Mutations in the progranulin gene (PGRN) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles ...leading to a 50% loss of progranulin transcript.
Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. We enrolled affected (n = 6) and unaffected at risk members (n = 73) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation; additionally, we included subjects affected by sporadic/familial FTLD (n = 65), controls (n = 75), and a family carrying the tau P301L mutation. The presence of mutations in PGRN and MAPT genes was investigated by direct sequencing of exonic and flanking intronic regions. Progranulin plasma and CSF levels were measured using ELISA.
We demonstrated that progranulin protein is strongly reduced (up to 3.93-fold) both in plasma and CSF of affected and unaffected subjects carrying mutations in progranulin gene (PGRN Leu271LeufsX10 and Q341X). We established a plasma progranulin protein cutoff level of 74.4 ng/mL that identifies, with specificity and sensitivity of 100%, mutation carriers among unaffected subjects. In FTLD, values <or=110.9 ng/mL give a specificity of 92.8% and a sensitivity of 100% for PGRN mutations.
We propose the dosage of plasma progranulin as a useful tool for a quick and inexpensive large-scale screening of carriers of progranulin mutations and for monitoring future treatments that might boost the level of this protein.
Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that ...soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.
Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the ...pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings.
The search for a novel technology, which is able to detect and reconstruct nuclear recoil events in the keV energy range, has become increasingly important now that vast regions of high mass ...weakly-interacting-massive-particle-like dark matter candidates have been excluded. Gaseous time projection chambers (TPC) with optical readout are very promising candidates combining the complete event information provided by the TPC technique with the high sensitivity and granularity of the latest generation light sensors. A TPC with an amplification at the anode, obtained with gas electron multipliers (GEMs), was tested at the Laboratori Nazionali di Frascati. Photons and neutrons from radioactive sources were employed to induce recoiling nuclei and electrons with kinetic energy in the range 1-100 keV. A He-CF4 (60/40) gas mixture was used at atmospheric pressure and the light produced during the multiplication in the GEM channels was acquired by a high-position resolution and low-noise complementary metal-oxide semiconductor camera and a photomultiplier. A multi-stage pattern recognition algorithm based on an advanced clustering technique is presented here. A number of cluster-shaped observables are used to identify nuclear recoils induced by neutrons, which originated from a AmBe source against x-ray 55Fe photoelectrons. An efficiency of 18% to detect nuclear recoils with an energy of about 6 keV is reached, while suppressing 96% of the 55Fe photoelectrons, making this optical read-out gas TPC a very promising candidate for future investigations of ultra-rare events such as directional direct dark matter searches.
In the last few years, an intense R &D activity on particle detectors for future HEP applications has been carried on with the aim of developing new techniques as well as studying the performance of ...already existing detectors when operated in a high rate environment. As for Resistive Plate Chamber detectors, the main challenges to face are the improvement of their detection capabilities and longevity at very high-rates, and the search for new eco-friendly gasmixtures free from greenhouse components. Results obtained in the framework of the RPC ECOGas@GIF++ Collaboration on a thin-Resistive Plate Chamber exposed at the CERN Gamma Irradiation Facility and operated with eco-friendly gas mixtures based on Tetrafluoropropene and Carbon dioxide will be discussed in this paper.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Results obtained by the RPC ECOgas@GIF++ Collaboration, using Resistive Plate Chambers operated with new, eco-friendly gas mixtures, based on tetrafluoropropene and carbon dioxide, are shown and ...discussed in this paper. Tests aimed to assess the performance of this kind of detectors in high-irradiation conditions, analogous to the ones foreseen for the coming years at the Large Hadron Collider experiments, were performed, and demonstrate a performance basically similar to the one obtained with the gas mixtures currently in use, based on tetrafluoroethane, which is being progressively phased out for its possible contribution to the greenhouse effect. Long term aging tests are also being carried out, with the goal to demonstrate the possibility of using these eco-friendly gas mixtures during the whole High Luminosity phase of the Large Hadron Collider.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to ...determine whether TMEM106B modulates GRN expression.
We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls.
In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)).
In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.
Resistive Plate Chamber detectors are largely used in current High Energy Physics experiments, typically operated in avalanche mode with large fractions of Tetrafluoroethane (C2H2F4), a gas recently ...banned by the European Union due to its high Global Warming Potential (GWP). An intense R&D activity is ongoing to improve RPC technology in view of future HEP applications. In the last few years the RPC EcoGas@GIF++ Collaboration has been putting in place a joint effort between the ALICE, ATLAS, CMS, LHCb/SHiP and EP-DT Communities to investigate the performance of present and future RPC generations with eco-friendly gas mixtures. Detectors with different layout and electronics have been operated with ecological gas mixtures, with and without irradiation at the CERN Gamma Irradiation Facility (GIF++). Results of these performance studies together with plans for an aging test campaign are discussed in this article.
CMS iRPC FEB development and validation Gouzevitch, M.; El Sawy, M.; Alves, G.A. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
07/2024, Letnik:
1064
Journal Article
Recenzirano
Odprti dostop
In view of the High Luminosity upgrade of the CERN LHC, the forward CMS Muon spectrometer will be extended with two new stations of improved Resistive Plate Chambers (iRPC) covering the ...pseudorapidity range from 1.8 to 2.4. Compared to the present RPC system, the gap thickness is reduced to lower the avalanche charge, and an innovative 2D strip readout geometry is proposed. These improvements will allow iRPC detector to cope with higher background rates. A new Front-End-Board (FEB) is designed to readout iRPC signals with a threshold as low as 30fC and an integrated Time Digital Converter with a resolution of 30ps. In addition, the communication bandwidth is significantly increased by using optical fibers. The history, final design, certification, and calibration of this FEB are presented.
Improved resistive plate chambers for HL-LHC upgrade of CMS Samalan, A.; Thiel, M.; Asilar, E. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
03/2024, Letnik:
1060, Številka:
C
Journal Article
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