Abstract We study the operator that corresponds to the measurement of volume, in non-perturbative quantum gravity, and we compute its spectrum. The operator is constructed in the loop representation, via a regularization procedure; it is finite, background independent, and diffeomorphism-invariant, and therefore well defined on the space of diffeomorphism invariant states (knot states). We find that the spectrum of the volume of any physical region is discrete. A family of eigenstates are in one to one correspondence with the spin networks, which were introduced by Penrose in a different context. We compute the corresponding component of the spectrum, and exhibit the eigenvalues explicitly. The other eigenstates are related to a generalization of the spin networks, and their eigenvalues can be computed by diagonalizing finite dimensional matrices. Furthermore, we show that the eigenstates of the volume diagonalize also the area operator. We argue that the spectra of volume and area determined here can be considered as predictions of the loop-representation formulation of quantum gravity on the outcomes of (hypothetical) Planck-scale sensitive measurements of the geometry of space.
This paper describes a new approach to end-to-end congestion control on a multi-user network. Rather than manually formulate each endpoint's reaction to congestion signals, as in traditional protocols, we developed a program called Remy that generates congestion-control algorithms to run at the endpoints. In this approach, the protocol designer specifies their prior knowledge or assumptions about the network and an objective that the algorithm will try to achieve, e.g., high throughput and low queueing delay. Remy then produces a distributed algorithm---the control rules for the independent endpoints---that tries to achieve this objective. In simulations with ns-2, Remy-generated algorithms outperformed human-designed end-to-end techniques, including TCP Cubic, Compound, and Vegas. In many cases, Remy's algorithms also outperformed methods that require intrusive in-network changes, including XCP and Cubic-over-sfqCoDel (stochastic fair queueing with CoDel for active queue management). Remy can generate algorithms both for networks where some parameters are known tightly a priori, e.g. datacenters, and for networks where prior knowledge is less precise, such as cellular networks. We characterize the sensitivity of the resulting performance to the specificity of the prior knowledge, and the consequences when real-world conditions contradict the assumptions supplied at design-time.
This talk is on a refined investigation on light flavor meson-baryon scatterings, using a dynamical coupled-channel approach, i.e. the Jülich-Bonn model. The previous channel space of $πN$, $πΔ$, $σN$, $ρN$, $ηN$, $K Λ$ and $K Σ$ is extended by adding the $ωN$ final state. The spectra of $N^*$ and $Δ$ resonances are extracted, based on the result of a global fit to a worldwide collection of data, in the energy region from the $πN$ threshold to center-of-mass energy $z=2.3$ GeV (approximately $300$ parameters against $9000$ data points). A negative value of the $ωN$ elastic spin-averaged scattering length has been extracted.
B. Majumder, U. Baraneedharan, S. Thiyagarajan
et al.
Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine. Efficacy of anticancer treatments vary across patients, imposing a need for personalized approaches. Here the authors show that responsiveness to chemotherapy can be predicted using tumour explant cultures in a patient-matched microenvironment, coupled with a machine-learning algorithm.
The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.
The exotic phenomenon of two-neutron halos and 2n-radioactivity are explored in the neutron-rich $^{40,42,44}$Mg by employing various variants of the relativistic mean-field approach. The extended tail of spatial density distributions including the enhanced neutron radii and skin thickness, pairing correlations, single-particle spectrum and wave functions predict $^{40,42,44}$Mg to be strong candidates for deformed neutron halos. Weakening of magicity at N$=$28 plays a significant role in the existence of a weakly bound halo in $^{40}$Mg which is currently the heaviest isotope of Mg accessible experimentally. Large deformation, mixing of f-p shell Nilsson orbitals and the valence neutron occupancy of p-states leads to a reduced centrifugal barrier and broader spatial density distributions that favour 2n-radioactivity in $^{42,44}$Mg.
Short sequence motifs are ubiquitous across the three major types of biomolecules: hundreds of classes and thousands of instances of DNA regulatory elements, RNA motifs and protein short linear motifs (SLiMs) have been characterised. The increase in complexity of transcriptional, post-transcriptional and post-translational regulation in higher Eukaryotes has coincided with a significant expansion of motif use. But how did the eukaryotic cell acquire such a vast repertoire of motifs? In this review, we curate the available literature on protein motif evolution and discuss the evidence that suggests SLiMs can be acquired by mutations, insertions and deletions in disordered regions. We propose a mechanism of ex nihilo SLiM evolution – the evolution of a novel SLiM from “nothing” – adding a functional module to a previously non-functional region of protein sequence. In our model, hundreds of motif-binding domains in higher eukaryotic proteins connect simple motif specificities with useful functions to create a large functional motif space. Accessible peptides that match the specificity of these motif-binding domains are continuously created and destroyed by mutations in rapidly evolving disordered regions, creating a dynamic supply of new interactions that may have advantageous phenotypic novelty. This provides a reservoir of diversity to modify existing interaction networks. Evolutionary pressures will act on these motifs to retain beneficial instances. However, most will be lost on an evolutionary timescale as negative selection and genetic drift act on deleterious and neutral motifs respectively. In light of the parallels between the presented model and the evolution of motifs in the regulatory segments of genes and (pre-)mRNAs, we suggest our understanding of regulatory networks would benefit from the creation of a shared model describing the evolution of transcriptional, post-transcriptional and post-translational regulation.
Background Nanoparticle exposure in utero might not be a major concern yet, but it could become more important with the increasing application of nanomaterials in consumer and medical products. Several epidemiologic and in vitro studies have shown that nanoparticles can have potential toxic effects. However, nanoparticles also offer the opportunity to develop new therapeutic strategies to treat specifically either the pregnant mother or the fetus. Previous studies mainly addressed whether nanoparticles are able to cross the placental barrier. However, the transport mechanisms underlying nanoparticle translocation across the placenta are still unknown. Objectives In this study we examined which transport mechanisms underlie the placental transfer of nanoparticles. Methods We used the ex vivo human placental perfusion model to analyze the bidirectional transfer of plain and carboxylate modified polystyrene particles in a size range between 50 and 300 nm. Results We observed that the transport of polystyrene particles in the fetal to maternal direction was significantly higher than for the maternal to fetal direction. Regardless of their ability to cross the placental barrier and the direction of perfusion, all polystyrene particles accumulated in the syncytiotrophoblast of the placental tissue. Conclusions Our results indicate that the syncytiotrophoblast is the key player in regulating nanoparticle transport across the human placenta. The main mechanism underlying this translocation is not based on passive diffusion, but is likely to involve an active, energy-dependent transport pathway. These findings will be important for reproductive toxicology as well as for pharmaceutical engineering of new drug carriers. Citation Grafmueller S, Manser P, Diener L, Diener PA, Maeder-Althaus X, Maurizi L, Jochum W, Krug HF, Buerki-Thurnherr T, von Mandach U, Wick P. 2015. Bidirectional transfer study of polystyrene nanoparticles across the placental barrier in an ex vivo human placental perfusion model. Environ Health Perspect 123:1280–1286; http://dx.doi.org/10.1289/ehp.1409271
The potential hazard of destructive tornado effects on nuclear facilities determines the necessity to study the climatic regime of tornado passage and arrange the appropriate protection of these facilities in conformity with the national and international radiation safety standards. One of the most characteristic features of the climate in recent decades is a significant increase in the number of dangerous meteorological events, including tornadoes. The purpose of this study is to assess the level of tornadoes hazard for nuclear facilities and to determine the design characteristics of tornadoes. The data on the tornado passage through the tornado-hazardous subzone A-L on the territory of the former USSR made it possible to estimate the probability of tornadoes passing through a hypothetical nuclear facility site, showing that it does not exceed the probability of the criterion in force in Russia ? the threshold probability of 10?4 per reactor per year. It is shown that such a threshold probability can be achieved if two or more tornadoes of intensity class F5 on the Fujita scale would pass through subzone A-L. For such a hypothetical scenario, the design characteristics of a probable tornado were determined. The need to improve the regulatory and technical base in the field of nuclear facilities safety is noted to ensure their reliable protection from the effects of tornadoes.