Range‐wide patterns of migratory connectivity in the western sandpiper Calidris mauri

Understanding the population dynamics of migratory animals and predicting the consequences of environmental change requires knowing how populations are spatially connected between different periods of the annual cycle. We used stable isotopes to examine patterns of migratory connectivity across the range of the western sandpiper Calidris mauri. First, we developed a winter isotope basemap from stable‐hydrogen (δD), ‐carbon (δ¹³C), and ‐nitrogen (δ¹⁵N) isotopes of feathers grown in wintering areas. δD and δ¹⁵N values from wintering individuals varied with the latitude and longitude of capture location, while δ¹³C varied with longitude only. We then tested the ability of the basemap to assign known‐origin individuals. Sixty percent of wintering individuals were correctly assigned to their region of origin out of seven possible regions. Finally, we estimated the winter origins of breeding and migrant individuals and compared the resulting empirical distribution against the distribution that would be expected based on patterns of winter relative abundance. For breeding birds, the distribution of winter origins differed from expected only among males in the Yukon‐Kuskokwim (Y‐K) Delta and Nome, Alaska. Males in the Y‐K Delta originated overwhelmingly from western Mexico, while in Nome, there were fewer males from western North America and more from the Baja Peninsula than expected. An unexpectedly high proportion of migrants captured at a stopover site in the interior United States originated from eastern and southern wintering areas, while none originated from western North America. In general, we document substantial mixing between the breeding and wintering populations of both sexes, which will buffer the global population of western sandpipers from the effects of local habitat loss on both breeding and wintering grounds.     

E4orf1 Limits the Oncolytic Potential of the E1B-55K Deletion Mutant Adenovirus

Clinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G₁ phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G₁ restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3′-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function.Conditionally replicating adenoviruses are a novel class of biological agents used to treat cancer (57). The E1B-55K deletion mutant virus ONYX-015, originally known as dl1520 (4), is one of the first of such agents (7). H101 is another E1B-55K deletion mutant adenovirus that is being used for tumor therapy in China (30, 78). We previously reported that cells infected during the G₁ phase of the cell cycle with E1B-55K deletion mutant adenoviruses exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less effectively killed than cells infected during S phase (34, 35, 66). These observations indicated that the E1B-55K deletion mutant virus ONYX-015 is restricted in cells infected in G₁. This restriction is significant because a large fraction of cells within a tumor exist in the G₁ phase of the cell cycle (71). Here we show that the G₁ restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1).The E4orf1-encoded protein is a small adapter molecule that associates with PDZ domain-containing proteins including MUPP1, PATJ, MAGI-1, ZO-2, and Dlg1 (46). PDZ domain-containing proteins often serve as scaffolds for the assembly of signaling complexes at the plasma membrane (64). Through its association with PDZ domain-containing proteins, the E4orf1-encoded protein promotes signaling through the phosphatidylinositol 3′-kinase (PI3-kinase) pathway to effectors such as protein kinase B (Akt), the mammalian target of rapamycin (mTOR), and the S6 ribosomal protein kinase (p70 S6K) (27, 54). Through these effectors, PI3-kinase alters protein synthesis and cell survival (21, 28). E4orf1 is the principal oncogenic determinant of species D adenovirus type 9 (42). The transforming ability of E4orf1 can be blocked by the PI3-kinase inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY249002","term_id":"1257710161","term_text":"LY249002"}}LY249002 (27). However, phosphorylation of p70 S6K can also proceed by pathways that are independent of PI3-kinase or Akt. For example, the Rho-like GTPase Rac1 can activate p70 S6K (17). Rac1 is itself regulated by cellular factors to which it binds, including the Rac1-specific guanine nucleotide exchange factor T-cell lymphoma invasion and metastasis 1 protein (Tiam1). Tiam1 and the neural tissue-associated F-actin-binding protein neurabin II or spinophilin recruit p70 S6K into a complex containing Rac1, resulting in increased phosphorylation of p70 S6K (12, 36, 50). Interestingly, both Tiam1 and neurabin II are PDZ-containing proteins. These observations provided a potential basis by which E4orf1 may modulate protein synthesis and cell survival.In this report, we show for the first time that E4orf1 restricts the abilities of the E1B-55K deletion mutant virus to produce viral progeny, to direct viral late protein synthesis, and to kill tumor cells. Drugs that are reported to prevent phosphorylation of p70 S6K or to disrupt the interaction between Tiam1 and Rac1 increase the cell-killing ability of the E1B-55K deletion mutant virus to nearly the same level observed for an E1B-55K/E4orf1 double mutant and the wild-type virus. By uncovering a role for E4orf1 in the course of a lytic adenovirus infection, this study presents novel genetic and pharmacological means by which the effectiveness of replicating oncolytic adenoviruses can be improved.     

Structural characterization of the human Nogo-A functional domains. Solution structure of Nogo-40, a Nogo-66 receptor antagonist enhancing injured spinal cord regeneration.

The recent discovery of the Nogo family of myelin inhibitors and the Nogo-66 receptor opens up a very promising avenue for the development of therapeutic agents for treating spinal cord injury. Nogo-A, the largest member of the Nogo family, is a multidomain protein containing at least two regions responsible for inhibiting central nervous system (CNS) regeneration. So far, no structural information is available for Nogo-A or any of its structural domains. We have subcloned and expressed two Nogo-A fragments, namely the 182 residue Nogo-A(567-748) and the 66 residue Nogo-66 in Escherichia coli. CD and NMR characterization indicated that Nogo-A(567-748) was only partially structured while Nogo-66 was highly insoluble. Nogo-40, a truncated form of Nogo-66, has been previously shown to be a Nogo-66 receptor antagonist that is able to enhance CNS neuronal regeneration. Detailed NMR examinations revealed that a Nogo-40 peptide had intrinsic helix-forming propensity, even in an aqueous environment. The NMR structure of Nogo-40 was therefore determined in the presence of the helix-stabilizing solvent trifluoroethanol. The solution structure of Nogo-40 revealed two well-defined helices linked by an unstructured loop, representing the first structure of Nogo-66 receptor binding ligands. Our results provide the first structural insights into Nogo-A functional domains and may have implications in further designs of peptide mimetics that would enhance CNS neuronal regeneration.     

Variation in fish community structure, richness, and diversity in 56 Danish lakes with contrasting depth, size, and trophic state: does the method matter?

Organisms inhabiting shallow near-shore waters are at risk of desiccation during water level fluctuations. Using laboratory experiments, we investigated the survival and behavioural defences of four freshwater amphipod species during substratum drying: three Ponto-Caspian invaders (Pontogammarus robustoides, Dikerogammarus haemobaphes and Dikerogammarus villosus) and the native Gammarus fossarum. We hypothesized that they would be able to survive air exposure events as well as to adjust their behaviour by following the decreasing water level and/or burying in the sediments. To test these hypotheses, we examined survival of each species on gradually drying sandy substratum as well as their horizontal and vertical migration behaviours. P. robustoides was most resistant to substratum drying and was the only species burying into the substratum. On the other hand, G. fossarum exhibited distinct horizontal migrations following the retreating waterline. These two species seem to be particularly well adapted to the drying environment. Defence mechanisms of D. haemobaphes and D. villosus were less efficient, though the former species also followed the retreating waterline to some extent. Our study demonstrates that exotic and native gammarids have several adaptations that enable them to invade and persist in habitats experiencing common water level fluctuations.     

Avoidable errors in the modelling of outbreaks of emerging pathogens, with special reference to Ebola

As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely used modelling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far overestimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola virus disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modelling response to future infectious disease outbreaks.     

Elevated blood Hsp60, its structural similarities and cross-reactivity with thyroid molecules,and its presence on the plasma membrane of oncocytes point to the chaperonin as an immunopathogenic factor in Hashimoto's thyroiditis

The role Hsp60 might play in various inflammatory and autoimmune diseases is under investigation, but little information exists pertaining to Hashimoto’s thyroiditis (HT). With the aim to fill this gap, in the present work, we directed our attention to Hsp60 participation in HT pathogenesis. We found Hsp60 levels increased in the blood of HT patients compared to controls. The chaperonin was immunolocalized in thyroid tissue specimens from patients with HT, both in thyrocytes and oncocytes (Hurthle cells) with higher levels compared to controls (goiter). In oncocytes, we found Hsp60 not only in the cytoplasm but also on the plasma membrane, as shown by double immunofluorescence performed on fine needle aspiration cytology. By bioinformatics, we found regions in the Hsp60 molecule with remarkable structural similarity with the thyroglobulin (TG) and thyroid peroxidase (TPO) molecules, which supports the notion that autoantibodies against TG and TPO are likely to recognize Hsp60 on the plasma membrane of oncocytes. This was also supported by data obtained by ELISA, showing that anti-TG and anti-TPO antibodies cross-react with human recombinant Hsp60. Antibody-antigen (Hsp60) reaction on the cell surface could very well mediate thyroid cell damage and destruction, perpetuating inflammation. Experiments with recombinant Hsp60 did not show stimulation of cytokine production by peripheral blood mononuclear cells from HT patients. All together, these results led us to hypothesize that Hsp60 may be an active player in HT pathogenesis via an antibody-mediated immune mechanism.     

Cross-talk between T cells and innate immune cells is crucial for IFN-gamma-dependent tumor rejection

Though the importance of IFN-gamma in tumor immunity has been well-demonstrated, little is known about its source and how it is induced. By using various bone marrow chimeric mice, we show here that IFN-gamma essential for tumor immunity is solely produced by hemopoietic cells. Surprisingly, IFN-gamma derived from T cells was not necessary for tumor immunity in this model. In the immunized mice, in which only innate immune cells have the IFN-gamma-producing potential, tumors were efficiently rejected. The innate immune cells, such as NK1.1(+) cells and CD11b(+) cells, can provide sufficient amounts of IFN-gamma which requires, however, the help of T cells. The close cooperation between T cells and innate immune cells during tumor regression is likely mediated by IL-2. Together, our results clearly illustrate how T cells cooperate with innate immune cells for IFN-gamma-mediated tumor rejection and this may have important indications for clinical trials of tumor immunotherapy.     

Empathy manipulation impacts music-induced emotions: a psychophysiological study on opera

This study investigated the effects of voluntarily empathizing with a musical performer (i.e., cognitive empathy) on music-induced emotions and their underlying physiological activity. N = 56 participants watched video-clips of two operatic compositions performed in concerts, with low or high empathy instructions. Heart rate and heart rate variability, skin conductance level (SCL), and respiration rate (RR) were measured during music listening, and music-induced emotions were quantified using the Geneva Emotional Music Scale immediately after music listening. Listening to the aria with sad content in a high empathy condition facilitated the emotion of nostalgia and decreased SCL, in comparison to the low empathy condition. Listening to the song with happy content in a high empathy condition also facilitated the emotion of power and increased RR, in comparison to the low empathy condition. To our knowledge, this study offers the first experimental evidence that cognitive empathy influences emotion psychophysiology during music listening.     

Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration

Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia. The human paralog Siglec‐8 was also upregulated on microglia in AD. Siglec‐F and Siglec‐8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV‐2 cell line and human stem cell‐derived microglia models. Siglec‐F overexpression activates an endocytic and pyroptotic inflammatory response in BV‐2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine‐based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV‐2 cells. Collectively, our results point to an important role for mouse Siglec‐F and human Siglec‐8 in regulating microglial activation during neurodegeneration.