5-ht inhibition of rat insulin 2 promoter cre recombinase transgene and proopiomelanocortin neuron excitability in the mouse arcuate nucleus

A number of anti-obesity agents have been developed that enhance hypothalamic 5-HT transmission. Various studies have demonstrated that arcuate neurons, which express proopiomelanocortin peptides (POMC neurons), and neuropeptide Y with agouti-related protein (NPY/AgRP) neurons, are components of the hypothalamic circuits responsible for energy homeostasis. An additional arcuate neuron population, rat insulin 2 promoter Cre recombinase transgene (RIPCre) neurons, has recently been implicated in hypothalamic melanocortin circuits involved in energy balance. It is currently unclear how 5-HT modifies neuron excitability in these local arcuate neuronal circuits. We show that 5-HT alters the excitability of the majority of mouse arcuate RIPCre neurons, by either hyperpolarization and inhibition or depolarization and excitation. RIPCre neurons sensitive to 5-HT, predominantly exhibit hyperpolarization and pharmacological studies indicate that inhibition of neuronal firing is likely to be through 5-HT1F receptors increasing current through a voltage-dependent potassium conductance. Indeed, 5-HT1F receptor immunoreactivity co-localizes with RIPCre green fluorescent protein expression. A minority population of POMC neurons also respond to 5-HT by hyperpolarization, and this appears to be mediated by the same receptor-channel mechanism. As neither POMC nor RIPCre neuronal populations display a common electrical response to 5-HT, this may indicate that sub-divisions of POMC and RIPCre neurons exist, perhaps serving different outputs

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the E¿-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic E¿-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors.The J.Y. laboratory is funded by the Spanish Ministerio de Economía, Industria y Competitividad (grant SAF2017-83565-R), Spanish Ministerio de Ciencia e Innovación (grant PID2020-112526RB-I00), and Fundación Científica de la Asociación Española Contra el Cáncer (grant PROYEI6018YÉLA). Work in the J.E.S. laboratory is supported by a core grant to the Laboratory of Molecular Biology from the Medical Research Council (U105178808). The F.D. laboratory is supported by a Laboratory of Excellence grant (ANR-10-LABX-0034_Medalis) to Strasbourg University, Centre National de la Recherche Scientifique. The P.N. laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III–Fondo Europeo de Desarrollo Regional (FEDER; PI17/00199 and PI20/00625) and the Generalitat de Catalunya (2017-SGR-225). The P.M. laboratory acknowledges support from Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for core support, the Spanish Ministry of Economy and Competitiveness (grant SAF-2019-108160-R), the Fundación Uno entre Cienmil, the Obra Social La Caixa (grant LCF/PR/HR19/52160011), and the German Josep Carreras Leukamie Stiftung. Work at the G.R. and P.M. laboratories are cofinanced by the European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program (project PROTEOblood; grant EFA360/19). The O.F.-C. laboratory is funded by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00; cofinanced with European FEDER funds) and the European Research Council (ERC-617840). T.V.-H. was supported by a Marie Sklodowska Curie fellowship (GA792923). The A.B. laboratory is supported by the Spanish Ministry of Economy and Competitiveness (grant PID2019-104695RB-I00)

Test beam performance measurements for the Phase I upgrade of the CMS pixel detector

A new pixel detector for the CMS experiment was built in order to cope with the instantaneous luminosities anticipated for the Phase I Upgrade of the LHC. The new CMS pixel detector provides four-hit tracking with a reduced material budget as well as new cooling and powering schemes. A new front-end readout chip mitigates buffering and bandwidth limitations, and allows operation at low comparator thresholds. In this paper, comprehensive test beam studies are presented, which have been conducted to verify the design and to quantify the performance of the new detector assemblies in terms of tracking efficiency and spatial resolution. Under optimal conditions, the tracking efficiency is (99.95 ± 0.05) %, while the intrinsic spatial resolutions are (4.80 ± 0.25) μm and (7.99 ± 0.21) μm along the 100 μm and 150 μm pixel pitch, respectively. The findings are compared to a detailed Monte Carlo simulation of the pixel detector and good agreement is found.Peer reviewe

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Evaluation of planar silicon pixel sensors with the RD53A readout chip for the Phase-2 Upgrade of the CMS Inner Tracker

The Large Hadron Collider at CERN will undergo an upgrade in order to increase its luminosity to 7.5 × 10³⁴ cm⁻²s⁻¹. The increased luminosity during this High-Luminosity running phase, starting around 2029, means a higher rate of proton-proton interactions, hence a larger ionizing dose and particle fluence for the detectors. The current tracking system of the CMS experiment will be fully replaced in order to cope with the new operating conditions. Prototype planar pixel sensors for the CMS Inner Tracker with square 50 μm × 50 μm and rectangular 100 μm × 25 μm pixels read out by the RD53A chip were characterized in the lab and at the DESY-II testbeam facility in order to identify designs that meet the requirements of CMS during the High-Luminosity running phase. A spatial resolution of approximately 3.4 μm (2 μm) is obtained using the modules with 50 μm × 50 μm (100 μm × 25 μm) pixels at the optimal angle of incidence before irradiation. After irradiation to a 1 MeV neutron equivalent fluence of Φeq = 5.3 × 10¹⁵ cm⁻², a resolution of 9.4 μm is achieved at a bias voltage of 800 V using a module with 50 μm × 50 μm pixel size. All modules retain a hit efficiency in excess of 99% after irradiation to fluences up to 2.1 × 10¹⁶ cm⁻². Further studies of the electrical properties of the modules, especially crosstalk, are also presented in this paper

P-Type Silicon Strip Sensors for the new CMS Tracker at HL-L-HC

Abstract: The upgrade of the LHC to the High-Luminosity LHC (HL-LHC) is expected to increase the LHC design luminosity by an order of magnitude. This will require silicon tracking detectors with a significantly higher radiation hardness. The CMS Tracker Collaboration has conducted an irradiation and measurement campaign to identify suitable silicon sensor materials and strip designs for the future outer tracker at the CMS experiment. Based on these results, the collaboration has chosen to use n-in-p type silicon sensors and focus further investigations on the optimization of that sensor type