The hadronic vacuum polarization contribution to aμa_{\mu} from full lattice QCD

We determine the contribution to the anomalous magnetic moment of the muon from the $\alpha^2_{\mathrm{QED}}$ hadronic vacuum polarization diagram using full lattice QCD and including $u/d$ quarks with physical masses for the first time. We use gluon field configurations that include $u$, $d$, $s$ and $c$ quarks in the sea at multiple values of the lattice spacing, multiple $u/d$ masses and multiple volumes that allow us to include an analysis of finite-volume effects. We obtain a result for $a_{\mu}^{\mathrm{HVP,LO}}$ of $667(6)(12)$, where the first error is from the lattice calculation and the second includes systematic errors from missing QED and isospin-breaking effects and from quark-line disconnected diagrams. Our result implies a discrepancy between the experimental determination of $a_{\mu}$ and the Standard Model of 3$\sigma$.Comment: 14 pages, 10 figures. Discussion of method extended with additional tests and figures added. Typographical errors correcte

Measuring Active-Sterile Neutrino Oscillations with a Stopped Pion Neutrino Source

The question of the existence of light sterile neutrinos is of great interest in many areas of particle physics, astrophysics, and cosmology. Furthermore, should the MiniBooNE experiment at Fermilab confirm the LSND oscillation signal, then new measurements are required to identify the mechanism responsible for these oscillations. Possibilities include sterile neutrinos, CP or CPT violation, variable mass neutrinos, Lorentz violation, and extra dimensions. In this paper, we consider an experiment at a stopped pion neutrino source to determine if active-sterile neutrino oscillations with delta-m greater than 0.1 eV2 can account for the signal. By exploiting stopped pi+ decay to produce a monoenergetic nu_mu source, and measuring the rate of the neutral current reaction nu_x + 12C -> nu_x +12C* as a function of distance from the source, we show that a convincing test for active-sterile neutrino oscillations can be performed.Comment: 10 pages, 9 figure

Inclusion and Analysis of Older Adults in RCTs

Surgical oncolog

Higher-order hadronic-vacuum-polarization contribution to the muon g-2 from lattice QCD

We introduce a new method for calculating the ${\rm O}(\alpha^3)$ hadronic-vacuum-polarization contribution to the muon anomalous magnetic moment from ${ab-initio}$ lattice QCD. We first derive expressions suitable for computing the higher-order contributions either from the renormalized vacuum polarization function $\hat\Pi(q^2)$, or directly from the lattice vector-current correlator in Euclidean space. We then demonstrate the approach using previously-published results for the Taylor coefficients of $\hat\Pi(q^2)$ that were obtained on four-flavor QCD gauge-field configurations with physical light-quark masses. We obtain $10^{10} a_\mu^{\rm HVP,HO} = -9.3(1.3)$, in agreement with, but with a larger uncertainty than, determinations from $e^+e^- \to {\rm hadrons}$ data plus dispersion relations.Comment: Expanded and clarified discussion and revised Figure 4. Results unchanged. 11 pages, 5 tables, 5 figures. Version accepted to Physical Review

Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-κB activation and sensitizes toward TNFα-induced cytotoxicity

Drug-induced liver injury (DILI) is an important problem both in the clinic and in the development of new safer medicines. Two pivotal adaptation and survival responses to adverse drug reactions are oxidative stress and cytokine signaling based on the activation of the transcription factors Nrf2 and NF-κB, respectively. Here, we systematically investigated Nrf2 and NF-κB signaling upon DILI-related drug exposure. Transcriptomics analyses of 90 DILI compounds in primary human hepatocytes revealed that a strong Nrf2 activation is associated with a suppression of endogenous NF-κB activity. These responses were translated into quantitative high-content live-cell imaging of induction of a selective Nrf2 target, GFP-tagged Srxn1, and the altered nuclear translocation dynamics of a subunit of NF-κB, GFP-tagged p65, upon TNFR signaling induced by TNFα using HepG2 cells. Strong activation of GFP-Srxn1 expression by DILI compounds typically correlated with suppression of NF-κB nuclear translocation, yet reversely, activation of NF-κB by TNFα did not affect the Nrf2 response. DILI compounds that provided strong Nrf2 activation, including diclofenac, carbamazepine and ketoconazole, sensitized toward TNFα-mediated cytotoxicity. This was related to an adaptive primary protective response of Nrf2, since loss of Nrf2 enhanced this cytotoxic synergy with TNFα, while KEAP1 downregulation was cytoprotective. These data indicate that both Nrf2 and NF-κB signaling may be pivotal in the regulation of DILI. We propose that the NF-κB-inhibiting effects that coincide with a strong Nrf2 stress response likely sensitize liver cells to pro-apoptotic signaling cascades induced by intrinsic cytotoxic pro-inflammatory cytokines

Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/⁺WAPCre mouse model

Insulin analogues are structurally modified molecules with altered pharmaco-kinetic and -dynamic properties compared to regular human insulin used by diabetic patients. While these compounds are tested for undesired mitogenic effects, an epidemiological discussion is ongoing regarding an association between insulin analogue therapy and increased cancer incidence, including breast cancer. Standard in vivo rodent carcinogenesis assays do not pick up this possible increased carcinogenic potential. Here we studied the role of insulin analogues in breast cancer development. For this we used the human relevant mammary gland specific p53R270H/⁺WAPCre mouse model. Animals received life long repeated treatment with four different insulin (-like) molecules: normal insulin, insulin glargine, insulin X10 (AspB10) or insulin-like growth factor 1 (IGF1). Insulin-like molecules with strong mitogenic signaling, insulin X10 and IGF1, significantly decreased the time for tumor development. Yet, insulin glargine and normal insulin, did not significantly decrease the latency time for (mammary gland) tumor development. The majority of tumors had an epithelial to mesenchymal transition phenotype (EMT), irrespective of treatment condition. Enhanced extracellular signaling related kinase (Erk) or serine/threonine kinase (Akt) mitogenic signaling was in particular present in tumors from the insulin X10 and IGF1 treatment groups. These data indicate that insulin-like molecules with enhanced mitogenic signaling increase the risk of breast cancer development. Moreover, the use of a tissue specific cancer model, like the p53R270H/⁺WAPCre mouse model, is relevant to assess the intrinsic pro-carcinogenic potential of mitogenic and non-mitogenic biologicals such as insulin analogues. INTRODUCTION METHODS RESULTS CONCLUSION

ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response

The unfolded protein response (UPR) pathway senses unfolded proteins and regulates proteostasis and cell fate through activity of the transcription factors ATM, ATF6, and XBP1 within a complex network of three main branches. Here, we investigated contributions of the three branches to UPR activity in single cells using microscopy-based quantification and dynamic modeling. BAC-GFP HepG2 reporter cell lines were exposed to tunicamydn, and activation of various UPR components was monitored for 24 h. We constructed a dynamic model to describe the adaptive UPR signaling network, for which incorporation of all three branches was required to match the data. Our calibrated model suggested that ATF6 shapes the early dynamics of pro-apoptotic CHOP. We confirmed this hypothesis by measurements beyond 24 h, by perturbing single siRNA knockdowns and by ATF6 measurements. Overall, our work indicates that ATF6 is an important regulator of CHOP, which in turn regulates cell fate decisions.Toxicolog

Endoplasmic reticulum stress proteins block oxidant-induced Ca2+ increases and cell death

Toxicologi

The Spatial and Temporal Expression Patterns of Integrin α9β1 and One of Its Ligands, the EIIIA Segment of Fibronectin, in Cutaneous Wound Healing

The fibronectins (FN) comprise a family of adhesive extracellular matrix proteins thought to mediate important functions in cutaneous wounds. Plasma fibronectin (pFN) extravasates for days from intact hyperpermeable vessels following injury whereas mRNAs encoding the cellular fibronectins (cFN) that include two segments, termed EIIIA (EDA) and EIIIB (EDB), are expressed by wound cells. Wounds in mice null for pFN appear to heal normally whereas those in EIIIA null mice exhibit defects, suggesting that cFN may play a role when pFN is missing. Integrin α9β1, a receptor for several extracellular matrix proteins as well as the EIIIA segment, is expressed normally in the basal layer of squamous epithelia. We report results from immunohistochemistry on healing wounds demonstrating that EIIIA-containing cFN are deposited abundantly but transiently from day 4 to 7 whereas EIIIB-containing cFN persist at least through day 14. Elevated expression of α9β1 is seen in basal and suprabasal epidermal keratinocytes in wounds. The spatial expression patterns of cFN and α9β1 are distinct, but overlap in the dermal–epidermal junction, and both are expressed contemporaneously. These observations suggest a role for α9β1–EIIIA interactions in wound keratinocyte function