Fertility choice, land, and the Malthusian hypothesis

In a standard overlapping generations growth model, with a fixed amount of land and endogenous fertility, the competitive economy converges to a steady state with a zero population growth rate and positive consumption per capita. The Malthusian hypothesis is interpreted as a positive statement about the relationship between population growth and consumption per-capita, when production exhibits diminishing returns to labor and there is a fixed amount of land essential for production. Even when individuals care only about the number of their children and not about their children's welfare, the equilibrium is such that they eventually would choose to have only one child for each adult. Hence, if Malthus's "positive check' on population is the result of the response of optimizing agents to competitively determined prices, Malthus's pessimistic conjecture is not necessarily true, even though his other assumptions hold. -from Authors

Chemotherapeutic compounds targeting the DNA double-strand break repair pathways : the good, the bad, and the promising

The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.

Emotional climate and high quality learning experiences in science teacher education

The role of emotion during learning encounters in science teacher education is under-researched and under-theorized. In this case study we explore the emotional climates, that is, the collective states of emotional arousal, of a preservice secondary science education class to illuminate practice for producing and reproducing high quality learning experiences for preservice science teachers. Theories related to the sociology of emotions informed our analyses from data sources such as preservice teachers’ perceptions of the emotional climate of their class, emotional facial expressions, classroom conversations, and cogenerative dialogue. The major outcome from our analyses was that even though preservice teachers reported high positive emotional climate during the professor’s science demonstrations, they also valued the professor’s in the moment reflections on her teaching that were associated with low emotional climate ratings. We co-relate emotional climate data and preservice teachers’ comments during cogenerative dialogue to expand our understanding of high quality experiences and emotional climate in science teacher education. Our study also contributes refinements to research perspectives on emotional climate.

Weaknesses in the initialisation process of the Common Scrambling Algorithm Stream Cipher

The Common Scrambling Algorithm Stream Cipher (CSASC) is a shift register based stream cipher designed to encrypt digital video broadcast. CSA-SC produces a pseudo-random binary sequence that is used to mask the contents of the transmission. In this paper, we analyse the initialisation process of the CSA-SC keystream generator and demonstrate weaknesses which lead to state convergence, slid pairs and shifted keystreams. As a result, the cipher may be vulnerable to distinguishing attacks, time-memory-data trade-off attacks or slide attacks.

Strategic targeting of the PI3K–NFκB axis in cisplatin-resistant NSCLC

Chemoresistance is a major therapeutic challenge to overcome in NSCLC, in order to improve the current survival rates of <15% at 5 years. We and others have shown increased PI3K signaling in NSCLC to be associated with a more aggressive disease, and a poorer prognosis. In this study, targeted inhibition of three strategic points of the PI3K–NFκB axis was performed with the aim of exploiting vulnerabilities in cisplatin-resistant NSCLC cells. Cisplatin-resistant cell lines were previously generated through prolonged exposure to the drug. Expression of PI3K and NFκB pathway-related genes were compared between cisplatin-resistant cells and their matched parent cells using a gene expression array, qRT-PCR, DNA sequencing, western blot, and immunofluorescence. Targeted inhibition was performed using GDC-0980, a dual PI3K–mTOR inhibitor currently in Phase II clinical trials in NSCLC, and DHMEQ, an inhibitor of NFκB translocation which has been used extensively both in vitro and in vivo. Effects of the two inhibitors were assessed by BrdU proliferation assay and multiparameter viability assay. NFKBIA was shown to be 12-fold overexpressed in cisplatin-resistant cells, with no mutations present in exons 3, 4, or 5 of the gene. Corresponding overexpression of IκBα was also observed. Treatment with DHMEQ (but not GDC-0980) led to significantly enhanced effects on viability and proliferation in cisplatin-resistant cells compared with parent cells. We conclude that NFκB inhibition represents a more promising strategy than PI3K–mTOR inhibition for treatment in the chemoresistance setting in NSCLC.

Reactive Oxygen Species and Reactive Nitrogen Species in Epigenetic Modifications

For the normal homeostasis of a cell, there must be a balance between radical oxygen species/radical nitrogen species (ROS/RNS) production and the neutralization of these species by antioxidant scavenging. In times of stress, this balance is not maintained, and the result is oxidative stress. This stress can affect many pathways in the body and result in pathological consequences. Recent evidence suggests that ROS/RNS can affect the epigenetic regulation of genes by affecting the function of histone and DNA modifying enzymes, thus affecting phenotypic changes within the cellular environment. In the following chapter, we provide a broad overview of how oxidative stress induced by ROS/RNS can affect epigenetics, and using lung disease as our model we link the connection between these processes.

CHURNs : freshness assurance for humans

We present CHURNs, a method for providing freshness and authentication assurances to human users. In computer-to-computer protocols, it has long been accepted that assurances of freshness such as random nonces are required to prevent replay attacks. Typically, no such assurance of freshness is presented to a human in a human-and-computer protocol. A Computer–HUman Recognisable Nonce (CHURN) is a computer-aided random sequence that the human has a measure of control over and input into. Our approach overcomes limitations such as ‘humans cannot do random’ and that humans will follow the easiest path. Our findings show that CHURNs are significantly more random than values produced by unaided humans; that humans may be used as a second source of randomness, and we give measurements as to how much randomness can be gained from humans using our approach; and that our CHURN-generator makes the user feel more in control, thus removing the need for complete trust in devices and underlying protocols. We give an example of how a CHURN may be used to provide assurances of freshness and authentication for humans in a widely used protocol.

Visions and values : the Children’s Book Council of Australia’s prizing of picture books in the twenty-first century

The Children’s Book Council of Australia (CBCA) administers the oldest national prize for children’s literature in Australia. Each year, the CBCA confers “Book of the Year” awards to literature for young people in five categories. In 2001, the establishment of an “Early Childhood” category opened up the venerable “Picture Book” category (first awarded in 1955) to books with an implied readership up to 18 years of age. As a result, this category has emerged in recent years as a highly visible space within which the CBCA can contest discourses of cultural marginalisation insofar as Australian (“colonial”) literature is constructed as inferior or adjunct to the major Anglophone literary traditions, and the consistent identification of children’s literature (and, indeed, of children) as lesser than its ‘adult’ counterparts. The CBCA is engaged in defining, evaluating, and legitimising a tradition of Australian children’s literature which is underpinned by a canonical impulse, and is a reflexive practice of self-definition, self-evaluation and self-legitimisation for the CBCA itself. While it is obviously problematic to identify award winners as a canon, it is equally obvious that literary prizing is a cultural practice derived from the logic of canonicity. In his discussion of the United States’s Newbery Medal, Kenneth Kidd notes that “Medal books are instant classics, the selection process an ostensible simulation of the test of time” (169) and that “the Medal is part of the canonical architecture of children's literature” (169). Thus, it is instructive to consider the visions and values of the national, of the social, and of the literary-aesthetic, in the picture books chosen by the Children’s Book Council of Australia (CBCA) as the “best” of the early twenty-first century. These books not only constitute a kind of canon for contemporary Australian children’s literature, but may well come to define what contemporary Australian children’s literature means in the wider literary field. The Book of the Year: Picture Book awards given by the CBCA since 2001 demonstrate that it is not only true of the Booker Prize that, “The choices of winning books reflect not only on the books themselves, then, but also back on the Prize, affecting its reputation and creating journalistic capital which is vital for the Prize to achieve its prominence and impact.” (81). Many of the twenty-first century CBCA award-winning picture books complicate traditional or comfortable understanding of Australianness, children’s literature, or “appropriate” modes of form and content, reminding us that “moments when texts resist or complicate recuperation into national discourses offer fruitful points for exploring the relationships between text and celebratory context” (Roberts 6). The CBCA has taken the opportunities offered by the liberation of the Picture Book category from an implied readership to challenge dominant constructions of children’s literature in Australia, and in so doing, are engaged in overt practices of canonicity with potentially long-lasting effects. Works Cited: Kidd, Kenneth. “Prizing Children’s Literature: The Case of Newbery Gold.” Children's Literature 35 (2007): 166-190. Roberts, Gillian. Prizing Literature: The Celebration and Circulation of National Culture. Toronto: U Toronto P, 2011. Squires, Claire. “Book Marketing and the Booker Prize.” Judging a Book by Its Cover: Fans, Publishers, Designers, and the Marketing of Fiction. Eds. Nicole Matthews and Nickianne Moody. Aldershot: Ashgate, 2007. 71-82.

Increased sensitivity to tryptophan bioavailability is a positive adaptation by the human strains of Chlamydia pneumoniae

One of the most significant activities induced by interferon-gamma against intracellular pathogens is the induction of IDO (indoleamine 2,3-dioxygenase) expression, which subsequently results in the depletion of tryptophan. We tested the hypothesis that human strains of Chlamydia pneumoniae are more sensitive to tryptophan limitation than animal C. pneumoniae strains. The human strains were significantly more sensitive to IFN-γ than the animal strains in a lung epithelia cell model (BEAS-2B), with exposure to 1 U ml(-1) IFN-γ resulting in complete loss of infectious yield of human strains, compared to the animal strains where reductions in infectious progeny were around 3.5-4.0 log. Strikingly, the IFN-γ induced loss of ability to form infectious progeny production was completely rescued by removal of the IFN-γ and addition of exogenous tryptophan for the human strains, but not the animal strains. In fact, a human heart strain was more capable of entering a non-infectious, viable persistent stage when exposed to IFN-γ and was also more effectively rescued, compared to a human respiratory strain. Exquisite susceptibility to IFN-γ, specifically due to tryptophan availability appears to be a core adaptation of the human C. pneumoniae strains, which may reflect the chronic nature of their infections in this host.

Synthesis and toxicological evaluation of a chitosan‑L‑leucine conjugate for pulmonary drug delivery applications

Herein are reported the synthesis of a conjugate of chitosan with L-leucine, the preparation of nanoparticles from both chitosan and the conjugate for use in pulmonary drug delivery, and the in vitro evaluation of toxicity and inflammatory effects of both the polymers and their nanoparticles on the bronchial epithelial cell line, BEAS-2B. The nanoparticles, successfully prepared both from chitosan and the conjugate, had a diameter in the range of 10−30 nm. The polymers and their nanoparticles were tested for their effects on cell viability by MTT assay, on trans-epithelial permeability by using sodium fluorescein as a fluid phase marker, and on IL-8 secretion by ELISA. The conjugate nanoparticles had a low overall toxicity (IC50 = 2 mg/mL following 48 h exposure; no induction of IL-8 release at 0.5 mg/mL concentration), suggesting that they may be safe for pulmonary drug delivery applications.

The ADAMTS1 protease gene is required for mammary tumor growth and metastasis

A disintegrin and metalloprotease with thrombospondin motifs protein 1 (ADAMTS1) is a protease commonly up-regulated in metastatic carcinoma. Its overexpression in cancer cells promotes experimental metastasis, but whether ADAMTS1 is essential for metastatic progression is unknown. To address this question, we investigated mammary cancer progression and spontaneous metastasis in the MMTV-PyMT mouse mammary tumor model in Adamts1 knockout mice. Adamts1−/−/PyMT mice displayed significantly reduced mammary tumor and lung metastatic tumor burden and increased survival, compared with their wild-type and heterozygous littermates. Histological examination revealed an increased proportion of tumors with ductal carcinoma in situ and a lower proportion of high-grade invasive tumors in Adamts1−/−/PyMT mice, compared with Adamts1+/+/PyMT mice. Increased apoptosis with unaltered proliferation and vascular density in the Adamts1−/−/PyMT tumors suggested that reduced cell survival accounts for the lower tumor burden in ADAMTS1-deficient mice. Furthermore, Adamts1−/− tumor stroma had significantly lesser amounts of proteolytically cleaved versican and increased numbers of CD45+ leukocytes. Characterization of immune cell gene expression indicated that cytotoxic cell activation was increased in Adamts1−/− tumors, compared with Adamts1+/+ tumors. This finding is supported by significantly elevated IL-12+ cell numbers in Adamts1−/− tumors. Thus, in vivo ADAMTS1 may promote mammary tumor growth and progression to metastasis in the PyMT model and is a potential therapeutic target to prevent metastatic breast cancer.

Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis

Background Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. Methods and Results Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCc1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. Conclusions Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.