1,037 research outputs found
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
Steps toward translocation-independent RNA polymerase inactivation by terminator ATPase Ï
Factor-dependent transcription termination mechanisms are poorly understood. We determined a series of cryoâelectron microscopy structures portraying the hexameric adenosine triphosphatase (ATPase) Ï on a pathway to terminating NusA/NusG-modified elongation complexes. An open Ï ring contacts NusA, NusG, and multiple regions of RNA polymerase, trapping and locally unwinding proximal upstream DNA. NusA wedges into the Ï ring, initially sequestering RNA. Upon deflection of distal upstream DNA over the RNA polymerase zinc-binding domain, NusA rotates underneath one capping Ï subunit, which subsequently captures RNA. After detachment of NusG and clamp opening, RNA polymerase loses its grip on the RNA:DNA hybrid and is inactivated. Our structural and functional analyses suggest that Ï, and other termination factors across life, may use analogous strategies to allosterically trap transcription complexes in a moribund state
The Fallout of Catastrophic Technogenic Emissions of Toxic Gases Can Negatively Affect Covid-19 Clinical Course
The coronavirus D-19 (Covid-19) pandemic has shaken almost every country in the world: as we stand, 6,3 million deaths from the infection have already been recorded, 167,000 and 380,000 of which are in Italy and the Russian Federation, respectively. In the first wave of the pandemic, Italy suffered an abnormally high death toll. A detailed analysis of available epidemiological data suggests that that rate was shockingly high in the Northern regions and in Lombardy, in particular, whilst in the southern region the situation was less dire. This inexplicably high mortality rate in conditions of a very well-developed health care system such as the one in Lombardy recognized as one of the best in Italy certainly cries for a convincing explanation. In 1976, the small city of Seveso, Lombardy, experienced a release of dioxin into the atmosphere after a massive technogenic accident. The immediate effects of the industrial disaster did not become apparent until a surge in the number of tumors in the affected population in the subsequent years. In this paper, we endeavor to prove our hypothesis that the release of dioxin was a negative cofactor that contributed to a worsening of the clinical course of COVID-19 in Lombardy
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
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)âongoing SARS-CoV-2 infectionâ 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 miceâa publicly available imitation of the ARDS caused by SARS-CoV-2. Our data read that two CâC chemokine receptor 5 (CCR5) ligands, macrophage inflammatory proteins (MIPs) MIP-1α/CCL3 and MIP-1ÎČ/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 3â5-fold level of serum cytokines and chemokines in animals with DAD, including CCR5 ligands MIP-1α/ÎČ, 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
Allosteric control of the RNA polymerase by the elongation factor RfaH
Efficient transcription of long polycistronic operons in bacteria frequently relies on accessory proteins but their molecular mechanisms remain obscure. RfaH is a cellular elongation factor that acts as a polarity suppressor by increasing RNA polymerase (RNAP) processivity. In this work, we provide evidence that RfaH acts by reducing transcriptional pausing at certain positions rather than by accelerating RNAP at all sites. We show that âfastâ RNAP variants are characterized by pause-free RNA chain elongation and are resistant to RfaH action. Similarly, the wild-type RNAP is insensitive to RfaH in the absence of pauses. In contrast, those enzymes that may be prone to falling into a paused state are hypersensitive to RfaH. RfaH inhibits pyrophosphorolysis of the nascent RNA and reduces the apparent MichaelisâMenten constant for nucleotides, suggesting that it stabilizes the post-translocated, active RNAP state. Given that the RfaH-binding site is located 75 Ă
away from the RNAP catalytic center, these results strongly indicate that RfaH acts allosterically. We argue that despite the apparent differences in the nucleic acid targets, the time of recruitment and the binding sites on RNAP, unrelated antiterminators (such as RfaH and λQ) utilize common strategies during both recruitment and anti-pausing modification of the transcription complex
Detector array for the H 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 --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
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 /(sm) was found in good agreement with other experiments at
LNGS at a depth of 3500~meter water equivalent.Comment: 7 pages, 6 figure
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