Are Granulins Copper Sequestering Proteins?

Granulins (GRN 1-7) are short (~6 kDa), cysteine-rich proteins that are generated upon the proteolytic processing of progranulin (PGRN). These peptides, along with their precursor, have been implicated in multiple pathophysiological roles, especially in neurodegenerative diseases. Previously we showed that GRN-3 and GRN-5 are fully disordered in the reduced form implicating redox sensitive attributes to the proteins. Redox-based modulations are often carried out by metalloproteins in mitigating oxidative stress and maintaining metal-homeostasis within cells. To probe whether GRNs play a role in metal sequestration, we tested the metal binding propensity of the reduced forms of GRNs −3 and − 5 under neutral and acidic pH mimicking cytosolic and lysosomal conditions, respectively. We found, at neutral pH, both GRNs selectively bind Cu and no other divalent metal cations, with a greater specificity for Cu(I). Binding of Cu did not result in a disorder-to-order structural transition but partly triggered the multimerization of GRNs via uncoordinated cystines at both pH conditions. Overall, the results indicate that GRNs −3 and − 5 have surprisingly strong affinity for Cu in the pM range, comparable to other known copper sequestering proteins. The results also hint at a potential of GRNs to reduce Cu(II) to Cu(I), a process that has significance in mitigating Cu-induced ROS cytotoxicity in cells. Together, this report uncovers metal-coordinating property of GRNs for the first time, which may have profound significance in their structure and pathophysiological functions

Performance of a Large-area GEM Detector Read Out with Wide Radial Zigzag Strips

A 1-meter-long trapezoidal Triple-GEM detector with wide readout strips was tested in hadron beams at the Fermilab Test Beam Facility in October 2013. The readout strips have a special zigzag geometry and run along the radial direction with an azimuthal pitch of 1.37 mrad to measure the azimuthal phi-coordinate of incident particles. The zigzag geometry of the readout reduces the required number of electronic channels by a factor of three compared to conventional straight readout strips while preserving good angular resolution. The average crosstalk between zigzag strips is measured to be an acceptable 5.5%. The detection efficiency of the detector is (98.4+-0.2)%. When the non-linearity of the zigzag-strip response is corrected with track information, the angular resolution is measured to be (193+-3) urad, which corresponds to 14% of the angular strip pitch. Multiple Coulomb scattering effects are fully taken into account in the data analysis with the help of a stand-alone Geant4 simulation that estimates interpolated track errors.Comment: 30 pages, 28 figures, submitted to NIM

Granulins Modulate Liquid-Liquid Phase Separation and Aggregation of Prion-Like C-Terminal Domain of the Neurodegeneration-Associated Protein TDP-43

Tar DNA binding protein 43 (TDP-43) has emerged as a key player in many neurodegenerative pathologies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Hallmarks of both FTLD and ALS are the toxic cytoplasmic inclusions of the prion-like C-terminal fragments of TDP-43 (TDP-43 CTD), formed upon proteolytic cleavage of full-length TDP-43 in the nucleus and subsequent transport to the cytoplasm. Both full-length TDP-43 and its CTD are also known to form stress granules (SGs) by coacervating with RNA in the cytoplasm during stress and may be involved in these pathologies. Furthermore, mutations in PGRN gene, leading to haploinsufficiency and diminished function of progranulin (PGRN) protein, are strongly linked to FTLD and ALS. Recent reports have indicated that proteolytic processing of PGRN to smaller protein modules called granulins (GRNs) contributes to FTLD and ALS progression, with specific GRNs exacerbating TDP-43–induced cytotoxicity. Here, we investigated the interactions between the proteolytic products of both TDP-43 and PGRN. Based on structural disorder and charge distributions, we hypothesized that GRNs -3 and -5 could interact with TDP-43 CTD. We also show that in both reducing and oxidizing conditions GRNs -3 and -5 interact with and differentially modulate TDP-43 CTD aggregation and/or liquid-liquid phase separation (LLPS) in vitro. While GRN-3 promoted insoluble aggregates of TDP-43 CTD, GRN-5 mediated LLPS. These results constitute the first observation of an interaction between GRNs and TDP-43, suggesting a mechanism by which attenuated PGRN function could lead to familial FTLD or ALS

Comparative Clinical Evaluation of Efficacy of Biodentine and Bromelain with Biodentine as Direct Pulp Capping Material

1.Objective: This study aimed to evaluate the efficacy of Biodentine and a combination of bromelain with Biodentine as direct pulp capping materials. 2.Material and Methods: This clinical study included 26 participants with mature permanent mandibular molars exhibiting deep carious lesions without pulpal exposure. The participants were divided into two groups: Group I received Biodentine alone, while Group II received a combination of bromelain and Biodentine. Clinical and radiographic follow-ups were performed at 1, 3, and 6 months to assess the success rates of the treatment modalities. 3.Results: The clinical success rate of Biodentine as a direct pulp capping agent was 92% at 1 month, 100% at 3 months, and 92% at 6 months follow-up. The radiographic success rate was 100% at all intervals. The clinical success rate of the bromelain with Biodentine group was 85% at 1 month, 91% at 3 months, and 100% at 6 months, with corresponding radiographic success rates of 92%, 91%, and 100% at the respective intervals. Statistical analysis revealed no significant difference in success rates between the two groups. 4.Conclusion: Both Biodentine and the combination of bromelain with Biodentine demonstrated high clinical and radiographic success rates in direct pulp capping. However, there was no statistically significant difference between the two groups, suggesting that bromelain may not provide additional benefits when combined with Biodentine. Further research with larger sample sizes and longer follow-up periods is needed to explore the potential of bromelain and other combinations for direct pulp capping. These findings contribute to our understanding of effective materials for vital pulp therapy and guide clinical decision-making in dental practice

Performance of a Large-Area GEM Detector Prototype for the Upgrade of the CMS Muon Endcap System

Gas Electron Multiplier (GEM) technology is being considered for the forward muon upgrade of the CMS experiment in Phase 2 of the CERN LHC. Its first implementation is planned for the GE1/1 system in the $1.5 < \mid\eta\mid < 2.2$ region of the muon endcap mainly to control muon level-1 trigger rates after the second long LHC shutdown. A GE1/1 triple-GEM detector is read out by 3,072 radial strips with 455 $\mu$rad pitch arranged in eight $\eta$-sectors. We assembled a full-size GE1/1 prototype of 1m length at Florida Tech and tested it in 20-120 GeV hadron beams at Fermilab using Ar/CO$_{2}$ 70:30 and the RD51 scalable readout system. Four small GEM detectors with 2-D readout and an average measured azimuthal resolution of 36 $\mu$rad provided precise reference tracks. Construction of this largest GEM detector built to-date is described. Strip cluster parameters, detection efficiency, and spatial resolution are studied with position and high voltage scans. The plateau detection efficiency is [97.1 $\pm$ 0.2 (stat)]\%. The azimuthal resolution is found to be [123.5 $\pm$ 1.6 (stat)] $\mu$rad when operating in the center of the efficiency plateau and using full pulse height information. The resolution can be slightly improved by $\sim$ 10 $\mu$rad when correcting for the bias due to discrete readout strips. The CMS upgrade design calls for readout electronics with binary hit output. When strip clusters are formed correspondingly without charge-weighting and with fixed hit thresholds, a position resolution of [136.8 $\pm$ 2.5 stat] $\mu$rad is measured, consistent with the expected resolution of strip-pitch/$\sqrt{12}$ = 131.3 $\mu$rad. Other $\eta$-sectors of the detector show similar response and performance.Comment: 8 pages, 32 figures, submitted to Proc. 2014 IEEE Nucl. Sci. Symposium, Seattle, WA, reference adde

A novel application of Fiber Bragg Grating (FBG) sensors in MPGD

We present a novel application of Fiber Bragg Grating (FBG) sensors in the construction and characterisation of Micro Pattern Gaseous Detector (MPGD), with particular attention to the realisation of the largest triple (Gas electron Multiplier) GEM chambers so far operated, the GE1/1 chambers of the CMS experiment at LHC. The GE1/1 CMS project consists of 144 GEM chambers of about 0.5 m2 active area each, employing three GEM foils per chamber, to be installed in the forward region of the CMS endcap during the long shutdown of LHC in 2108-2019. The large active area of each GE1/1 chamber consists of GEM foils that are mechanically stretched in order to secure their flatness and the consequent uniform performance of the GE1/1 chamber across its whole active surface. So far FBGs have been used in high energy physics mainly as high precision positioning and re-positioning sensors and as low cost, easy to mount, low space consuming temperature sensors. FBGs are also commonly used for very precise strain measurements in material studies. In this work we present a novel use of FBGs as flatness and mechanical tensioning sensors applied to the wide GEM foils of the GE1/1 chambers. A network of FBG sensors have been used to determine the optimal mechanical tension applied and to characterise the mechanical tension that should be applied to the foils. We discuss the results of the test done on a full-sized GE1/1 final prototype, the studies done to fully characterise the GEM material, how this information was used to define a standard assembly procedure and possible future developments.Comment: 4 pages, 4 figures, presented by Luigi Benussi at MPGD 2015 (Trieste, Italy). arXiv admin note: text overlap with arXiv:1512.0848

Operational experience with the GEM detector assembly lines for the CMS forward muon upgrade

The CMS Collaboration has been developing large-area triple-gas electron multiplier (GEM) detectors to be installed in the muon Endcap regions of the CMS experiment in 2019 to maintain forward muon trigger and tracking performance at the High-Luminosity upgrade of the Large Hadron Collider (LHC); 10 preproduction detectors were built at CERN to commission the first assembly line and the quality controls (QCs). These were installed in the CMS detector in early 2017 and participated in the 2017 LHC run. The collaboration has prepared several additional assembly and QC lines for distributed mass production of 160 GEM detectors at various sites worldwide. In 2017, these additional production sites have optimized construction techniques and QC procedures and validated them against common specifications by constructing additional preproduction detectors. Using the specific experience from one production site as an example, we discuss how the QCs make use of independent hardware and trained personnel to ensure fast and reliable production. Preliminary results on the construction status of CMS GEM detectors are presented with details of the assembly sites involvement

Development and performance of Triple-GEM detectors for the upgrade of the muon system of the CMS experiment

The CMS Collaboration is evaluating GEM detectors for the upgrade of the muon system. This contribution will focus on the R&D performed on chambers design features and will discuss the performance of the upgraded detector

Overview of large area triple-GEM detectors for the CMS forward muon upgrade

In order to cope with the harsh environment expected from the high luminosity LHC, the CMS forward muon system requires an upgrade. The two main challenges expected in this environment are an increase in the trigger rate and increased background radiation leading to a potential degradation of the particle ID performance. Additionally, upgrades to other subdetectors of CMS allow for extended coverage for particle tracking, and adding muon system coverage to this region will further enhance the performance of CMS

Charged particle detection performance of Gas Electron Multiplier (GEM) detectors for the upgrade of CMS endcap muon system at the CERN LHC

The Compact Muon Solenoid (CMS) detector is one of the two general-purpose detectors at the CERN LHC. LHC will provide exceptional high instantaneous and integrated luminosity after second long shutdown. The forward region |η| ≥ 1:5 of CMS detector will face extremely high particle rates in tens of kHz/cm2 and hence it will affect the momentum resolution, efficiency and longevity of the muon detectors. Here, η is pseudorapidity defined as η = -ln(tan(θ/2)), where θ is the polar angle measured from z-axis. To overcome these issues the CMSGEM collaboration has proposed to install new large size rate capable Triple Gas Electron Multiplier (GEM) detectors in the forward region of CMS muon system. The first set of Triple GEM detectors will be installed in the GE1/1 region (1:6 <; |η| <; 2.2) of the muon endcap during the long shutdown 2 (LS2) of the LHC. Towards this goal, full size CMS Triple GEM detectors have been fabricated and tested at the CERN SPS, H2 and H4 test beam facility. The GEM detectors were operated with two gas mixtures: Ar/CO2 (70/30) and Ar/CO2/CF4 (45/15/40). In 2014, good quality data was collected during test beam campaigns. In this paper, the performance of the detectors is summarized based on their tracking efficiency and time resolution