Insensitivity of flavoured leptogenesis to low energy CP violation

If the baryon asymmetry of the Universe is produced by leptogenesis, CP violation is required in the lepton sector. In the seesaw extension of the Standard Model with three hierarchical right-handed neutrinos, we show that the baryon asymmetry is insensitive to the PMNS phases: thermal leptogenesis can work for any value of the observable phases. This result was well-known when there are no flavour effects in leptogenesis; we show that it remains true when flavour effects are included.Comment: 4 pages, 1 figure; version accepted for publication, added explanations, notation clarifie

Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS

Adrenomedullin (ADM) is upregulated independently by hypoxia and LPS, two key factors in the pathogenesis of acute lung injury (ALI). This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O2) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O2). ADM expression was analyzed by in situ hybridization, Northern blot, Western blot, and RIA analyses. In the rat lung, combination of hypoxia and LPS treatments overcomes ADM induction occurring after each treatment alone. With in situ techniques, the synergistic effect of both stimuli mainly correlates with ADM expression in inflammatory cells within blood vessels and, to a lesser extent, to cells in the lung parenchyma and bronchiolar epithelial cells. In the in vitro model, hypoxia and hypoxia LPS treatments caused a similar strong induction of ADM expression and secretion in epithelial and endothelial cell lines. In alveolar macrophages, however, LPS-induced ADM expression and secretion were further increased by the concomitant exposure to hypoxia, thus paralleling the in vivo response. In conclusion, ADM expression is highly induced in a variety of key lung cell types in this rat model of ALI by combination of hypoxia and LPS, suggesting an essential role for this mediator in this syndrom

Effects of acute hypoxia and lipopolysaccharide on nitric oxide synthase-2 expression in acute lung injury

The potential role of nitric oxide synthase-2 (NOS2) in acute lung injury (ALI) has gained increasing attention. This study evaluates the effects of hypoxia, an important feature of ALI, on NOS2 expression in a rat model of ALI caused by exposure to hypoxia and LPS. Exposure to hypoxia alone had no effect on the expression of NOS2 in rat lungs. LPS treatment resulted in a significant increase in NOS2 in the lungs, which was further enhanced by concomitant exposure to hypoxia. Immunohistochemical analysis and in situ hybridization showed no changes in the expression of NOS2 in lung resident cells under any conditions. The increase in NOS2 levels is mainly due to the influx of NOS2-expressing inflammatory cells. By morphologic analysis, these inflammatory cells were identified as neutrophils, lymphocytes, and monocytes. In vitro experiments of lung epithelial and endothelial cell lines showed no detectable expression of NOS2 with any of the treatments. In a macrophage cell line, LPS-induced NOS2 expression was not affected by the concomitant exposure to hypoxia. In conclusion, LPS increases NOS2 expression in rat lungs through the recruitment of NOS2-producing leukocytes. Simultaneous exposure to LPS and hypoxia results in a greater influx of inflammatory cells that further enhances NOS2 expression

Adrenomedullin in mammalian embryogenesis

Here are summarized data supporting that adrenomedullin (AM) is a multifunctional factor involved in the complex regulatory mechanisms of mammalian development. During rodent embryogenesis, AM is first expressed in the heart, followed by a broader but also defined spatio-temporal pattern of expression in vascular, neural, and skeletal-forming tissues as well as in the main embryonic internal organs. AM pattern of expression is suggestive of its involvement in the control of embryonic invasion, proliferation, and differentiation processes, probably through autocrine or paracrine modes of action. AM levels in fetoplacental tissues, uterus, maternal and umbilical plasma are highly increased during normal gestation. These findings in addition to other physiological and gene targeting studies support the importance of AM as a vasorelaxant factor implicated in the regulation of maternal vascular adaptation to pregnancy, as well as of fetal and fetoplacental circulations. AM is also present in amniotic fluid and milk, which is suggestive of additional functions in the maturation and immunological protection of the fetus. Altered expression of AM has been found in some gestational pathologies, although it is not yet clear whether this corresponds to causative or compensatory mechanisms. Future studies in regard to the distribution and expression levels of the molecules known to function as AM receptors, together with data on the action of complement factor H (an AM binding protein), may help to better define the roles of AM during embryonic development

On the full Boltzmann equations for Leptogenesis

We consider the full Boltzmann equations for standard and soft leptogenesis, instead of the usual integrated Boltzmann equations which assume kinetic equilibrium for all species. Decays and inverse decays may be inefficient for thermalising the heavy-(s)neutrino distribution function, leading to significant deviations from kinetic equilibrium. We analyse the impact of using the full kinetic equations in the case of a previously generated lepton asymmetry, and find that the washout of this initial asymmetry due to the interactions of the right-handed neutrino is larger than when calculated via the integrated equations. We also solve the full Boltzmann equations for soft leptogenesis, where the lepton asymmetry induced by the soft SUSY-breaking terms in sneutrino decays is a purely thermal effect, since at T=0 the asymmetry in leptons cancels the one in sleptons. In this case, we obtain that in the weak washout regime (K ~< 1) the final lepton asymmetry can change up to a factor four with respect to previous estimates.Comment: 34 pages, 6 figures, to be published in JCA

Neutrino masses from higher than d=5 effective operators

We discuss the generation of small neutrino masses from effective operators higher than dimension five, which open new possibilities for low scale see-saw mechanisms. In order to forbid the radiative generation of neutrino mass by lower dimensional operators, extra fields are required, which are charged under a new symmetry. We discuss this mechanism in the framework of a two Higgs doublet model. We demonstrate that the tree level generation of neutrino mass from higher dimensional operators often leads to inverse see-saw scenarios in which small lepton number violating terms are naturally suppressed by the new physics scale. Furthermore, we systematically discuss tree level generalizations of the standard see-saw scenarios from higher dimensional operators. Finally, we point out that higher dimensional operators can also be generated at the loop level. In this case, we obtain the TeV scale as new physics scale even with order one couplings.Comment: 22 pages, 3 figures, 2 tables. Some references adde

Full Boltzmann equations for leptogenesis including scattering

We study the evolution of a cosmological baryon asymmetry produced via leptogenesis by means of the full classical Boltzmann equations, without the assumption of kinetic equilibrium and including all quantum statistical factors. Beginning with the full mode equations we derive the usual equations of motion for the right-handed neutrino number density and integrated lepton asymmetry, and show explicitly the impact of each assumption on these quantities. For the first time, we investigate also the effects of scattering of the right-handed neutrino with the top quark to leading order in the Yukawa couplings by means of the full Boltzmann equations. We find that in our full Boltzmann treatment the final lepton asymmetry can be suppressed by as much as a factor of 1.5 in the weak wash-out regime (K<1), compared to the usual integrated approach which assumes kinetic equilibrium and neglects quantum statistics. This suppression is in contrast with the enhancement seen in some previous studies that considered only decay and inverse decay of the right-handed neutrino. However, this suppression quickly decreases as we increase K. In the strong wash-out regime (K>1), the full Boltzmann treatment and the integrated approach give nearly identical final lepton asymmetries (within 10 % of each other at K>3). Finally, we show that the opposing effects of quantum statistics on decays/inverse decays and the scattering processes tend to reduce the net importance of scattering on leptogenesis in the full treatment compared to the integrated approach.Comment: 39 pages, 8 figures, typos corrected, replaced to match published versio

Soft leptogenesis in the inverse seesaw model

We consider leptogenesis induced by soft supersymmetry breaking terms ("soft leptogenesis"), in the context of the inverse seesaw mechanism. In this model there are lepton number (L) conserving and L-violating soft supersymmetry-breaking B-terms involving the singlet sneutrinos which, together with the -- generically small-- L-violating parameter responsible of the neutrino mass, give a small mass splitting between the four singlet sneutrino states of a single generation. In combination with the trilinear soft supersymmetry breaking terms they also provide new CP violating phases needed to generate a lepton asymmetry in the singlet sneutrino decays. We obtain that in this scenario the lepton asymmetry is proportional to the L-conserving soft supersymmetry-breaking B-term, and it is not suppressed by the L-violating parameters. Consequently we find that, as in the standard see-saw case, this mechanism can lead to sucessful leptogenesis only for relatively small value of the relevant soft bilinear coupling. The right-handed neutrino masses can be sufficiently low to elude the gravitino problem. Also the corresponding Yukawa couplings involving the lightest of the right-handed neutrinos are constrained to be \sum |Y_{1k}|^2\lesssim 10^{-7} which generically implies that the neutrino mass spectrum has to be strongly hierarchical.Comment: 28 pages, 1 figure; some references added; final version to appear in JHE

Biological Background of Resistance to Current Standards of Care in Multiple Myeloma

A high priority problem in multiple myeloma (MM) management is the development of resistance to administered therapies, with most myeloma patients facing successively shorter periods of response and relapse. Herewith, we review the current knowledge on the mechanisms of resistance to the standard backbones in MM treatment: proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies (mAbs). In some cases, strategies to overcome resistance have been discerned, and an effort should be made to evaluate whether resensitization to these agents is feasible in the clinical setting. Additionally, at a time in which we are moving towards precision medicine in MM, it is equally important to identify reliable and accurate biomarkers of sensitivity/refractoriness to these main therapeutic agents with the goal of having more efficacious treatments and, if possible, prevent the development of relapse.Funding: E.M.O. was supported by an Inplant grant fromIDIVALand TP by a grant fromAECC(INVES18043PAÍN). E.M.A. and A.D.-T. received a grant from the Regional Council from Castilla y León, and P.M. from the Institute for Biomedical Research from Salamanca. This work was supported by funding from Spanish FIS (PI15/00067, PI15/02156 and PI18/01600) and FEDER, AECC (GCB120981SAN), Ramón Areces Foundation (FRA16/003); the Regional Council from Castilla y León (GRS 1604/A/17, GRS 1880/A/18 and Centro en Red de Medicina Regenerativa y Terapia Celular), and the Institute for Biomedical Research from Salamanca (IBY17/00008)

The role of adrenomedullin as a growth regulatory peptide in the normal and malignant setting

Adrenomedullin (AM ) is a recently discovered pluripo1ent peptide initially isolated fraro a human adrenal gland tumor (pheochromocytoma). Adrenomedullin has been shown to have an ancient origin with immunoreactive species fOWld in maromals, birds, reptiles, amphibians, fish , and eemnoderms (s t a r fish ). Given its highly conserved evolutionary expression, AM is thought te playa critica! !•ole in spedes survival. This peptide has been show lo mediate a variety of physiological fu netlons, of which iis involvement in growth r egulation wil1 be tbe central focus of this papero In the following text, we will review the cited Iiterature in this area and inelude our own observations regarding AM express10n in carcinogenesis, embryogenesis, and wound r epair. Adrenomedullin will be shown to induce both growth promotian or growth suppression depending on the taTget cell examined aud the sUITounding nutritional environment in which the analysis was done. Its implied role as a mitogen, aogiogenic fador, and apoplosis survival factor will be critiqued and evaluated relative to its impor tance in the cel! proHferation process. Finally, we will review the a ntimicrobiaJ effect AM has on severa1 human pathogens ( Es•cherichia coli and Candidn albi.cans) and demonstrate its partieipation in the host immune response syslem as a first line defense peptide