Modelling heterogeneity in viral-tumour dynamics: The effects of gene-attenuation on viral characteristics

The use of viruses as a cancer treatment is becoming increasingly more robust; however, there is still a long way to go before a completely successful treatment is formulated. One major challenge in the field is to select which virus, out of a burgeoning number of oncolytic viruses and engineered derivatives, can maximise both treatment spread and anticancer cytotoxicity. To assist in solving this problem, an in-depth understanding of the virus-tumour interaction is crucial. In this article, we present a novel integro-differential system with distributed delays embodying the dynamics of an oncolytic adenovirus with a fixed population of tumour cells in vitro, allowing for heterogeneity to exist in the virus and cell populations. The parameters of the model are optimised in a hierarchical manner, the purpose of which is not to obtain a perfect representation of the data. Instead, we place our parameter values in the correct region of the parameter space. Due to the sparse nature of the data it is not possible to obtain the parameter values with any certainty, but rather we demonstrate the suitability of the model. Using our model we quantify how modifications to the viral genome alter the viral characteristics, specifically how the attenuation of the E1B 19 and E1B 55 gene affect the system performance, and identify the dominant processes altered by the mutations. From our analysis, we conclude that the deletion of the E1B 55 gene significantly reduces the replication rate of the virus in comparison to the deletion of the E1B 19 gene. We also found that the deletion of both the E1B 19 and E1B 55 genes resulted in a long delay in the average replication start time of the virus. This leads us to propose the use of E1B 19 gene-attenuated adenovirus for cancer therapy, as opposed to E1B 55 gene-attenuated adenoviruses.</p

Ancient starch analysis of grinding stones from Kokatha Country, South Australia

Identifying the range of plants and/or animals processed by pounding and/or grinding stones has been a rapidly developing research area in world prehistory. In Australia, grinding and pounding stones are ubiquitous across the semi-arid and arid zones and the associated tasks have been mostly informed by ethnographic case studies. More recently, plant microfossil studies have provided important insights to the breadth of plants being exploited in a range of contexts and over long time periods. The preservation of starch and/or phytoliths on the used surfaces of these artefacts is well documented, though the factors determining the survival or destruction of use-related starch residues are still largely unknown. Some of these artefacts have also been used for grinding up small animals and these tasks can be identified by specific staining methods for organic remains such as collagen. In this study, 25 grinding and pounding stones identified during an archaeological project in arid South Australia, were examined for starch and collagen residues. The artefacts were from 3 locations in central South Australia, all located in exposed settings. Of these localities, Site 11 in the Western Valley near Woomera is an important Aboriginal landscape specifically associated with male ceremonial practice in the recent past. The remaining two sites, one in the adjacent Nurrungar Valley and the other near Andamooka 100 km distant, have unrestricted access and potentially a different suite of residues. The Kokatha Mula Nations, the Traditional Owners of Woomera, requested that this study be undertaken to explore the range of plants that may have been processed here. It provided an opportunity to investigate the preservation potential of starch and collagen on grinding stones; explore the range of taphonomic factors involved in the persistence of residues in extreme environmental conditions; and test the methodological developments in identifying specific plant origin of starch residues. Of the 25 grinding/pounding stones tested, 7 yielded starch grains. Geometric morphometric analysis identified 3 economic grass species, Crinum flaccidum (Andamooka Lily) and Typha domingensis (Bulrush/Cumbungi). Folded collagen was identified on one artefact. Oral histories recount the movement between Andamooka and Nurrungar/Western Valley for men's ceremonies, and documented in the movement of stone resources, e.g. oolytic chert. The survival of residues in this environment and the identification of economic plant taxa complement the current knowledge of ceremonial activities and the movement of people and resources across significant distances in arid South Australia

65,000-years of continuous grinding stone use at Madjedbebe, Northern Australia

Grinding stones and ground stone implements are important technological innovations in later human evolution, allowing the exploitation and use of new plant foods, novel tools (e.g., bone points and edge ground axes) and ground pigments. Excavations at the site of Madjedbebe recovered Australia’s (if not one of the world’s) largest and longest records of Pleistocene grinding stones, which span the past 65 thousand years (ka). Microscopic and chemical analyses show that the Madjedbebe grinding stone assemblage displays the earliest known evidence for seed grinding and intensive plant use, the earliest known production and use of edge-ground stone hatchets (aka axes), and the earliest intensive use of ground ochre pigments in Sahul (the Pleistocene landmass of Australia and New Guinea). The Madjedbebe grinding stone assemblage reveals economic, technological and symbolic innovations exemplary of the phenotypic plasticity of Homo sapiens dispersing out of Africa and into Sahul

Emergence of a Neolithic in highland New Guinea by 5000 to 4000 years ago

The emergence of agriculture was one of the most notable behavioral transformations in human history, driving innovations in technologies and settlement globally, referred to as the Neolithic. Wetland agriculture originated in the New Guinea highlands during the mid-Holocene (8000 to 4000 years ago), yet it is unclear if there was associated behavioral change. Here, we report the earliest figurative stone carving and formally manufactured pestles in Oceania, dating to 5050 to 4200 years ago. These discoveries, at the highland site of Waim, occur with the earliest planilateral axe-adzes in New Guinea, the first evidence for fibercraft, and interisland obsidian transfer. The combination of symbolic social systems, complex technologies, and highland agricultural intensification supports an independent emergence of a Neolithic ~1000 years before the arrival of Neolithic migrants (Lapita) from Southeast Asia

Cluster Analysis of Insulin Action in Adipocytes Reveals a Key Role for Akt at the Plasma Membrane*

The phosphatidylinositol 3-kinase/Akt pathway regulates many biological processes, including insulin-regulated GLUT4 insertion into the plasma membrane. However, Akt operates well below its capacity to facilitate maximal GLUT4 translocation. Thus, reconciling modest changes in Akt expression or activity as a cause of metabolic dysfunction is complex. To resolve this, we examined insulin regulation of components within the signaling cascade in a quantitative kinetic and dose-response study combined with hierarchical cluster analysis. This revealed a strong relationship between phosphorylation of Akt substrates and GLUT4 translocation but not whole cell Akt phosphorylation. In contrast, Akt activity at the plasma membrane strongly correlated with GLUT4 translocation and Akt substrate phosphorylation. Additionally, two of the phosphorylated sites in the Akt substrate AS160 clustered separately, with Thr(P)-642 grouped with other Akt substrates. Further experiments suggested that atypical protein kinase Cζ phosphorylates AS160 at Ser-588 and that these two sites are mutually exclusive. These data indicate the utility of hierarchical cluster analysis for identifying functionally related biological nodes and highlight the importance of subcellular partitioning of key signaling components for biological specificity