Loss of insulin-mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance

Aim: The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin-mediated microvascular perfusion occurs early in the onset of insulin resistance. Materials and methods: Hooded Wistar rats were fed either a normal diet (ND) or a high-fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic clamp (3 or 10 mU/min/kg × 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2-deoxy-d-glucose (R′g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1-methylxanthine disappearance (1-MXD, an index of microvascular perfusion). Results: Compared with ND-fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the clamps, HFD rats showed an impairment of insulin-mediated action on GIR, hindleg glucose uptake, R′g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin-mediated microvascular perfusion as assessed by 1-MXD. Interestingly, 1-MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin. Conclusions: We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin-mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.

Does reduced mobility through fragmented landscapes explain patch extinction patterns for three honeyeaters?

1.Habitat loss and associated fragmentation are major drivers of biodiversity decline, and understanding how they affect population processes (e.g. dispersal) is an important conservation goal. In a large-scale test employing 10 × 10 km units of replication, three species of Australian birds, the fuscous honeyeater, yellow-tufted honeyeater and white-plumed honeyeater, responded differently to fragmentation. The fuscous and yellow-tufted honeyeaters are ‘decliners’ that disappeared from suitable habitat in landscapes where levels of tree-cover fell below critical thresholds of 17 and 8%, respectively. The white-plumed honeyeater is a ‘tolerant’ species whose likelihood of occurrence in suitable habitat was independent of landscape-level tree-cover. 2.To determine whether the absence of the two decliner species in low tree-cover landscapes can be explained by reduced genetic connectivity, we looked for signatures of reduced mobility and gene flow in response to fragmentation across agricultural landscapes in the Box-Ironbark region of north-central Victoria, Australia. 3.We compared patterns of genetic diversity and population structure at the regional scale and across twelve 100 km2 landscapes with different tree-cover extents. We used genetic data to test landscape models predicting reduced dispersal through the agricultural matrix. We tested for evidence of sex-biased dispersal and sex-specific responses to fragmentation. 4.Reduced connectivity may have contributed to the disappearance of the yellow-tufted honey-eater from low tree-cover landscapes, as evidenced by male bias and increased relatedness among males in low tree-cover landscapes and signals of reduced gene flow and mobility through the agricultural matrix. We found no evidence for negative effects of fragmentation on gene flow in the other decliner, the fuscous honeyeater, suggesting that undetected pressures act on this species. As expected, there was no evidence for decreased movement through fragmented landscapes for the tolerant white-plumed honeyeater. 5.We demonstrated effects of habitat loss and fragmentation (stronger patterns of genetic differentiation, increased relatedness among males) on the yellow-tufted honeyeater above the threshold at which probability of occurrence dropped. Increasing extent and structural connectivity of habitat should be an appropriate management action for this species and other relatively sedentary woodland specialist species for which it can be taken as representative.

The poetic presentation of philosophy:Leo Strauss on Plato’s “symposium”

This essay undertakes a close analysis of Leo Strauss’s remarkable but undertreated Leo Strauss on Plato’s “Symposium,” reading it as opening a privileged purview of his own (and his students’) wider understandings of philosophy, poetry, and politics. The essay begins by drawing out Strauss’s three framing justifications for his manner of reading the Symposium as a document in the “ancient quarrel” of philosophy and poetry concerning which of the two should rightly shape the culture and ethical ideals of the Greeks (part 1). Then, following the course of Plato’s Symposium, the essay ascends through Strauss’s readings of the first five speeches in Plato’s dialogue (part 2) toward the highlight of Strauss’s reading, namely, his three remarkable sessions on Socrates’s speech. Part 3 analyses Strauss’s reading of this speech up to its climax, which Strauss argues involves the philosophical “demotion of poetry”: a criticism of poets as motivated by the Eros of fame and of tragic poetry as at its best creating captivating images of gods and heroes which reflect their creators’ self-love and patriotic love of “one’s own,”as against any transpolitical truth. Part 4 then looks at Strauss’s unusual reading of the culmination of Socrates’s great speech (Diotima on the “higher mysteries”) alongside Alkibiades’s speech in the Symposium as representing Plato’s “poetic presentation of philosophy.” The essay becomes more critical as it proceeds. Strauss’s reading of the Symposium, like his reading of the Republic, is remarkable for its own “demotion of metaphysics” in Plato, and in my concluding remarks, I will question this status, or disappearance, of metaphysics in Strauss’s Platonism and whether this disappearance compromises Strauss' ability to differentiate philosophy as he sees it from poetry.

Late Permian marine ecosystem collapse began in deeper waters: Evidence from brachiopod diversity and body size changes

Analysis of Permian-Triassic brachiopod diversity and body size changes from different water depths spanning the continental shelf to basinal facies in South China provides insights into the process of environmental deterioration. Comparison of the temporal changes of brachiopod diversity between deepwater and shallow-water facies demonstrates that deepwater brachiopods disappeared earlier than shallow-water brachiopods. This indicates that high environmental stress commenced first in deepwater settings and later extended to shallow waters. This environmental stress is attributed to major volcanic eruptions, which first led to formation of a stratified ocean and a chemocline in the outer shelf and deeper water environments, causing the disappearance of deep marine benthos including brachiopods. The chemocline then rapidly migrated upward and extended to shallow waters, causing widespread mass extinction of shallow marine benthos. We predict that the spatial and temporal patterns of earlier onset of disappearance/extinction and ecological crisis in deeper water ecosystems will be recorded during other episodes of rapid global warming.

Effect of cell-surface components and metabolites of lactic acid bacteria and probiotic organisms on cytokine production and induction of CD25 expression in human peripheral mononuclear cells

In the current study, the relative contribution of cell-surface components (CSC) and cell-free supernatants (CFS) in the immuno-modulatory properties of 17 strains of probiotic and lactic acid bacteria (LAB) was assessed. The production of pro- and antiinflammatory cytokines including IL-2, IL-4, IL-10, IL-12 p70, IFN-γ, tumor necrosis factor-α (TNF-α), and transforming growth factor-β was measured at different time points after stimulation of buffy coat derived-peripheral blood mononuclear cells (PBMC) from healthy donors with CSC and CFS of probiotic and LAB. Results showed that CSC of probiotic and LAB strains induced production of T helper 1 and 2 type cytokines. Transforming growth factor-β was stimulated at highest concentrations, followed by IL-10 and TNF-α. The CFS of all tested bacterial strains induced PBMC for significantly high levels of IL-10 secretion compared with unstimulated cells, but the values were less than lipopolysaccharide-stimulated cells. Cytokines due to CFS stimulation showed declined concentration for IL-2, TNF-α, and IL-4, and complete disappearance of IL-12, IFN-γ, and transforming growth factor-β in the cultured medium at 96 h of incubation. Results of cytokine data demonstrate proinflammatory TNF-α immune responses are mainly directed through cell-surface structures of probiotic and LAB, but antiinflammatory immune responses are mediated both by metabolites and cell-surfaces of these bacteria. The induction of CD4(+)CD25(+) regulatory T cells after stimulation of PBMC with CSC and CFS of probiotic and LAB showed regulatory T cell activity appeared to be influenced both by the CSC and metabolites, but was principally triggered by cell surfaces of probiotic and LAB strains.

Lynsey Martin: A case study in 1970s Australian experimental animation

Lynsey Martin’s short experimental Animations remain largely unknown internationally. His graphic 16mm films Approximately Water (4 minutes 1972), Whitewash (1973, 4 minutes), Interview (25 minutes 1973) and Leading Ladies (1975 5 minutes) are analysed for their technique and cultural position, artifacts of a productive if marginalized period of artist made films. These graphic films stand as critical works at the heart experimental filmmaking in Australia and speak through their design and production method to current trends in digital media. Martin’s work includes the use of collage and its erasure, the grain of the photographic image and handpainting and drawing imagery directly on the film surface. Martin deals with the graphic and material elements of the filmstrip, the nature of filmic movement and the nature of photography in public space. For martin his films deal with films deal abstraction and illusionism, elements of chance, the deconstruction of film language, the diary film and process as content. These films stand as historic aesthetic traces of an immediate hands-on approach to image making that came into crisis in Australia through the disappearance of technical education in the 1980s when Martin taught graphic design in technical schools.

Superior performance of aptamer in tumor penetration over antibody : implication of aptamer-based theranostics in solid tumors

Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging.

Sequential polyandry through divorce and re-pairing in a cooperatively breeding bird reduces helper-offspring relatedness

Polyandry is an important component of both sexual selection and kin structuring within cooperatively breeding species. A female may have multiple partners within a single reproductive attempt (simultaneous polyandry) or across multiple broods within and/or across years (sequential polyandry). Both types of polyandry confer a range of costs and benefits to individuals and alter the genetic structure of social groups over time. To date, many molecular studies of cooperative breeders have examined the evolution of cooperative breeding in relation to simultaneous polyandry. However, cooperatively breeding vertebrates are iteroparous, and thus sequential polyandry is also likely, but more rarely considered in this context. We examined sequential polyandry in a cooperatively breeding bird that has a low level of within-brood polyandry. Over a 5-year period (2006–2010), we monitored individual mating relationships using molecular markers in a population of individually marked apostlebirds (Struthidea cinerea). Divorce occurred between reproductive seasons in 17 % (8/48) of pairs and appeared to be female-driven. The level of sequential polyandry was also driven by the disappearance of males after breeding, and over 90 % of females, for whom we had suitable data, bred with multiple males over the period of study. This sequential polyandry significantly altered the relatedness of group members to the offspring in the nest. However, in about half of the cases, the second male was related (first- or second-order relative) to the first male of a sequentially polyandrous female and this alleviated the reduction in relatedness caused by polyandry. Our findings suggest that even in species with high within-brood parentage certainty, helper-offspring relatedness values can quickly erode through sequential polyandry.

Ascorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: findings of a randomized controlled study

AIM/HYPOTHESIS: Skeletal muscle insulin resistance and oxidative stress are characteristic metabolic disturbances in people with type 2 diabetes. Studies in insulin resistant rodents show an improvement in skeletal muscle insulin sensitivity and oxidative stress following antioxidant supplementation. We therefore investigated the potential ameliorative effects of antioxidant ascorbic acid (AA) supplementation on skeletal muscle insulin sensitivity and oxidative stress in people with type 2 diabetes. METHODS: Participants with stable glucose control commenced a randomized cross-over study involving four months of AA (2×500mg/day) or placebo supplementation. Insulin sensitivity was assessed using a hyperinsulinaemic, euglycaemic clamp coupled with infusion of 6,6-D2 glucose. Muscle biopsies were measured for AA concentration and oxidative stress markers that included basal measures (2',7'-dichlorofluorescin [DCFH] oxidation, ratio of reduced-to-oxidized glutathione [GSH/GSSG] and F2-Isoprostanes) and insulin-stimulated measures (DCFH oxidation). Antioxidant concentrations, citrate synthase activity and protein abundances of sodium-dependent vitamin C transporter 2 (SVCT2), total Akt and phosphorylated Akt (ser473) were also measured in muscle samples. RESULTS: AA supplementation significantly increased insulin-mediated glucose disposal (delta rate of glucose disappearance; ∆Rd) (p=0.009), peripheral insulin-sensitivity index (p=0.046), skeletal muscle AA concentration (p=0.017) and muscle SVCT2 protein expression (p=0.008); but significantly decreased skeletal muscle DCFH oxidation during hyperinsulinaemia (p=0.007) when compared with placebo. Total superoxide dismutase activity was also lower following AA supplementation when compared with placebo (p=0.006). Basal oxidative stress markers, citrate synthase activity, endogenous glucose production, HbA1C and muscle Akt expression were not significantly altered by AA supplementation. CONCLUSIONS/INTERPRETATION: In summary, oral AA supplementation ameliorates skeletal muscle oxidative stress during hyperinsulinaemia and improves insulin-mediated glucose disposal in people with type 2 diabetes. Findings implicate AA supplementation as a potentially inexpensive, convenient, and effective adjunct therapy in the treatment of insulin resistance in people with type 2 diabetes.

Hierarchical dirichlet process for tracking complex topical structure evolution and its application to autism research literature

In this paper we describe a novel framework for the discovery of the topical content of a data corpus, and the tracking of its complex structural changes across the temporal dimension. In contrast to previous work our model does not impose a prior on the rate at which documents are added to the corpus nor does it adopt the Markovian assumption which overly restricts the type of changes that the model can capture. Our key technical contribution is a framework based on (i) discretization of time into epochs, (ii) epoch-wise topic discovery using a hierarchical Dirichlet process-based model, and (iii) a temporal similarity graph which allows for the modelling of complex topic changes: emergence and disappearance, evolution, splitting and merging. The power of the proposed framework is demonstrated on the medical literature corpus concerned with the autism spectrum disorder (ASD) - an increasingly important research subject of significant social and healthcare importance. In addition to the collected ASD literature corpus which we made freely available, our contributions also include two free online tools we built as aids to ASD researchers. These can be used for semantically meaningful navigation and searching, as well as knowledge discovery from this large and rapidly growing corpus of literature.