THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS

The \u3b17 nicotine acetylcholine receptor (\u3b17nAChR, CHRNA7) is a homo-pentameric ligand-gated ion channel widely expressed in the Central Nervous System (CNS). Recent evidence has demonstrated its expression also in non-neuronal tissues, including monocytes and macrophages, where it mediates the Cholinergic Anti-Inflammatory Pathway, a neuronal reflex providing the central control of systemic inflammation. Recently, the human-restricted duplicated gene of the \u3b17nAChR, called CHRFAM7A (\u3b17dup) has been discovered. It is the product of the partial duplication and fusion of exon 5-10 of CHRNA7 gene with the novel exons D, C, B and A belonging to the FAM7A gene, of unknown function. The CHRFAM7A gene is expressed in human immune cells and in the CNS and is translated into two proteins, of 45 kDa and 36 kDa, which are the result of alternative splicing. The \u3b17dup protein assembles with the \u3b17 conventional subunits and exerts a dominant negative regulation on the \u3b17nAChR function. The importance of the \u3b17dup protein in the human inflammatory process has been confirmed by the demonstration of its responsiveness to pro-inflammatory stimuli: indeed, the Lipopolysaccharide (LPS) treatment of THP-1 monocytic cells and of human primary monocytes and macrophages down-regulates CHRFAM7A transcript and protein through a transcriptional mechanism reliant on the NF-\u3baB transcription factor. Moreover, unpublished data demonstrated that LPS has the opposite effect on the \u3b17 transcript in monocytes and macrophages, leading to CHRNA7 up-regulation. In this study, we have investigated the transcriptional mechanisms leading to CHRFAM7A expression in the THP-1 monocytic cells and in neuroblastoma SH-SY5Y cells and we demonstrate that the CHRFAM7A gene is endowed with several complex transcriptional mechanisms leading to fine expression modulation, including the presence of alternative and tissue-specific Transcription Start Site (TSS), alternative splicing mechanism, tissue-specific transcriptional elements and intronic silencer elements. Moreover, we demonstrated that the CHRFAM7A down-regulation exerted by LPS involve the chromatin remodeling of CHRFAM7A promoter in THP-1 cells. Increasing evidence has linked CHRNA7 expressional and functional dysregulation to several neurodegenerative disorders, including Alzheimer\u2019s disease. The treatment with the acetylcholinesterase inhibitor Donepezil is effective in temporary ameliorating the cognitive symptoms of AD, by increasing the synaptic levels of ACh and counteracting the cholinergic loss, which is characteristic of AD. However, emerging findings sustained that Donepezil can exert its therapeutic effect also by modulating the immune response and potentiating the Cholinergic Anti-Inflammatory Pathway. So far, the role of CHRFAM7A gene in AD pathogenesis or pharmacological response has not been elucidated. In the present study, we have investigated the expression profile of CHRNA7 and CHRFAM7A genes in human nervous and immune tissues obtained from AD patients, highlighting expressional alterations of both the \u3b17 conventional and duplicated form. Moreover, we have investigated the effect of the AChEI Donepezil on CHRFAM7A and CHRNA7 transcription in THP-1 cells, human primary macrophages and SH-SY5Y cells, collecting new insights about the possible role of the \u3b17dup gene as a pharmacological target in AD therapy

Transverse effects in the production of x rays with a free-electron laser based on an optical undulator

The interaction between high-brilliance electron beams and counterpropagating laser pulses produces x rays via Thomson backscattering. If the laser source is long and intense enough, the electrons of the beam can bunch on the scale of the emitted x-ray wavelength and a regime of collective effects can establish. In this case of dominating collective effects, the FEL instability can develop and the system behaves like a free-electron laser based on an optical undulator. Coherent x rays can be irradiated, with a bandwidth very much thinner than that of the corresponding incoherent emission. The emittance of the electron beam and the distribution nonuniformity of the laser energy are the principal quantities that limit the growth of the x-ray signal. In this work we analyze with a 3D code the transverse effects in the emission produced by a relativistic electron beam when it is under the action of an optical laser pulse and the x-ray spectra obtained. The scalings typical of the optical wiggler, characterized by very short gain lengths and overall time durations of the process, make possible considerable emission also in violation of the Pellegrini criterion for static wigglers. A generalized form of this criterion is validated on the basis of the numerical evidence

Compensation of Non-Linear Bandwidth Broadening by Laser Chirping in Thomson Sources

A new laser chirping prescription is derived by means of the phase-stationary method for an inci- dent Gaussian laser pulse in conjunction with a Li enard-Wiechert calculation of the scattered radia- tion flux and spectral brilliance. This particularly efficient laser chirp has been obtained using the electric field of the laser and for electrons and radiation on axis. The frequency modulation is some- what reduced with respect to that proposed in the previous literature, allowing the application of this procedure to lasers with larger values of the parameter a0. Numerical calculations have been performed using mildly focused and narrow bandwidth laser pulses, confirming a larger efficiency of the chirp prescription here introduced. The chirp efficiency has been analysed as a function of the laser parameter and focusing. Published by AIP Publishing

High intensity X/ γ photon beams for nuclear physics and photonics

In this manuscript we review the challenges of Compton back-scattering sources in advancing photon beam performances in the1−20MeVenergy range, underlining the design criteria bringing tomaximum spectral luminosity and briefly describing the main achieve-ments in conceiving and developing new devices (multi-bunch RF cav-ities and Laser recirculators) for the case of ELI-NP Gamma BeamSystem (ELI-NP-GBS)

The External-Injection experiment at the SPARC_LAB facility

At the SPARC_LAB facility of INFN-LNF we are installing a transport lines for ultra-short electron bunches and another for ultra-intense laser pulses,generated by the SPARC photo-injector and by the FLAME laser in asynchronized fashion at the tens of fs level,to co-propagate inside a hydrogen filled glass capillary,in order to perform acceleration of the electron bunch by a plasma wave driven by the laser pulse.The main aim of this experiment is to demonstrate that a high brightness electron beam can be accelerated by a plasma wave without any significant degradation of its quality.Motivations of the technical choices are made and expected performances are reporte

The PLASMONX Project for advanced beam physics experiments

The Project PLASMONX is well progressing into its design phase and has entered as well its second phase of procurements for main components. The project foresees the installation at LNF of a Ti:Sa laser system (peak power > 170 TW), synchronized to the high brightness electron beam produced by the SPARC photo-injector. The advancement of the procurement of such a laser system is reported, as well as the construction plans of a new building at LNF to host a dedicated laboratory for high intensity photon beam experiments (High Intensity Laser Laboratory). Several experiments are foreseen using this complex facility, mainly in the high gradient plasma acceleration field and in the field of mono- chromatic ultra-fast X-ray pulse generation via Thomson back-scattering. Detailed numerical simulations have been carried out to study the generation of tightly focused electron bunches to collide with laser pulses in the Thomson source: results on the emitted spectra of X-rays are presented

Evaluation of rK39 rapid diagnostic tests for canine visceral leishmaniasis : longitudinal study and meta-analysis

Canine visceral leishmaniasis is a vector-borne disease caused by the intracellular parasite Leishmania infantum. It is an important veterinary disease, and dogs are also the main animal reservoir for human infection. The disease is widespread in the Mediterranean area, and parts of Asia and South and Central America, and is potentially fatal in both dogs and humans unless treated. Diagnosis of canine infections requires serological or molecular tests. Detection of infection in dogs is important prior to treatment, and in epidemiological studies and control programmes, and a sensitive and specific rapid diagnostic test would be very useful. Rapid diagnostic tests (RDTs) have been developed, but their diagnostic performance has been reported to be variable. We evaluated the sensitivity of a RDT based on serological detection of the rK39 antigen in a cohort of naturally infected Brazilian dogs. The sensitivity of the test to detect infection was relatively low, but increased with time since infection and the severity of infection. We then carried out a meta-analysis of published studies of rK39 RDTs, evaluating the sensitivity to detect disease and infection. The results suggest that rK39 RDTs may be useful in a veterinary clinical setting, but the sensitivity to detect infection is too low for operational control programmes

Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: Two randomized controlled trials

Context Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)–conjugated mammalian recombinant uricase, was developed to fulfill this need. Objective To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout. Design, Setting, and Patients Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. Intervention Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group). Main Outcome Measure Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6. Results In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). Conclusion Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo