Histamine H(1) receptor signaling regulates effector T cell responses and susceptibility to coxsackievirus B3-induced myocarditis

Susceptibility to autoimmune myocarditis has been associated with histamine release by mast cells during the innate immune response to coxsackievirus B3 (CVB3) infection. To investigate the contribution of histamine H(1) receptor (H(1)R) signaling to CVB3-induced myocarditis, we assessed susceptibility to the disease in C57BL/6J (B6) H(1)R(-/-) mice. No difference was observed in mortality between CVB3-infected B6 and H(1)R(-/-) mice. However, analysis of their hearts revealed a significant increase in myocarditis in H(1)R(-/-) mice that is not attributed to increased virus replication. Enhanced myocarditis susceptibility correlated with a significant expansion in pathogenic Th1 and Vγ4(+) γδ T cells in the periphery of these animals. Furthermore, an increase in regulatory T cells was observed, yet these cells were incapable of controlling myocarditis in H(1)R(-/-) mice. These data establish a critical role for histamine and H(1)R signaling in regulating T cell responses and susceptibility to CVB3-induced myocarditis in B6 mice.     

Perspectives on the potential of entomopathogenic fungi in biological control of ticks

Ticks are serious health threats for humans, and both domestic and wild animals. Ticks are controlled mostly by application of chemical products; but these acaricides have several negative side effects, including toxicity to animals, environmental contamination, and induction of chemical resistance in some tick populations. Entomopathogenic fungi infect arthropods in nature and can occur at enzootic or epizootic levels in their host populations. Laboratory studies clearly demonstrate that these fungi can cause high mortality in all developmental stages of several tick species, and also reduce oviposition of infected engorged females. Tick mortality following application of fungi in the field, however, often is less than that suggested by laboratory tests. This is due to many negative biotic and climatic factors. To increase efficacy of fungal agents for biological control of ticks under natural conditions, several points need consideration: (1) select effective isolates (viz., high virulence; and tolerance to high temperature, ultraviolet radiation and desiccation); (2) understand the main factors that affect virulence of fungal isolates to their target arthropods including the role of toxic metabolites of the fungal isolates; and (3) define with more precision the immune response of ticks to infection by entomopathogenic fungi. The current study reviews recent literature on biological control of ticks, and comments on the relevance of these results to advancing the development of fungal biocontrol agents, including improving formulation of fungal spores for use in tick control, and using entomopathogenic fungi in integrated pest (tick) management programs.     

Targeting the vaginal mucosa with human papillomavirus pseudovirion vaccines delivering simian immunodeficiency virus DNA

The majority of HIV infections occur via mucosal transmission. Vaccines that induce memory T and B cells in the female genital tract may prevent the establishment and systemic dissemination of HIV. We tested the immunogenicity of a vaccine that uses human papillomavirus (HPV)-based gene transfer vectors, also called pseudovirions (PsVs), to deliver SIV genes to the vaginal epithelium. Our findings demonstrate that this vaccine platform induces gene expression in the genital tract in both cynomolgus and rhesus macaques. Intravaginal vaccination with HPV16, HPV45, and HPV58 PsVs delivering SIV Gag DNA induced Gag-specific Abs in serum and the vaginal tract, and T cell responses in blood, vaginal mucosa, and draining lymph nodes that rapidly expanded following intravaginal exposure to SIV(mac251.) HPV PsV-based vehicles are immunogenic, which warrant further testing as vaccine candidates for HIV and may provide a useful model to evaluate the benefits and risks of inducing high levels of SIV-specific immune responses at mucosal sites prior to SIV infection.     

Investigating extracellular in situ EGFR structure and conformational changes using FRET microscopy

The crystallographic structures of functional fragments of ErbBs have provided excellent insights into the geometry of growth factor binding and receptor dimerization. By placing together receptor fragments to build structural models of entire receptors, we expect to understand how these enzymes are allosterically regulated; however, several predictions from these models are inconsistent with experimental evidence from cells. The opening of this gap underlines the need to investigate intact ErbBs by combining cellular and structural studies into a full picture.     

A functional interaction between the MAGUK protein hDlg and the gap junction protein connexin 43 in cervical tumour cells

Gap junctions, composed of Cxs (connexins), allow direct intercellular communication. Gap junctions are often lost during the development of malignancy, although the processes behind this are not fully understood. Cx43 is a widely expressed Cx with a long cytoplasmic C-terminal tail that contains several potential protein-interaction domains. Previously, in a model of cervical carcinogenesis, we showed that the loss of gap junctional communication correlated with relocalization of Cx43 to the cytoplasm late in tumorigenesis. In the present study, we demonstrate a similar pattern of altered expression for the hDlg (human discs large) MAGUK (membrane-associated guanylate kinase) family tumour suppressor protein in cervical tumour cells, with partial co-localization of Cx43 and hDlg in an endosomal/lysosomal compartment. Relocalization of these proteins is not due to a general disruption of cell membrane integrity or Cx targeting. Cx43 (via its C-terminus) and hDlg interact directly in vitro and can form a complex in cells. This novel interaction requires the N- and C-termini of hDlg. hDlg is not required for Cx43 internalization in W12GPXY cells. Instead, hDlg appears to have a role in maintaining a cytoplasmic pool of Cx43. These results demonstrate that hDlg is a physiologically relevant regulator of Cx43?in transformed epithelial cells.     

Eye Images Increase Charitable Donations: Evidence From an Opportunistic Field Experiment in a Supermarket

A number of studies have shown that the presence of simple images of eyes in the environment increases prosocial behaviour in humans. However, questions remain about the robustness of the effect, its explanation and the factors promoting it. In particular, it is not yet clear whether this effect is restricted to contexts where there is a normative requirement to behave prosocially and thus where punishment is a likely consequence of failing to do so. In an 11‐wk field experiment in a supermarket, we displayed either eye images or control images on charity collection buckets. There was no normative requirement to donate in this setting, and most people did not do so. However, the presence of eye images increased donations by 48% relative to control images. The effect of eye images was significantly stronger at times when the supermarket was quiet rather than busy. Results are consistent with models of the evolution of prosociality through reputation‐based partner choice and have potential practical benefits for those involved in charitable fundraising.     

Comparison of regression methods for phenology

Several methods exist for investigation of the relationship between records and weather data. These can be broadly classified into models that attempt to incorporate information about underlying biological processes, such as those based on the concept of thermal time, and linear regression methods. The latter are less driven by the biology but have the advantages of ease of use and flexibility. Regression can be used where there is no obvious mechanistic model or to suggest the form of a mechanistic or empirical model where there are several to choose from. Stepwise regression is commonly used in phenology. However, it requires aggregation of the weather records, resulting in loss of information. Penalised signal regression (PSR) was recently introduced to overcome this weakness. Here, we introduce a further method to the phenology context called fusion, which is a sparse version of PSR. In this paper, we compare the performance of these three regression methods based on simulations from two types of mechanistic models, the spring warming and sequential models. Given a suitable choice of temperature days as regression covariates, PSR and fusion performed better than stepwise regression for the spring warming model and PSR performed best for the sequential model. However, if a large number of redundant temperature days were included as covariates, the performance of PSR fell off whilst fusion was quite robust to this change. For this reason, it is best to use PSR and fusion methods in tandem, and to vary the number of covariates included.     

Draft genome sequence of the nontoxigenic Clostridium difficile strain CD37

Here we report the draft genome sequence of Clostridium difficile strain CD37, the first nontoxigenic strain sequenced. Every sequenced strain of Clostridium difficile has been shown to contain multiple different mobile genetic elements. The draft genome sequence of strain CD37 reveals the presence of two putative conjugative transposons.     

High connectivity among habitats precludes the relationship between dispersal and range size in tropical reef fishes

The hypothesis that pelagic larval duration (PLD) influences range size in marine species with a benthic adult stage and a pelagic larval period is intuitively attractive; yet, studies conducted to date have failed to support it. A possibility for the lack of a relationship between PLD and range size may stem from the failure of past studies to account for the effect of species evolutionary ages, which may add to the dispersal capabilities of species. However, if dispersal over ecological (i.e. PLD) and across evolutionary (i.e. species evolutionary age) time scales continues to show no effect on range size then an outstanding question is why? Here we collected data on PLD, evolutionary ages and range sizes of seven tropical fish families (five families were reef‐associated and two have dwell demersal habitats) to explore the independent and interactive effects of PLD and evolutionary age on range size. Separate analyses on each family showed that even after controlling for evolutionary age, PLD has an insignificant or a very small effect on range size. To shed light on why dispersal has such a limited effect on range size, we developed a global ocean circulation model to quantify the connectivity among tropical reefs relative to the potential dispersal conferred by PLD. We found that although there are several areas of great isolation in the tropical oceans, most reef habitats are within the reach of most species given their PLDs. These results suggest that the lack of habitat isolation can potentially render the constraining effect of dispersal on range size insignificant and explain why dispersal does not relate to range size in reef fishes.     

The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47

Matricellular proteins play diverse roles in modulating cell behavior by engaging specific cell surface receptors and interacting with extracellular matrix proteins, secreted enzymes, and growth factors. Studies of such interactions involving thrombospondin-1 have revealed several physiological functions and roles in the pathogenesis of injury responses and cancer, but the relatively mild phenotypes of mice lacking thrombospondin-1 suggested that thrombospondin-1 would not be a central player that could be exploited therapeutically. Recent research focusing on signaling through its receptor CD47, however, has uncovered more critical roles for thrombospondin-1 in acute regulation of cardiovascular dynamics, hemostasis, immunity, and mitochondrial homeostasis. Several of these functions are mediated by potent and redundant inhibition of the canonical nitric oxide pathway. Conversely, elevated tissue thrombospondin-1 levels in major chronic diseases of aging may account for the deficient nitric oxide signaling that characterizes these diseases, and experimental therapeutics targeting CD47 show promise for treating such chronic diseases as well as acute stress conditions that are associated with elevated thrombospondin-1 expression.