Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells

Cellular responses to DNA-damaging agents involve the activation of various DNA damage signaling and transduction pathways. Using quantitative and high-resolution tandem mass spectrometry, we determined global changes in protein level and phosphorylation site profiles following treatment of SILAC (stable isotope labeling by amino acids in cell culture)-labeled murine embryonic stem cells with the anticancer drug cisplatin. Network and pathway analyses indicated that processes related to the DNA damage response and cytoskeleton organization were significantly affected. Although the ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) consensus sequence (S/T-Q motif) was significantly overrepresented among hyperphosphorylated peptides, about half of the >2-fold-upregulated phosphorylation sites based on the consensus sequence were not direct substrates of ATM and ATR. Eleven protein kinases mainly belonging to the mitogen-activated protein kinase (MAPK) family were identified as being regulated in their kinase domain activation loop. The biological importance of three of these kinases (cyclin-dependent kinase 7 [CDK7], Plk1, and KPCD1) in the protection against cisplatin-induced cytotoxicity was demonstrated by small interfering RNA (siRNA)-mediated knockdown. Our results indicate that the cellular response to cisplatin involves a variety of kinases and phosphatases not only acting in the nucleus but also regulating cytoplasmic targets, resulting in extensive cytoskeletal rearrangements. Integration of transcriptomic and proteomic data revealed a poor correlation between changes in the relative levels of transcripts and their corresponding proteins, but a large overlap in affected pathways at the levels of mRNA, protein, and phosphoprotein. This study provides an integrated view of pathways activated by genotoxic stress and deciphers kinases that play a pivotal role in regulating cellular processes other than the DNA damage response

Benefits and barriers to expanding the availability of take-home naloxone in Australia: A qualitative interview study with service providers

Aims: To investigate the perspectives and experiences of service providers regarding provision of take-home naloxone to people who use opioids in Victoria, Australia. Methods: Content analysis of qualitative semi-structured interviews with 15 service providers who are either involved with take-home naloxone programs or whose work brings them in contact with people who use opioids. Findings: Statements about take-home naloxone were universally positive. Both direct and indirect benefits of take-home naloxone were described. Alongside potential reductions in opioid overdose-related harms, service providers highlighted the empowering effects of providing people who use opioids with take-home naloxone. No significant risks were described. Service providers supported the expansion of naloxone availability, but also identified several intertwined barriers to doing so. Key among these were costs, current regulations and scheduling, availability of prescribers and stigma related to illicit and injecting drug use. Conclusions: Expanding the availability of naloxone is a key component of strategies to reduce harms associated with opioid overdose. Our article provides Australian evidence of the successful operational implementation of peer-to-peer THN delivery within a range of drug primary health services and needle syringe programs. Further research is required to better understand the implications of and impediments to scale-up of this potentially life-saving public health intervention

Measurements of J/psi Decays into 2(pi+pi-)eta and 3(pi+pi-)eta

Based on a sample of 5.8X 10^7 J/psi events taken with the BESII detector, the branching fractions of J/psi--> 2(pi+pi-)eta and J/psi-->3(pi+pi-)eta are measured for the first time to be (2.26+-0.08+-0.27)X10^{-3} and (7.24+-0.96+-1.11)X10^{-4}, respectively.Comment: 11 pages, 6 figure

BESII Detector Simulation

A Monte Carlo program based on Geant3 has been developed for BESII detector simulation. The organization of the program is outlined, and the digitization procedure for simulating the response of various sub-detectors is described. Comparisons with data show that the performance of the program is generally satisfactory.Comment: 17 pages, 14 figures, uses elsart.cls, to be submitted to NIM

The σ\sigma pole in J/ψ→ωπ+π−J/\psi \to \omega \pi^+ \pi^-

Using a sample of 58 million $J/\psi$ events recorded in the BESII detector, the decay $J/\psi \to \omega \pi^+ \pi^-$ is studied. There are conspicuous $\omega f_2(1270)$ and $b_1(1235)\pi$ signals. At low $\pi \pi$ mass, a large broad peak due to the $\sigma$ is observed, and its pole position is determined to be $(541 \pm 39)$ - $i$ $(252 \pm 42)$ MeV from the mean of six analyses. The errors are dominated by the systematic errors.Comment: 15 pages, 6 figures, submitted to PL

Study of J/ψ→ωK+K−J/\psi \to \omega K^+K^-

New data are presented on $J/\psi \to \omega K^+K^-$ from a sample of 58M $J/\psi$ events in the upgraded BES II detector at the BEPC. There is a conspicuous signal for $f_0(1710) \to K^+K^-$ and a peak at higher mass which may be fitted with $f_2(2150) \to K\bar K$. From a combined analysis with $\omega \pi ^+ \pi ^-$ data, the branching ratio $BR(f_0(1710)\to\pi\pi)/BR(f_0(1710) \to K\bar K)$ is $< 0.11$ at the 95% confidence level.Comment: 11 pages, 5 figures. Submitted to Phys. Lett.

Search for the Lepton Flavor Violation Processes J/ψ→J/\psi \to μτ\mu\tau and eτe\tau

The lepton flavor violation processes $J/\psi \to \mu\tau$ and $e\tau$ are searched for using a sample of 5.8$\times 10^7$ $J/\psi$ events collected with the BESII detector. Zero and one candidate events, consistent with the estimated background, are observed in $J/\psi \to \mu\tau, \tau\to e\bar\nu_e\nu_{\tau}$ and $J/\psi\to e\tau, \tau\to\mu\bar\nu_{\mu}\nu_{\tau}$ decays, respectively. Upper limits on the branching ratios are determined to be $Br(J/\psi\to\mu\tau)<2.0 \times 10^{-6}$ and $Br(J/\psi \to e\tau) < 8.3 \times10^{-6}$ at the 90% confidence level (C.L.).Comment: 9 pages, 2 figure

Observation of the decay \psip\rar\kstark

Using 14 million $\psi(2S)$ events collected with the BESII detector, branching fractions of \psip\rar\kstarkpm and \kstarknn are determined to be: \calB(\psip\rar\kstarkpm)=(2.9^{+1.3}_{-1.7}\pm0.4)\times 10^{-5} and \calB(\psip\rar\kstarknn)=(13.3^{+2.4}_{-2.7}\pm1.9)\times 10^{-5}. The results confirm the violation of the "12%" rule for these two decay channels with higher precision. A large isospin violation between the charged and neutral modes is observed.Comment: 5 pages, 3 figure