An Exceptional SSM from E6 Orbifold GUTs with intermediate LR symmetry

We propose a class of E6-based local orbifold Grand Unified Theories (GUTs) which yield an exceptional supersymmetric standard model as their low energy theory including leptoquark and unhiggs exotics and a Z' at the TeV scale. Unification is achieved in two steps through an intermediate scale symmetry breaking.Comment: Minor typos corrected, and extended conclusions a bi

Under-dominance constrains the evolution of negative autoregulation in diploids

Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is exceedingly rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is all the more surprising because E. coli and S. cerevisiae otherwise have remarkably similar profiles of network motifs. In this study we first show that regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this fundamental difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance - mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploid's ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution

Cation‐π Interactions between Methylated Ammonium Groups and Tryptophan in the CHARMM36 Additive Force Field

Cation-π interactions between tryptophan and choline or trimethylated lysines are vital for many biological processes. The performance of the additive CHARMM36 force field against target quantum mechanical data is shown to reproduce QM equilibrium geometries but required modified Lennard-Jones potentials to accurately reproduce the QM interaction energies. The modified parameter set allows accurate modeling, including free energies, of cation-π indole-choline and indole-trimethylated lysines interactions relevant for protein–ligand, protein–membrane, and protein–protein interfaces.acceptedVersio

Fractal space-times under the microscope: A Renormalization Group view on Monte Carlo data

The emergence of fractal features in the microscopic structure of space-time is a common theme in many approaches to quantum gravity. In this work we carry out a detailed renormalization group study of the spectral dimension $d_s$ and walk dimension $d_w$ associated with the effective space-times of asymptotically safe Quantum Einstein Gravity (QEG). We discover three scaling regimes where these generalized dimensions are approximately constant for an extended range of length scales: a classical regime where $d_s = d, d_w = 2$, a semi-classical regime where $d_s = 2d/(2+d), d_w = 2+d$, and the UV-fixed point regime where $d_s = d/2, d_w = 4$. On the length scales covered by three-dimensional Monte Carlo simulations, the resulting spectral dimension is shown to be in very good agreement with the data. This comparison also provides a natural explanation for the apparent puzzle between the short distance behavior of the spectral dimension reported from Causal Dynamical Triangulations (CDT), Euclidean Dynamical Triangulations (EDT), and Asymptotic Safety.Comment: 26 pages, 6 figure

Functional rescue of the glomerulosclerosis phenotype in Mpv17 mice by transgenesis with the human Mpv17 homologue

The germ line insertion of a defective retrovirus into the Mpv17 gene of mice is associated with a recessive phenotype. Mice homozygous for the integration develop glomerulosclerosis at a young age. The phenotype resembles human glomerulosclerosis in its physiological parameters as well as in histology. A human homologue of the Mpv17 gene has been identified, isolated and analyzed. We here show that this gene, which has a role in the production of reactive oxygen species, can rescue the phenotype of Mpv17 deficient mice when introduced by transgenesis. This provides formal proof for the hypothesis that the phenotype is caused by the loss of function of the Mpv17 gene. It also provides evidence for the functional conservation of the Mpv17 gene in mammals and points to a potential role of this gene in human kidney disease

Maintenance of Elective Patient Care at Berlin University Children's Hospital During the COVID-19 Pandemic

Background: In Germany, so far the COVID-19 pandemic evolved in two distinct waves, the first beginning in February and the second in July, 2020. The Berlin University Children's Hospital at Charité (BCH) had to ensure treatment for children not infected and infected with SARS-CoV-2. Prevention of nosocomial SARS-CoV-2 infection of patients and staff was a paramount goal. Pediatric hospitals worldwide discontinued elective treatments and established a centralized admission process. Methods: The response of BCH to the pandemic adapted to emerging evidence. This resulted in centralized admission via one ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatment during the first wave, but maintenance of elective care and decentralized admissions during the second wave. We report numbers of patients treated and of nosocomial SARS-CoV-2 infections during the two waves of the pandemic. Results: During the first wave, weekly numbers of inpatient and outpatient cases declined by 37% (p < 0.001) and 29% (p = 0.003), respectively. During the second wave, however, inpatient case numbers were 7% higher (p = 0.06) and outpatient case numbers only 6% lower (p = 0.25), compared to the previous year. Only a minority of inpatients were tested positive for SARS-CoV-2 by RT-PCR (0.47% during the first, 0.63% during the second wave). No nosocomial infection of pediatric patients by SARS-CoV-2 occurred. Conclusion: In contrast to centralized admission via a ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatments, maintenance of elective care and decentralized admission allowed the almost normal use of hospital resources, yet without increased risk of nosocomial infections with SARS-CoV-2. By this approach unwanted sequelae of withheld specialized pediatric non-emergency treatment to child and adolescent health may be avoided

Improving the force field description of tyrosine-choline cation-π interactions : QM investigation of phenol-N(Me)₄⁺ interactions

Cation-pi interactions between tyrosine amino acids and compounds containing N,N,N-trimethylethanolammonium (N(CH3)(3)) are involved in the recognition of histone tails by chromodomains and in the recognition of phosphatidylcholine (PC) phospholipids by membrane-binding proteins. Yet, the lack of explicit polarization or charge transfer effects in molecular mechanics force fields raises questions about the reliability of the representation of these interactions in biomolecular simulations. Here, we investigate the nature of phenol tetramethylammonium (TMA) interactions using quantum mechanical (QM) calculations, which we also use to evaluate the accuracy of the additive CHARIVIM36 and Drude polarizable force fields in modeling tyrosine-choline interactions. We show that the potential energy surface (PES) obtained using SAPT2+/aug-cc-pVDZ compares well with the large basis-set CCSD(T) PES when TMA approaches the phenol ring perpendicularly. Furthermore, the SAPT energy decomposition reveals comparable contributions from electrostatics and dispersion in phenol-TMA interactions. We then compared the SAPT2+/augcc-pVDZ PES obtained along various approach directions to the corresponding PES obtained with CHARMM, and we show that the force field accurately reproduces the minimum distances while the interaction energies are underestimated. The use of the Drude polarizable force field significantly improves the interaction energies but decreases the agreement on distances at energy minima. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones terms for atom pairs involved in the phenol-TMA cation-pi interactions. This is further shown to improve the correlation between the occupancy of tyrosine-choline cation-pi interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants

Spin Manipulation by Creation of Single-Molecule Radical Cations

All-trans-retinoic acid (ReA), a closed-shell organic molecule comprising only C, H, and O atoms, is investigated on a Au(111) substrate using scanning tunneling microscopy and spectroscopy. In dense arrays single ReA molecules are switched to a number of states, three of which carry a localized spin as evidenced by conductance spectroscopy in high magnetic fields. The spin of a single molecule may be reversibly switched on and off without affecting its neighbors. We suggest that ReA on Au is readily converted to a radical by the abstraction of an electron.Comment: 5 pages, 3 figures, accepted for publication in Phys. Rev. Let