Introducing Quantum Ricci Curvature

Motivated by the search for geometric observables in nonperturbative quantum gravity, we define a notion of coarse-grained Ricci curvature. It is based on a particular way of extracting the local Ricci curvature of a smooth Riemannian manifold by comparing the distance between pairs of spheres with that of their centres. The quantum Ricci curvature is designed for use on non-smooth and discrete metric spaces, and to satisfy the key criteria of scalability and computability. We test the prescription on a variety of regular and random piecewise flat spaces, mostly in two dimensions. This enables us to quantify its behaviour for short lattices distances and compare its large-scale behaviour with that of constantly curved model spaces. On the triangulated spaces considered, the quantum Ricci curvature has good averaging properties and reproduces classical characteristics on scales large compared to the discretization scale.Comment: 43 pages, 27 figure

How round is the quantum de Sitter universe?

We investigate the quantum Ricci curvature, which was introduced in earlier work, in full, four-dimensional quantum gravity, formulated nonperturbatively in terms of Causal Dynamical Triangulations (CDT). A key finding of the CDT approach is the emergence of a universe of de Sitter-type, as evidenced by the successful matching of Monte Carlo measurements of the quantum dynamics of the global scale factor with a semiclassical minisuperspace model. An important question is whether the quantum universe exhibits semiclassicality also with regard to its more local geometric properties. Using the new quantum curvature observable, we examine whether the (quasi-)local properties of the quantum geometry resemble those of a constantly curved space. We find evidence that on sufficiently large scales the curvature behaviour is compatible with that of a four-sphere, thus strengthening the interpretation of the dynamically generated quantum universe in terms of a de Sitter space.Comment: 24 pages, 8 figure

Bridging the translational gap:adenosine as a modulator of neuropathic pain in preclinical models and humans

Objectives: This review aims to analyse the published data on preclinical and human experimental and clinical adenosine modulation for pain management. We summarise the translatability of the adenosine pathway for further drug development and aim to reveal subgroups of pain patients that could benefit from targeting the pathway. Content: Chronic pain patients suffer from inadequate treatment options and drug development is generally impaired by the low translatability of preclinical pain models. Therefore, validating the predictability of drug targets is of high importance. Modulation of the endogenous neurotransmitter adenosine gained significant traction in the early 2000s but the drug development efforts were later abandoned. With the emergence of new drug modalities, there is a renewed interest in adenosine modulation in pain management. In both preclinical, human experimental and clinical research, enhancing adenosine signalling through the adenosine receptors, has shown therapeutic promise. A special focus has been on the A 1 and A 3 receptors both of which have shown great promise and predictive validity in neuropathic pain conditions. Summary: Adenosine modulation shows predictive validity across preclinical, human experimental and clinical investigations. The most compelling evidence is in the field of neuropathic pain, where adenosine has been found to alleviate hyperexcitability and has the potential to be disease-modifying. Outlook: Adenosine modulation show therapeutic potential in neuropathic pain if selective and safe drugs can be developed. New drug modalities such as RNA therapeutics and cell therapies may provide new options.</p

Geometric flux formula for the gravitational Wilson loop

Finding diffeomorphism-invariant observables to characterize the properties of gravity and spacetime at the Planck scale is essential for making progress in quantum gravity. The holonomy and Wilson loop of the Levi-Civita connection are potentially interesting ingredients in the construction of quantum curvature observables. Motivated by recent developments in nonperturbative quantum gravity, we establish new relations in three and four dimensions between the holonomy of a finite loop and certain curvature integrals over the surface spanned by the loop. They are much simpler than a gravitational version of the nonabelian Stokes' theorem, but require the presence of totally geodesic surfaces in the manifold, which follows from the existence of suitable Killing vectors. We show that the relations are invariant under smooth surface deformations, due to the presence of a conserved geometric flux.Comment: 36 pages, 5 figures; minor text changes, clarifying the role of diffeomorphism invariance; agrees with published versio

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. Abbreviations 2’-MOE: 2’-O-(2-methoxyethyl); 2’-O-Me: 2’-O-methyl; 2’-F: 2’-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyreti

Højre, venstre eller midte? Et empirisk perspektiv på partirummet i dansk politik

”Right, left or centre? An empirical perspective on the party space of Danish politics”: In order to predict the outcomes of parliamentary voting and coalition formation, etc., it is necessary to have information about how the political actors are located relative to each other. We identify four different data sources that have been used to establish the empirical location of parties in the Danish political space along a uni-dimensional left-right continuum: Voter surveys; expert and elite surveys; voting data; coding of political texts. Furthermore, we identify a large number of quantitative methods with which such data, covering the years 1920-2007, have been aggregated into party spaces. A tentative comparison of two selected sub-periods displays a considerable consistency between the different methods, although a few methods seem visibly less consistent with the rest. The tales of the demise of the left-right scale seems exaggerated in the case of Danish politics; while policies may change, the underlying dimension seems more or less unchanged

Højre, venstre eller midte? Et empirisk perspektiv på partirummet i dansk politik

”Right, left or centre? An empirical perspective on the party space of Danish politics”: In order to predict the outcomes of parliamentary voting and coalition formation, etc., it is necessary to have information about how the political actors are located relative to each other. We identify four different data sources that have been used to establish the empirical location of parties in the Danish political space along a uni-dimensional left-right continuum: Voter surveys; expert and elite surveys; voting data; coding of political texts. Furthermore, we identify a large number of quantitative methods with which such data, covering the years 1920-2007, have been aggregated into party spaces. A tentative comparison of two selected sub-periods displays a considerable consistency between the different methods, although a few methods seem visibly less consistent with the rest. The tales of the demise of the left-right scale seems exaggerated in the case of Danish politics; while policies may change, the underlying dimension seems more or less unchanged

DNA Damage Repair and Drug Efflux as Potential Targets for Reversing Low or Intermediate Ciprofloxacin Resistance in E. coli K-12

Ciprofloxacin is a potent antibacterial drug that is widely used in human clinical applications. As a consequence of its extensive use, resistance has emerged in almost all clinically relevant bacterial species. A mean to combat the observed ciprofloxacin resistance is by reversing it via co-administration of a potentiating compound, also known as a helper drug. Here, we report on the current advances in identifying ciprofloxacin helper drugs, and put them into perspective of our own findings. We searched for potential helper drug targets in Escherichia coli strains with different levels of ciprofloxacin resistance using transcriptomics i.e., RNAseq and by deletion of genes associated with hyper-susceptibility to ciprofloxacin. Differential gene expression analysis of the highly ciprofloxacin resistant uropathogenic E. coli strain, ST131 UR40, treated with a clinically relevant concentration of ciprofloxacin (2 μg/mL), showed that the transcriptome was unaffected. Conversely, genetic screening of 23 single gene deletions in the high-level ciprofloxacin resistant laboratory derived E. coli strain, LM693, led to a significant decrease in the minimal inhibitory concentration for several genes, including genes encoding the AcrAB-TolC efflux pump, SOS-response proteins and the global regulator Fis. In addition, deletion of acrA, tolC, recA, or recC rendered two E. coli strains with intermediate susceptibility to ciprofloxacin fully susceptible according to the CLSI recommended breakpoint. Our results corroborate the AcrAB-TolC efflux pump and the SOS response proteins, RecA and RecC, as potential targets for ciprofloxacin helper drugs in treatment of human bacterial infections caused by E. coli strains with intermediate sensitivity to ciprofloxacin

Structure-Activity Study of an All-d Antimicrobial Octapeptide D2D

The increasing emergence of multi-drug resistant bacteria is a serious threat to public health worldwide. Antimicrobial peptides have attracted attention as potential antibiotics since they are present in all multicellular organisms and act as a first line of defence against invading pathogens. We have previously identified a small all-d antimicrobial octapeptide amide kk(1-nal)fk(1-nal)k(nle)-NH2 (D2D) with promising antimicrobial activity. In this work, we have performed a structure-activity relationship study of D2D based on 36 analogues aimed at discovering which elements are important for antimicrobial activity and toxicity. These modifications include an alanine scan, probing variation of hydrophobicity at lys5 and lys7, manipulation of amphipathicity, N-and C-termini deletions and lys-arg substitutions. We found that the hydrophobic residues in position 3 (1-nal), 4 (phe), 6 (1-nal) and 8 (nle) are important for antimicrobial activity and to a lesser extent cationic lysine residues in position 1, 2, 5 and 7. Our best analogue 5, showed MICs of 4 &micro;g/mL against A. baumannii, E. coli, P. aeruginosa and S. aureus with a hemolytic activity of 47% against red blood cells. Furthermore, compound 5 kills bacteria in a concentration-dependent manner as shown by time-kill kinetics. Circular dichroism (CD) spectra of D2D and compounds 1&ndash;8 showed that they likely fold into &alpha;-helical secondary structure. Small angle x-ray scattering (SAXS) experiments showed that a random unstructured polymer-like chains model could explain D2D and compounds 1, 3, 4, 6 and 8. Solution structure of compound 5 can be described with a nanotube structure model, compound 7 can be described with a filament-like structure model, while compound 2 can be described with both models. Lipid interaction probed by small angle X-ray scattering (SAXS) showed that a higher amount of compound 5 (~50&ndash;60%) inserts into the bilayer compared to D2D (~30&ndash;50%). D2D still remains the lead compound, however compound 5 is an interesting antimicrobial peptide for further investigations due to its nanotube structure and minor improvement to antimicrobial activity compared to D2D