Smc5/6 is required for repair at collapsed replication forks.

In eukaryotes, three pairs of structural-maintenance-of-chromosome (SMC) proteins are found in conserved multisubunit protein complexes required for chromosomal organization. Cohesin, the Smc1/3 complex, mediates sister chromatid cohesion while two condensin complexes containing Smc2/4 facilitate chromosome condensation. Smc5/6 scaffolds an essential complex required for homologous recombination repair. We have examined the response of smc6 mutants to the inhibition of DNA replication. We define homologous recombination-dependent and -independent functions for Smc6 during replication inhibition and provide evidence for a Rad60-independent function within S phase, in addition to a Rad60-dependent function following S phase. Both genetic and physical data show that when forks collapse (i.e., are not stabilized by the Cds1Chk2 checkpoint), Smc6 is required for the effective repair of resulting lesions but not for the recruitment of recombination proteins. We further demonstrate that when the Rad60-dependent, post-S-phase Smc6 function is compromised, the resulting recombination-dependent DNA intermediates that accumulate following release from replication arrest are not recognized by the G2/M checkpoint

Smc5/6 maintains stalled replication forks in a recombination-competent conformation

The Smc5/6 structural maintenance of chromosomes complex is required for efficient homologous recombination (HR). Defects in Smc5/6 result in chromosome missegregation and fragmentation. By characterising two Schizosaccharomyces pombe smc6 mutants, we define two separate functions for Smc5/6 in HR. The first represents the previously described defect in processing recombination-dependent DNA intermediates when replication forks collapse, which leads to increased rDNA recombination. The second novel function defines Smc5/6 as a positive regulator of recombination in the rDNA and correlates mechanistically with a requirement to load RPA and Rad52 onto chromatin genome-wide when replication forks are stably stalled by nucleotide depletion. Rad52 is required for all HR repair, but Rad52 loading in response to replication fork stalling is unexpected and does not correlate with damage-induced foci. We propose that Smc5/6 is required to maintain stalled forks in a stable recombination-competent conformation primed for replication restart

Detection of continuous variable entanglement without coherent local oscillators

We propose three criteria for identifying continuous variable entanglement between two many-particle systems with no restrictions on the quantum state of the local oscillators used in the measurements. Mistakenly asserting a coherent state for the local oscillator can lead to incorrectly identifying the presence of entanglement. We demonstrate this in simulations with 100 particles, and also find that large number fluctuations do not prevent the observation of entanglement. Our results are important for quantum information experiments with realistic Bose-Einstein condensates or in optics with arbitrary photon states.Comment: 7 Pages, 4 Figure

Perceptual adaptation by normally hearing listeners to a simulated "hole" in hearing

Simulations of cochlear implants have demonstrated that the deleterious effects of a frequency misalignment between analysis bands and characteristic frequencies at basally shifted simulated electrode locations are significantly reduced with training. However, a distortion of frequency-to-place mapping may also arise due to a region of dysfunctional neurons that creates a "hole" in the tonotopic representation. This study simulated a 10 mm hole in the mid-frequency region. Noise-band processors were created with six output bands (three apical and three basal to the hole). The spectral information that would have been represented in the hole was either dropped or reassigned to bands on either side. Such reassignment preserves information but warps the place code, which may in itself impair performance. Normally hearing subjects received three hours of training in two reassignment conditions. Speech recognition improved considerably with training. Scores were much lower in a baseline (untrained) condition where information from the hole region was dropped. A second group of subjects trained in this dropped condition did show some improvement; however, scores after training were significantly lower than in the reassignment conditions. These results are consistent with the view that speech processors should present the most informative frequency range irrespective of frequency misalignment. 0 2006 Acoustical Society of America

Defect-dependent colossal negative thermal expansion in UiO-66(Hf) metal-organic framework

Thermally-densified hafnium terephthalate UiO-66(Hf) is shown to exhibit the strongest isotropic negative thermal expansion (NTE) effect yet reported for a metal-organic framework (MOF). Incorporation of correlated vacancy defects within the framework affects both the extent of thermal densification and the magnitude of NTE observed in the densified product. We thus demonstrate that defect inclusion can be used to tune systematically the physical behaviour of a MOF.Comment: 8 pages, 4 figures, revise

Narrow-line Laser Cooling by Adiabatic Transfer

We propose and demonstrate a novel laser cooling mechanism applicable to particles with narrow-linewidth optical transitions. By sweeping the frequency of counter-propagating laser beams in a sawtooth manner, we cause adiabatic transfer back and forth between the ground state and a long-lived optically excited state. The time-ordering of these adiabatic transfers is determined by Doppler shifts, which ensures that the associated photon recoils are in the opposite direction to the particle's motion. This ultimately leads to a robust cooling mechanism capable of exerting large forces via a weak transition and with reduced reliance on spontaneous emission. We present a simple intuitive model for the resulting frictional force, and directly demonstrate its efficacy for increasing the total phase-space density of an atomic ensemble. We rely on both simulation and experimental studies using the 7.5~kHz linewidth $^1$S$_0$ to $^3$P$_1$ transition in $^{88}$Sr. The reduced reliance on spontaneous emission may allow this adiabatic sweep method to be a useful tool for cooling particles that lack closed cycling transitions, such as molecules.Comment: 5 pages, 4 figure

Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL

Revisiting James Madison University: A Case Analysis of Program Restructuring Following So Called ‘Title IX’ Cuts

The purpose of this study was to revisit one of the most highly publicized cases alleging Title IX harmed male athletes at James Madison University (JMU) following a decision that cuts would be made to the athletic program in 2006. Using budget data and publicly available information about the JMU athletic program, comparisons were made between the academic years 2006–2007 and 2010–2011. The authors conclude that the cuts in the JMU program were motivated far more by forces associated with the upward drift phenomenon in intercollegiate athletics, as evidenced in an institutional commitment to an expansion project costing $62 million for the football stadium in 2009 than concerns about Title IX. As the analysis reveals, despite public concern that Title IX had harmed male athletes, the athletic department restructuring at JMU did not increase opportunities for female athletes, did not result in the disappearance of men’s teams although those teams were demoted to club status, and did not inhibit the assumption of significant institutional debt to support the football program

COLLISION DYNAMICS OF HIGHLY ORIENTED SUPER ROTOR MOLECULES FROM AN OPTICAL CENTRIFUGE

Sophisticated optical methods provide some of the most promising tools for complete control of a molecule’s energy and orientation, which enables a more complete understanding of chemical reactivity and structure. This dissertation investigates the collision dynamics of molecular super rotors with oriented angular momentum prepared in an optical centrifuge. Molecules with anisotropic polarizabilities are trapped in the electric field of linearly polarized light and then angularly accelerated from 0 to 35 THz over the duration of the optical pulse. This process drives molecules to extreme rotational states and the ensemble of molecules has a unidirectional sense of rotation determined by the propagation of the optical field. High resolution transient IR absorption spectroscopy of the super rotor molecules reveals the dynamics of collisional energy transfer. These studies show that high energy CO2 and CO rotors release large amounts of translational energy through impulsive collisions. Time-evolution of the translational energy distribution of the CO2 J=0-100 state shows that depletion from low J states involves molecules with sub-thermal velocities. Polarization-dependent Doppler profiles of CO rotors show anisotropic kinetic energy release and reveal a majority population of molecular rotors in the initial plane of rotation. Experimental modifications improved signal to noise levels by a factor of 10, enabling new transient studies in the low-pressure, single-collision regime. Polarization-dependent studies show that CO2 rotors in the J=54-100 states retain their initial angular momentum orientation, and that this effect increases as a function of rotational angular momentum. These studies show that rotating molecules behave like classical gyroscopes. Polarization-dependent measurements of CO2 rotors in the presence of He and Ar buffer gases show that CO2 super rotors are more strongly relaxed by He collisions, demonstrating the importance of rotational adiabaticity in the relaxation process. Quantum scattering calculations of the He-CO2 and Ar-CO2 collision systems were performed to interpret the qualitative features of the experimental results. This work provides a detailed mechanistic understanding of the unique collisional dynamics of super rotor molecules