The protein kinase Akt is one of the primary effectors of growth factor signaling in the cell. Akt responds specifically to the lipid second messengers phosphatidylinositol-3,4,5-trisphosphate ...PI(3,4,5)P3 and phosphatidylinositol-3,4-bisphosphate PI(3,4)P2 via its PH domain, leading to phosphorylation of its activation loop and the hydrophobic motif of its kinase domain, which are critical for activity. We have now determined the crystal structure of Akt1, revealing an autoinhibitory interface between the PH and kinase domains that is often mutated in cancer and overgrowth disorders. This interface persists even after stoichiometric phosphorylation, thereby restricting maximum Akt activity to PI(3,4,5)P3- or PI(3,4)P2-containing membranes. Our work helps to resolve the roles of lipids and phosphorylation in the activation of Akt and has wide implications for the spatiotemporal control of Akt and potentially lipid-activated kinase signaling in general.
We present the performance of a semantic segmentation network, sparsessnet, that provides pixel-level classification of MicroBooNE data. The MicroBooNE experiment employs a liquid argon time ...projection chamber for the study of neutrino properties and interactions. sparsessnet is a submanifold sparse convolutional neural network, which provides the initial machine learning based algorithm utilized in one of MicroBooNEs νe-appearance oscillation analyses. The network is trained to categorize pixels into five classes, which are reclassified into two classes more relevant to the current analysis. The output of sparsessnet is a key input in further analysis steps. This technique, used for the first time in liquid argon time projection chambers data and is an improvement compared to a previously used convolutional neural network, both in accuracy and computing resource utilization. The accuracy achieved on the test sample is ≥ 99 %. For full neutrino interaction simulations, the time for processing one image is ≈ 0.5 sec , the memory usage is at 1 GB level, which allows utilization of most typical CPU worker machine.
The protein kinase Akt is one of the primary effectors of growth factor signaling in the cell. Akt responds specifically to the lipid second messengers phosphatidylinositol-3,4,5-trisphosphate ...PI(3,4,5)P
and phosphatidylinositol-3,4-bisphosphate PI(3,4)P
via its PH domain, leading to phosphorylation of its activation loop and the hydrophobic motif of its kinase domain, which are critical for activity. We have now determined the crystal structure of Akt1, revealing an autoinhibitory interface between the PH and kinase domains that is often mutated in cancer and overgrowth disorders. This interface persists even after stoichiometric phosphorylation, thereby restricting maximum Akt activity to PI(3,4,5)P
- or PI(3,4)P
-containing membranes. Our work helps to resolve the roles of lipids and phosphorylation in the activation of Akt and has wide implications for the spatiotemporal control of Akt and potentially lipid-activated kinase signaling in general.
Precise calorimetric reconstruction of 5–50 MeV electrons in liquid argon time projection chambers (LArTPCs) will enable the study of astrophysical neutrinos in DUNE and could enhance the physics ...reach of oscillation analyses. Liquid argon scintillation light has the potential to improve energy reconstruction for low-energy electrons over charge-based measurements alone. Here we demonstrate light-augmented calorimetry for low-energy electrons in a single-phase LArTPC using a sample of Michel electrons from decays of stopping cosmic muons in the LArIAT experiment at Fermilab. Michel electron energy spectra are reconstructed using both a traditional charge-based approach as well as a more holistic approach that incorporates both charge and light. A maximum-likelihood fitter, using LArIAT's well-tuned simulation, is developed for combining these quantities to achieve optimal energy resolution. A sample of isolated electrons is simulated to better determine the energy resolution expected for astrophysical electron-neutrino charged-current interaction final states. In LArIAT, which has very low wire noise and an average light yield of 18 pe / MeV , an energy resolution of σ / E ≃ 9.3 % / √ E ⊕ 1.3 % is achieved. Samples are then generated with varying wire noise levels and light yields to gauge the impact of light-augmented calorimetry in larger LArTPCs. At a charge-readout signal-to-noise of S / N ≃ 30 , for example, the energy resolution for electrons below 40 MeV is improved by ≈ 10 % , ≈ 20 % , and ≈ 40 % over charge-only calorimetry for average light yields of 10 pe / MeV , 20 pe / MeV , and 100 pe / MeV , respectively.
The NuTeV Collaboration has extracted the electroweak parameter sin(2)theta(W) from the measurement of the ratios of neutral current to charged current nu and (-)nu cross sections. Our value, ...sin(2)theta((on-shell))(W) = 0.2277 +/- 0.0013(stat) +/- 0.0009(syst), is 3 standard deviations above the standard model prediction. We also present a model independent analysis of the same data in terms of neutral-current quark couplings.
A detailed knowledge of the thickness of the lithosphere in the north Atlantic is an important parameter for understanding plate tectonics in that region. We achieve this goal with as yet ...unprecedented detail using the seismic technique of S-receiver functions. Clear positive signals from the crust–mantle boundary and negative signals from a mantle discontinuity beneath Greenland, Iceland and Jan Mayen are observed. According to seismological practice, we call the negative phase the lithosphere–asthenosphere boundary (LAB). The seismic lithosphere under most of the Iceland and large parts of central Greenland is about 80 km thick. This depth in Iceland is in disagreement with estimates of the thickness of the elastic lithosphere (10–20 km) found from postglacial rebound data. In the region of flood basalts in eastern Greenland, which overlies the proposed Iceland plume track, the lithosphere is only 70 km thick, about 10 km less than in Iceland which is located directly above the proposed plume. At the western Greenland coast, the lithosphere thickens to 100–120 km, with no indication of the Iceland plume track identified. Below Jan Mayen the lithospheric thickness varies between 40 and 60 km.
Selection programs for fish frequently target growth rate as a breeding goal, yet surprisingly little is known about which mechanisms underlying the growth process are being targeted. The aim of this ...study was thus to examine whether the process of artificial selection of Atlantic salmon (Salmo salar) that has resulted in higher growth rate resulted in underlying changes in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis of endocrine growth regulation. This was tested by comparing similarly reared seventh-generation farm salmon with wild salmon from the principal founder population of the farm strain at three life stages. Not unexpectedly, the domesticated fish outgrew their wild counterparts; this was most evident in salt water, where they averaged three times the weight by the end. Pituitary GH content was positively correlated with growth rate and correspondingly was significantly higher in the faster growing domesticated fish than in the wild fish. Plasma GH levels were also significantly higher in the domesticated fish, whereas IGF-I levels did not differ. These findings provide some of the first direct evidence indicating a link between domestication selection for growth and its endocrine regulation, whereby individuals with more active endocrine growth regulatory components are targeted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein ...kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. Aim: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. Methods: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. Results: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p<0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). Conclusion: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.
The structure of class IB PI3K (p110γ-p101) reveals mechanism of GPCR activation and differences from class IA PI3Ks.
The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of ...immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here, we report the cryo–electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activation through its Gβγ-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gβγ-binding site in p110γ. Mutations at the p110γ-p101 and p110γ–adaptor binding domain interfaces enhanced Gβγ activation. A nanobody that specifically binds to the p101-Gβγ interface blocks activation, providing a novel tool to study and target p110γ-p101–specific signaling events in vivo.
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