Programmable viscoelastic matrices from artificial proteins

Extracellular matrix compliance influences cellular adhesion and migration, proliferation and apoptosis, and differentiation. Much of our current knowledge of the effects of substrate stiffness on cellular behavior is based on elastic substrates, in particular cross‐linked polyacrylamide hydrogels. Biological tissues, however, are viscoelastic and exhibit stress relaxation and energy dissipation on physiologically relevant timescales. While emerging evidence suggests that these physical properties also influence cellular behavior, materials in which viscoelasticity can be precisely engineered are currently lacking. Here, we describe programmable hydrogel matrices assembled from artificial recombinant proteins designed to be cross‐linked by covalent bonds involving cysteine residues, by association of helical domains as coiled coils, or by both mechanisms. Using these proteins, we construct chemical, physical, and chemical‐physical hydrogel networks that deform elastically or viscoelastically depending on the type of cross‐linking (Dooling et al., Adv. Mater., 2016, 28, 4651–4657). In viscoelastic networks, the amount of stress relaxation is tuned by controlling the ratio of physical cross‐linking to chemical crosslinking, and the timescale for stress relaxation is tuned over five orders of magnitude by single point mutations to the coiled‐coil physical cross‐linking domain (Dooling and Tirrell, ACS Cent. Sci., 2016, 2, 812–819). The genetic engineering approach also allows biological activity to be encoded directly within the protein sequence in the form of cell‐adhesive domains and proteolytic cleavage sites. The capacity to program the viscoelasticity and biological activity of hydrogel matrices is anticipated to have applications in studying and engineering cell‐matrix interactions

Auditory brainstem responses in the Eastern Screech Owl: An estimate of auditory thresholds

The auditory brainstem response (ABR), a measure of neural synchrony, was used to estimate auditory sensitivity in the eastern screech owl (Megascops asio). The typical screech owl ABR waveform showed two to three prominent peaks occurring within 5 ms of stimulus onset. As sound pressure levels increased, the ABR peak amplitude increased and latency decreased. With an increasing stimulus presentation rate, ABR peak amplitude decreased and latency increased. Generally, changes in the ABR waveform to stimulus intensity and repetition rate are consistent with the pattern found in several avian families. The ABR audiogram shows that screech owls hear best between 1.5 and 6.4 kHz with the most acute sensitivity between 4–5.7 kHz. The shape of the average screech owl ABR audiogram is similar to the shape of the behaviorally measured audiogram of the barn owl, except at the highest frequencies. Our data also show differences in overall auditory sensitivity between the color morphs of screech owls

Report of the Beyond the MSSM Subgroup for the Tevatron Run II SUSY/Higgs Workshop

There are many low-energy models of supersymmetry breaking parameters which are motivated by theoretical and experimental considerations. Here, we discuss some of the lesser-known theories of low-energy supersymmetry, and outline their phenomenological consequences. In some cases, these theories have more gauge symmetry or particle content than the Minimal Supersymmetric Standard Model. In other cases, the parameters of the Lagrangian are unusual compared to commonly accepted norms (e.g., Wino LSP, heavy gluino LSP, light gluino, etc.). The phenomenology of supersymmetry varies greatly between the different models. Correspondingly, particular aspects of the detectors assume greater or lesser importance. Detection of supersymmetry and the determination of all parameters may well depend upon having the widest possible view of supersymmetry phenomenology.Comment: 78 pages, 49 figures, to appear in the Proceedings of the Tevatron Run II SUSY/Higgs Workshop. Editor: J. F. Gunion; BTMSSM Convenors: M. Chertok, H. Dreiner, G. Landsberg, J. F. Gunion, J.D. Well

CP Violation from Dimensional Reduction: Examples in 4+1 Dimensions

We provide simple examples of the generation of complex mass terms and hence CP violation through dimensional reduction.Comment: 6 pages, typos corrected, 1 reference adde

Rephasing Invariants of CP and T Violation in the Four-Neutrino Mixing Models

We calculate the rephasing invariants of CP and T violation in a favorable parametrization of the 4x4 lepton flavor mixing matrix. Their relations with the CP- and T-violating asymmetries in neutrino oscillations are derived, and the matter effects are briefly discussed.Comment: RevTex 9 pages. Slight changes. Phys. Rev. D (in press

A novel retinoblastoma therapy from genomic and epigenetic analyses.

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss

The hidden sterile neutrino and the (2+2) sum rule

We discuss oscillations of atmospheric and solar neutrinos into sterile neutrinos in the 2+2 scheme. A zeroth order sum rule requires equal probabilities for oscillation into nu_s and nu_tau in the solar+atmospheric data sample. Data does not favor this claim. Here we use scatter plots to assess corrections of the zeroth order sum rule when (i) the 4 x 4 neutrino mixing matrix assumes its full range of allowed values, and (ii) matter effects are included. We also introduce a related "product rule". We find that the sum rule is significantly relaxed, due to both the inclusion of the small mixing angles (which provide a short-baseline contribution) and to matter effects. The product rule is also dramatically altered. The observed relaxation of the sum rule weakens the case against the 2+2 model and the sterile neutrino. To invalidate the 2+2 model, a global fit to data with the small mixing angles included seems to be required.Comment: 43 pages, 11 figures (same as v2, accidental replacement

Four--Neutrino Oscillation Solutions of the Solar Neutrino Problem

We present an analysis of the neutrino oscillation solutions of the solar neutrino problem in the framework of four-neutrino mixing where a sterile neutrino is added to the three standard ones. We perform a fit to the full data set corresponding to the 825-day Super-Kamiokande data sample as well as to Chlorine, GALLEX and SAGE and Kamiokande experiments. In our analysis we use all measured total event rates as well as all Super-Kamiokande data on the zenith angle dependence and the recoil electron energy spectrum. We consider both transitions via the Mikheyev-Smirnov-Wolfenstein (MSW) mechanism as well as oscillations in vacuum (just-so) and find the allowed solutions for different values of the additional mixing angles. This framework permits transitions into active or sterile neutrinos controlled by the additional parameter $\cos^2(\vartheta_{23}) \cos^2(\vartheta_{24})$ . We discuss the maximum allowed values of this additional mixing parameter for the different solutions.Comment: 28 pages Latex file using RevTeX. 8 postscript figures included (bitmapped for compression). Detailed explanation of criterion 3 and lower two graphs of Fig. 8. Misprints corrected in table II.A full version of the paper can be found at http://ific.uv.es/~penya/papers/four

The atmospheric neutrino anomaly without maximal mixing?

We consider a pattern of neutrino masses in which there is an approximate mass degeneracy between the two mass eigenstates most coupled to the $\nu_\mu$ and $\nu_\tau$ flavour eigenstates. Earth-matter effects can lift this degeneracy and induce an effectively maximal mixing between these two generations. This occurs if $\nu_e$'s contain comparable admixtures of the degenerate eigenstates, even rather small ones. This provides an explanation of the atmospheric neutrino anomaly in which the {\it ab initio} introduction of a large mixing angle is not required. To test this possibility we perform a novel and detailed analysis of the 52 kiloton-year SuperKamiokande data, and we find that in a large region of parameter space the corresponding confidence levels are excellent. The most recent results from the Chooz reactor experiment, however, severely curtail this region, so that the conventional scenario with nearly maximal mixing angles --which we also analyse in detail-- is supported by the data.Comment: Some relevant references added and a misprint correcte

Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle.

Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation