Shimura varieties in the Torelli locus via Galois coverings of elliptic curves

We study Shimura subvarieties of $\mathsf{A}_g$ obtained from families of Galois coverings $f: C \rightarrow C'$ where $C'$ is a smooth complex projective curve of genus $g' \geq 1$ and $g= g(C)$. We give the complete list of all such families that satisfy a simple sufficient condition that ensures that the closure of the image of the family via the Torelli map yields a Shimura subvariety of $\mathsf{A}_g$ for $g' =1,2$ and for all $g \geq 2,4$ and for $g' > 2$ and $g \leq 9$. In a previous work of the first and second author together with A. Ghigi [FGP] similar computations were done in the case $g'=0$. Here we find 6 families of Galois coverings, all with $g' = 1$ and $g=2,3,4$ and we show that these are the only families with $g'=1$ satisfying this sufficient condition. We show that among these examples two families yield new Shimura subvarieties of $\mathsf{A}_g$, while the other examples arise from certain Shimura subvarieties of $\mathsf{A}_g$ already obtained as families of Galois coverings of $\mathbb{P}^1$ in [FGP]. Finally we prove that if a family satisfies this sufficient condition with $g'\geq 1$, then $g \leq 6g'+1$.Comment: 18 pages, to appear in Geometriae Dedicat

Strong time operators associated with generalized Hamiltonians

Let the pair of operators, $(H, T)$, satisfy the weak Weyl relation: $Te^{-itH} = e^{-itH}(T + t)$, where $H$ is self-adjoint and $T$ is closed symmetric. Suppose that g is a realvalued Lebesgue measurable function on \RR such that $g \in C^2(R K)$ for some closed subset K \subset \RR with Lebesgue measure zero. Then we can construct a closed symmetric operator $D$ such that $(g(H), D)$ also obeys the weak Weyl relation.Comment: 10 page

L-infinity algebra connections and applications to String- and Chern-Simons n-transport

We give a generalization of the notion of a Cartan-Ehresmann connection from Lie algebras to L-infinity algebras and use it to study the obstruction theory of lifts through higher String-like extensions of Lie algebras. We find (generalized) Chern-Simons and BF-theory functionals this way and describe aspects of their parallel transport and quantization. It is known that over a D-brane the Kalb-Ramond background field of the string restricts to a 2-bundle with connection (a gerbe) which can be seen as the obstruction to lifting the PU(H)-bundle on the D-brane to a U(H)-bundle. We discuss how this phenomenon generalizes from the ordinary central extension U(1) -> U(H) -> PU(H) to higher categorical central extensions, like the String-extension BU(1) -> String(G) -> G. Here the obstruction to the lift is a 3-bundle with connection (a 2-gerbe): the Chern-Simons 3-bundle classified by the first Pontrjagin class. For G = Spin(n) this obstructs the existence of a String-structure. We discuss how to describe this obstruction problem in terms of Lie n-algebras and their corresponding categorified Cartan-Ehresmann connections. Generalizations even beyond String-extensions are then straightforward. For G = Spin(n) the next step is "Fivebrane structures" whose existence is obstructed by certain generalized Chern-Simons 7-bundles classified by the second Pontrjagin class.Comment: 100 pages, references and clarifications added; correction to section 5.1 and further example to 9.3.1 adde

Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis

Transmission and immunopathology of the avian influenza virus A/Anhui/1/2013 (H7N9) human isolate in three commonly commercialized avian species

H7N9 virus infection is a global concern, given that it can cause severe infection and mortality in humans. However, the understanding of H7N9 epidemiology, animal reservoir species and zoonotic risk remains limited. This work evaluates the pathogenicity, transmissibility and local innate immune response of three avian species harbouring different respiratory distribution of α2,6 and α2,3 SA receptors. Muscovy ducks, European quails and SPF chickens were intranasally inoculated with 105 embryo infectious dose (EID)50 of the human H7N9 (A/Anhui/1/2013) influenza isolate. None of the avian species showed clinical signs or macroscopic lesions, and only mild microscopic lesions were observed in the upper respiratory tract of quail and chickens. Quail presented more severe histopathologic lesions and avian influenza virus (AIV) positivity by immunohistochemistry (IHC), which correlated with higher IL‐6 responses. In contrast, Muscovy ducks were resistant to disease and presented higher IFNα and TLR7 response. In all species, viral shedding was higher in the respiratory than in the digestive tract. Higher viral shedding was observed in quail, followed by chicken and ducks, which presented similar viral titres. Efficient transmission was observed in all contact quail and half of the Muscovy ducks, while no transmission was observed between chicken. All avian species showed viral shedding in drinking water throughout infection.info:eu-repo/semantics/acceptedVersio

Oncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa

BACKGROUND: Oxaliplatin and 5-fluorouracil (5-FU) currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumour responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that oncogenic KRAS in colorectal tumour cells sensitises these cells to chemotherapy. METHODS: FACS analysis was used to determine cell-cycle distribution and the percentage of apoptotic and mitotic cells. A multiplexed RT-PCR assay was used to identify KRAS-controlled apoptosis regulators after exposure to 5-FU or oxaliplatin. Lentiviral expression of short-hairpin RNAs was used to suppress p53 or Noxa. RESULTS: Oncogenic KRAS sensitised colorectal tumour cells to oxaliplatin and 5-FU in a p53-dependent manner and promoted p53 phosphorylation at Ser37 and Ser392, without affecting p53 stabilisation, p21 induction, or cell-cycle arrest. Chemotherapy-induced expression of the p53 target gene Noxa was selectively enhanced by oncogenic KRAS. Suppression of Noxa did not affect p21 induction or cell-cycle arrest, but reduced KRAS/p53-dependent apoptosis after exposure to chemotherapy in vitro and in tumour xenografts. Noxa suppression did not affect tumour growth per se, but strongly reduced the response of these tumours to chemotherapy. CONCLUSION: Oncogenic KRAS determines the cellular response to p53 activation by oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa. British Journal of Cancer (2010) 102, 1254-1264. doi: 10.1038/sj.bjc.6605633 www.bjcancer.com Published online 30 March 2010 (C) 2010 Cancer Research U

Palmitate-induced ER stress and inhibition of protein synthesis in cultured myotubes does not require Toll-like receptor 4

Saturated fatty acids, such as palmitate, are elevated in metabolically dysfunctional condi- tions like type 2 diabetes mellitus. Palmitate has been shown to impair insulin sensitivity and suppress protein synthesis while upregulating proteolytic systems in skeletal muscle. Increased sarco/endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response may contribute to the palmitate-induced impairment of muscle protein synthesis. In some cell types, ER stress occurs through activation of the Toll-like receptor 4 (TLR4). Given the link between ER stress and suppression of protein synthesis, we investigated whether palmitate induces markers of ER stress and protein synthesis by activating TLR4 in cultured mouse C2C12 myotubes. Myotubes were treated with vehicle, a TLR4-specific ligand (lipopolysaccharides), palmitate, or a combination of palmitate plus a TLR4-specific inhibitor (TAK-242). Inflammatory indicators of TLR4 activation (IL-6 and TNFα) and markers of ER stress were measured, and protein synthesis was assessed using puromycin incorporation. Palmitate substantially increased the levels of IL-6, TNF-α, CHOP, XBP1s, and ATF 4 mRNAs and augmented the levels of CHOP, XBP1s, phospho- PERK and phospho-eIF2α proteins. The TLR4 antagonist attenuated both acute palmitate and LPS-induced increases in IL-6 and TNFα, but did not reduce ER stress signaling with either 6 h or 24 h palmitate treatment. Similarly, treating myotubes with palmitate for 6 h caused a 43% decline in protein synthesis consistent with an increase in phospho-eIF2α, and the TLR4 antagonist did not alter these responses. These results suggest that palmitate does not induce ER stress through TLR4 in muscle, and that palmitate impairs protein syn- thesis in skeletal muscle in part by induction of ER stress

Effect of Hypoxia on Expression of Selected Proteins Involved in Regulation of Apoptotic Activity in Striatum of Newborn Piglets

The levels of selected neuroregulatory proteins that inhibit or promote apoptotic cell death were measured in the striatum of piglets subjected to precisely controlled 1 h hypoxic insult followed by 0, 2 and 4 h recovery and compared to sham operated animals. The anti-apoptotic proteins: there were increases in Survivin at 0 (157%, P = 0.031) and 4 h (171%, P = 0.033), in Bcl-XL at 0 (138%, P = 0.028) and 4 h (143%, P = 0.007), in VEGF at 4 h (185%, P = 0.019) and Hsp27 at 2 h (144%, P = 0.05) and 4 h (143%, P = 0.05). The pro-apoptotic proteins: caspases-1 and 7 increased at 4 h (135%, P = 0.05) and (129%, P = 0.038), respectively. Bim increased after 4 h (115%, P = 0.028), Apoptosis Inducing Factor after 2 h (127%, P = 0.048) and Calpain after 4 h (143% of control, P = 0.04). Hypoxia causes increase in levels of both anti- and pro-apoptotic proteins. Their relative activity determines the outcome in terms of cell damage and neuronal deficit