Engineering mono- and multi-valent inhibitors on a modular scaffold.

Here we exploit the simple, ultra-stable, modular architecture of consensus-designed tetratricopeptide repeat proteins (CTPRs) to create a platform capable of displaying both single as well as multiple functions and with diverse programmable geometrical arrangements by grafting non-helical short linear binding motifs (SLiMs) onto the loops between adjacent repeats. As proof of concept, we built synthetic CTPRs to bind and inhibit the human tankyrase proteins (hTNKS), which play a key role in Wnt signaling and are upregulated in cancer. A series of mono-valent and multi-valent hTNKS binders was assembled. To fully exploit the modular scaffold and to further diversify the multi-valent geometry, we engineered the binding modules with two different formats, one monomeric and the other trimeric. We show that the designed proteins are stable, correctly folded and capable of binding to and inhibiting the cellular activity of hTNKS leading to downregulation of the Wnt pathway. Multivalency in both the CTPR protein arrays and the hTNKS target results in the formation of large macromolecular assemblies, which can be visualized both in vitro and in the cell. When delivered into the cell by nanoparticle encapsulation, the multivalent CTPR proteins displayed exceptional activity. They are able to inhibit Wnt signaling where small molecule inhibitors have failed to date. Our results point to the tremendous potential of the CTPR platform to exploit a range of SLiMs and assemble synthetic binding molecules with built-in multivalent capabilities and precise, pre-programmed geometries.BBSRC Doctoral Training Programme (DTP) scholarship Oliver Gatty Studentship AstraZeneca PhD studentship. UK Medical Research Foundation. CRUK Pioneer Award (C17838/A22676) CRUK BTERP Award (C17838/A27225) Leverhulme Trust (RPG-2014-089) Cambridge Newton Trust BBSRC project grant (BB/T002697/1)

Observation of Bs->Ds(*)+Ds(*)- using e+e- collisions and a determination of the Bs-Bsbar width difference \Delta\Gamma_s

We have made the first observation of Bs->Ds(*)+Ds(*)- decays using 23.6 fb-1 of data recorded by the Belle experiment running on the Upsilon(5S) resonance. The branching fractions are measured to be B(B^0_s\ra D^+_s D^-_s) = (1.0\,^{+0.4}_{-0.3}\,^{+0.3}_{-0.2})%, B(B^0_s\ra D^{*\pm}_s D^{\mp}_s) = (2.8\,^{+0.8}_{-0.7}\,\pm 0.7)%, and B(B^0_s\ra D^{*+}_s D^{*-}_s) = (3.1\,^{+1.2}_{-1.0}\,\pm 0.8)%; the sum is B(B^0_s\ra D^{(*)+}_s D^{(*)-}_s) = (6.9\,^{+1.5}_{-1.3}\,\pm 1.9)%. Assuming Bs->Ds(*)+Ds(*)- saturates decays to CP-even final states, the branching fraction determines the ratio \Delta\Gamma_s/cos(\phi), where \Delta\Gamma_s is the difference in widths between the two Bs-Bsbar mass eigenstates, and \phi is a CP-violating weak phase. Taking CP violation to be negligibly small, we obtain \Delta\Gamma_s/\Gamma_s = 0.147^{+0.036}_{-0.030}(stat.)^{+0.044}_{-0.042}(syst.), where \Gamma_s is the mean decay width.Comment: 13 pages, 2 figures, 2 tables. v2: text added for clarification, version published in Phys. Rev. Letter

Observation of B+ -> Dbar*0 tau+ nu_tau and Evidence for B+ -> Dbar^0 tau+ nu_tau at Belle

We present measurements of B+ -> Dbar*0 tau+ nu_tau and B+ -> Dbar^0 tau+ nu_tau decays in a data sample of 657 x 10^6 BBbar pairs collected with the Belle detector at the KEKB asymmetric-energy e+e- collider. We find 446^{+58}_{-56} events of the decay B+ -> Dbar*0 tau+ nu_tau with a significance of 8.1 standard deviations, and 146^{+42}_{-41} events of the decay B+ -> Dbar0 tau+ nu_tau with a significance of 3.5 standard deviations. The latter signal provides the first evidence for this decay mode. The measured branching fractions are B(B+ -> Dbar*0 tau+ nu_tau)=(2.12^{+0.28}_{-0.27} (stat) +- 0.29 (syst)) % and B(B+ -> Dbar0 tau+ nu_tau)=(0.77 +- 0.22 (stat) +- 0.12 (syst)) %.Comment: 6 pages, 4 figures, submitted to Phys. Rev. Let

Measurement of CP violating asymmetries in B^0 -> K^+K^- K^0_S decays with a time-dependent Dalitz approach

We report a measurement of $CP$ violating asymmetries in $B^0(\overline{B}^0) \to K^+ K^- K^0_S$ decays with a time-dependent Dalitz approach. This analysis is based on a data sample of $657\times 10^6$ $B\overline{B}$ pairs accumulated at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB asymmetric-energy $e^+e^-$ collider. As the result of an unbinned maximum likelihood fit to the selected candidates, the mixing-induced and direct $CP$ violation parameters, $\phi^{\rm eff}_1$ and ${\cal A}_{CP}$ are obtained for $B^0 \to \phi(1020) K^0_S$, $B^0 \to f_0(980) K^0_S$ and other $B^0 \to K^+ K^- K^0_S$ decays. We find four solutions that describe the data. There are \{eqnarray*} \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (32.2 \pm 9.0 \pm 2.6 \pm 1.4)^{\circ}; \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (26.2 \pm 8.8 \pm 2.7 \pm 1.2)^{\circ};\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (27.3 \pm 8.6 \pm 2.8 \pm 1.3)^{\circ}\; {\rm and}\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (24.3 \pm 8.0 \pm 2.9 \pm 5.2)^{\circ}.{eqnarray*}\ The values for the $CP$ violating phase in $B^0\to \phi(1020) K^0_S$ are similar but other properties of the Dalitz plot are quite different for the four solutions. These four solutions have consistent $\phi^{\rm eff}_1$ values for all three $B$ meson decay channels and none of them deviates significantly from the values measured in $B \to (c\bar{c}) K^0$ decays with the currently available statistics. In addition, we find no significant direct $CP$ violation.Comment: submitted to PR

Search for Lepton Flavor and Lepton Number Violating tau Decays into a Lepton and Two Charged Mesons

We search for lepton flavor and lepton number violating tau decays into a lepton (ell = electron or muon) and two charged mesons (h,h' = pi^\pm or K^\pm), tau- -> ell-h+h'- and tau- -> ell+h-h'-, using 671 fb^{-1} of data collected with the Belle detector at the KEKB asymmetric-energy e+e- collider. We obtain 90% C.L. upper limits on the branching fractions in the range (4.4-8.8)x10^{-8} for tau -> ehh', and (3.3-16)x10^{-8} for tau -> muhh' processes. These results improve upon previously published upper limits by factors between 1.6 to 8.8.Comment: 15 page, 7 figures, submitted to Phys. Lett.

Search for CP violation in the decays D(s)+→KS0π+D^+_{(s)} \to K_S^0\pi^+ and D(s)+→KS0K+D^+_{(s)} \to K_S^0K^+

We have searched for CP violation in the charmed meson decays $D^{+}_{(s)}\to K^0_S\pi^+$ and $D^{+}_{(s)}\to K^0_S K^+$ using 673 fb$^{-1}$ of data collected with the Belle detector at the KEKB asymmetric-energy $e^+e^-$ collider. No evidence for CP violation is observed. We report the most sensitive CP asymmetry measurements to date for these decays: $A_{CP}^{D^+\to K^0_S\pi^+}=(-0.71\pm0.19\pm0.20)$, $A_{CP}^{D^+_s\to K^0_S\pi^+}=(+5.45\pm2.50\pm0.33)$, $A_{CP}^{D^+\to K^0_S K^+}=(-0.16\pm0.58\pm0.25)$, and $A_{CP}^{D^+_s\to K^0_S K^+}=(+0.12\pm0.36\pm0.22)$, where the first uncertainties are statistical and the second are systematic

Measurement of CP asymmetries in B0→K0π0B^0 \to K^0\pi^0 decays

We report measurements of CP violation parameters in $B^0 \to K^0 \pi^0$ decays based on a data sample of $657 \times 10^6 B\bar{B}$ pairs collected with the Belle detector at the KEKB $e^+ e^-$ asymmetric-energy collider. We use $B^0 \to K^0_S \pi^0$ decays for both mixing-induced and direct $CP$ violating asymmetry measurements and $B^0 \to K^0_L \pi^0$ decays for the direct CP violation measurement. The CP violation parameters obtained are $\sin 2 \phi_1^{\rm eff} = +0.67 \pm 0.31{(stat)} \pm 0.08 {(syst)}$ and $\mathcal{A}_{K^0 \pi^0} = +0.14 \pm 0.13{(stat)} \pm 0.06 {(syst)}$. The branching fraction of $B^0 \to K^0 \pi^0$ decay is measured to be $\mathcal{B}(B^0 \to K^0 \pi^0) = (8.7\pm0.5 (\rm{stat.})\pm0.6 (\rm{syst.}))\times 10^{-6}$. The observed $\mathcal{A}_{K^0 \pi^0}$ value differs by 1.9 standard deviations from the value expected from an isospin sum rule.Comment: 6 pages, 3 figure

Measurement of CP violating asymmetries in B^0 -> K^+K^- K^0_S decays with a time-dependent Dalitz approach

We report a measurement of $CP$ violating asymmetries in $B^0(\overline{B}^0) \to K^+ K^- K^0_S$ decays with a time-dependent Dalitz approach. This analysis is based on a data sample of $657\times 10^6$ $B\overline{B}$ pairs accumulated at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB asymmetric-energy $e^+e^-$ collider. As the result of an unbinned maximum likelihood fit to the selected candidates, the mixing-induced and direct $CP$ violation parameters, $\phi^{\rm eff}_1$ and ${\cal A}_{CP}$ are obtained for $B^0 \to \phi(1020) K^0_S$, $B^0 \to f_0(980) K^0_S$ and other $B^0 \to K^+ K^- K^0_S$ decays. We find four solutions that describe the data. There are \{eqnarray*} \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (32.2 \pm 9.0 \pm 2.6 \pm 1.4)^{\circ}; \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (26.2 \pm 8.8 \pm 2.7 \pm 1.2)^{\circ};\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (27.3 \pm 8.6 \pm 2.8 \pm 1.3)^{\circ}\; {\rm and}\\ \phi_1^{\rm eff}(B^0\to \phi(1020) K^0_S) & = & (24.3 \pm 8.0 \pm 2.9 \pm 5.2)^{\circ}.{eqnarray*}\ The values for the $CP$ violating phase in $B^0\to \phi(1020) K^0_S$ are similar but other properties of the Dalitz plot are quite different for the four solutions. These four solutions have consistent $\phi^{\rm eff}_1$ values for all three $B$ meson decay channels and none of them deviates significantly from the values measured in $B \to (c\bar{c}) K^0$ decays with the currently available statistics. In addition, we find no significant direct $CP$ violation.Comment: submitted to PR

First Measurement of Inclusive B -> X_s eta Decays

We report a first measurement of inclusive B -> X_s eta decays, where X_s is a charmless state with unit strangeness. The measurement is based on a pseudo-inclusive reconstruction technique and uses a sample of 657 x 10^6 BB-bar pairs accumulated with the Belle detector at the KEKB e^+e^- collider. For M_{X_s} < 2.6 GeV/c^2, we measure a branching fraction of (26.1 +/- 3.0 (stat) +1.9 -2.1 (syst) +4.0 -7.1 (model)) x 10^-5 and a direct CP asymmetry of A_{CP} = -0.13 +/- 0.04 +0.02 -0.03. Over half of the signal occurs in the range M_{X_s} > 1.8 GeV/c^2.Comment: 6 pages, 1 figure, 1 table, submitted to Physical Review Letter

Measurement of D+→KS0K+D^+ \to K_S^0 K^+ and Ds+→KS0π+D^+_s \to K_S^0 \pi^+ branching ratios

We report an improved measurement of $D^+ \to K_S^0 K^+$ and $D^+_s\to K_S^0 \pi^+$ branching ratios using 605 fb$^{-1}$ of data collected with the Belle detector at the KEKB asymmetric-energy $e^+ e^-$ collider. The measured branching ratios with respect to the Cabibbo-favored modes are $\mathcal{B}(D^+ \to K_S^0 K^+)/\mathcal{B}(D^+ \to K_S^0 \pi^+)$ = 0.1899$\pm0.0011\pm$0.0022 and $\mathcal{B}(D^+_s \to K_S^0 \pi^+)/\mathcal{B}(D^+_s \to K_S^0 K^+)$ = 0.0803$\pm0.0024\pm$0.0019 where the first uncertainties are statistical and the second are systematic