Physiological responses of three crustacean species to infection by the dinoflagellate-like protist Hematodinium (Alveolata: Syndinea)

This is the first study comparing physiological responses of three decapod species to infection by parasites of the genus Hematodinium, which belongs to the dinoflagellate-like Syndinea. Responses varied profoundly between the crabs Carcinus maenas and Cancer pagurus (Brachyura), but also differed to those of hermit crabs, Pagurus bernhardus (Anomura). Osmoregulatory capacity was reduced significantly in Hematodinium-infected C. maenas, haemolymph pH increased in parasitised C. pagurus and P. bernhardus, and L-lactate concentration decreased in infected P. bernhardus. Changes to tissues and exoskeletons were observed in C. pagurus, but not in C. maenas and P. bernhardus.     

A nonlethal young domesticated ferret (Mustela putorius furo) model for studying pandemic influenza virus A/California/04/2009 (H1N1)

Recent events have heightened the need for the rapid development of vaccines directed against pandemic influenza H1N1 viruses circulating during 2009 to 2010. The current study was conducted to establish a virus challenge dose for a subsequent CA/04 vaccine efficacy study in 3-mo-old domesticated ferrets. An additional consideration in using CA/04 in ferrets is the selection of endpoints on which to base the challenge dose, given the potential nonlethality of this particular model. Four doses ranging from 10(4) to 10(7) TCID(50) units of CA/04 per animal were administered by intranasal instillation to groups of male and female ferrets, and virus titers in nasal washes obtained 1, 3, and 5 d thereafter were determined in MDCK cells. Dosed ferrets developed clinically mild infections. Peak virus titers occurred on day 3 after instillation regardless of dose. Virus-treated ferrets had less weight gain than did untreated ferrets. In conclusion, 3-mo-old ferrets can be infected with doses as low as 10(4) TCID(50) units of CA/04, and virus titers in nasal washes and decreased body weight gain can be used to assess the course of nonlethal infection of 3-mo-old ferrets by CA/04.     

Archaeological Support for the Three-Stage Expansion of Modern Humans across Northeastern Eurasia and into the Americas

Background

Understanding the dynamics of the human range expansion across northeastern Eurasia during the late Pleistocene is central to establishing empirical temporal constraints on the colonization of the Americas [1]. Opinions vary widely on how and when the Americas were colonized, with advocates supporting either a pre-[2] or post-[1], [3], [4], [5], [6] last glacial maximum (LGM) colonization, via either a land bridge across Beringia [3], [4], [5], a sea-faring Pacific Rim coastal route [1], [3], a trans-Arctic route [4], or a trans-Atlantic oceanic route [5]. Here we analyze a large sample of radiocarbon dates from the northeast Eurasian Upper Paleolithic to identify the origin of this expansion, and estimate the velocity of colonization wave as it moved across northern Eurasia and into the Americas.

Methodology/Principal Findings

We use diffusion models [6], [7] to quantify these dynamics. Our results show the expansion originated in the Altai region of southern Siberia ∼46kBP , and from there expanded across northern Eurasia at an average velocity of 0.16 km per year. However, the movement of the colonizing wave was not continuous but underwent three distinct phases: 1) an initial expansion from 47-32k calBP; 2) a hiatus from ∼32-16k calBP, and 3) a second expansion after the LGM ∼16k calBP. These results provide archaeological support for the recently proposed three-stage model of the colonization of the Americas [8], [9]. Our results falsify the hypothesis of a pre-LGM terrestrial colonization of the Americas and we discuss the importance of these empirical results in the light of alternative models.

Conclusions/Significance

Our results demonstrate that the radiocarbon record of Upper Paleolithic northeastern Eurasia supports a post-LGM terrestrial colonization of the Americas falsifying the proposed pre-LGM terrestrial colonization of the Americas. We show that this expansion was not a simple process, but proceeded in three phases, consistent with genetic data, largely in response to the variable climatic conditions of late Pleistocene northeast Eurasia. Further, the constraints imposed by the spatiotemporal gradient in the empirical radiocarbon record across this entire region suggests that North America cannot have been colonized much before the existing Clovis radiocarbon record suggests.     

Vascular Occlusion Training for Inclusion Body Myositis: A Novel Therapeutic Approach

Inclusion body myositis (IBM) is a rare idiopathic inflammatory myopathy. It is known to produces remarkable muscle weakness and to greatly compromise function and quality of life. Moreover, clinical practice suggests that, unlike other inflammatory myopathies, the majority of IBM patients are not responsive to treatment with immunosuppressive or immunomodulatory drugs to counteract disease progression¹. Additionally, conventional resistance training programs have been proven ineffective in restoring muscle function and muscle mass in these patients^2,3. Nevertheless, we have recently observed that restricting muscle blood flow using tourniquet cuffs in association with moderate intensity resistance training in an IBM patient produced a significant gain in muscle mass and function, along with substantial benefits in quality of life⁴. Thus, a new non-pharmacological approach for IBM patients has been proposed. Herein, we describe the details of a proposed protocol for vascular occlusion associated with a resistance training program for this population.Download video file.^{(106M, mp4)}     

Maternal Insulin Sensitivity During Pregnancy Predicts Infant Weight Gain and Adiposity at 1 Year of Age

Emerging evidence suggests that fetal environmental exposures impact on future development of obesity. The objectives of this study were to assess the relationships between (i) maternal insulin sensitivity and glucose tolerance status in pregnancy and (ii) early infant weight gain and adiposity in the first year of life. In this prospective cohort study, 301 women underwent oral glucose tolerance testing for assessment of glucose tolerance status and insulin sensitivity (IS_OGTT) in pregnancy. Their infants underwent anthropometric assessment at 12 months of age, including determination of weight gain in the first year of life and sum of skinfold thickness (SFT), a measure of infant adiposity. Infant weight gain and sum of SFT at 12 months did not differ according to maternal glucose tolerance status. On univariate analyses, weight gain from 0 to 12 months and sum of SFT were negatively associated with maternal IS_OGTT during pregnancy. On multiple linear regression analysis, negative independent predictors of weight gain from 0 to 12 months were maternal IS_OGTT during pregnancy (t = ?2.73; P = 0.007), infant female gender (t = ?3.16; P = 0.002), and parental education (t = ?1.98; P = 0.05), whereas white ethnicity was a positive independent predictor (t = 2.68; P = 0.008). Maternal IS_OGTT (t = ?2.7; P = 0.008) and parental education (t = ?2.58; P = 0.01) were independent negative predictors of sum of SFT at 12 months. Independent of maternal glucose tolerance status, maternal insulin resistance during pregnancy is associated with increased infant weight gain and adiposity over the first year of life. Further longitudinal study to evaluate obesity in this group of children will increase our understanding of the contribution of the intrauterine environment to their long‐term health.     

Differential Modulation of Angiogenesis by Erythropoiesis-Stimulating Agents in a Mouse Model of Ischaemic Retinopathy

Background

Erythropoiesis stimulating agents (ESAs) are widely used to treat anaemia but concerns exist about their potential to promote pathological angiogenesis in some clinical scenarios. In the current study we have assessed the angiogenic potential of three ESAs; epoetin delta, darbepoetin alfa and epoetin beta using in vitro and in vivo models.

Methodology/Principal Findings

The epoetins induced angiogenesis in human microvascular endothelial cells at high doses, although darbepoetin alfa was pro-angiogenic at low-doses (1–20 IU/ml). ESA-induced angiogenesis was VEGF-mediated. In a mouse model of ischaemia-induced retinopathy, all ESAs induced generation of reticulocytes but only epoetin beta exacerbated pathological (pre-retinal) neovascularisation in comparison to controls (p<0.05). Only epoetin delta induced a significant revascularisation response which enhanced normality of the vasculature (p<0.05). This was associated with mobilisation of haematopoietic stem cells and their localisation to the retinal vasculature. Darbepoetin alfa also increased the number of active microglia in the ischaemic retina relative to other ESAs (p<0.05). Darbepoetin alfa induced retinal TNFα and VEGF mRNA expression which were up to 4 fold higher than with epoetin delta (p<0.001).

Conclusions

This study has implications for treatment of patients as there are clear differences in the angiogenic potential of the different ESAs.     

Phosphatidylinostitol-3 kinase and phospholipase C enhance CSF-1-dependent macrophage survival by controlling glucose uptake

Colony stimulating factor-1 (CSF-1)-dependent macrophages play crucial roles in the development and progression of several pathological conditions including atherosclerosis and breast cancer metastasis. Macrophages in both of these pathologies take up increased amounts of glucose. Since we had previously shown that CSF-1 stimulates glucose uptake by macrophages, we have now investigated whether glucose metabolism is required for the survival of CSF-1-dependent macrophages as well as examined the mechanism by which CSF-1 stimulates glucose uptake. Importantly, we found that CSF-1-induced macrophage survival required metabolism of the glucose taken up in response to CSF-1 stimulation. Kinetic studies showed that CSF-1 stimulated an increase in the number of glucose transporters at the plasma membrane, including Glut1. The uptake of glucose induced by CSF-1 required intact PI3K and PLC signalling pathways, as well as the downstream effectors Akt and PKC, together with a dynamic actin cytoskeleton. Expression of constitutively active Akt partially restored glucose uptake and macrophage survival in the absence of CSF-1, suggesting that Akt is necessary but not sufficient for optimal glucose uptake and macrophage survival. Taken together, these results suggest that CSF-1 regulates macrophage survival, in part, by stimulating glucose uptake via Glut1, and PI3K and PLC signalling pathways.