Thick GEM-like multipliers - a simple solution for large area UV-RICH detectors

We report on the properties of thick GEM-like (THGEM) electron multipliers made of 0.4 mm thick double-sided Cu-clad G-10 plates, perforated with a dense hexagonal array of 0.3 mm diameter drilled holes. Photon detectors comprising THGEMs coupled to semi-transparent CsI photocathodes or reflective ones deposited on the THGEM surface were studied with Ar/CO2 (70:30), Ar/CH4 (95:5), CH4 and CF4. Gains of ~100000 or exceeding 1000000 were reached with single- or double-THGEM, respectively; the signals have 5-10 ns rise times. The electric field configurations at the THGEM electrodes result in an efficient extraction of photoelectrons and their focusing into the holes; this occurs already at rather low gains, below 100. These detectors, with single-photon sensitivity and with expected sub-millimeter localization, can operate at MHz/mm2 rates. We discuss their prospects for large-area UV-photon imaging for RICH.Comment: 5 pages, 6 figure

Thick GEM-like hole multipliers: properties and possible applications

The properties of thick GEM-like (TGEM) gaseous electron multipliers, operated at 1-740 Torr are presented. They are made of a G-10 plate, perforated with millimeter-scale diameter holes. In single-multiplier elements, effective gains of about 104, 106, and 105 were reached at respective pressures of 1, 10 Torr isobutane and 740 Torr Ar/5%CH4, with pulse rise-times in the few nanosecond scale. The high effective gain at atmospheric pressure was measured with a TGEM coated with a CsI photocathode. The detector was operated in single and cascaded modes. Potential applications in ion and photon detection are discussed.Comment: Contribution to the 2004 Vienna Conference on Instrumentatio

Advances in Thick GEM-like gaseous electron multipliers. Part I: atmospheric pressure operation

Thick GEM-like (THGEM) gaseous electron multipliers are made of standard printed-circuit board perforated with sub-millimeter diameter holes, etched at their rims. Effective gas multiplication factors of 100000 and 10000000 and fast pulses in the few nanosecond rise-time scale were reached in single- and cascaded double-THGEM elements, in atmospheric-pressure standard gas mixtures with single photoelectrons. High single-electron detection efficiency is obtained in photon detectors combining THGEMs and semitransparent UV-sensitive CsI photocathodes or reflective ones deposited on the top THGEM face; the latter benefits of a reduced sensitivity to ionizing background radiation. Stable operation was recorded with photoelectron fluxes exceeding MHz/mm2. The properties and some potential applications of these simple and robust multipliers are discussed.Comment: 41 pages, 27 figures. Submitted to Nucl. Instr. and Meth. A, Dec 21, 200

Technology challenges for space interferometry: the option of mid-infrared integrated optics

Nulling interferometry is a technique providing high angular resolution which is the core of the space missions Darwin and the Terrestrail Planet Finder. The first objective is to reach a deep degree of starlight cancelation in the range 6 -- 20 microns, in order to observe and to characterize the signal from an Earth-like planet. Among the numerous technological challenges involved in these missions, the question of the beam combination and wavefront filtering has an important place. A single-mode integrated optics (IO) beam combiner could support both the functions of filtering and the interferometric combination, simplifying the instrumental design. Such a perspective has been explored in this work within the project Integrated Optics for Darwin (IODA), which aims at developing a first IO combiner in the mid-infrared. The solutions reviewed here to manufacture the combiner are based on infrared dielectric materials on one side, and on metallic conductive waveguides on the other side. With this work, additional inputs are offered to pursue the investigation on mid-infrared photonics devices.Comment: Accepted in Adv. in Space Researc

The global dynamics of RNA stability orchestrates responses to cellular activation

Transcriptomics is used to quantify changes in accumulated levels of mRNAs following cellular activation. These changes arise from the opposing fluxes of transcription and mRNA decay, both of which affect the functional dynamics of global gene expression. A study published recently in BMC Genomics focuses on the contribution made by mRNA stability in shaping the kinetics of gene responses in mammalian cells

Transcriptome Kinetics Is Governed by a Genome-Wide Coupling of mRNA Production and Degradation: A Role for RNA Pol II

Transcriptome dynamics is governed by two opposing processes, mRNA production and degradation. Recent studies found that changes in these processes are frequently coordinated and that the relationship between them shapes transcriptome kinetics. Specifically, when transcription changes are counter-acted with changes in mRNA stability, transient fast-relaxing transcriptome kinetics is observed. A possible molecular mechanism underlying such coordinated regulation might lay in two RNA polymerase (Pol II) subunits, Rpb4 and Rpb7, which are recruited to mRNAs during transcription and later affect their degradation in the cytoplasm. Here we used a yeast strain carrying a mutant Pol II which poorly recruits these subunits. We show that this mutant strain is impaired in its ability to modulate mRNA stability in response to stress. The normal negative coordinated regulation is lost in the mutant, resulting in abnormal transcriptome profiles both with respect to magnitude and kinetics of responses. These results reveal an important role for Pol II, in regulation of both mRNA synthesis and degradation, and also in coordinating between them. We propose a simple model for production-degradation coupling that accounts for our observations. The model shows how a simple manipulation of the rates of co-transcriptional mRNA imprinting by Pol II may govern genome-wide transcriptome kinetics in response to environmental changes

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy