Algebraic and analytic Dirac induction for graded affine Hecke algebras

We define the algebraic Dirac induction map \Ind_D for graded affine Hecke algebras. The map \Ind_D is a Hecke algebra analog of the explicit realization of the Baum-Connes assembly map in the $K$-theory of the reduced $C^*$-algebra of a real reductive group using Dirac operators. The definition of \Ind_D is uniform over the parameter space of the graded affine Hecke algebra. We show that the map \Ind_D defines an isometric isomorphism from the space of elliptic characters of the Weyl group (relative to its reflection representation) to the space of elliptic characters of the graded affine Hecke algebra. We also study a related analytically defined global elliptic Dirac operator between unitary representations of the graded affine Hecke algebra which are realized in the spaces of sections of vector bundles associated to certain representations of the pin cover of the Weyl group. In this way we realize all irreducible discrete series modules of the Hecke algebra in the kernels (and indices) of such analytic Dirac operators. This can be viewed as a graded Hecke algebra analogue of the construction of discrete series representations for semisimple Lie groups due to Parthasarathy and Atiyah-Schmid.Comment: 37 pages, revised introduction, updated references, minor correction

Tuning the Reactivity of TEMPO during Electrocatalytic Alcohol Oxidations in Room-Temperature Ionic Liquids

2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) is a promising, sustainable, metal-free mediator for oxidation of alcohols. In this contribution, we describe how the selectivity of TEMPO for electrocatalytic alcohol oxidations in room-temperature ionic liquids (RTILs) can be changed by design of the solvent medium. Cyclic voltammetry of TEMPO in a series of ammonium-, phosphonium-, and imidazolium-based RTILs reveals that the potential at which TEMPO is oxidized increases from 677 mV (vs. the potential of the decamethylferrocene/ decamethylferrocinium, dmFc/dmFc+, redox couple) to 788 mV as the H-bond basicity of the RTIL anions decreases. The increase in potential is accompanied by an increase in the rate constant for oxidation of benzyl alcohol from about 0.1 dm3 mol−1 s−1 to about 0.7 dm3 mol−1 s−1, demonstrating the ability to manipulate the reactivity of TEMPO by judicious choice of the RTIL anions. The rate of alcohol oxidation in a series of RTILs increases in the order 2-butanol < 1phenylethanol < octanol < benzyl alcohol, and the RTIL 1-octyl-3-methylmidazolium bis(trifluoromethanesulfonyl)imide ([NTf2]–) shows clear selectivity towards the oxidation of primary alcohols. In addition, the reaction kinetics and selectivity are better in [NTf2]–-based RTILs than in acetonitrile, often the solvent-of-choice in indirect alcohol electrooxidations. Finally, we demonstrate that electrolytic TEMPO-mediated alcohol oxidations can be performed using RTILs in a flow-electrolysis system, with excellent yields and reaction selectivity, demonstrating the opportunities offered by such systems

Revealing Hidden Potentials of the q-Space Signal in Breast Cancer

Mammography screening for early detection of breast lesions currently suffers from high amounts of false positive findings, which result in unnecessary invasive biopsies. Diffusion-weighted MR images (DWI) can help to reduce many of these false-positive findings prior to biopsy. Current approaches estimate tissue properties by means of quantitative parameters taken from generative, biophysical models fit to the q-space encoded signal under certain assumptions regarding noise and spatial homogeneity. This process is prone to fitting instability and partial information loss due to model simplicity. We reveal unexplored potentials of the signal by integrating all data processing components into a convolutional neural network (CNN) architecture that is designed to propagate clinical target information down to the raw input images. This approach enables simultaneous and target-specific optimization of image normalization, signal exploitation, global representation learning and classification. Using a multicentric data set of 222 patients, we demonstrate that our approach significantly improves clinical decision making with respect to the current state of the art.Comment: Accepted conference paper at MICCAI 201

Analyzing Longitudinal wb-MRI Data and Clinical Course in a Cohort of Former Smoldering Multiple Myeloma Patients: Connections between MRI Findings and Clinical Progression Patterns

The purpose of this study was to analyze size and growth dynamics of focal lesions (FL) as well as to quantify diffuse infiltration (DI) in untreated smoldering multiple myeloma (SMM) patients and correlate those MRI features with timepoint and cause of progression. We investigated 199 whole-body magnetic resonance imaging (wb-MRI) scans originating from longitudinal imaging of 60 SMM patients and 39 computed tomography (CT) scans for corresponding osteolytic lesions (OL) in 17 patients. All FLs >5 mm were manually segmented to quantify volume and growth dynamics, and DI was scored, rating four compartments separately in T1- and fat-saturated T2-weighted images. The majority of patients with at least two FLs showed substantial spatial heterogeneity in growth dynamics. The volume of the largest FL (p = 0.001, c-index 0.72), the speed of growth of the fastest growing FL (p = 0.003, c-index 0.75), the DI score (DIS, p = 0.014, c-index 0.67), and its dynamic over time (DIS dynamic, p < 0.001, c-index 0.67) all significantly correlated with the time to progression. Size and growth dynamics of FLs correlated significantly with presence/appearance of OL in CT within 2 years after the respective MRI assessment (p = 0.016 and p = 0.022). DIS correlated with decrease of hemoglobin (p < 0.001). In conclusion, size and growth dynamics of FLs correlate with prognosis and local bone destruction. Connections between MRI findings and progression patterns (fast growing FL—OL; DIS—hemoglobin decrease) might enable more precise diagnostic and therapeutic approaches for SMM patients in the future

Calendar age and puberty-related development of regional gray matter volume and white matter tracts during adolescence

Background Adolescence is a critical time for brain development. Findings from previous studies have been inconsistent, failing to distinguish the influence of pubertal status and aging on brain maturation. The current study sought to address these inconsistencies, addressing the trajectories of pubertal development and aging by longitudinally tracking structural brain development during adolescence. Methods Two cohorts of healthy children were recruited (cohort 1: 9–10 years old; cohort 2: 12–13 years old at baseline). MRI data were acquired for gray matter volume and white matter tract measures. To determine whether age, pubertal status, both or their interaction best modelled longitudinal data, we compared four multi-level linear regression models to the null model (general brain growth indexed by total segmented volume) using Bayesian model selection. Results Data were collected at baseline (n = 116), 12 months (n = 97) and 24 months (n = 84) after baseline. Findings demonstrated that the development of most regional gray matter volume, and white matter tract measures, were best modelled by age. Interestingly, precentral and paracentral regions of the cortex, as well as the accumbens demonstrated significant preference for the pubertal status model. None of the white matter tract measures were better modelled by pubertal status. Limitations: The major limitation of this study is the two-cohort recruitment. Although this allowed a faster coverage of the age span, a complete per person trajectory over 6 years of development (9–15 years) could not be investigated. Conclusions Comparing the impact of age and pubertal status on regional gray matter volume and white matter tract measures, we found age to best predict longitudinal changes. Further longitudinal studies investigating the differential influence of puberty status and age on brain development in more diverse samples are needed to replicate the present results and address mechanisms underlying norm-variants in brain development

Representation of Time-Varying Stimuli by a Network Exhibiting Oscillations on a Faster Time Scale

Sensory processing is associated with gamma frequency oscillations (30–80 Hz) in sensory cortices. This raises the question whether gamma oscillations can be directly involved in the representation of time-varying stimuli, including stimuli whose time scale is longer than a gamma cycle. We are interested in the ability of the system to reliably distinguish different stimuli while being robust to stimulus variations such as uniform time-warp. We address this issue with a dynamical model of spiking neurons and study the response to an asymmetric sawtooth input current over a range of shape parameters. These parameters describe how fast the input current rises and falls in time. Our network consists of inhibitory and excitatory populations that are sufficient for generating oscillations in the gamma range. The oscillations period is about one-third of the stimulus duration. Embedded in this network is a subpopulation of excitatory cells that respond to the sawtooth stimulus and a subpopulation of cells that respond to an onset cue. The intrinsic gamma oscillations generate a temporally sparse code for the external stimuli. In this code, an excitatory cell may fire a single spike during a gamma cycle, depending on its tuning properties and on the temporal structure of the specific input; the identity of the stimulus is coded by the list of excitatory cells that fire during each cycle. We quantify the properties of this representation in a series of simulations and show that the sparseness of the code makes it robust to uniform warping of the time scale. We find that resetting of the oscillation phase at stimulus onset is important for a reliable representation of the stimulus and that there is a tradeoff between the resolution of the neural representation of the stimulus and robustness to time-warp. Author Summary Sensory processing of time-varying stimuli, such as speech, is associated with high-frequency oscillatory cortical activity, the functional significance of which is still unknown. One possibility is that the oscillations are part of a stimulus-encoding mechanism. Here, we investigate a computational model of such a mechanism, a spiking neuronal network whose intrinsic oscillations interact with external input (waveforms simulating short speech segments in a single acoustic frequency band) to encode stimuli that extend over a time interval longer than the oscillation's period. The network implements a temporally sparse encoding, whose robustness to time warping and neuronal noise we quantify. To our knowledge, this study is the first to demonstrate that a biophysically plausible model of oscillations occurring in the processing of auditory input may generate a representation of signals that span multiple oscillation cycles.National Science Foundation (DMS-0211505); Burroughs Wellcome Fund; U.S. Air Force Office of Scientific Researc

Adaptive optics with an infrared pyramid wavefront sensor at Keck

The study of cold or obscured, red astrophysical sources can significantly benefit from adaptive optics (AO) systems employing infrared (IR) wavefront sensors. One particular area is the study of exoplanets around M-dwarf stars and planet formation within protoplanetary disks in star-forming regions. Such objects are faint at visible wavelengths but bright enough in the IR to be used as a natural guide star for the AO system. Doing the wavefront sensing at IR wavelengths enables high-resolution AO correction for such science cases, with the potential to reach the contrasts required for direct imaging of exoplanets. To this end, a new near-infrared pyramid wavefront sensor (PyWFS) has been added to the Keck II AO system, extending the performance of the facility AO system for the study of faint red objects. We present the Keck II PyWFS, which represents a number of firsts, including the first PyWFS installed on a segmented telescope and the first use of an IR PyWFS on a 10-m class telescope. We discuss the scientific and technological advantages offered by IR wavefront sensing and present the design and commissioning of the Keck PyWFS. In particular, we report on the performance of the Selex Avalanche Photodiode for HgCdTe InfraRed Array detector used for the PyWFS and highlight the novelty of this wavefront sensor in terms of the performance for faint red objects and the improvement in contrast. The system has been commissioned for science with the vortex coronagraph in the NIRC2 IR science instrument and is being commissioned alongside a new fiber injection unit for NIRSPEC. We present the first science verification of the system—to facilitate the study of exoplanets around M-type stars

Protocol of the IntenSify-Trial:An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.</p