Characterizing the Initial Phase of Epidemic Growth on some Empirical Networks

A key parameter in models for the spread of infectious diseases is the basic reproduction number $R_0$, which is the expected number of secondary cases a typical infected primary case infects during its infectious period in a large mostly susceptible population. In order for this quantity to be meaningful, the initial expected growth of the number of infectious individuals in the large-population limit should be exponential. We investigate to what extent this assumption is valid by performing repeated simulations of epidemics on selected empirical networks, viewing each epidemic as a random process in discrete time. The initial phase of each epidemic is analyzed by fitting the number of infected people at each time step to a generalised growth model, allowing for estimating the shape of the growth. For reference, similar investigations are done on some elementary graphs such as integer lattices in different dimensions and configuration model graphs, for which the early epidemic behaviour is known. We find that for the empirical networks tested in this paper, exponential growth characterizes the early stages of the epidemic, except when the network is restricted by a strong low-dimensional spacial constraint, such as is the case for the two-dimensional square lattice. However, on finite integer lattices of sufficiently high dimension, the early development of epidemics shows exponential growth.Comment: To be included in the conference proceedings for SPAS 2017 (International Conference on Stochastic Processes and Algebraic Structures), October 4-6, 201

Antiandrogens prevent stable DNA-binding of the androgen receptor

The androgen receptor (AR) is essential for development of the male gender and in the growth of the majority of prostate cancers. Agonists as well as most antagonists induce translocation of the receptor to the nucleus, whereas only agonists can activate AR function. Antagonists are therefore used in the therapy of metastasized prostate cancer. To obtain insight into the mechanism by which antagonists block AR function in living cells, we studied nuclear mobility and localization of green fluorescent protein (GFP)-tagged AR in the presence of either the agonist R1881 or the antagonists bicalutamide and hydroxyflutamide. As controls we investigated a non-DNA-binding AR mutant (A573D) and two mutants (W741C and T877A) with broadened ligand specificity. We demonstrate that in the presence of R1881, AR localizes in numerous intranuclear foci and, using complementary fluorescence recovery after photobleaching (FRAP) approaches and computer modelling, that a fraction of AR ( approximately 10-15%) is transiently immobilized in a DNA-binding-dependent manner (individual ARs being immobile for approximately 45 seconds). By contrast, antagonist-bound GFP-AR showed no detectable immobile fraction and the mobility was similar to that of the R1881-liganded non-DNA-binding mutant (A573D), indicating that antagonists do not induce the relatively stable DNA-binding-dependent immobilization observed with agonist-bound AR. Moreover, in the presence of bicalutamide and hydroxyflutamide GFP-AR was homogeneously distributed in the nucleus. Binding of bicalutamide and hydroxyflutamide to GFP-AR(W741C) and GFP-AR(T877A), respectively, resulted in similar mobility and heterogeneous nuclear distribution as observed for R1881-liganded GFP-AR. The live cell studies indicate that the investigated antagonists interfere with events early in the transactivation function of the AR

Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2)

Previous studies in yeast and mammalian cells showed a functional interaction between the amino-terminal domain and the carboxy-terminal, ligand-binding domain (LBD) of the human androgen receptor (AR). In the present study, the AR subdomains involved in this in vivo interaction were determined in more detail. Cotransfection experiments in Chinese hamster ovary (CHO) cells and two-hybrid experiments in yeast revealed that two regions in the NH2-terminal domain are involved in the functional interaction with the LBD: an interacting domain at the very NH2 terminus, located between amino acid residues 3 and 36, and a second domain, essential for transactivation, located between residues 370 and 494. Substitution of glutamic acid by glutamine at position 888 (E888Q) in the AF-2 activation domain (AD) core region in the LBD, markedly decreased the interaction with the NH2-terminal domain. This mutation neither influenced hormone binding nor LBD homodimerization, suggesting a role of the AF-2 AD core region in the functional interaction between the NH2-terminal domain and the LBD. The AF-2 AD core region was also involved in the interaction with the coactivator TIF2 (transcriptional intermediary factor 2), as the E888Q mutation decreased the stimulatory effect of TIF2 on AR AF-2 activity. Cotransfection of TIF2 and the AR NH2-terminal domain expression vectors did not result in synergy between both factors in the induction of AR AF-2 activity. TIF2 highly induced AR AF-2 activity on a complex promoter [mouse mammary tumor virus (MMTV)], but it was hardly active on a minimal promoter (GRE-TATA). In contrast, the AR NH2-terminal domain induced AR AF-2 activity on both promoter constructs. These data indicate that both the AR NH2-terminal domain and the coactivator TIF2 functionally interact, either directly or indirectly, with the AF-2 AD core region in the AR-LBD, but the level of transcriptional response induced by TIF2 depends on the promoter context

Constraining the radial drift of millimeter-sized grains in the protoplanetary disks in Lupus

Recent ALMA surveys of protoplanetary disks have shown that for most disks the extent of the gas emission is greater than the extent of the thermal emission of the millimeter-sized dust. Both line optical depth and the combined effect of radially dependent grain growth and radial drift may contribute to this observed effect. For a sample of 10 disks from the Lupus survey we investigate how well dust-based models without radial dust evolution reproduce the observed 12CO outer radius, and determine whether radial dust evolution is required to match the observed gas-dust size difference. We used the thermochemical code DALI to obtain 12CO synthetic emission maps and measure gas and dust outer radii (Rco, Rmm) using the same methods as applied to the observations, which were compared to observations on a source-by-source basis. For 5 disks we find that the observed gas-dust size difference is larger than the gas-dust size difference due to optical depth, indicating that we need both dust evolution and optical depth effects to explain the observed gas-dust size difference. For the other 5 disks the observed gas-dust size difference can be explained using only line optical depth effects. We also identify 6 disks not included in our initial sample but part of a survey of the same star-forming region that show significant 12CO emission beyond 4 x Rmm. These disks, for which no Rco is available, likely have gas-dust size differences greater than 4 and are difficult to explain without substantial dust evolution. Our results suggest that radial drift and grain growth are common features among both bright and fain disks. The effects of radial drift and grain growth can be observed in disks where the dust and gas radii are significantly different, while more detailed models and deeper observations are needed to see this effect in disks with smaller differences.Comment: 17 pages, 11 figures, accepted in A&

Inferring R0 in emerging epidemics: the effect of common population structure is small

When controlling an emerging outbreak of an infectious disease, it is essential to know the key epidemiological parameters, such as the basic reproduction number R0 and the control effort required to prevent a large outbreak. These parameters are estimated from the observed incidence of new cases and information about the infectious contact structures of the population in which the disease spreads. However, the relevant infectious contact structures for new, emerging infections are often unknown or hard to obtain. Here, we show that, for many common true underlying heterogeneous contact structures, the simplification to neglect such structures and instead assume that all contacts are made homogeneously in the whole population results in conservative estimates for R0 and the required control effort. This means that robust control policies can be planned during the early stages of an outbreak, using such conservative estimates of the required control effort

Amino acids 3-13 and amino acids in and flanking the 23FxxLF27 motif modulate the interaction between the N-terminal and ligand-binding domain of the androgen receptor

The N-terminal domain (NTD) and the ligand-binding domain (LBD) of the androgen receptor (AR) exhibit a ligand-dependent interaction (N/C interaction). Amino acids 3-36 in the NTD (AR3-36) play a dominant role in this interaction. Previously, it has been shown that a PhixxPhiPhi motif in AR3-36, 23FxxLF27, is essential for LBD interaction. We demonstrate in the current study that AR3-36 can be subdivided into two functionally distinct fragments: AR3-13 and AR16-36. AR3-13 does not directly interact with the AR LBD, but rather contributes to the transactivation function of the AR.NTD-AR.LBD complex. AR16-36, encompassing the 23FxxLF27 motif, is predicted to fold into a long amphipathic alpha-helix. A second PhixxPhiPhi candidate protein interaction motif within the helical structure, 30VREVI34, shows no affinity to the LBD. Within AR16-36, amino acid residues in and flanking the 23FxxLF27 motif are demonstrated to modulate N/C interaction. Substitution of Q24 and N25 by alanine residues enhances N/C interaction. Substitution of amino acids flanking the 23FxxLF27 motif by alanines are inhibitory to LBD interaction

The rat androgen receptor gene promoter

The androgen receptor (AR) is activated upon binding of testosterone or dihydrotestosterone and exerts regulatory effects on gene expression in androgen target cells. To study transcriptional regulation of the rat AR gene itself, the 5' genomic region of this gene was cloned from a genomic library and the promoter was identified. S1-nuclease protection analysis showed two major transcription start sites, located between 1010 and 1023 bp upstream from the translation initiation codon. The area surrounding these start sites was cloned in both orientations in a CAT reporter plasmid. Upon transfection of the constructs into COS cells, part of the promoter stimulated transcription in an orientation-independent manner, but the full promoter showed a higher and unidirectional activity. In the promoter/reporter gene constructs, transcription initiated from the same positions as in the native gene. Sequence analysis showed that the promoter of the rat AR gene lacks typical TATA and CCAAT box elements, but one SP1 site is located at about 60 bp upstream from the major start site of transcription. Other possible promoter elements are TGTYCT sequences at positions -174 to -179, -434 to -439., -466 to -471, and -500 to -505, resembling half-sites of the glucocorticoid-responsive element (GRE). Furthermore, a homopurine stretch containing a total of 8 GGGGA elements and similar to sequences that are present in several other GC-rich promoters, is located between -89 and -146 bp upstream from the major start site of transcriptio