Mammals of the Upper Henty River Region, Western Tasmania

A mammal survey was conducted in the Upper Henty River Region in western Tasmania. The area had been subject to much disturbance from mining, forestry and frequent fires and was covered by a maze of roads and tracks. Nineteen native species (including bats) were recorded. Four of the species listed in 1983 as occurring in the Lower Gordon Region, 80 km south of the present study area, were not recorded during our survey. It is considered that three of these species would probably have been found in the area with further searching. The fourth species, Mastacomysfuscus, is thought not to be present due to increased fire frequency in the sedgeland areas compared with the Lower Gordon Region. Potorous tridactylus is recorded for the first time from rainforest. Microhabitat selection by Rattus lutreolus and Pseudomys higginsi differed from that previously reported. Disturbance from road construction led to the creation of a new food source for Thylogale billardierii. The abundance of tracks in the area increased ease of movement for carnivorous mammals. Only one introduced species Felis catus, which is also known to occur in the Lower Gordon, was recorded. Disturbance had thus not led to an invasion of exotics

An oral bait vaccination approach for the Tasmanian devil facial tumor diseases

Introduction: The Tasmanian devil (Sarcophilus harrisii) is the largest extant carnivorous marsupial. Since 1996, its population has declined by 77% primarily due to a clonal transmissible tumor, known as devil facial tumor (DFT1) disease. In 2014, a second transmissible devil facial tumor (DFT2) was discovered. DFT1 and DFT2 are nearly 100% fatal.Areas covered: We review DFT control approaches and propose a rabies-style oral bait vaccine (OBV) platform for DFTs. This approach has an extensive safety record and was a primary tool in large-scale rabies virus elimination from wild carnivores across diverse landscapes. Like rabies virus, DFTs are transmitted by oral contact, so immunizing the oral cavity and stimulating resident memory cells could be advantageous. Additionally, exposing infected devils that already have tumors to OBVs could serve as an oncolytic virus immunotherapy. The primary challenges may be identifying appropriate DFT-specific antigens and optimization of field delivery methods.Expert opinion: DFT2 is currently found on a peninsula in southern Tasmania, so an OBV that could eliminate DFT2 should be the priority for this vaccine approach. Translation of an OBV approach to control DFTs will be challenging, but the approach is feasible for combatting ongoing and future disease threats

Variability in Test Interval Is Linked to Glycated Haemoglobin (HbA1c) Trajectory over Time

Aims. We previously showed that the glycated haemoglobin (HbA1c) testing frequency links to diabetes control. Here, we examine the effect of variability in test interval, adjusted for the frequency, on change in HbA1c (delta HbA1c). Materials & Methods. HbA1c results were collected on 83,872 people with HbA1c results at baseline and 5 years (+/- 3 months) later and >= 6 tests during this period. We calculated the standard deviation (SD) of test interval for each individual and examined the link between deciles of SD of the test interval and delta HbA1c level, stratified by baseline HbA1c. Results. In general, less variability in testing frequency (more consistent monitoring) was associated with better diabetes control. This was most evident with moderately raised baseline HbA1c levels (7.0-9.0% (54-75 mmol/mol)). For example, in those with a starting HbA1c of 7.0-7.5% (54-58 mmol/mol), the lowest SD decile was associated with little change in HbA1c over 5 years, while for those with the highest decile, HbA1c rose by 0.4-0.6% (4-6 mmol/mol; p < 0.0001). Multivariate analysis showed that the association was independent of the age/sex/hospital site. Subanalysis suggested that the effect was most pronounced in those aged < 65 years with baseline HbA1c of 7.0-7.5% (54-58 mmol/mol). We observed a 6.7-fold variation in the proportion of people in the top-three SD deciles across general practices. Conclusions. These findings indicate that the consistency of testing interval, not the just number of tests/year, is important in maintaining diabetes control, especially in those with moderately raised HbA1c levels. Systems to improve regularity of HbA1c testing are therefore needed, especially given the impact of COVID-19 on diabetes monitoring

The transcriptional response of Caenorhabditis elegans to ivermectin exposure identifies novel genes involved in the response to reduced food intake

We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n=10) and multiple (n=12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter- and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways

Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation:a role in restraining mast cell degranulation

Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). Here we show expression and activity of 11β-HSD1, but not 11β-HSD2, in mouse mast cells with 11β-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11β-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11β-HSD1-deficient than control mice. These findings suggest that 11β-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses

Effect of different cytokines on mammaglobin and maspin gene expression in normal leukocytes: possible relevance to the assays for the detection of micrometastatic breast cancer

In cancer patients, the ability to detect disseminated tumour cells in peripheral blood or bone marrow could improve prognosis and consent both early detection of metastatic disease and monitoring of the efficacy of systemic therapy. These objectives remain elusive mainly due to the lack of specific genetic markers for solid tumours. The use of surrogate tissue-specific markers can reduce the specificity of the assays and give rise to a clinically unacceptable false-positive rate. Mammaglobin (MAM) and maspin are two putative breast tissue-specific markers frequently used for detection of occult tumour cells in the peripheral blood, bone marrow and lymph nodes of breast cancer patients. In this study, it was evaluated whether MAM and maspin gene expression may be induced in the normal blood and bone marrow cells exposed to a panel of cytokines, including chemotactic factors (C5a, interleukin (IL)-8), LPS, proinflammatory cytokines (TNF-α, IL-1β) and growth factors (IL-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor). The experimental data show that all cytokines included in the panel, except for IL-8, were able to induce maspin expression; on the contrary, MAM gene was never induced. These results suggest that MAM is more specific than maspin and that the possible interference of cytokines should be taken into account in interpreting molecular assays for detection of isolated tumour cells

Boundary Conditions for Elastohydrodynamics of Circular Point Contacts

The paper presents the solution of an elastohydrodynamic point contact condition using inlet and outlet lubricant entrainment with partial counter-flow. The inlet and outlet boundaries are determined using potential flow analysis for the pure rolling of contiguous surfaces. This shows that Swift–Stieber boundary conditions best conform to the observed partial counter-flow at the inlet conjunction, satisfying the compatibility condition. For the outlet region, the same is true when Prandtl–Hopkins boundary conditions are employed. Using these boundary conditions, the predictions conform closely to the measured pressure distribution using a deposited pressure-sensitive micro-transducer in a ball-to-flat race contact. Furthermore, the predicted conjunctional shape closely conforms to the often observed characteristic keyhole conjunction through optical interferometry. The combined numerical–experimental analysis with realistic boundary conditions described here has not hitherto been reported in the literature