipositing mosquitoes, as well as other species, can detect biotic factors that affect fitness. However, a female mosquito seeking a high quality oviposition site (e.g. one with low risk of predation and competition to her progeny) must often balance the competing risk of increasing probability of mortality to herself while she continues to search, against increased probability of finding a high quality site. Such oviposition site selection may affect adult population size. We examined a female mosquito’s expected strategy of oviposition site selection under conditions of varying predator prevalence and adult mortality risk, by combining a detailed structured population model with a Markov chain implementation of the adult behavioural process. We used parameter values from the specific mosquito-predator system, Culiseta longiareolata-Notonecta maculata, although the overall results can be generalised to many mosquito species. Our model finds the evolutionarily stable strategy of oviposition site selection for different parameter combinations. Our model predicts that oviposition strategy does not vary smoothly with varying environmental risk of adult mortality, but that certain oviposition strategies become unstable at some parameter values. Mosquitoes will distribute their reproductive effort between breeding sites of varying predation risk only when adult mortality is low or larval competition high. Our model predicts that females will continue searching for predator-free pools, rather than oviposit in the first site encountered, regardless of the risk of mortality to the adult. The ecological basis for a reproductive strategy with alternative behaviours is important for understanding the effect of biotic factors on the population dynamics of mosquitoes, and for the development of biological control strategies, such as the dissemination of predator-cue chemicals.     

The Encoding of Individual Identity in Dolphin Signature Whistles: How Much Information Is Needed?

Bottlenose dolphins (Tursiops truncatus) produce many vocalisations, including whistles that are unique to the individual producing them. Such “signature whistles” play a role in individual recognition and maintaining group integrity. Previous work has shown that humans can successfully group the spectrographic representations of signature whistles according to the individual dolphins that produced them. However, attempts at using mathematical algorithms to perform a similar task have been less successful. A greater understanding of the encoding of identity information in signature whistles is important for assessing similarity of whistles and thus social influences on the development of these learned calls. We re-examined 400 signature whistles from 20 individual dolphins used in a previous study, and tested the performance of new mathematical algorithms. We compared the measure used in the original study (correlation matrix of evenly sampled frequency measurements) to one used in several previous studies (similarity matrix of time-warped whistles), and to a new algorithm based on the Parsons code, used in music retrieval databases. The Parsons code records the direction of frequency change at each time step, and is effective at capturing human perception of music. We analysed similarity matrices from each of these three techniques, as well as a random control, by unsupervised clustering using three separate techniques: k-means clustering, hierarchical clustering, and an adaptive resonance theory neural network. For each of the three clustering techniques, a seven-level Parsons algorithm provided better clustering than the correlation and dynamic time warping algorithms, and was closer to the near-perfect visual categorisations of human judges. Thus, the Parsons code captures much of the individual identity information present in signature whistles, and may prove useful in studies requiring quantification of whistle similarity.     

Going down together: invasive host,Charybdis longicollis (Decapoda: Brachyura: Portunidae) and invasive parasite,Heterosaccus dollfusi (Cirripedia: Rhizocephala: Sacculinidae) on the upper slope off the Mediterranean coast of Israel

The swimming crab Charybdis longicollis, native to the western Indian Ocean, was first recorded in the Mediterranean in 1954. It is now established from Egypt to Greece, and dominates the sandy-mud bottoms at 25–80?m in the southeastern Mediterranean. The success of C. longicollis is attributed to its high fecundity, agonistic behaviour and omnivorous diet, as well as the rise in seawater temperature. Since the early 1990s its populations in Israel and Turkey have been heavily parasitized by the alien rhizocephalan Heterosaccus dollfusi, which impacts its host’s behaviour, growth and fecundity, and causes mortality. Yet, 60 years after its first record in the Mediterranean, the population of C. longicollis seems durable, and has recently spread to the lower shelf and upper slope off Israel, where it is common at 80?m and is found down to 250?m, greatly increasing its spatial spread. The maximal percentage of parasitization was 87.2%, 88.8%, 75.5% and 81.8% at depths of 40, 60, 80, 100?m, respectively, and 50% at 120 and 250?m. Here, we hypothesize on the possible contribution of the depletion of its putative fish predators, mainly rays, to the prevalence of C. longicollis on the lower shelf.