Network Structures from Selection Principles

We present an analysis of the topologies of a class of networks which are optimal in terms of the requirements of having as short a route as possible between any two nodes while yet keeping the congestion in the network as low as possible. Strikingly, we find a variety of distinct topologies and novel phase transitions between them on varying the number of links per node. Our results suggest that the emergence of the topologies observed in nature may arise both from growth mechanisms and the interplay of dynamical mechanisms with a selection process.Comment: 4 pages, 5 figure

The “Who?” Question in the Hate Speech Debate: Part 1: Consistency, Practical, and Formal Approaches

This two-part article addresses the “Who?” question in the hate speech debate: namely, which characteristics, social identities or statuses should or should not be treated as protected characteristics within a body of hate speech laws? Using United Kingdom incitement to hatred laws as a focal point, the article outlines and critically appraises five broad approaches to specification. Part 1 deals with consistency specification, which highlights norms of consistency both within incitement to hatred law itself and in relation to other laws, practical specification, which focuses on the ostensible goals or apparent aims of incitement to hatred laws, and formal specification, which looks at the formal qualities of the characteristics themselves and to the different forms of people’s relationships with those characteristics. And Part 2 considers functional specification, which concentrates on the underlying or real functions, purposes or objectives of incitement to hatred laws, and democratic specification, which appeals to democratic procedures as well as to democratic values, norms and principles that speak to the proper scope of incitement to hatred laws. Along the way I shall also critically assess a range of substantive arguments about which particular characteristics should or should not be covered by incitement to hatred laws given the aforementioned approaches. My main conclusion shall be that each of the approaches has its strengths and weakness and that, partly because of this, no single approach is adequate by itself as a tool for specifying the proper scope of incitement to hatred laws, but also, by the same token, no approach should be ruled out entirely. Instead, the best strategy is one that combines together all five approaches in reasonable ways given the law, the characteristic and the context

A hiperkoleszterinemiához és az inzulin rezisztenciához társult iszkémiás szívbetegség kezelésének új farmakoterápiás stratégiái. Endogén kardioprotektív mechanizmusok farmakológiai kihasználása = Novel pharmacotherapeutic strategies of ishaemic heart disease associated with hypercholesterolaemia and insulin resistance. Pharmacological exploitation of endogenous cardioproctective mechanisms

A kutatás során fény derült arra, hogy az insulin rezisztenciához társult iszkémiás szívbetegség farmakoterápiája során egy újonnan felismert endogén insulin érzékenyítő mechanizmus, a HISS (hepatic insulin sensitizing substance) mechanizmus igen fontos lehet. Felderítettük, hogy ez a mechanizmus NO donorokkal és ciklikus GMP foszfodiészteráz gátlókkal a terápia számára kiaknázható. Bizonyítottuk azt is, hogy az említett gyógyszercsoportok különböző tagjai alacsonyabb dózisban képesek insulin érzékenyítő hatást elérni, mint ''klasszikus'' indikációikban (hypertonia, congestív szívelégtelenség, iszkémiás szívbetegség. Az eredmények alapján gyógyszerfejlesztési folyamatok indultak meg. | The resuts achieved revealed the potential of a novel endogenous insulin sensitizing mechanism, the HISS process: hepatic insulin sensitizing substance mechanism) in treatment and prevention of cardiovascular disease underpinned by the insulin resistance syndrome. Our findings provided evidence for the use of cyclic GMP phosphodiesterase inhibitors and nitric oxide donors as tools for pharmacological exploitation of this mechanism. Moreover, it has also benn shown that drugs in these groups acieve insulin sensitization at doses much lower than those necessary to produce effects in theis ''classical'' indications such as sustained arterial hypertension, congestive heart failure and ischaemic heart disease. The resulds obtained promoted two drug development pharmaceutical projects

Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development

Background: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed

Interactions between genetic variation and cellular environment in skeletal muscle gene expression

From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discover cis-acting genotype-environment interactions (GxE)-genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate environmental response expression quantitative trait loci (reQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.Peer reviewe

On the Coupling Time of the Heat-Bath Process for the Fortuin–Kasteleyn Random–Cluster Model

We consider the coupling from the past implementation of the random-cluster heat-bath process, and study its random running time, or coupling time. We focus on hypercubic lattices embedded on tori, in dimensions one to three, with cluster fugacity at least one. We make a number of conjectures regarding the asymptotic behaviour of the coupling time, motivated by rigorous results in one dimension and Monte Carlo simulations in dimensions two and three. Amongst our findings, we observe that, for generic parameter values, the distribution of the appropriately standardized coupling time converges to a Gumbel distribution, and that the standard deviation of the coupling time is asymptotic to an explicit universal constant multiple of the relaxation time. Perhaps surprisingly, we observe these results to hold both off criticality, where the coupling time closely mimics the coupon collector's problem, and also at the critical point, provided the cluster fugacity is below the value at which the transition becomes discontinuous. Finally, we consider analogous questions for the single-spin Ising heat-bath process

Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms