In the last decades, the improvement of high energy instruments has enabled a deeper understanding of the Cosmic Ray origin issue. In particular, the γ -ray satellites AGILE (Astrorivelatore Gamma ad ...Immagini LEggero) and Fermi-LAT (Fermi-Large Area Telescope) have strongly contributed to the confirmation of direct involvement of Supernova Remnants in Cosmic Ray energization. Despite several attempts to fit experimental data assuming the presence of freshly accelerated particles, the scientific community is now aware that the role of pre-existing Cosmic Ray re-acceleration cannot be neglected. In this work, we highlight the importance of pre-existing Cosmic Ray re-acceleration in the Galaxy showing its fundamental contribution in middle aged Supernova Remnant shocks and in the forward shock of stellar winds.
The recent detection of 12 γ-ray galactic sources well above E>100 TeV by the LHAASO observatory has been a breakthrough in the context of the search for the origin of cosmic rays (CR). Although most ...of these sources remain unidentified, they are often spatially correlated with leptonic accelerators, such as pulsar and pulsar wind nebulae (PWNe). This dramatically affects the paradigm for which a γ-ray detection at E>100 TeV implies the presence of a hadronic accelerator of PeV particles (PeVatron). Moreover, the LHAASO results support the idea that sources other than the standard candidates, supernova remnants, can accelerate galactic CRs. In this context, the good angular resolution of future Cherenkov telescopes, such as the ASTRI Mini-Array and CTA, and the higher sensitivity of future neutrino detectors, such as KM3NeT and IceCube-Gen2, will be of crucial importance. In this brief review, we want to summarize the efforts made up to now, from both theoretical and experimental points of view, to fully understand the LHAASO results in the context of the CR acceleration issue.
In the 1960s, the remnants of supernova explosions (SNRs) were indicated as a possible source of galactic cosmic rays through the Diffusive Shock Acceleration (DSA) mechanism. Since then, the ...observation of gamma-ray emission from relativistic ions in these objects has been one of the main goals of high-energy astrophysics. A few dozen SNRs have been detected at GeV and TeV photon energies in the last two decades. However, these observations have shown a complex phenomenology that is not easy to reduce to the standard paradigm based on DSA acceleration. Although the understanding of these objects has greatly increased, and their nature as efficient electron and proton accelerators has been observed, it remains to be clarified whether these objects are the main contributors to galactic cosmic rays. Here, we review the observations of γ-ray emission from SNRs and the perspectives for the future.
Since from their discovery in 1912, Cosmic-Rays (CRs) are one of the most debated issues of the high energy astrophysics. Their origin is still a fundamental problem and is the subject of very ...intense research. Until now, the best candidate sources of Galactic CR component are Supernova Remnants (SNRs) but final proof for the origin of CRs up to the knee can only be obtained through two fundamental signatures, the detection of a clear gamma-ray signature of π0 decay in Galactic sources and the identification of sources emitting a photon spectrum up to PeV energies. Both indications are quite difficult to obtain. The two gamma-ray satellites, AGILE and Fermi, together with ground telescopes operating in the TeV energy range (HESS, VERITAS and MAGIC), collected a great amount of data from SNRs. In spite of the recent discovery of the neutral pion spectral signature in the SNR W44 spectrum by AGILE (and confirmed by Fermi-LAT), all gamma-ray data collected at GeV and TeV energies for several young and middle-aged SNRs provide interesting challenges to current theoretical models. The emerging view from gamma-ray and particle detection is intriguing and lead to revisit the CR-SNR paradigm, considering also the contribution of other kind of sources.
While from the energetic point of view SNRs are viable sources of Galactic CRs, the issue of whether they can accelerate protons up to PeV remains unsolved. Here we discuss particle acceleration at ...the forward shock of SN and discuss the possibility that the escaping particle current may excite a non-resonant instability that in turn leads to the formation of resonant modes confining particles close to the shock and increasing the maximum energy. This mechanism works throughout the expansion of the SN explosion, from the ejecta dominated (ED) to the Sedov-Taylor (ST) phase. Because of their higher explosion rate,we focus on type II SNae expanding in the slow, dense red supergiant wind. When the explosion occurs in such winds, the transition between the ED and the ST phase is likely to take place within a few tens of years. As a result, the spectrum of accelerated particles shows a break in the slope, at the maximum energy (EM) achieved at the beginning of the ST phase. Above this energy, the spectrum becomes steeper but remains a power law than developing an exponential cutoff. We show that for type II SNae typical parameters, proton EM can easily reach PeV energies, confirming that type II SNRs are the best candidate sources for CRs at the knee. We have tried to fit KASCADE-Grande, ARGO -YBJ and YAC1-Tibet Array data with our model but we could not find any parameter combination that could explain all data sets. Indeed the recent measurement of the proton and helium spectra in the knee region, with the ARGO-YBJ and YAC1-Tibet Array, has made the situation very confused. These measurements suggest that the knee in the light component is at 650 TeV, appreciably below the overall spectrum knee. This finding would resolve the problem of reaching very high energies in SNae, but, on the other hand, it would open a critical issue in the transition region between Galactic and extragalactic CRs.
B cell receptor Immunoglobulin (BcR IG) repertoire of Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of quasi-identical BcR IG. These are observed in approximately 30% of ...patients, defined as stereotyped receptors and subdivided into subsets based on specific VH CDR3 aa motifs and phylogenetically related IGHV genes. Although relevant to CLL ontogeny, the distribution of CLL-biased stereotyped immunoglobulin rearrangements (CBS-IG) in normal B cells has not been so far specifically addressed using modern sequencing technologies. Here, we have investigated the presence of CBS-IG in splenic B cell subpopulations (s-BCS) and in CD5
and CD5
B cells from the spleen and peripheral blood (PB).
Fractionation of splenic B cells into 9 different B cell subsets and that of spleen and PB into CD5
and CD5
cells were carried out by FACS sorting. cDNA sequences of BcR IG gene rearrangements were obtained by NGS. Identification of amino acidic motifs typical of CLL stereotyped subsets was carried out on IGHV1-carrying gene sequences and statistical evaluation has been subsequently performed to assess stereotypes distribution.
CBS-IG represented the 0.26% average of IGHV1 genes expressing sequences, were detected in all of the BCS investigated. CBS-IG were more abundant in splenic and circulating CD5
B (0.57%) cells compared to CD5
B cells (0.17%). In all instances, most CBS IG did not exhibit somatic hypermutation similar to CLL stereotyped receptors. However, compared to CLL, they exhibited a different CLL subset distribution and a broader utilization of the genes of the IGHV1 family.
CBS-IG receptors appear to represent a part of the "public" BcR repertoire in normal B cells. This repertoire is observed in all BCS excluding the hypothesis that CLL stereotyped BcR accumulate in a specific B cell subset, potentially capable of originating a leukemic clone. The different relative representation of CBS-IG in normal B cell subgroups suggests the requirement for additional selective processes before a full transformation into CLL is achieved.
B-cell chronic lymphocytic leukemia (CLL) results from accumulation of leukemic cells that are subject to iterative re-activation cycles and clonal expansion in lymphoid tissues. The effects of the ...well-tolerated alkaloid Berberine (BRB), used for treating metabolic disorders, were studied on ex-vivo leukemic cells activated in vitro by microenvironment stimuli. BRB decreased expression of survival/proliferation-associated molecules (e.g. Mcl-1/Bcl-xL) and inhibited stimulation-induced cell cycle entry, irrespective of TP53 alterations or chromosomal abnormalities. CLL cells rely on oxidative phosphorylation for their bioenergetics, particularly during the activation process. In this context, BRB triggered mitochondrial dysfunction and aberrant cellular energetic metabolism. Decreased ATP production and NADH recycling, associated with mitochondrial uncoupling, were not compensated by increased lactic fermentation. Antioxidant defenses were affected and could not correct the altered intracellular redox homeostasis. The data thus indicated that the cytotoxic/cytostatic action of BRB at 10-30 μM might be mediated, at least in part, by BRB-induced impairment of oxidative phosphorylation and the associated increment of oxidative damage, with consequent inhibition of cell activation and eventual cell death. Bioenergetics and cell survival were instead unaffected in normal B lymphocytes at the same BRB concentrations. Interestingly, BRB lowered the apoptotic threshold of ABT-199/Venetoclax, a promising BH3-mimetic whose cytotoxic activity is counteracted by high Mcl-1/Bcl-xL expression and increased mitochondrial oxidative phosphorylation. Our results indicate that, while CLL cells are in the process of building their survival and cycling armamentarium, the presence of BRB affects this process.
Chronic lymphocytic leukemia (CLL) clones contain subpopulations differing in time since the last cell division (“age”): recently born, proliferative (PF; CXCR4DimCD5Bright), intermediate (IF; ...CXCR4IntCD5Int), and resting (RF; CXCR4BrightCD5Dim) fractions. Herein, we used deuterium (2H) incorporation into newly synthesized DNA in patients to refine the kinetics of CLL subpopulations by characterizing two additional CXCR4/CD5 fractions, i.e., double dim (DDF; CXCR4DimCD5Dim) and double bright (DBF; CXCR4BrightCD5Bright); and intraclonal fractions differing in surface membrane (sm) IgM and IgD densities. Although DDF was enriched in recently divided cells and DBF in older cells, PF and RF remained the most enriched in youngest and oldest cells, respectively. Similarly, smIgMHigh and smIgDHigh cells were the youngest, and smIgMLow and smIgDLow were the oldest, when using smIG levels as discriminator. Surprisingly, the cells closest to the last stimulatory event bore high levels of smIG, and stimulating via TLR9 and smIG yielded a phenotype more consistent with the in vivo setting. Finally, older cells were less sensitive to in vivo inhibition by ibrutinib. Collectively, these data define additional intraclonal subpopulations with divergent ages and phenotypes and suggest that BCR engagement alone is not responsible for the smIG levels found in vivo, and the differential sensitivity of distinct fractions to ibrutinib might account, in part, for therapeutic relapse.
Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5
+
B cells with low surface immunoglobulins (IG). About 40% of CLL clones utilize quasi-identical B cell ...receptors, defined as stereotyped BCR. CLL-like stereotyped-IG rearrangements are present in normal B cells as a part of the public IG repertoire. In this study, we collected details on the representation and features of CLL-like stereotyped-IG in the IGH repertoire of B-cell subpopulations purified from the peripheral blood of nine healthy donors. The B-cell subpopulations were also fractioned according to the expression of surface CD5 molecules and IG light chain, IGκ and IGλ. IG rearrangements, obtained by high throughput sequencing, were scanned for the presence of CLL-like stereotyped-IG. CLL-like stereotyped-IG did not accumulate preferentially in the CD5
+
B cells, nor in specific B-cell subpopulations or the CD5
+
cell fraction thereof, and their distribution was not restricted to a single IG light chain type. CLL-like stereotyped-IG shared with the corresponding CLL stereotype rearrangements the IGHV mutational status. Instead, for other features such as IGHV genes and frequency, CLL stereotyped-IGs presented a CLL-like subset specific behavior which could, or could not, be consistent with CLL stereotyped-IGs. Therefore, as opposed to the immuno-phenotype, the features of the CLL stereotyped-IG repertoire suggest a CLL stereotyped subset-specific ontogeny. Overall, these findings suggest that the immune-genotype can provide essential details in tracking and defining the CLL cell of origin.
While from the energetic point of view supernova remnants are viable sources of Galactic cosmic rays (CRs), the issue of whether they can accelerate protons up to a few PeV remains unsolved. Here we ...discuss particle acceleration at the forward shock of supernovae, and discuss the possibility that the current of escaping particles may excite a non-resonant instability that in turn leads to the formation of resonant modes that confine particles close to the shock, thereby increasing the maximum energy. This mechanism is at work throughout the expansion of the supernova explosion, from the ejecta dominated (ED) phase to the Sedov–Taylor (ST) phase. The transition from one stage to the other reflects in a break in the spectrum of injected particles. Because of their higher explosion rate, we focus our work on type II SNe expanding in the slow, dense wind, produced by the red super-giant progenitor stars. When the explosion occurs in such winds, the transition between the ED and the ST phase is likely to take place within a few tens of years. The highest energies are reached at even earlier times, when, however, a small fraction of the mass of ejecta has been processed. As a result, the spectrum of accelerated particles shows a break in the slope, at an energy that is the maximum energy (EM) achieved at the beginning of the ST phase. Above this characteristic energy, the spectrum becomes steeper but remains a power law rather than developing an exponential cutoff. An exponential cut is eventually present at much higher energies but it does not have a phenomenological relevance. We show that for parameters typical of type II supernovae, EM for protons can easily reach values in the PeV range, confirming that type II SNRs are the best candidate sources for CRs at the knee.
From the point of view of implications of this scenario on the measured particle spectra, we have tried to fit KASCADE-Grande, ARGO -YBJ and YAC1-Tibet Array data with our model but we could not find any combination of the parameters that could explain all data sets. Indeed the recent measurement of the proton and helium spectra in the knee region, with the ARGO-YBJ and YAC1-Tibet Array, has made the situation very confused. These measurements suggest that the knee in the light component is at ∼650TeV, appreciably below the knee in the overall spectrum. On one hand this finding would resolve the problem of reaching very high energies in supernovae, but on the other it would open a critical issue in the transition region between Galactic and extragalactic CRs.
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