At the cutting edge against cancer: A perspective on immunoproteasome and immune checkpoints modulation as a potential therapeutic intervention

Simple Summary:& nbsp;Immunoproteasome plays a key role in the generation of antigenic peptides. Immune checkpoints therapy is a front-line treatment of advanced/metastatic tumors, and to improve its efficacy, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is mandatory. The scope of this review is to offer a picture of the role of immunoproteasome in antigen presentation to fuel the hypothesis of novel therapeutic interventions based on the modulation of this proteolytic complex and immune checkpoints.Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers

Scintillation proportional Xe counter with WLS fiber readout for low-energy X-rays

A gas Xe based scintillation proportional counter with cylindrical geometry and wavelength shifting (WLS) fiber readout for X-rays of energy 0.5 - 100 keV is proposed. With such a design large sizes and sensitive area of the counter with a fairly well uniformity is possible. The counter could be used for "dark matter" search and neutrino magnetic moment measurement and for detection of small amounts or traces of radioactive elements in substances or environment.Comment: LaTeX 4 pages, 3 figures in eps, Submitted to NI

Lineage-specific variations in the trigger loop modulate RNA proofreading by bacterial RNA polymerases

RNA cleavage by bacterial RNA polymerase (RNAP) has been implicated in transcriptional proofreading and reactivation of arrested transcription elongation complexes but its molecular mechanism is less understood than the mechanism of nucleotide addition, despite both reactions taking place in the same active site. RNAP from the radioresistant bacterium Deinococcus radiodurans is characterized by highly efficient intrinsic RNA cleavage in comparison with Escherichia coli RNAP. We find that the enhanced RNA cleavage activity largely derives from amino acid substitutions in the trigger loop (TL), a mobile element of the active site involved in various RNAP activities. The differences in RNA cleavage between these RNAPs disappear when the TL is deleted, or in the presence of GreA cleavage factors, which replace the TL in the active site. We propose that the TL substitutions modulate the RNA cleavage activity by altering the TL folding and its contacts with substrate RNA and that the resulting differences in transcriptional proofreading may play a role in bacterial stress adaptation.</p

Detector array for the 7^7H nucleus multi-neutron decay study

Setup fitting the requirements for the detailed study of the five-body decay of the 7H nucleus obtained as a result of the proton transfer from the 8He projectiles to the deuterium target nuclei is being built at the radioactive beam line of ACCULINNA-2 separator in the G.N. Flerov Laboratory of Nuclear Reactions. Described here is the assembly of 100 BC-404 plastic scintillators, intended for neutron detection, the annular Si detector telescope for the 3He recoils, and the detector array providing the $\Delta E$-$E$-TOF registration of 3H nuclei emitted at the 7H decay. Results obtained by the Monte Carlo simulations made for the energy values and flight passes of all these particles are given together with the luminosity expected for the discussed experiments

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome

Introduction: The acute respiratory distress syndrome (ARDS), secondary to viral pneumonitis, is one of the main causes of high mortality in patients with COVID-19 (novel coronavirus disease 2019)—ongoing SARS-CoV-2 infection— reached more than 0.7 billion registered cases.Methods: Recently, we elaborated a non-surgical and reproducible method of the unilateral total diffuse alveolar damage (DAD) of the left lung in ICR mice–a publicly available imitation of the ARDS caused by SARS-CoV-2. Our data read that two C–C chemokine receptor 5 (CCR5) ligands, macrophage inflammatory proteins (MIPs) MIP-1α/CCL3 and MIP-1β/CCL4, are upregulated in this DAD model up to three orders of magnitude compared to the background level.Results: Here, we showed that a nonpeptide compound TAK-779, an antagonist of CCR5/CXCR3, readily prevents DAD in the lung with a single injection of 2.5 mg/kg. Histological analysis revealed reduced peribronchial and perivascular mononuclear infiltration in the lung and mononuclear infiltration of the wall and lumen of the alveoli in the TAK-779-treated animals. Administration of TAK-779 decreased the 3–5-fold level of serum cytokines and chemokines in animals with DAD, including CCR5 ligands MIP-1α/β, MCP-1, and CCL5. Computed tomography revealed rapid recovery of the density and volume of the affected lung in TAK-779-treated animals.Discussion: Our pre-clinical data suggest that TAK-779 is more effective than the administration of dexamethasone or the anti-IL6R therapeutic antibody tocilizumab, which brings novel therapeutic modality to TAK-779 and other CCR5 inhibitors for the treatment of virus-induced hyperinflammation syndromes, including COVID-19

Flux Modulations seen by the Muon Veto of the GERDA Experiment

The GERDA experiment at LNGS of INFN is equipped with an active muon veto. The main part of the system is a water Cherenkov veto with 66~PMTs in the water tank surrounding the GERDA cryostat. The muon flux recorded by this veto shows a seasonal modulation. Two effects have been identified which are caused by secondary muons from the CNGS neutrino beam (2.2 %) and a temperature modulation of the atmosphere (1.4 %). A mean cosmic muon rate of $I^0_{\mu} = (3.477 \pm 0.002_{\textrm{stat}} \pm 0.067_{\textrm{sys}}) \times 10^{-4}$/(s$\cdot$m$^2$) was found in good agreement with other experiments at LNGS at a depth of 3500~meter water equivalent.Comment: 7 pages, 6 figure

Challenges in QCD matter physics --The scientific programme of the Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sNN= 2.7--4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (μB&gt; 500 MeV), effects of chiral symmetry, and the equation of state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2024, in the context of the worldwide efforts to explore high-density QCD matter

The background in the neutrinoless double beta decay experiment GERDA

The GERmanium Detector Array (GERDA) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double beta decay of 76Ge. The signature of the signal is a monoenergetic peak at 2039 keV, the Q-value of the decay, Q_bb. To avoid bias in the signal search, the present analysis does not consider all those events, that fall in a 40 keV wide region centered around Q_bb. The main parameters needed for the neutrinoless double beta decay analysis are described. A background model was developed to describe the observed energy spectrum. The model contains several contributions, that are expected on the basis of material screening or that are established by the observation of characteristic structures in the energy spectrum. The model predicts a flat energy spectrum for the blinding window around Q_bb with a background index ranging from 17.6 to 23.8*10^{-3} counts/(keV kg yr). A part of the data not considered before has been used to test if the predictions of the background model are consistent. The observed number of events in this energy region is consistent with the background model. The background at Q-bb is dominated by close sources, mainly due to 42K, 214Bi, 228Th, 60Co and alpha emitting isotopes from the 226Ra decay chain. The individual fractions depend on the assumed locations of the contaminants. It is shown, that after removal of the known gamma peaks, the energy spectrum can be fitted in an energy range of 200 kev around Q_bb with a constant background. This gives a background index consistent with the full model and uncertainties of the same size

The 6^{6}H states studied in the d(8He,α)d(^8\text{He},\alpha) reaction and evidence of extremely correlated character of the 5^{5}H ground state

The extremely neutron-rich system $^{6}$H was studied in the direct $^2\text{H}(^8\text{He},{^4\text{He}})^{6}$H transfer reaction with a 26 $A$ MeV secondary $^{8}$He beam. The measured missing mass spectrum shows a resonant state in $^{6}$H at $6.8(3)$ MeV relative to the $^3$H+$3n$ threshold. The population cross section of the presumably $p$-wave states in the energy range from 4 to 8 MeV is $d\sigma/d\Omega_{\text{c.m.}} \simeq 190(40)$ $\mu$b/sr in the angular range $5^{\circ}<\theta_{\text{c.m.}}<16^{\circ}$. The obtained missing mass spectrum is free of the $^{6}$H events below 3.5 MeV ($d\sigma/d\Omega_{\text{c.m.}} \lesssim 3$ $\mu$b/sr in the same angular range). The steep rise of the $^{6}$H missing mass spectrum at 3 MeV allows to show that $4.5(3)$ MeV is the lower limit for the possible resonant state energy in $^{6}$H tolerated by our data. According to paring energy estimates, such a $4.5(3)$ MeV resonance is a realistic candidate for the $^{6}$H ground state (g.s.). The obtained results confirm that the decay mechanism of the $^{7}$H g.s.\ (located at 2.2 MeV above the $^{3}$H+$4n$ threshold) is the ``true'' (or simultaneous) $4n$ emission. The resonance energy profiles and the momentum distributions of the sequential $^{6}$H \,\rightarrow \, ^5H(g.s.)+n\, \rightarrow \, ^3H+$3n$ decay fragments were analyzed by the theoretically-updated direct four-body-decay and sequential-emission mechanisms. The measured momentum distributions of the $^{3}$H fragments in the $^{6}$H rest frame indicate very strong ``dineutron-type'' correlations in the $^{5}$H ground state decay.Comment: 9 pages, 11 figure