NF-κB inhibitor alpha has a cross-variant role during SARS-CoV-2 infection in ACE2-overexpressing human airway organoids

As SARS-CoV-2 continues to spread worldwide, tractable primary airway cell models that accurately recapitulate the cell-intrinsic response to arising viral variants are needed. Here we describe an adult stem cell-derived human airway organoid model overexpressing the ACE2 receptor that supports robust viral replication while maintaining 3D architecture and cellular diversity of the airway epithelium. ACE2-OE organoids were infected with SARS-CoV-2 variants and subjected to single-cell RNA-sequencing. NF-{kappa}B inhibitor alpha was consistently upregulated in infected epithelial cells, and its mRNA expression positively correlated with infection levels. Confocal microscopy showed more I{kappa}B expression in infected than bystander cells, but found concurrent nuclear translocation of NF-{kappa}B that I{kappa}B usually prevents. Overexpressing a nondegradable I{kappa}B mutant reduced NF-{kappa}B translocation and increased viral infection. These data demonstrate the functionality of ACE2-OE organoids in SARS-CoV-2 research and identify an incomplete NF-{kappa}B feedback loop as a rheostat of viral infection that may promote inflammation and severe disease.

Implications of the Upper Bound on h→µ

The upper bounds from the ATLAS and CMS experiments on the decay rate of the Higgs boson to two muons provide the strongest constraint on an imaginary part of the muon Yukawa coupling. This bound is more than an order of magnitude stronger than bounds from CP-violating observables, specifically the electric dipole moment of the electron. It excludes a scenario-which had been viable prior to these measurements-that a complex muon Yukawa coupling is the dominant source of the baryon asymmetry. Even with this bound, the muon source can still contribute O(16%) of the asymmetry.

Implications of Higgs searches on the four-generation standard model.

Within the four-generation standard model, the Higgs couplings to gluons and to photons deviate in a significant way from the predictions of the three-generation standard model. As a consequence, large departures in several Higgs production and decay channels are expected. Recent Higgs search results, presented by ATLAS, CMS, and CDF, hint on the existence of a Higgs boson with a mass around 125 GeV. Using these results and assuming such a Higgs boson, we derive exclusion limits on the four-generation standard model. For m(H)=125 GeV, the model is excluded above 99.95% confidence level. For 124.5 GeV≤m(H)≤127.5 GeV, an exclusion limit above 99% confidence level is found.

Relating direct CP violation in D decays and the forward-backward asymmetry in tt[over ¯] production.

The CDF and LHCb experiments have recently provided two intriguing hints for new physics: a large forward-backward asymmetry in tt[over ¯] production and a direct CP asymmetry in D decays of order of a percent. In both cases, flavor nonuniversal interactions are required in the up sector, raising the possibility that the two effects come from one and the same new physics source. We show that a minimal model, with an extra scalar doublet, previously suggested to explain the top data, gives-without any modifications or additions-a contribution to CP violation in charm decays that is of the right size.

Asymmetric Higgsino dark matter.

In the supersymmetric framework, prior to the electroweak phase transition, the existence of a baryon asymmetry implies the existence of a Higgsino asymmetry. We investigate whether the Higgsino could be a viable asymmetric dark matter candidate. We find that this is indeed possible. Thus, supersymmetry can provide the observed dark matter abundance and, furthermore, relate it with the baryon asymmetry, in which case the puzzle of why the baryonic and dark matter mass densities are similar would be explained. To accomplish this task, two conditions are required. First, the gauginos, squarks, and sleptons must all be very heavy, such that the only electroweak-scale superpartners are the Higgsinos. With this spectrum, supersymmetry does not solve the fine-tuning problem. Second, the temperature of the electroweak phase transition must be low, in the (1-10) GeV range. This condition requires an extension of the minimal supersymmetric standard model.

Testing new indirect CP violation.

If new CP violating physics contributes to neutral meson mixing, but its contribution to CP violation in decay amplitudes is negligible, then there is a model independent relation between four (generally independent) observables related to the mixing: the mass splitting (x), the width splitting (y), the CP violation in mixing (1-|q/p|), and the CP violation in the interference of decays with and without mixing (phi). For the four neutral meson systems, this relation can be written in a simple approximate form: y tan phi approximately x(1-|q/p|). In the K system, all four observables have been measured and obey the relation to excellent accuracy. For the B(s) and D systems, new predictions are provided. The success or failure of these relations will probe the physics that is responsible for the CP violation.

Combining K0-K0 mixing and D0-D0 mixing to constrain the flavor structure of new physics.

New physics at high energy scale often contributes to K0-K0 and D0-D0 mixings in an approximately SU(2)L invariant way. In such a case, the combination of measurements in these two systems is particularly powerful. The resulting constraints can be expressed in terms of misalignments and flavor splittings.

Importance of the heavier singlet neutrinos in leptogenesis.

We argue that fast interactions of the lightest singlet neutrino N1 would project part of a preexisting lepton asymmetry L{p} onto a direction that is protected from N1 washout effects, thus preventing it from being erased. In particular, we consider an asymmetry generated in N2 decays, assuming that N1 interactions are fast enough to bring N1 into full thermal equilibrium. If N1 decays occur at T > or = 10{9} GeV, that is, before the muon Yukawa interactions enter into thermal equilibrium, then generically part of L{p} survives. In this case some of the constraints implied by the standard N1 leptogenesis scenario hold only if L{p} approximately 0. For T < or = 10{9} GeV, L{p} is generally erased, unless special alignment or orthogonality conditions in flavor space are realized.

Constraining the phase of Bs-Bs mixing.

New physics contributions to Bs-Bs mixing can be parametrized by the size (rs2) and the phase (2thetas) of the total mixing amplitude relative to the standard model amplitude. The phase has so far been unconstrained. We first use the D0 measurement of the semileptonic CP asymmetry ASL to obtain the first constraint on the semileptonic CP asymmetry in Bs decays, ASLs=-0.008+/-0.011. Then we combine recent measurements by the CDF and D0 Collaborations--the mass difference (DeltaMs), the width difference (DeltaGammas), and ASL;s--to constrain 2thetas. The errors on DeltaGammas and ASL;s should still be reduced to have a sensitive probe of the phase, yet the central values are such that the regions around 2thetas approximately 3pi/2 and, in particular, 2thetas approximately pi/2, are disfavored.

Baryogenesis from the Kobayashi-Maskawa phase.

The smallness of quark masses suppresses the CP violation from the Kobayashi-Maskawa phase to a level that is many orders of magnitude below what is required to explain the observed baryon asymmetry. We point out that if, as a result of time variation in the Yukawa couplings, quark masses were large at the time of the electroweak phase transition, then the Kobayashi-Maskawa mechanism could be the source of the asymmetry. The Froggatt-Nielsen mechanism provides a plausible framework where the Yukawa couplings could all be of order 1 at that time, and settle to their present values before nucleo-synthesis. The problems related to a strong first order electroweak phase transition may also be alleviated in this framework. Our scenario reveals a loophole in the commonly held view that the Kobayashi-Maskawa mechanism cannot be the dominant source of CP violation to play a role in baryogenesis.

Leptogenesis from supersymmetry breaking.

We show that soft supersymmetry breaking terms involving the heavy sneutrinos can lead to sneutrino-antisneutrino mixing and to new sources of CP violation, which are present even if a single generation is considered. These terms are naturally present in supersymmetric versions of leptogenesis scenarios, and they induce indirect CP violation in the decays of the heavy sneutrinos, eventually generating a baryon asymmetry. This new contribution can be comparable to or even dominate over the asymmetry produced in traditional leptogenesis scenarios.