Blocking the PCNA/NKp44 Checkpoint to Stimulate NK Cell Responses to Multiple Myeloma

Simple SummaryMembrane-associated PCNA is expressed on the surface of human MM cell lines and primary MM cells. Mab 14-25-9 interacts with membrane-associated PCNA and blocks its binding to NK-expressed NKp44, thus activating NK function. We showed that mAb 14-25-9 can serve as an immune checkpoint blocker, enhancing the function of NK cells on target human MM cell lines and primary cells.AbstractMultiple Myeloma (MM) is a devastating malignancy that evades immune destruction using multiple mechanisms. The NKp44 receptor interacts with PCNA (Proliferating Cell Nuclear Antigen) and may inhibit NK cells’ functions. Here we studied in vitro the expression and function of PCNA on MM cells. First, we show that PCNA is present on the cell membrane of five out of six MM cell lines, using novel anti-PCNA mAb developed to recognize membrane-associated PCNA. Next, we stained primary bone marrow (BM) mononuclear cells from MM patients and showed significant staining of membrane-associated PCNA in the fraction of CD38⁺CD138⁺ BM cells that contain the MM cells. Importantly, blocking of the membrane PCNA on MM cells enhanced the activity of NK cells, including IFN-γ-secretion and degranulation. Our results highlight the possible blocking of the NKp44-PCNA immune checkpoint by the mAb 14-25-9 antibody to enhance NK cell responses against MM, providing a novel treatment option.     

Complex and dynamic population structures: synthesis, open questions, and future directions

The population structure of an evolutionary algorithm influences the dissemination and mixing of advantageous alleles, and therefore affects search performance. Much recent attention has focused on the analysis of complex population structures, characterized by heterogeneous connectivity distributions, non-trivial clustering properties, and degree–degree correlations. Here, we synthesize the results of these recent studies, discuss their limitations, and highlight several open questions regarding (1) unsolved theoretical issues and (2) the practical utility of complex population structures for evolutionary search. In addition, we will discuss an alternative complex population structure that is known to significantly influence dynamical processes, but has yet to be explored for evolutionary optimization. We then shift our attention toward dynamic population structures, which have received markedly less attention than their static counterparts. We will discuss the strengths and limitations of extant techniques and present open theoretical and experimental questions and directions for future research. In particular, we will focus on the prospects of “active linking,” wherein edges are dynamically rewired according to the genotypic or phenotypic properties of individuals, or according to the success of prior inter-individual interactions.     

Web-conference supervision for advanced psychotherapy training: A practical guide.

The advent of readily accessible, inexpensive Web-conferencing applications has opened the door for distance psychotherapy supervision, using video recordings of treated clients. Although relatively new, this method of supervision is advantageous given the ease of use and low cost of various Internet applications. This method allows periodic supervision from point to point around the world, with no travel costs and no long gaps between direct training contacts. Web-conferencing permits face-to-face training so that the learner and supervisor can read each other's emotional responses while reviewing case material. It allows group learning from direct supervision to complement local peer-to-peer learning methods. In this article, we describe the relevant literature on this type of learning method, the practical points in its utilization, its limitations, and its benefits. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Detection performance of the reduced-rank linear predictor ROCKET

This paper assesses the frequency detection capabilities of a new signal-dependent reduced-rank linear predictor applied to autoregressive spectrum estimation. The new technique is called reduced-order correlation kernel estimation technique (ROCKET). Its detection performance is examined by comparison to a full-rank autoregressive (FR-AR) estimator and two reduced-rank principal component autoregressive (PC-AR) estimators based on both the standard signal-independent version and a modified signal-dependent method. The performance of the new autoregressive estimator is also compared as a function of rank to the popular pseudo-spectrum estimator MUSIC. The performance metrics examined are the probability of detection (P/sub D/) and the false alarm rate (FAR) of detecting the spatial frequencies of plane waves impinging on a uniform line array in additive white Gaussian noise. These metrics are studied as a function of subspace rank, sample support, and signal-to-noise ratio (SNR). Simulations show that the signal-dependent reduced-rank estimators significantly outperform both the signal-independent version of PC-AR and the FR-AR estimator for low sample support and low SNR environments. One notable characteristic of ROCKET that highlights its distinct subspace selection is its performance as a function of subspace rank. It is observed that for equal powered signals, its peak performance is nearly invariant to signal rank and that at almost any subspace rank ROCKET meets or exceeds FR-AR performance. This provides an extra degree of robustness when the signal rank is unknown.     

Optical power equalization for multiwavelength fiber-amplifiercascades using periodic inhomogeneous broadening

Inhomogeneously broadened fiber amplifiers inserted periodically in an amplifier cascade are shown to provide significant interchannel power equalization in wavelength-multiplexed systems. Interchannel power variations in a six-amplifier cascade are reduced from 16 dB in a conventional system to about 5 dB when power equalizers are inserted     

Broadband multiwavelength simultaneous dispersion compensation near 1550 nm through singlemode fibres optimised for 1310 nm

Broadband dispersion compensation is demonstrated at 2.5 and 10 Gbit/s using an optical-fibre equaliser in combination with pulse compression. At 2.5 Gbit/s, simultaneous penalty-free dispersion compensation is achieved in a four-wavelength system operating at 1550 nm through 67 km of 1310 nm-optimised singlemode fibre. Low penalties are obtained over the full 20 nm gain bandwidth of the erbium-doped fibre amplifier, with the receiver sensitivity slightly enhanced at the short-wavelength end.<>     

Highly Efficient Rapid Annealing of Thin Polar Polymer Film Ferroelectric Devices at Sub‐Glass Transition Temperature

An unexpected rapid anneal of electrically active defects in an ultrathin (15.5 nm) polar polyimide film at and below glass transition temperature (T_g) is reported. The polar polymer is the gate dielectric of a thin‐film‐transistor. Gate leakage current density (J_g) through the polymer initially increases with temperature, as expected, but decreases rapidly at T_g ? 60 °C. After ≈2 min at T_g, the leakage is reduced by nearly three orders of magnitude. A concomitant observation is that the drain current (I_d)–gate voltage (V_g) hysteresis decreases with temperature, reaching zero at nearly the same temperature at which J_g collapses. As J_g drops further, the drain current hysteresis increases again but in the opposite direction. This combination strongly supports the interpretation of rapid defect annealing.     

Tunable 3D Nanoresonators for Gas‐Sensing Applications

The detection of gas species with high sensitivity is a significant task for fundamental sciences as well as for industrial applications. Similarly, the ongoing trend for device miniaturization brings new challenges for advanced fabrication including on‐demand functionality tuning. Following this motivation, here the additive, direct‐write fabrication of freestanding 3D nanoarchitectures is introduced, which can be brought into mechanical resonance via electric AC fields. Specifically, this study focuses on the 3D nanostructure synthesis, the subsequent determination of Young's modulus, and demonstrates a postgrowth procedure, which can precisely tune the material modulus. As‐fabricated resonators reveal a Young's modulus of 9–13 GPa, which can be increased by a factor greater than 5. Next, the electric readout of the resonance behavior is demonstrated via electric current measurement as an essential element for the resonance sensor applications. Finally, the implications of gas‐physisorption and gas‐chemisorption on the resonance frequencies are studied, representing a proof‐of‐principle for sensing applications by the here presented approach.     

Design and implementation of a hands-free electrolarynx device controlled by neck strap muscle electromyographic activity

The electrolarynx (EL) voice prosthesis is widely used, but suffers from the inconvenience of requiring manual control. Therefore, a hands-free EL triggered by neck muscle electromyographic (EMG) activity was developed (EMG-EL). Signal processing circuitry in a belt-mounted control unit transforms EMG activity into control signals for initiation and termination of voicing. These control signals are then fed to an EL held against the neck by an inconspicuous brace. Performance of the EMG-EL was evaluated by comparison to normal voice, manual EL voice, and tracheo-esophageal (TE) voice in a series of reaction time experiments in seven normal subjects and one laryngectomy patient. The normal subjects produced voice initiation with the EMG-EL that was as fast as both normal voice and the manual EL. The laryngectomy subject produced voice initiation that was slower than with the manual EL, but faster than with TE voice. Voice termination with the EMG-EL was slower than normal voice for the normal subjects, but not significantly different than with the manual EL. The laryngectomy subject produced voice termination with the EMG-EL that was slower than with TE or manual EL. The EMG-EL threshold was set at 10% of the range of vocal-related EMG activity above baseline. Simulations of EMG-EL behavior showed that the 10% threshold was not significantly different from the optimum threshold produced through the process of error minimization. The EMG-EL voice reaction time appears to be adequate for use in a day-to-day conversation.