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The origin of high-energy cosmic rays, and their behavior in astrophysical sources, remains an open question. Recently, new ways to address this question have been made possible by the observation of a new astrophysical messenger, namely neutrinos. The IceCube telescope has detected a diffuse flux of astrophysical neutrinos in the TeV-PeV energy range, likely produced in astrophysical sources accelerating cosmic rays, and more recently it has reported on a few candidate individual neutrino sources. Future experiments will be able to improve on these measurements quantitatively, by the detection of more events, and qualitatively, by extending the measurement into the EeV energy range. In this paper, we review the main features of the neutrino emission and sources observed by IceCube, as well as the main candidate sources that could contribute to the diffuse neutrino flux. As a parallel question, we review the status of high-energy neutrinos as a probe of Beyond the Standard Model physics coupling to the neutrino sector.

The symmetry of the theory of relativity under diffeomorphisms strongly depends on the equivalence principle. Violation of Equivalence Principle (VEP) can be tested by looking for deviations from the standard framework of neutrino oscillations. In recent works, it has been shown that strong constraints on the VEP parameter space can be placed by means of the atmospheric neutrinos observed by the IceCube neutrino telescope. In this paper, we focus on the KM3NeT neutrino telescope and perform a forecast analysis to assess its capacity to probe VEP. Most importantly, we examine the crucial role played by systematic uncertainties affecting the neutrino observations. We find that KM3NeT will constrain VEP parameters times the local gravitational potential at the level of 10−27. Due to the systematic-dominated regime, independent analyses from different neutrino telescopes are fundamental for robustly testing the equivalence principle.

Spiramycin is a 16-membered macrolide antibiotic currently used in therapy to treat infections caused by Gram-positive bacteria responsible for respiratory tract infections, and it is also effective against some Gram-negative bacteria and against Toxoplasma spp. In contrast, Pseudomonas aeruginosa , which is one of the pathogens of most concern globally, is intrinsically resistant to spiramycin. In this study we show that spiramycin inhibits the expression of virulence determinants in P. aeruginosa in the absence of any significant effect on bacterial multiplication. In vitro experiments demonstrated that production of pyoverdine and pyocyanin by an environmental strain of P. aeruginosa was markedly reduced in the presence of spiramycin, as were biofilm formation, swarming motility, and rhamnolipid production. Moreover, treatment of P. aeruginosa with spiramycin sensitized the bacterium to H 2 O 2 exposure. The ability of spiramycin to dampen the virulence of the P. aeruginosa strain was confirmed in a Galleria mellonella animal model. The results demonstrated that when G. mellonella larvae were infected with P. aeruginosa, the mortality after 24 h was >90%. In contrast, when the spiramycin was injected together with the bacterium, the mortality dropped to about 50%. Furthermore, marked reduction in transcript levels of the antimicrobial peptides gallerimycin, gloverin and moricin, and lysozyme was found in G. mellonella larvae infected with P. aeruginosa and treated with spiramycin, compared to the larvae infected without spiramycin treatment suggesting an immunomodulatory activity of spiramycin. These results lay the foundation for clinical studies to investigate the possibility of using the spiramycin as an anti-virulence and anti-inflammatory drug for a more effective treatment of P. aeruginosa infections, in combination with other antibiotics.

While in recent years the key role of non-coding RNAs (ncRNAs) in the regulation of gene expression has become increasingly evident, their interaction with the global regulatory circuits is still obscure. Here we analyzed the structure and organization of the transcriptome of Streptomyces ambofaciens , the producer of spiramycin. We identified ncRNAs including 45 small-RNAs (sRNAs) and 119 antisense-RNAs (asRNAs I) that appear transcribed from dedicated promoters. Some sRNAs and asRNAs are unprecedented in Streptomyces and were predicted to target mRNAs encoding proteins involved in transcription, translation, ribosomal structure and biogenesis, and regulation of morphological and biochemical differentiation. We then compared ncRNA expression in three strains: (i) the wild-type strain; (ii) an isogenic pirA -defective mutant with central carbon metabolism imbalance, "relaxed" phenotype, and repression of antibiotic production; and (iii) a pirA -derivative strain harboring a "stringent" RNA polymerase that suppresses pirA -associated phenotypes. Data indicated that the expression of most ncRNAs was correlated to the stringent/relaxed phenotype suggesting novel effector mechanisms of the stringent response.