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Figure S1. Synthesis of [3H]apratoxin A. Figure S2. Synthesis of C.18-epi-apratoxin A. Figure S3. Apratoxin A in vitro IC50 against panels of human cancer cell lines. Table S1. Summary table for in vivo efficacy studies. Figure S4. Apratoxin A concentration kinetics in plasma and various tissues in A549 human lung cancer xenograft tumor-bearing mice after a single IV dose (1 mg/kg). Figure S5. Apratoxin A and HUN-7293 have different binding sites on the Sec61 complex. Figure S6. Sec61α and Sec61β protein expression levels among different cell lines.

Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo. Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A–treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a 3H-labeled apratoxin A probe and specific Sec 61α/β antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure. Mol Cancer Ther; 15(6); 1208–16. ©2016 AACR.

Figure S1. Synthesis of [3H]apratoxin A. Figure S2. Synthesis of C.18-epi-apratoxin A. Figure S3. Apratoxin A in vitro IC50 against panels of human cancer cell lines. Table S1. Summary table for in vivo efficacy studies. Figure S4. Apratoxin A concentration kinetics in plasma and various tissues in A549 human lung cancer xenograft tumor-bearing mice after a single IV dose (1 mg/kg). Figure S5. Apratoxin A and HUN-7293 have different binding sites on the Sec61 complex. Figure S6. Sec61α and Sec61β protein expression levels among different cell lines.

Image-based profiling has emerged as a powerful technology for various steps in basic biological and pharmaceutical discovery, but the community has lacked a large, public reference set of data from chemical and genetic perturbations. Here we present data generated by the Joint Undertaking for Morphological Profiling (JUMP)-Cell Painting Consortium, a collaboration between 10 pharmaceutical companies, six supporting technology companies, and two non-profit partners. When completed, the dataset will contain images and profiles from the Cell Painting assay for over 116,750 unique compounds, over-expression of 12,602 genes, and knockout of 7,975 genes using CRISPR-Cas9, all in human osteosarcoma cells (U2OS). The dataset is estimated to be 115 TB in size and capturing 1.6 billion cells and their single-cell profiles. File quality control and upload is underway and will be completed over the coming months at the Cell Painting Gallery:https://registry.opendata.aws/cellpainting-gallery. A portal to visualize a subset of the data is available athttps://phenaid.ardigen.com/jumpcpexplorer/.

Impacted mandibular third molar extraction is one of the most frequent procedures performed in the field of oral surgery. Oral surgeons sometimes face cases that cannot be extracted using the conventional procedure because of atypical tooth structure or irregular tooth position in the mandible. Here, we report an unusual impacted third mandibular molar with atypical root form, which was extracted by buccal cortex osteotomy of the mandibular ramus. A 42-year-old Japanese female presented with a complaint of discomfort in the left molar region. Radiographical examination showed an impacted third molar with a mushroom-like root overlapping the mandibular canal. This lesion was radiographically diagnosed as cemental hyperplasia. The tooth could not be extracted using the conventional procedure, and buccal cortex osteotomy was applied. Briefly, bones necessary for extraction were removed once from the mandibular ramus. After extraction, the bony fragment was repositioned in the original position. The patient experienced no postoperative complications such as nerve paralysis, mandibular angle fracture, and infections. Buccal cortex osteotomy is a simple and easy technique to extract impacted mandibular third molars that cannot be extracted by conventional methods.

Summary Introgression from one species in a specific environment to another may facilitate colonization of the environment by the recipient species. However, such environment‐dependent introgression has been clarified in limited plant taxa.In northern Japan, there are two interfertile oak species: Quercus dentata (Qd) in coastal areas and Q. mongolica var. crispula (Qc) in inland areas. However, at higher latitudes where Qd is rare, a coastal Qc ecotype with Qd‐like traits is distributed in the coastal areas. We distinguished inland Qc, coastal Qc, and coastal Qd populations based on genome‐wide genotypes and multitrait phenotypes and verified introgression from coastal Qd to coastal Qc using reduced library sequencing.Genotypes and phenotypes differed among the populations, and coastal Qc was intermediate between inland Qc and coastal Qd. The ABBA–BABA test showed introgression from coastal Qd to coastal Qc. In coastal Qc, we found various stages of introgression after the first generation of backcross but detected no genomic regions where introgression was enhanced.Overall, we show evidence for introgression from a coastal species to an ecotype of an inland species, which has colonized the coastal environment. It remains unclear whether introgressed alleles are selected in the coastal environment., See also the Editorial on this article by https://doi.org/10.1111/nph.16560.

An internal radiator made of a carbon wire is employed to produce bremsstrahlung-photon beams for meson photoproduction experiments from circulating electrons in a synchrotron at the Research Center for Electron Photon Science, Tohoku University. The horizontal electron-beam size at the radiator location is determined from the decay rate of the resultant photon intensity as a function of the distance between the fixed position of the radiator and the centroid of the electron beam. The horizontal beam size at the radiator location is determined to be 0.74 mm with a statical error less than 0.01 mm for 1.3-GeV circulating electrons. The horizontal correlation between the position and momentum direction of the electron beam is also measured. The horizontal size and correlation are well-reproduced by the design values of the parameters of the synchrotron.

Coherent double neutral-pion photoproduction on the deuteron, γ d → π 0 π 0 d , has been experimentally studied at incident photon energies ranging from 0.75 to 1.15 GeV. The total cross section as a function of the γd center-of-mass energy shows resonance-like behavior, which peaks at approximately 2.47 and 2.63 GeV. The measured angular distribution of deuteron emission is rather flat, which cannot be reproduced by the kinematics of quasi-free π 0 π 0 production with deuteron coalescence. In π 0 d invariant-mass distributions, a clear peak is observed at 2.14 ± 0.01 GeV / c 2 with a width of 0.09 ± 0.01 GeV / c 2 . The spin-parity of this state is restricted to 1 + , 2 + or 3 − from the angular distributions of the two π 0 s. The present work shows strong evidence for the existence of an isovector dibaryon resonance with a mass of 2.14 GeV / c 2 . The 2 + assignment is consistent with the theoretically predicted D 12 state, and also with the energy dependence of the πd partial-wave amplitude P 2 3 for the π ± d → π ± d and π + d → p p reactions.

We measured missing mass spectrum of the ^{12}C(γ,p) reaction for the first time in coincidence with potential decay products from η^{'} bound nuclei. We tagged an (η+p) pair associated with the η^{'}N→ηN process in a nucleus. After applying kinematical selections to reduce backgrounds, no signal events were observed in the bound-state region. An upper limit of the signal cross section in the opening angle cosθ_{lab}^{ηp}

The non-strange \(B=2\) system (dibaryon) has been studied using coherent neutral-meson photoproduction from the deuteron, \(\gamma d\rightarrow \pi ^0\pi ^0d\) and \(\gamma d\rightarrow \pi ^0\eta d\), measured with the FOREST detector at the ELPH facility. A rather flat angular distribution of deuteron emission and a peak in the \(\pi ^0d\) invariant-mass distribution give evidence for the 2.15-GeV isovector dibaryon. The excitation function of the total cross section as a function of the \(\gamma d\) center-of-mass energy for the former reaction shows the evidence for the existence of 2.47- and 2.63-GeV isoscalar dibaryons.

Although the ω meson is one of the best established hadrons, its fundamental properties such as the interaction with the nucleon is not known yet due to the difficulties in realizing scattering experiments. Recently, we have performed high-precision photoproduction experiment of the ω meson from the proton near the threshold. The total cross sections are determined at incident energies ranging from 1.08 to 1.15 GeV. The 1/2 and 3/2 spin-averaged scattering length aωN and effective range rωN between the ω meson and nucleon are extracted from the excitation function of the total cross section using a model with the final-state ωN interaction based on the Lippmann-Schwinger equation. The obtained values are aωp=(−0.97−0.16+0.16)+i(0.07−0.14+0.15) fm and rωp=(+2.78−0.54+0.68)+i(−0.01−0.50+0.46) fm, suggesting a strong repulsion force.

The current experimental information about interactions between the \(\eta \) meson and nucleon (N) is not enough to understand the nature of the \(\eta \) meson in a nucleus. We installed a new spectrometer and started an experiment to determine the \(\eta N\) scattering parameters at the Research Center for Electron Photon Science, Tohoku University. We present the current status of the experiment.

A transmittance monitor has been developed for the second tagged-photon beamline at the Research Center for Electron Photon Science, Tohoku University, Japan. In this beamline, an internal radiator is employed to produce the bremsstrahlung photon beam out of circulating electrons in a synchrotron. The transmittance, which is defined as the probability of finding a photon coming to the target position when an electron is detected with a photon-tagging counter, should be determined to deduce cross sections for photo-induced reactions. The developed monitor consists of a telescope of thin plastic scintillators with a positron and electron converter, and a dedicated circuit implemented in a field-programmable gate array chip. The transmittance can be measured with this monitor for high-intensity photon beams corresponding to 20 MHz tagging signals. The measured transmittance is found to be constant with respect to the photon intensity for each photon-tagging channel.

We have developed a charge-to-time converting (QTC) leading-edge discriminator for plastic-scintillator signals, which is packaged in a NIM-standard double-width module. The pulse width of the discriminator output is approximately proportional to the charge integration of input signals up to 40–50 pC. The non-linearity is 20%, 10%, 4%, and 2% at maximum for the input charges below 7 pC, for 7–10 pC, for 10–20 pC, and above 20 pC, respectively, for the minimum input charges larger than 2 pC. The discriminator could be suitable in the measurement of the timing and charge of plastic-scintillator signals together with a multi-hit time-to-digital converter (TDC) module.

An electromagnetic calorimeter, BGOegg, composed of 1320 BGO crystals, has been constructed at the Research Center for Electron Photon Science, Tohoku University to study the structure of hadrons in detail using photo-induced reactions. The design of the new electromagnetic calorimeter and the basic characteristics of the manufactured BGO crystals are described. A performance test has been conducted for the prototype, which consists of 25 crystals arranged in a 5×5 matrix, using positron beams at energies ranging from 100 to 800 MeV. The obtained energy resolution is ( σ E / E ) 2 = ( 0.63 % ) 2 + ( 1.15 % ± 0.04 % ) 2 / ( E / GeV ) + ( 0.42 % ± 0.03 % ) 2 / ( E / GeV ) 2 at room temperature. The energy resolution corresponds to 1.38 % ± 0.05 % for 1-GeV positrons. The position resolution is found to be σ r / mm = ( 3.07 ± 0.03 ) ( E / GeV ) − 0.202 ± 0.008 which corresponds to an angular resolution of approximately 1 ° for 1-GeV positrons.

An electromagnetic calorimeter complex, FOREST, has been constructed for meson photoproduction experiments at the Research Center for Electron Photon Science, Tohoku University. It consists of three types of calorimeters, which are made of pure cesium-iodide crystals, lead scintillating-fiber modules, and lead glass Cherenkov counters. Each calorimeter is equipped with a plastic scintillator hodoscope to identify charged particles. The design and performance of FOREST are described. The energy responses of test calorimeters have been investigated by using 100–800 MeV positron beams. The energy resolutions of the three calorimeters are found to be approximately 3%, 7%, and 5% for 1-GeV photons, respectively. A cryogenic hydrogen/deuterium target system fitted to the FOREST experiments and a newly developed data acquisition system are also presented.

Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo. Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A–treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a 3H-labeled apratoxin A probe and specific Sec 61α/β antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure. Mol Cancer Ther; 15(6); 1208–16. ©2016 AACR.

A fast beam-profile monitor has been developed for high-energy photon beamlines at the Research Center for Electron Photon Science, Tohoku University. The position of the photon converted into an electron–positron pair in a 0.5 mm-thick aluminum plate is measured with two hodoscopes made of scintillating fibers with cross-sections of 3 × 3 mm 2 . Events in which charged particles are produced upstream are rejected with a charge veto plastic scintillator placed in front of the plate, and pair-production events are identified with a trigger plastic scintillator placed behind the plate. The position is determined by a developed logic module with a field-programmable gate array. The dead time for processing an event is 35 ns, and a high data acquisition efficiency ( ~ 100 % ) can be achieved with this monitor for high-intensity photon beams corresponding to 20 MHz tagging signals.

The B = 2 bound/resonance state (dibaryon) is an interesting object, which can be a molecule consisting of two baryons or a spatially compact hexaquark hadron object. The yd ^ n°n°d reaction has been experimentally investigated at incident energies ranging from 0.58 to 1.15 GeV to study non-strange dibaryons. The angular distributions of deuteron emission in the yd center-of-mass energy cannot be reproduced by quasi-free production of two neutral pions followed by deuteron coalescence. Additionally a 2.14-GeV peak is observed in the n°d invariant mass distribution. These suggest a sequential process such as yd ^ RIS ^ n°RIV ^ n°n°d with an isoscalar dibaryon RIS and an isovector dibaryon RIV. Since the mass of the observed isoscalar dibaryons are close to the sum of the nucleon (N) and nucleon resonance (N*) masses, an S-wave NN* molecule may play a role as a doorway to a dibaryon.

Differential cross sections and photon-beam asymmetries for the γ[over →]p→π^{-}Δ^{++}(1232) reaction have been measured for 0.7

We report the measurement of the $\gamma p \rightarrow K^{+}\Lambda$ and $\gamma p \rightarrow K^{+}\Sigma^{0}$ reactions at SPring-8. The differential cross sections and photon-beam asymmetries are measured at forward $K^{+}$ production angles using linearly polarized tagged-photon beams in the range of $E_{\gamma}=1.5$--3.0 GeV. With increasing photon energy, the cross sections for both $\gamma p \rightarrow K^{+}\Lambda$ and $\gamma p \rightarrow K^{+}\Sigma^{0}$ reactions decrease slowly. Distinct narrow structures in the production cross section have not been found at $E_{\gamma}=1.5$--3.0 GeV. The forward peaking in the angular distributions of cross sections, a characteristic feature of $t$-channel exchange, is observed for the production of $\Lambda$ in the whole observed energy range. A lack of similar feature for $\Sigma^{0}$ production reflects a less dominant role of $t$-channel contribution in this channel. The photon-beam asymmetries remain positive for both reactions, suggesting the dominance of $K^{*}$ exchange in the $t$ channel. These asymmetries increase gradually with the photon energy, and have a maximum value of +0.6 for both reactions. Comparison with theoretical predictions based on the Regge trajectory in the $t$ channel and the contributions of nucleon resonances indicates the major role of $t$-channel contributions as well as non-negligible effects of nucleon resonances in accounting for the reaction mechanism of hyperon photoproduction in this photon energy regime.

Photo-production of hadrons is experimentally studied using 0.8 – 1.2 GeV photon beams at the Research Center for Electron Photon Science, Tohoku University, Japan. Photons areproduced at the bremsstrahlung process by inserting a carbon fiber into the circulating electrons in the 1.3 GeV electron synchrotron. The energy of each photon is determined from the trajectory of the corresponding recoil electron. The energy resolution and time resolution of the current photontagging system is not enough high for the next-generation physics program. We have developed a new system called TaggerIIs. The angular resolution should be higher than 5° to reject the background particles coming from other points than the carbon fiber. The time resolution is required to be less than 200 ps to identify the bunch corresponding to a produced photon. We have adopted a combined system of a multi wire drift chamber and plastic-scintillator hodoscope for the new system. The wire chamber has a frame with length of 1000 mm along pole shape of a bending magnet and consists of 3 sense wire planes (X, X’, X) of wire length of 116 mm. A shape of the cell is hexagonal andthe spacing of the sense wires is 6 mm. The hodoscope consists of 60 plastic scintillators (EJ212) of 30 mm height and 5mm thickness. The width of each scintillator is designed from 5 mm to 30 mm. A performance of the new system has been tested using positron beams. As a result, weachieved that the detection efficiency of the wire chamber was 99%, the angler resolution was 0.60\ensuremath{\unicode{0x25E6 \textbf{and the timing resolution of the hodoscope was 165.8 ps.

We have measured the cross sections for $\pi^0\pi^\pm$ photoproduction on the nucleon in the deuteron with an electromagnetic calorimeter system, FOREST, at the Research Center for Electron Photon Science, Tohoku University, Japan. The incident photon energy ranges from 570 to 1150 MeV, corresponding to the $\gamma N$ center of mass, $W_{\gamma N}$, from 1400 to 1750 MeV. The baryon resonances coupling to $\rho^+ n$ and $\rho^-p$ are observed as intermediate states together with $\Delta$-Kroll-Ruderman background components. The angular distributions for the produced $\rho^+$ and $\rho^-$ mesons are convex downward and upward at high energies ($W_{\gamma N}\sim 1720$ MeV), respectively.

Background The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. Materials and methods We performed a comprehensive analysis of plasma TGF-β1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-β1 and BMP-2 were measured at each time point using a solid-phase ELISA. Results TGF-β1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-β1 was found at 3-week. In normal union group, TGF-β1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-β1 or BMP-2 level was not significantly different between normal union and nonunion groups. Conclusion The expression levels of TGF-β1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.