Photocrosslinking Activity-Based Probes for Ubiquitin RING E3 Ligases

Summary: Activity-based protein profiling is an invaluable technique for studying enzyme biology and facilitating the development of therapeutics. Ubiquitin E3 ligases (E3s) are one of the largest enzyme families and regulate a host of (patho)physiological processes. The largest subtype are the RING E3s of which there are >600 members. RING E3s have adaptor-like activity that can be subject to diverse regulatory mechanisms and have become attractive drug targets. Activity-based probes (ABPs) for measuring RING E3 activity do not exist. Here we re-engineer ubiquitin-charged E2 conjugating enzymes to produce photocrosslinking ABPs. We demonstrate activity-dependent profiling of two divergent cancer-associated RING E3s, RNF4 and c-Cbl, in response to their native activation signals. We also demonstrate profiling of endogenous RING E3 ligase activation in response to epidermal growth factor (EGF) stimulation. These photocrosslinking ABPs should advance E3 ligase research and the development of selective modulators against this important class of enzymes

Locating Community among People with Schizophrenia living in a Diverse Urban Environment

Increasing the community participation of people with severe mental illness is a primary goal of recovery-oriented services. Despite this emphasis, the construct of community remains understudied and poorly articulated. This study provides an in-depth examination of the experiences, beliefs, behaviors, and spaces that constitute community participation for a highly diverse group of people with schizophrenia who are urban dwellers. An in-depth, longitudinal qualitative design was employed with 30 individuals with schizophrenia residing in inner-city neighborhoods in Canada’s largest city. For these individuals, community participation is a dynamic process, shaped by illness and non-illness-associated social relationships and spaces, self-concept, and the resources accessible to the person. The complexity of factors that are associated with “community” for people with schizophrenia, with overlays of culture, poverty, victimization, and discrimination, calls for a critical examination of the community rhetoric employed in practice and policy contexts

High-Gain On-Chip Antenna Design on Silicon Layer with Aperture Excitation for Terahertz Applications

This letter investigates the feasibility of designing a high gain on-chip antenna on silicon technology for subterahertz applications over a wide-frequency range. High gain is achieved by exciting the antenna using an aperture fed mechanism to couple electromagnetics energy froma metal slot line, which is sandwiched between the silicon and polycarbonate substrates, to a 15-element array comprising circular and rectangular radiation patches fabricated on the top surface of the polycarbonate layer. An open ended microstrip line, which is orthogonal to the metal slot-line, is implemented on the underside of the silicon substrate. When the open ended microstrip line is excited it couples the signal to the metal slot-line which is subsequently coupled and radiated by the patch array. Measured results show the proposed on-chip antenna exhibits a reflection coefficient of less than -10 dB across 0.290-0.316 THz with a highest gain and radiation efficiency of 11.71 dBi and 70.8%, respectively, occurred at 0.3 THz. The antenna has a narrow stopband between 0.292 and 0.294 THz. The physical size of the presented subterahertz on-chip antenna is 20 x 3.5 x 0.126 mm(3)

UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4

UBR4 is a 574 kDa E3 ligase (E3) of the N-degron pathway with roles in neurodevelopment, age-associated muscular atrophy and cancer. The catalytic module that carries out ubiquitin (Ub) transfer remains unknown. Here we identify and characterize a distinct E3 module within human UBR4 consisting of a ‘hemiRING’ zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzyme (E2). The structure of an E2–E3 complex provides atomic-level insight into the specificity determinants of the hemiRING toward the cognate E2s UBE2A/UBE2B. Via an allosteric mechanism, the UZI subdomain modestly activates the Ub-loaded E2 (E2∼Ub). We propose attenuated activation is complemented by the intrinsically high lysine reactivity of UBE2A, and their cooperation imparts a reactivity profile important for substrate specificity and optimal degradation kinetics. These findings reveal the mechanistic underpinnings of a neuronal N-degron E3, its specific recruitment of UBE2A, and highlight the underappreciated architectural diversity of cross-brace domains with Ub E3 activity.</p

Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity.

MYCBP2 is a ubiquitin (Ub) E3 ligase (E3) that is essential for neurodevelopment and regulates axon maintenance. MYCBP2 transfers Ub to nonlysine substrates via a newly discovered RING-Cys-Relay (RCR) mechanism, where Ub is relayed from an upstream cysteine to a downstream substrate esterification site. The molecular bases for E2-E3 Ub transfer and Ub relay are unknown. Whether these activities are linked to the neural phenotypes is also unclear. We describe the crystal structure of a covalently trapped E2~Ub:MYCBP2 transfer intermediate revealing key structural rearrangements upon E2-E3 Ub transfer and Ub relay. Our data suggest that transfer to the dynamic upstream cysteine, whilst mitigating lysine activity, requires a closed-like E2~Ub conjugate with tempered reactivity, and Ub relay is facilitated by a helix-coil transition. Furthermore, neurodevelopmental defects and delayed injury-induced degeneration in RCR-defective knock-in mice suggest its requirement, and that of substrate esterification activity, for normal neural development and programmed axon degeneration

Herschel-ATLAS/GAMA: A difference between star formation rates in strong-line and weak-line radio galaxies

We have constructed a sample of radio-loud objects with optical spectroscopy from the Galaxy and Mass Assembly (GAMA) project over the Herschel Astrophysical Terahertz Large Area Survey (Herschel-ATLAS) Phase 1 fields. Classifying the radio sources in terms of their optical spectra, we find that strong-emission-line sources ('high-excitation radio galaxies') have, on average, a factor of ~4 higher 250-μm Herschel luminosity than weak-line ('lowexcitation') radio galaxies and are also more luminous than magnitude-matched radio-quiet galaxies at the same redshift. Using all five H-ATLAS bands, we show that this difference in luminosity between the emission-line classes arises mostly from a difference in the average dust temperature; strong-emission-line sources tend to have comparable dust masses to, but higher dust temperatures than, radio galaxies with weak emission lines. We interpret this as showing that radio galaxies with strong nuclear emission lines are much more likely to be associated with star formation in their host galaxy, although there is certainly not a one-to-one relationship between star formation and strong-line active galactic nuclei (AGN) activity. The strong-line sources are estimated to have star formation rates at least a factor of 3-4 higher than those in the weak-line objects. Our conclusion is consistent with earlier work, generally carried out using much smaller samples, and reinforces the general picture of high-excitation radio galaxies as being located in lower-mass, less evolved host galaxies than their low-excitation counterparts.Peer reviewe

Optimum power transfer in RF front end systems using adaptive impedance matching technique

Matching the antenna's impedance to the RF-front-end of a wireless communications system is challenging as the impedance varies with its surround environment. Autonomously matching the antenna to the RF-front-end is therefore essential to optimize power transfer and thereby maintain the antenna's radiation efficiency. This paper presents a theoretical technique for automatically tuning an LC impedance matching network that compensates antenna mismatch presented to the RF-front-end. The proposed technique converges to a matching point without the need of complex mathematical modelling of the system comprising of non-linear control elements. Digital circuitry is used to implement the required matching circuit. Reliable convergence is achieved within the tuning range of the LC-network using control-loops that can independently control the LC impedance. An algorithm based on the proposed technique was used to verify its effectiveness with various antenna loads. Mismatch error of the technique is less than 0.2%. The technique enables speedy convergence (&lt;5 s) and is highly accurate for autonomous adaptive antenna matching networks

A comprehensive survey on 'circular polarized antennas' for existing and emerging wireless communication technologies

Circular polarized (CP) antennas are well suited for long-distance transmission attainment. In order to be adaptable for beyond 5G communication, a detailed and systematic investigation of their important conventional features is required for expected enhancements. The existing designs employing millimeter wave, microwave, and ultra-wideband (UWB) frequencies form the elementary platform for future studies. The 3.4-3.8 GHz frequency band has been identified as a worthy candidate for 5G communications because of spectrum availability. This band comes under UWB frequencies (3.1-10.6 GHz). In this survey, a review of CP antennas in the selected areas to improve the understanding of early-stage researchers specially experienced antenna designers has presented for the first time as best of our knowledge. Design implementations involving size, axial ratio, efficiency, and gain improvements are covered in detail. Besides that, various design approaches to realize CP antennas including (a) printed CP antennas based on parasitic or slotted elements, (b) dielectric resonator CP antennas, (c) reconfigurable CP antennas, (d) substrate integrated waveguide CP antennas, (e) fractal CP antennas, (f) hybrid techniques CP antennas, and (g) 3D printing CP antennas with single and multiple feeding structures have investigated and analyzed. The aim of this work is to provide necessary guidance for the selection of CP antenna geometries in terms of the required dimensions, available bandwidth, gain, and useful materials for the integration and realization in future communication systems

Metamaterial-inspired antenna array for application in microwave breast imaging systems for tumor detection

This paper presents a study of a planar antenna-array inspired by the metamaterial concept where the resonant elements have sub-wavelength dimensions for application in microwave medical imaging systems for detecting tumors in biological tissues. The proposed antenna consists of square-shaped concentric-rings which are connected to a central patch through a common feedline. The array structure comprises several antennas that are arranged to surround the sample breast model. One antenna at a time in the array is used in transmission-mode while others are in receive-mode. The antenna array operates over 2-12 GHz amply covering the frequency range of existing microwave imaging systems. Measured results show that compared to a standard patch antenna array the proposed array with identical dimensions exhibits an average radiation gain and efficiency improvement of 4.8 dBi and 18%, respectively. The average reflection-coefficient of the array over its operating range is better than S-11 &lt;= -20 dB making it highly receptive to weak signals and minimizing the distortion encountered with the transmission of short duration pulse-trains. Moreover, the proposed antenna-array exhibits high-isolation on average of 30dB between radiators. This means that antennas in the array (i) can be closely spaced to accommodate more radiators to achieve higher-resolution imaging scans, and (ii) the imagining scans can be done over a wider frequency range to ascertain better contrast in electrical parameters between malignant tumor-tissue and the surrounding normal breast-tissue to facilitate the detection of breast-tumor. It is found that short wavelength gives better resolution. In this experimental study a standard biomedical breast model that mimics a real-human breast in terms of dielectric and optical properties was used to demonstrate the viability of the proposed antenna over a standard patch antenna in the detection and the localization of tumor. These results are encouraging for clinical trials and further refinement of the antenna-array

Bandwidth and gain enhancement of composite right left handed metamaterial transmission line planar antenna employing a non foster impedance matching circuit board

The paper demonstrates an effective technique to significantly enhance the bandwidth and radiation gain of an otherwise narrowband composite right/left-handed transmission-line (CRLH-TL) antenna using a non-Foster impedance matching circuit (NF-IMC) without affecting the antenna's stability. This is achieved by using the negative reactance of the NF-IMC to counteract the input capacitance of the antenna. Series capacitance of the CRLH-TL unit-cell is created by etching a dielectric spiral slot inside a rectangular microstrip patch that is grounded through a spiraled microstrip inductance. The overall size of the antenna, including the NF-IMC at its lowest operating frequency is 0.335 lambda (0)x0.137 lambda (0)x0.003 lambda (0), where lambda (0) is the free-space wavelength at 1.4 GHz. The performance of the antenna was verified through actual measurements. The stable bandwidth of the antenna for |S-11|&lt;= -18 dB is greater than 1 GHz (1.4-2.45 GHz), which is significantly wider than the CRLH-TL antenna without the proposed impedance matching circuit. In addition, with the proposed technique the measured radiation gain and efficiency of the antenna are increased on average by 3.2 dBi and 31.5% over the operating frequency band