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

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

The NHS England 100,000 Genomes Project:feasibility and utility of centralised genome sequencing for children with cancer

Background: Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally. Methods: Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value. Results: Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36). Conclusion: Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.</p

Attempting to prevent postnatal depression by targeting the mother–infant relationship: a randomised controlled trial

Aim: The purpose of the study was to investigate whether a supportive psychotherapeutic intervention which focussed on enhancing the quality of the other-infant relationship would prevent the development of postnatal depression (PND) and the associated impairments in parenting and adverse effects on child development. Background: Recent meta-analytic examinations report a modest preventive effect of psychological treatments for women vulnerable to the development of postnatal depression. However, given the strong evidence for an impact of PND on the quality of the mother-infant relationship and on child development, it is notable that there are limited data on the impact of preventive interventions on these outcomes. This is clearly a question that requires research attention. Accordingly, a randomized controlled trial was conducted of such a preventive intervention. Methods: A large sample of pregnant women was screened to identify those at risk of PND. 91 were randomly assigned to the index intervention and received home visits from research health visitors, and 99 were assigned to a control group who received normal care. In an adjacent area 76 women received the index intervention from trained NHS health visitors. The index intervention involved 11 home visits, two antenatally and nine postnatally. They were supportive in nature, with specific measures to enhance maternal sensitivity to infant communicative signals. Independent assessments were made at18 weeks postpartum, and at 12 and 18 months postpartum of maternal mood, maternal sensitivity in mother-infant engagement, and infant behaviour problems, attachment and cognition. Findings: The index intervention, whether delivered by research or NHS health visitors, had no discernible impact on maternal mood or the quality of the maternal parenting behaviours. Neither did it benefit the infant outcomes assessed. For girl children a benefit of the intervention was found for cognitive development. Overall the findings indicate that this approach to preventing PND cannot be recommended