Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from ...screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity-based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.
Abstract Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds ...are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN’s Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations.
Scattering-type scanning near-field optical microscopy (S-SNOM) has enormous potential as a spectroscopy tool in the infrared spectral range where it can probe phonon resonances and carrier dynamics ...at the nanometer lengths scales. However, its applicability is limited by the lack of practical and affordable table-top light sources emitting intense broadband infrared radiation in the 100 cm
to 2,500 cm
spectral range. This paper introduces a high temperature plasma light source that is both ultra-broadband and has much more radiant power in the infrared spectral range than conventional, table-top thermal light sources such as the globar. We implement this plasma lamp in our near-field optical spectroscopy set up and demonstrate its capability as a broadband infrared nano-spectroscopy light source by obtaining near-field infrared amplitude and phase spectra of the phonon resonances of SiO
and SrTiO
.
Caudal regression syndrome (sacral agenesis), which impairs development of the caudal region of the body, occurs with a frequency of about 2 live births per 100 000 newborns although this incidence ...rises to 1 in 350 infants born to mothers with gestational diabetes. The lower back and limbs can be affected as well as the genitourinary and gastrointestinal tracts. The axial skeleton is formed during embryogenesis through the process of somitogenesis in which the paraxial mesoderm periodically segments into bilateral tissue blocks, called somites. Somites are the precursors of vertebrae and associated muscle, tendons and dorsal dermis. Vertebral anomalies in caudal regression syndrome may arise through perturbation of somitogenesis or, alternatively, could result from defective bone formation and patterning. We discovered that MBTPS1/SKI-1/S1P, which proteolytically activates a class of transmembrane transcription factors, plays a critical role in somitogenesis and the pathogenesis of lumbar/sacral vertebral anomalies. Conditional deletion of Mbtps1 yields a viable mouse with misshapen, fused and reduced number of lumbar and sacral vertebrae, under-developed hind limb bones and a kinky, shortened tail. We show that Mbtps1 is required to (i) maintain the Fgf8 'wavefront' in the presomitic mesoderm that underpins axial elongation, (ii) sustain the Lfng oscillatory 'clock' activity that governs the periodicity of somite formation and (iii) preserve the composition and character of the somitic extracellular matrix containing fibronectin, fibrillin2 and laminin. Based on this spinal phenotype and known functions of MBTPS1, we reason that loss-of-function mutations in Mbtps1 may cause the etiology of caudal regression syndrome.
Cattle were the basis of the most important social institutions in pre-colonial southern Africa, and so archaeologists have been interested in identifying cattle enclosures in Iron Age settlements. ...Occasionally, but of note, these byres are vitrified. Archaeologists usually explain this vitrification in terms of natural causes, such as internal combustion, lightning strikes and veld fires. Our present study in the Limpopo Valley, in conjunction with previous research, eliminates internal combustion because the greatest vitrification occurred in the open around the wooden fence. Higher levels of K2O and CaO in vitrified samples, determined by standard XRF analyses, support this conclusion. Moreover, spatial locations eliminate lightning as a likely cause, and the uneven distribution of vitrified dung through time, as well as the practical difficulty in burning abandoned pens, makes veld fires equally unlikely. Ethnographic information, on the other hand, indicates that villagers intentionally set the dung alight for hygienic and ideological reasons when their animals died unexpectedly.
► Modelled, satellite and in situ soil moisture data sets were compared to yield. ► Soil moisture data showed significant relationship to yield over the growing season. ► In situ data showed ...strongest relationship to yield, with surface better than depth. ► Modelled and satellite soil moisture showed weaker relationship to yield. ► Satellite moisture will be improved by better parameterization over mixed landcover.
Soil moisture is a critical variable in determining crop productivity in the Canadian prairies. Methods to estimate and measure soil moisture extremes all have limitations related to spatial coverage, data accuracy and temporal record length. Three soil moisture data sets (in situ, satellite and modelled) were evaluated to determine how well they capture extreme moisture conditions that impact crop productivity. The limited temporal baseline of satellite datasets appears to provide a relatively robust measure of normal conditions, with a bias toward capturing drier than normal conditions. In situ soil moisture measurements showed few weeks with a significant relationship to agricultural yield, but the relationship was strong when it was significant, suggesting that accurate soil moisture could be a good indicator of yield anomalies if more spatially distributed data were available. Surface satellite and surface layer modelled soil moisture from the Canadian Land Surface Scheme (CLASS) showed a stronger relationship to yield during critical growth stages than did modelled soil moisture at depth. This observation indicates that improvements in the CLASS soil hydrology estimation procedure are needed, particularly for deeper soil layers. Overall, while models and satellite-detected soil moisture show promise for capturing crop yield variation, improvements are needed to increase accuracy in both approaches if they are to be used in routine agricultural monitoring. The use of agricultural productivity as a means of evaluating errors and limitations of soil moisture data sets provides an alternative to traditional data validation as it focuses on the application of the data rather than the absolute accuracy.
ATLAS has formed strip CMOS project to study the use of CMOS MAPS devices as silicon strip sensors for the Phase-II Strip Tracker Upgrade. This choice of sensors promises several advantages over the ...conventional baseline design, such as better resolution, less material in the tracking volume, and faster construction speed. At the same time, many design features of the sensors are driven by the requirement of minimizing the impact on the rest of the detector. Hence the target devices feature long pixels which are grouped to form a virtual strip with binary-encoded z position. The key performance aspects are radiation hardness compatibility with HL-LHC environment, as well as extraction of the full hit position with full-reticle readout architecture. To date, several test chips have been submitted using two different CMOS technologies. The AMS 350nm is a high voltage CMOS process (HV-CMOS), that features the sensor bias of up to 120V. The TowerJazz 180nm high resistivity CMOS process (HR-CMOS) uses a high resistivity epitaxial layer to provide the depletion region on top of the substrate. We have evaluated passive pixel performance, and charge collection projections. The results strongly support the radiation tolerance of these devices to radiation dose of the HL-LHC in the strip tracker region. We also describe design features for the next chip submission that are motivated by our technology evaluation.
Charge collection in irradiated HV-CMOS detectors Hiti, B.; Affolder, A.; Arndt, K. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2019, Letnik:
924, Številka:
C
Journal Article
Recenzirano
Odprti dostop
Active silicon detectors built on p-type substrate are a promising technological solution for large area silicon trackers such as those at the High Luminosity LHC, but the radiation hardness of this ...novel approach has to be evaluated. Active n-in-p strip detector prototypes CHESS2 for ATLAS with different substrate resistivities in the range of 20–1000 Ωcm were irradiated with neutrons and protons up to a fluence of 2×1015neqcm−2 and 3.6×1015neqcm−2. Charge collection in passive test structures on the chip was evaluated using Edge-TCT and minimum ionising electrons from 90Sr. Results were used to assess radiation hardness of the detector in the given fluence range and to determine parameters of initial acceptor removal in different substrates.
•Irradiated samples of different initial resistivity between 20 and a few 1000 Ω cm.•Characterisation with edge transient current technique and 90Sr beta electrons.•Sensitive region increases after irradiation due to acceptor removal.•Parameters of acceptor removal estimated for neutron irradiation.•After proton irradiation larger sensitive region than after neutron irradiation.
Study of CMOS strip sensor for future silicon tracker Han, Y.; Zhu, H.; Affolder, A. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
11/2020, Letnik:
981, Številka:
C
Journal Article
Recenzirano
Odprti dostop
Monolithic silicon sensors developed with High-Voltage CMOS (HV-CMOS) processes have become highly attractive for charged particle tracking. Compared with the standard CMOS sensors, HV-CMOS sensors ...can provide larger and deeper depletion regions that lead to larger signals and faster charge collection. They can provide high position resolution, low material budget, high radiation hardness and low cost that are desirable for high performance tracking in harsh collision environment. Various studies have been conducted to explore the technology feasibility for the large-area tracking systems at future collider experiments.
CHESS (CMOS HV/HR Evaluation for Strip Sensor) sensor series have been developed as an alternative solution to the conventional silicon micro-strip detectors for the ATLAS inner tracker upgrade. The first prototype (named CHESS1) was to evaluate the diode geometry and the in-pixel analog electronics. Obtained test results were used to optimize the second prototype (named CHESS2). CHESS2 was implemented with a full digital readout architecture and realized as a full reticle sized monolithic sensor. In this paper, the basic characteristics of the CHESS2 prototype sensors and their performance in response to different input signals are presented.
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