Innate immunity and intracellular trafficking : insights for novel anti-HIV-1 therapeutics

It is now evident that host cells have evolved a remarkable variety of antiretroviral activities to defend themselves against viral invaders and in return viruses have developed ingenious ways to circumvent these defences and, in some cases, actually hijack cellular proteins in order to facilitate their replication. Study of this cat and mouse interplay between viruses and their host cells throughout evolution has lead to the identification of some of the most sophisticated antiviral strategies that mammals have developed to prevent viral infection. Recently, a wave of publications has significantly enhanced our understanding of the relationship between human immunodeficiency virus type 1 (HIV-1) and its host, including: 1) the HIV-1 protein Vif and its interaction with host cell nucleic acid editing enzymes; 2) the host cell restrictive factors that provide protection against retroviral infection, such as TRIM5; and 3) the late domains of retroviruses and their relationship with the host cell vacuolar protein sorting pathway. The focus of this review is to provide an up-to-date account of these important areas of HIV-1 research and highlight how some of these new discoveries can potentially be exploited for the development of novel anti-retroviral therapeutics.

Innate immunity in the mammary gland and the role of the milk peptidome

 This research investigated how the mammary gland responds to disease states such as mastitis and how the milk plays a protective role. An in vitro mammary model was developed and shown to replicate the same responses to the breast when challenged with bacterial proteins demonstrating the usefulness of this model for future investigation of therapeutic interventions.

Upregulation of sodium iodide symporter (NIS) protein expression by an innate immunity component: promising potential for targeting radiosensitive retinoblastoma

Retinoblastoma (RB), a malignant tumour of the eye arising from developing retina, is the most frequent primary intraocular malignancy of childhood. Its primary management with chemotherapy involves combination regimen of etoposide, vincristine and carboplatin and intra vitreal chemotherapy using melphalan when vitreous seeds develop. Radiotherapy is another effective mode in treating RB. We recently explored the notion if radiotherapy in RB can be mediated via Sodium Iodide Symporter (NIS), an intrinsic membrane glycoprotein which is a key regulator of iodide access to thyroid gland. Its expression has been exploited successfully for diagnostic imaging and molecular radionuclide-based therapy of thyroid cancer. We determined that NIS is expressed endogenously in RB tumour tissues, and in retinoblastoma cell lines Y79 and Weri-Rb-1, and therefore made an attempt to enhance the endogenously low expression of NIS protein in both Y79 and Weri-Rb-1 cells. Here we report about the potential of bovine lactoferrin (bLf) which is a known chemo preventive and emerging safe anti-cancer bio drug, as well as a natural transcriptional activator of genes, to enhance the endogenous expression of NIS in Y79 and Weri-Rb-1 cells. Real time PCR revealed that both cell lines express mRNA of lactoferrin receptors while flow cytometry and confocal microscopy showed the cells efficiently internalize bLf which upregulates NIS expression. These findings highlight an important step that could be taken towards the development of less harmful approaches for the treatment of RB by employing natural supplement bLf (with its clinically proven safe profile), and warrants further studies in future, focussing on enhancing NIS expression in RB cells and NIS functional assays in these cells.

Older patients are immunocompromised by cytokine depletion and loss of innate immune function after hip fracture surgery

PURPOSE/INTRODUCTION: We have examined the immune status of elderly patients who underwent surgery for a hip fracture, an injury associated with poor postoperative outcomes, to identify specific immune defects. METHODS: In a cohort observational study, 16 patients undergoing surgery for hip fractures had immune function evaluation prior to surgery, and then at 3 and 7 days postoperatively, using flow cytometry for phenotype and for monocyte and granulocyte phagocytic function and respiratory burst. Serum samples were stored and batch analyzed using a human cytokine 25-plex panel. RESULTS: We report significant loss of innate immune function, related specifically to reduced granulocyte numbers by day 7 (P < .0001, flow cytometry; P < .05 white blood cells), and although granulocyte ability to take up opsonized Escherichia coli was increased (P < .05), the ability of those cells to generate a respiratory burst was reduced at days 3 and 7 (P < .05). Monocyte respiratory burst was also significantly reduced (P < .05). Serum cytokine levels indicated very poor T-cell function. CONCLUSION: We have demonstrated that the antimicrobial immune response is profoundly reduced after surgery in elderly patients with hip fractures. The effect was sustained up to 7 days postoperatively, identifying these patients as particularly vulnerable to bacterial infections.

Personality and innate immune defenses in a wild bird: evidence for the pace-of-life hypothesis

We tested the two main evolutionary hypotheses for an association between immunity and personality. The risk-of-parasitism hypothesis predicts that more proactive (bold, exploratory, risk-taking) individuals have more vigorous immune defenses because of increased risk of parasite exposure. In contrast, the pace-of-life hypothesis argues that proactive behavioral styles are associated with shorter lifespans and reduced investment in immune function. Mechanistically, associations between immunity and personality can arise because personality differences are often associated with differences in condition and stress responsiveness, both of which are intricately linked with immunity. Here we investigate the association between personality (measured as proactive exploration of a novel environment) and three indices of innate immune function (the non-specific first line of defense against parasites) in wild superb fairy-wrens Malurus cyaneus. We also quantified body condition, hemoparasites (none detected), chronic stress (heterophil:lymphocyte ratio) and circulating corticosterone levels at the end of the behavioral test (CORT, in a subset of birds). We found that fast explorers had lower titers of natural antibodies. This result is consistent with the pace-of-life hypothesis, and with the previously documented higher mortality of fast explorers in this species. There was no interactive effect of exploration score and duration in captivity on immune indices. This suggests that personality-related differences in stress responsiveness did not underlie differences in immunity, even though behavioral style did modulate the effect of captivity on CORT. Taken together these results suggest reduced constitutive investment in innate immune function in more proactive individuals.

RE Kevin and the right of transsexual persons to marry in Australia

This article considers the decision of the Family Court of Australia in Re Kevin (Validity of Marriage of a Transsexual) [2001] FamCA 1074, which was upheld by the Full Court of the Family Court of Australia in February 2003. Re Kevin was the first case in Australia to deal directly with the question of whether a transsexual person could marry under Australian law. In the past, Australia had adhered to the judgement of Ormrod J in Corbett v Corbett [1971] P. 83, which set the benchmark for what is ‘male’ and what is ‘female’ under the common law. Prior to Re Kevin the question of what is a man and what is a woman for the purposes of marriage in Australia mirrored the strict biological test established in Corbett. In other words, the Australian courts relied upon biological factors, as espoused by Ormrod J, when determining a person's true sex. In Re Kevin, Chisholm J examined in detail what it is to be a man or woman, but unlike Ormrod J considered ‘brain sex’ to have a significant impact on a person's view of their own innate sexual identity. The Full Court of the Family Court agreed with the powerful and well-reasoned judgement of Chisholm J at first instance.

Moving towards a model of professional identity formation in midwifery through conversations and positioning theory

The disciplines of nursing and midwifery both uphold a powerful oral tradition that can impact upon student learning. Students enrolled in a Graduate Diploma of Midwifery are supervised and assessed by midwives during their placements in midwifery practice settings by a program of 'preceptorship' support and where conversations are innate. Positioning theory, eveloped by Harre and others, is a metaphorical concept in which an individual 'positions' herself/himself within entities of encompassing people, institutions and societies where conversations are conducted either privately or publicly. As construction sites of professional learning, conversations are underpinned by reflective practices.In unravelling conversations, positioning may be applied as an analytical tool by educators to interpret the emerging meanings and themes in their discussions with students, reflective journals by students and in meetings with preceptors/midwives.

Graphical authentication : an architectural design specification

Graphical authentication is proposed as an alternative to password, smartcard, and biometric authentication as it uses the innate ability of humans to recognise visual stimuli. Despite passionate debate surrounding their privacy and invasiveness issues, smartcards and biometrics require an excessive amount of extra hardware for widespread deployment. Conversely graphical authentication extends existing infrastructure as it builds largely on the foundations of passwords with one important difference: it takes humans into account as they are better at recognising visual stimuli than recalling text-based passwords. This paper follows a preceding proof of concept paper and essentially outlines the architectural and technical design for a graphical authentication solution.

Professionalisation and accounting in China: a historical and comparative review

While applied broadly within the setting of accounting and some other occupations, “a profession” is a particularly Western concept with peculiarly British origins. Additionally, the significance of such status and the process of “professionalisation” by which it is acquired remain beset by lingering uncertainties. Examination of the sociology of the accounting occupation within non-Western locations can contribute to exposing and clarifying these problematic and contingent aspects of occupational stratification, as well as assist in redressing the bias towards English-speaking and European countries within the accounting history literature. Proceeding from these theoretical premises, a historical and comparative study of the accounting occupation within China is undertaken. This seeks to integrate the world’s most populous nation into the historical narrative of the professionalisation of accounting, and reinforces – often vividly – that accountants’ work status is not bound to any predetermined trajectory which is innate to the occupation. Instead, the variety of localised and time-specific variables which constitute the occupational context are shown to exert a dominating influence.

Emerging host cell targets for hepatitis C therapy

Chronic hepatitis C virus (HCV) infection is a major burden on humanity. The current HCV therapy has limited efficacy, and there is pressing need for new and more effective therapies. Host cell factors that are required for HCV infection, replication and/or pathogenesis represent potential therapeutic targets. Of particular interest are cellular receptors that mediate HCV entry, factors that facilitate HCV replication and assembly, and intracellular pathways involving lipid biosynthesis, oxidative stress and innate immune response. A crucial challenge now is to manipulate such cellular targets pharmacologically for chronic HCV treatment, without being limited by side effects.

The modelling ability of non-major chemistry students and their understanding of the sub-microscopic level

This case study examined the ability of three first year non-major chemistry students to understand chemical concepts according to Johnstone’s three levels of chemical representations of matter. Students’ background knowledge in chemistry proved to be a powerful factor in their understanding of the submicroscopic level. The results show that modelling ability is not necessarily innate, but it is a skill to be learnt. Each of the students’ modelling abilities with chemical representations improved with instruction and practice. Generally, as modelling skills improved so did students’ understanding of the relevant chemical concept. Modelling ability is described according to Grosslight et al.’s three–tiered level and the ability to traverse the three levels of chemical representation of matter.

Characterization of the zebrafish matrix metalloproteinase 9 gene and its developmental expression pattern

Members of the matrix metalloproteinase (MMP) family are important for the remodeling of the extracellular matrix in a number of biological processes including a variety of immune responses. Two members of the family, MMP2 and MMP9, are highly expressed in specific myeloid cell populations in which they play a role in the innate immune response. To further expand the repertoire of molecular reagents available to study zebrafish myeloid cell development, the matrix metalloproteinase 9 (mmp9) gene from this organism has been identified and characterized. The encoded protein is 680 amino acids with high homology to known MMP9 proteins, particularly those of other teleost fish. Maternal transcripts of mmp9 are deposited in the oocyte and dispersed throughout the early embryo. These are replaced by specific zygotic transcripts in the notochord from 12 h post fertilization (hpf) and also transiently in the anterior mesoderm from 14 to 16 h post fertilization. From 24 h post fertilization, mmp9 expression was detected in a population of circulating white blood cells that are distinct from macrophages, and which migrate to the site of trauma, and so likely represent zebrafish heterophils. In the adult, mmp9 expression was most prominent in the splenic cords, a site occupied by mature myeloid cells in other species. These results suggest that mmp9 will serve as a useful marker of mature myeloid cells in the zebrafish.

Making the pedagogic relay inclusive for indigenous Australian students in mathematics classrooms

Many students are unsuccessful in the study of school mathematics, not because of some innate ability, but because of pedagogical practices. Bernstein (1996) has argued that pedagogy serves as a mechanism for cultural reproduction, so that for those students whose cultures are different from that represented in and through pedagogy, the task of constructing school mathematics is made more difficult. The paper explores the ways in which a teacher changes the pedagogic relay in order to be more inclusive of her students. Her practice is informed by understanding the ways in which pedagogy is a subtle tool for marginalization in mathematics.

UV-induced DNA damage promotes resistance to the biotrophic pathogen Hyaloperonospora parasitica in Arabidopsis

Plant innate immunity to pathogenic microorganisms is activated in response to recognition of extracellular or intracellular pathogen molecules by transmembrane receptors or resistance proteins, respectively. The defense signaling pathways share components with those involved in plant responses to UV radiation, which can induce expression of plant genes important for pathogen resistance. Such intriguing links suggest that UV treatment might activate resistance to pathogens in normally susceptible host plants. Here, we demonstrate that pre-inoculative UV (254 nm) irradiation of Arabidopsis (Arabidopsis thaliana) susceptible to infection by the biotrophic oomycete Hyaloperonospora parasitica, the causative agent of downy mildew, induces dose- and time-dependent resistance to the pathogen detectable up to 7 d after UV exposure. Limiting repair of UV photoproducts by postirradiation incubation in the dark, or mutational inactivation of cyclobutane pyrimidine dimer photolyase, (6-4) photoproduct photolyase, or nucleotide excision repair increased the magnitude of UV-induced pathogen resistance. In the absence of treatment with 254-nm UV, plant nucleotide excision repair mutants also defective for cyclobutane pyrimidine dimer or (6-4) photoproduct photolyase displayed resistance to H. parasitica, partially attributable to short wavelength UV-B (280–320 nm) radiation emitted by incubator lights. These results indicate UV irradiation can initiate the development of resistance to H. parasitica in plants normally susceptible to the pathogen and point to a key role for UV-induced DNA damage. They also suggest UV treatment can circumvent the requirement for recognition of H. parasitica molecules by Arabidopsis proteins to activate an immune response.