A pathway for mitotic chromosome formation

Mitotic chromosomes fold as compact arrays of chromatin loops. To identify the pathway of mitotic chromosome formation, we combined imaging and Hi-C analysis of synchronous DT40 cell cultures with polymer simulations. Here we show that in prophase, the interphase organization is rapidly lost in a condensin-dependent manner, and arrays of consecutive 60-kilobase (kb) loops are formed. During prometaphase, ~80-kb inner loops are nested within ~400-kb outer loops. The loop array acquires a helical arrangement with consecutive loops emanating from a central spiral staircase condensin scaffold. The size of helical turns progressively increases to ~12 megabases during prometaphase. Acute depletion of condensin I or II shows that nested loops form by differential action of the two condensins, whereas condensin II is required for helical winding

Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

Multi-layer scintillation detector for the MOON double beta decay experiment: Scintillation photon responses studied by a prototype detector MOON-1

An ensemble of multi-layer scintillators is discussed as an option of the high-sensitivity detector Mo Observatory Of Neutrinos (MOON) for spectroscopic measurements of neutrino-less double beta decays. A prototype detector MOON-1, which consists of 6 layer plastic-scintillator plates, was built to study the sensitivity of the MOON-type detector. The scintillation photon collection and the energy resolution, which are key elements for the high-sensitivity experiments, are found to be 1835+/-30 photo-electrons for 976 keV electrons and sigma = 2.9+/-0.1% (dE/E = 6.8+/-0.3 % in FWHM) at the Qbb ~ 3 MeV region, respectively. The multi-layer plastic-scintillator structure with good energy resolution as well as good background suppression of beta-gamma rays is crucial for the MOON-type detector to achieve the inverted hierarchy neutrino mass sensitivity.Comment: 8 pages, 16 figures, submitted to Nucl.Instrum.Met

Supervised machine learning algorithms can classify open-text feedback of doctor performance with human-level accuracy

Background: Machine learning techniques may be an effective and efficient way to classify open-text reports on doctor’s activity for the purposes of quality assurance, safety, and continuing professional development. Objective: The objective of the study was to evaluate the accuracy of machine learning algorithms trained to classify open-text reports of doctor performance and to assess the potential for classifications to identify significant differences in doctors’ professional performance in the United Kingdom. Methods: We used 1636 open-text comments (34,283 words) relating to the performance of 548 doctors collected from a survey of clinicians’ colleagues using the General Medical Council Colleague Questionnaire (GMC-CQ). We coded 77.75% (1272/1636) of the comments into 5 global themes (innovation, interpersonal skills, popularity, professionalism, and respect) using a qualitative framework. We trained 8 machine learning algorithms to classify comments and assessed their performance using several training samples. We evaluated doctor performance using the GMC-CQ and compared scores between doctors with different classifications using t tests. Results: Individual algorithm performance was high (range F score=.68 to .83). Interrater agreement between the algorithms and the human coder was highest for codes relating to “popular” (recall=.97), “innovator” (recall=.98), and “respected” (recall=.87) codes and was lower for the “interpersonal” (recall=.80) and “professional” (recall=.82) codes. A 10-fold cross-validation demonstrated similar performance in each analysis. When combined together into an ensemble of multiple algorithms, mean human-computer interrater agreement was .88. Comments that were classified as “respected,” “professional,” and “interpersonal” related to higher doctor scores on the GMC-CQ compared with comments that were not classified (P.05). Conclusions: Machine learning algorithms can classify open-text feedback of doctor performance into multiple themes derived by human raters with high performance. Colleague open-text comments that signal respect, professionalism, and being interpersonal may be key indicators of doctor’s performance

Auxin-induced rapid degradation of inhibitor of caspase-activated DNase (ICAD) induces apoptotic DNA fragmentation, caspase activation, and cell death:a cell suicide module

Caspase-activated DNase (CAD) is a major apoptotic nuclease, responsible for DNA fragmentation and chromatin condensation during apoptosis. CAD is normally activated in apoptosis as a result of caspase cleavage of its inhibitory chaperone ICAD. Other aspects of CAD regulation are poorly understood. In particular, it has been unclear whether direct CAD activation in non-apoptotic living cells can trigger cell death. Taking advantage of the auxin-inducible degron (AID) system, we have developed a suicide system with which ICAD is rapidly degraded in living cells in response to the plant hormone auxin. Our studies demonstrate that rapid ICAD depletion is sufficient to activate CAD and induce cell death in DT40 and yeast cells. In the vertebrate cells, ectopic CAD activation triggered caspase activation and subsequent hallmarks of caspase-dependent apoptotic changes, including phosphatidylserine exposure and nuclear fragmentation. These observations not only suggest that CAD activation drives apoptosis through a positive feedback loop, but also identify a unique suicide system that can be used for controlling gene-modified organisms