Variations on the Vev Flip-Flop: Instantaneous Freeze-out and Decaying Dark Matter

In this work we consider a simple model for dark matter and identify regions of parameter space where the relic abundance is set via kinematic thresholds, which open and close due to thermal effects. We discuss instantaneous freeze-out, where dark matter suddenly freezes-out when the channel connecting dark matter to the thermal bath closes, and decaying dark matter, where dark matter freezes-out while relativistic and later decays when a kinematic threshold temporarily opens. These mechanisms can occur in the vicinity of a one-step or a two-step phase transition. In all cases thermal effects provide this dynamic behaviour, while ensuring that dark matter remains stable until the present day.Comment: 23 pages, 13 figures; v2: version matched to journal (JHEP), added a detailed discussion of further two-to-two processe

Dynamic Freeze-In: Impact of Thermal Masses and Cosmological Phase Transitions on Dark Matter Production

The cosmological abundance of dark matter can be significantly influenced by the temperature dependence of particle masses and vacuum expectation values. We illustrate this point in three simple freeze-in models. The first one, which we call kinematically induced freeze-in, is based on the observation that the effective mass of a scalar temporarily becomes very small as the scalar potential undergoes a second order phase transition. This opens dark matter production channels that are otherwise forbidden. The second model we consider, dubbed vev-induced freeze-in, is a fermionic Higgs portal scenario. Its scalar sector is augmented compared to the Standard Model by an additional scalar singlet, $S$, which couples to dark matter and temporarily acquires a vacuum expectation value (a two-step phase transition or `vev flip-flop'). While $\langle S \rangle \neq 0$, the modified coupling structure in the scalar sector implies that dark matter production is significantly enhanced compared to the $\langle S \rangle = 0$ phases realised at very early times and again today. The third model, which we call mixing-induced freeze-in, is similar in spirit, but here it is the mixing of dark sector fermions, induced by non-zero $\langle S \rangle$, that temporarily boosts the dark matter production rate. For all three scenarios, we carefully dissect the evolution of the dark sector in the early Universe. We compute the DM relic abundance as a function of the model parameters, emphasising the importance of thermal corrections and the proper treatment of phase transitions in the calculation.Comment: 26 pages, 11 figures, v2: matches journal version, change to the value of a benchmark coupling in section II, impact of thermal masses increase

Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth

Searching for physics beyond the Standard Model in an off-axis DUNE near detector

Next generation neutrino oscillation experiments like DUNE and T2HK are multi-purpose observatories, with a rich physics program beyond oscillation measurements. A special role is played by their near detector facilities, which are particularly well-suited to search for weakly coupled dark sector particles produced in the primary target. In this paper, we demonstrate this by estimating the sensitivity of the DUNE near detectors to the scattering of sub-GeV DM particles and to the decay of sub-GeV sterile neutrinos (“heavy neutral leptons”). We discuss in particular the importance of the DUNE-PRISM design, which allows some of the near detectors to be moved away from the beam axis. At such off-axis locations, the signal-to-background ratio improves for many new physics searches. We find that this leads to a dramatic boost in the sensitivity to boosted DM particles interacting mainly with hadrons, while for boosted DM interacting with leptons, data taken on-axis leads to marginally stronger exclusion limits. Searches for heavy neutral leptons perform equally well in both configurations

Workflow for high-content, individual cell quantification of fluorescent markers from universal microscope data, supported by open source software

Advances in understanding the control mechanisms governing the behavior of cells in adherent mammalian tissue culture models are becoming increasingly dependent on modes of single-cell analysis. Methods which deliver composite data reflecting the mean values of biomarkers from cell populations risk losing subpopulation dynamics that reflect the heterogeneity of the studied biological system. In keeping with this, traditional approaches are being replaced by, or supported with, more sophisticated forms of cellular assay developed to allow assessment by high-content microscopy. These assays potentially generate large numbers of images of fluorescent biomarkers, which enabled by accompanying proprietary software packages, allows for multi-parametric measurements per cell. However, the relatively high capital costs and overspecialization of many of these devices have prevented their accessibility to many investigators. Described here is a universally applicable workflow for the quantification of multiple fluorescent marker intensities from specific subcellular regions of individual cells suitable for use with images from most fluorescent microscopes. Key to this workflow is the implementation of the freely available Cell Profiler software(1) to distinguish individual cells in these images, segment them into defined subcellular regions and deliver fluorescence marker intensity values specific to these regions. The extraction of individual cell intensity values from image data is the central purpose of this workflow and will be illustrated with the analysis of control data from a siRNA screen for G1 checkpoint regulators in adherent human cells. However, the workflow presented here can be applied to analysis of data from other means of cell perturbation (e.g., compound screens) and other forms of fluorescence based cellular markers and thus should be useful for a wide range of laboratories

TRIM27 (tripartite motif containing 27)

Review on TRIM27 (tripartite motif containing 27), with data on DNA, on the protein encoded, and where the gene is implicated

Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb

BACKGROUND: The product of the retinoblastoma-susceptibility gene (pRb) is a substrate for Protein Phosphatase 1 (PP1). At mitotic exit, all three PP1 isoforms, α, γ1 and δ, bind to pRb and dephosphorylate its Ser/Thr sites in a sequential and site-specific way. The pRb-C terminal has been reported to be necessary and sufficient for PP1α binding. The present study investigated whether the three PP1 isoforms from mitotic or asynchronous HeLa cells associate differentially with wild-type and pRb mutants, as well as the holoenzyme composition of the pRb-directed PP1. RESULTS: The requirement for the entire pRb molecule to achieve optimal PP1-binding was indicated by the fact that full-length pRb displayed the highest affinity for all three PP1 isoforms. Ser/Thr-to-Ala substitution for up to 14 pRb sites did not affect the ability of pRb to bind the PP1 isoforms derived from mitotic or asynchronous HeLa cells, thus suggesting that the phosphate-accepting residues on pRb do not regulate the interaction with PP1. To probe for the presence of PP1 targeting subunits in the pRb-directed PP1 complex, PP1 from mitotic or asynchronous HeLa cells was isolated by affinity chromatography on GST-Rb (either full-length or its deletion mutants Rb-big pocket or Rb-C-terminal). The PP1 was always obtained as free catalytic subunit, displaying all three isoforms, thus suggesting direct interaction between pRb and PP1. The direct association was confirmed by the ability of pRb to pull-down purified PP1 catalytic subunits and by in vitro reconstitution of a complex between PP1 catalytic subunit and the pRb-C-terminal. CONCLUSION: The work indicated that the full length of the pRb molecule is required for optimal interaction with the PP1 isoforms and that the association between pRb and PP1 isoforms is direct