Engineered Knottin Peptide Enables Noninvasive Optical Imaging of Intracranial Medulloblastoma

Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to α β , α β , and α β integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α β integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging

Observation of the nonlinear Hall effect under time reversal symmetric conditions

The electrical Hall effect is the production of a transverse voltage under an out-of-plane magnetic field. Historically, studies of the Hall effect have led to major breakthroughs including the discoveries of Berry curvature and the topological Chern invariants. In magnets, the internal magnetization allows Hall conductivity in the absence of external magnetic field. This anomalous Hall effect (AHE) has become an important tool to study quantum magnets. In nonmagnetic materials without external magnetic fields, the electrical Hall effect is rarely explored because of the constraint by time-reversal symmetry. However, strictly speaking, only the Hall effect in the linear response regime, i.e., the Hall voltage linearly proportional to the external electric field, identically vanishes due to time-reversal symmetry. The Hall effect in the nonlinear response regime, on the other hand, may not be subject to such symmetry constraints. Here, we report the observation of the nonlinear Hall effect (NLHE) in the electrical transport of the nonmagnetic 2D quantum material, bilayer WTe2. Specifically, flowing an electrical current in bilayer WTe2 leads to a nonlinear Hall voltage in the absence of magnetic field. The NLHE exhibits unusual properties sharply distinct from the AHE in metals: The NLHE shows a quadratic I-V characteristic; It strongly dominates the nonlinear longitudinal response, leading to a Hall angle of about 90 degree. We further show that the NLHE directly measures the "dipole moment" of the Berry curvature, which arises from layer-polarized Dirac fermions in bilayer WTe2. Our results demonstrate a new Hall effect and provide a powerful methodology to detect Berry curvature in a wide range of nonmagnetic quantum materials in an energy-resolved way

Zinc Coordination Is Required for and Regulates Transcription Activation by Epstein-Barr Nuclear Antigen 1

Epstein-Barr Nuclear Antigen 1 (EBNA1) is essential for Epstein-Barr virus to immortalize naïve B-cells. Upon binding a cluster of 20 cognate binding-sites termed the family of repeats, EBNA1 transactivates promoters for EBV genes that are required for immortalization. A small domain, termed UR1, that is 25 amino-acids in length, has been identified previously as essential for EBNA1 to activate transcription. In this study, we have elucidated how UR1 contributes to EBNA1's ability to transactivate. We show that zinc is necessary for EBNA1 to activate transcription, and that UR1 coordinates zinc through a pair of essential cysteines contained within it. UR1 dimerizes upon coordinating zinc, indicating that EBNA1 contains a second dimerization interface in its amino-terminus. There is a strong correlation between UR1-mediated dimerization and EBNA1's ability to transactivate cooperatively. Point mutants of EBNA1 that disrupt zinc coordination also prevent self-association, and do not activate transcription cooperatively. Further, we demonstrate that UR1 acts as a molecular sensor that regulates the ability of EBNA1 to activate transcription in response to changes in redox and oxygen partial pressure (pO2). Mild oxidative stress mimicking such environmental changes decreases EBNA1-dependent transcription in a lymphoblastoid cell-line. Coincident with a reduction in EBNA1-dependent transcription, reductions are observed in EBNA2 and LMP1 protein levels. Although these changes do not affect LCL survival, treated cells accumulate in G0/G1. These findings are discussed in the context of EBV latency in body compartments that differ strikingly in their pO2 and redox potential

Observation of J/ψJ/\psi decays to e+e−e+e−e^{+}e^{-}e^{+}e^{-} and e+e−μ+μ−e^{+}e^{-}\mu^{+}\mu^{-}

Using a data sample of $4.481\times 10^8$ $\psi(3686)$ events collected with the BESIII detector, we report the first observation of the four-lepton-decays $J/\psi\to e^+e^-e^+e^-$ and $J/\psi\to e^+e^-\mu^+\mu^-$ utilizing the process $\psi(3686)\to \pi^+\pi^- J/\psi$. The branching fractions are determined to be $[4.32\pm0.26~(\rm stat)\pm0.19~(\rm syst)]\times 10^{-5}$ and $[2.45~\pm0.21~(\rm stat)\pm0.10~(\rm syst)]\times 10^{-5}$, respectively. The results deviate from theoretical predictions, by 2.8 and 5.2 $\sigma$, respectively. No significant signal is observed for $J/\psi\to \mu^+\mu^-\mu^+\mu^-$, and an upper limit on the branching fraction is set at $1.6\times 10^{-6}$ at the 90$\%$ confidence level. A CP asymmetry observable is constructed for the first two channels, which is measured to be $(-0.019\pm0.067\pm0.025)$ and $(-0.016\pm0.081\pm0.003)$, respectively. No evidence for CP violation is observed in this process.Comment: 9 pages, 1 figur

Amplitude analysis of Ds+→π+π−π+D_s^{+} \rightarrow \pi^{+} \pi^{-} \pi^{+}

Utilizing the data set corresponding to an integrated luminosity of $3.19$ fb$^{-1}$ collected by the BESIII detector at a center-of-mass energy of 4.178 GeV, we perform an amplitude analysis of the $D_s^+\to\pi^+\pi^-\pi^+$ decay. The sample contains 13,797 candidates with a signal purity of $\sim$80%. The amplitude and phase of the contributing $\pi\pi$ ${\cal S}$ wave are measured based on a quasi-model-independent approach, along with the amplitudes and phases of the ${\cal P}$ and ${\cal D}$ waves parametrized by Breit-Wigner models. The fit fractions of different intermediate decay channels are also reported.Comment: 14 pages, 6 figure

Search for New Hadronic Decays of hch_c and Observation of hc→K+K−π+π−π0h_c\rightarrow K^{+}K^{-}\pi^{+}\pi^{-}\pi^{0}

Ten hadronic final states of the $h_c$ decays are investigated via the process $\psi(3686)\rightarrow \pi^0 h_c$, using a data sample of $(448.1 \pm 2.9) \times 10^6$ $\psi(3686)$ events collected with the BESIII detector. The decay channel $h_c\rightarrow K^{+}K^{-}\pi^{+}\pi^{-}\pi^{0}$ is observed for the first time with a significance of $6.0 \sigma$. The corresponding branching fraction is determined to be $\mathcal{B}(h_c\rightarrow K^{+}K^{-}\pi^{+}\pi^{-}\pi^{0}) =(3.3 \pm 0.6 \pm 0.6)\times 10^{-3}$ (the first uncertainty is statistical and the second systematical). Evidence for the decays $h_c\rightarrow \pi^{+} \pi^{-} \pi^{0} \eta$ and $h_c\rightarrow K^{0}_{S}K^{\pm}\pi^{\mp}\pi^{+}\pi^{-}$ is found with a significance of $3.6 \sigma$ and $3.8 \sigma$, respectively. The corresponding branching fractions (and upper limits) are obtained to be $\mathcal{B}(h_c\rightarrow \pi^{+} \pi^{-} \pi^{0} \eta ) =(7.2 \pm 1.8 \pm 1.3)\times 10^{-3}$ $(< 1.8 \times 10^{-2})$ and $\mathcal{B}(h_c\rightarrow K^{0}_{S}K^{\pm}\pi^{\mp}\pi^{+}\pi^{-}) =(2.8 \pm 0.9 \pm 0.5)\times 10^{-3}$ $(<4.7\times 10^{-3})$. Upper limits on the branching fractions for the final states $h_c \rightarrow K^{+}K^{-}\pi^{0}$, $K^{+}K^{-}\eta$, $K^{+}K^{-}\pi^{+}\pi^{-}\eta$, $2(K^{+}K^{-})\pi^{0}$, $K^{+}K^{-}\pi^{0}\eta$, $K^{0}_{S}K^{\pm}\pi^{\mp}$, and $p\bar{p}\pi^{0}\pi^{0}$ are determined at a confidence level of 90\%.Comment: 10 pages, 2 figure

Measurement of Branching Fractions of Singly Cabibbo-suppressed Decays Λc+→Σ0K+\Lambda_c^+ \rightarrow \Sigma^{0} K^+ and Σ+KS0\Sigma^{+} K_{S}^0

Based on a sample of 4.4 $\mathrm{fb}^{-1}$ of $e^{+}e^{-}$ annihilation data collected in the energy region between 4.6 GeV and 4.7 GeV with the BESIII detector at BEPCII, two singly Cabibbo-suppressed decays $\Lambda_c^+ \rightarrow \Sigma^0 K^+$ and $\Lambda_{c}^{+} \rightarrow \Sigma^+ K_{S}^0$ are studied. The ratio of the branching fraction $\mathcal{B}(\Lambda_c^+ \rightarrow \Sigma^0 K^+)$ relative to $\mathcal{B}(\Lambda_c^+ \rightarrow \Sigma^0 \pi^+)$ is measured to be $0.0361 \pm 0.0073(\mathrm{stat.}) \pm 0.0005(\mathrm{syst.})$, and the ratio of $\mathcal{B}(\Lambda_c^+ \rightarrow \Sigma^+ K_{S}^0)$ relative to $\mathcal{B}(\Lambda_{c}^{+} \rightarrow \Sigma^+ \pi^+ \pi^-)$ is measured to be $0.0106 \pm 0.0031(\mathrm{stat.}) \pm 0.0004(\mathrm{syst.})$. After taking the world-average branching fractions of the reference decay channels, the branching fractions $\mathcal{B}(\Lambda_c^+ \rightarrow \Sigma^0 K^+)$ and $\mathcal{B}(\Lambda_{c}^{+} \rightarrow \Sigma^+ K_{S}^0)$ are determined to be $(4.7\pm 0.9(\mathrm{stat.})\pm 0.1(\mathrm{syst.}) \pm 0.3(\mathrm{ref.}))\times10^{-4}$ and $(4.8\pm 1.4(\mathrm{stat.})\pm 0.2(\mathrm{syst.}) \pm 0.3(\mathrm{ref.}))\times10^{-4}$, respectively. The branching fraction of the $\Lambda_{c}^{+} \rightarrow \Sigma^+ K_{S}^0$ decay is measured for the first time.Comment: 13 pages, 4 figure