Endemic dengue associated with the co-circulation of multiple viral lineages and localized density-dependent transmission

Dengue is one of the most important infectious diseases of humans and has spread throughout much of the tropical and subtropical world. Despite this widespread dispersal, the determinants of dengue transmission in endemic populations are not well understood, although essential for virus control. To address this issue we performed a phylogeographic analysis of 751 complete genome sequences of dengue 1 virus (DENV-1) sampled from both rural (Dong Thap) and urban (Ho Chi Minh City) populations in southern Viet Nam during the period 2003-2008. We show that DENV-1 in Viet Nam exhibits strong spatial clustering, with likely importation from Cambodia on multiple occasions. Notably, multiple lineages of DENV-1 co-circulated in Ho Chi Minh City. That these lineages emerged at approximately the same time and dispersed over similar spatial regions suggests that they are of broadly equivalent fitness. We also observed an important relationship between the density of the human host population and the dispersion rate of dengue, such that DENV-1 tends to move from urban to rural populations, and that densely populated regions within Ho Chi Minh City act as major transmission foci. Despite these fluid dynamics, the dispersion rates of DENV-1 are relatively low, particularly in Ho Chi Minh City where the virus moves less than an average of 20 km/year. These low rates suggest a major role for mosquito-mediated dispersal, such that DENV-1 does not need to move great distances to infect a new host when there are abundant susceptibles, and imply that control measures should be directed toward the most densely populated urban environments.     

The β-Amyloid Precursor Protein (APP) and Alzheimer's Disease: Does the Tail Wag the Dog?

The β-amyloid precursor protein has been the focus of much attention from the Alzheimer's disease community for the past decade and a half. The β-amyloid precursor protein holds a pivotal position in Alzheimer's disease research because it is the precursor to the amyloid β-protein which many believe plays a central role in Alzheimer's disease pathogenesis. It was also the first gene in which mutations associated with inherited Alzheimer's disease were found. Although the molecular details of the generation of amyloid β-protein from β-amyloid precursor protein are being unraveled, the actual physiological functions of β-amyloid precursor protein are far from clear. This situation is changing as accumulating new evidence suggests that the C-terminal cytosolic tail of β-amyloid precursor protein may have multiple biological activities, ranging from axonal transport to nuclear signaling. This article reviews the current state of knowledge about the biological functions of β-amyloid precursor protein .     

Precision of host sanctions in the fig tree–fig wasp mutualism: consequences for uncooperative symbionts

Host sanctions that reduce the relative fitness of uncooperative symbionts provide a mechanism that can limit cheating and thus stabilise mutualisms over evolutionary timescales. Sanctions have been demonstrated empirically in several mutualisms. However, if multiple individual symbionts interact with each host, the precision with which individual cheating symbionts are targeted by host sanctions is critical to their short‐ and long‐term effectiveness. No previous empirical study has directly addressed this issue. Here, we report the precision of host sanctions in the mutualism between fig trees and their pollinating wasps. Using field experiments and molecular parentage analyses, we show that sanctions in Ficus nymphaeifolia act at the level of entire figs (syconia), not at the level of the individual flowers within. Such fig‐level sanctions allow uncooperative wasps, which do not bring pollen, to avoid sanctions in figs to which other wasps bring pollen. We discuss the relevance of sanction precision to other mutualisms.     

Deducing the temporal order of cofactor function in ligand-regulated gene transcription: theory and experimental verification

Cofactors are intimately involved in steroid-regulated gene expression. Two critical questions are (1) the steps at which cofactors exert their biological activities and (2) the nature of that activity. Here we show that a new mathematical theory of steroid hormone action can be used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors relative to a concentration limiting step (CLS) and to each other. The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, are validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells. The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter. Thus new tools to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics are now available.     

Red mangrove life history variables along latitudinal and anthropogenic stress gradients

Mangroves migrate northward in Florida and colonize marshes historically dominated by salt marsh species. In theory, this migration should be facilitated by greater numbers of propagules stemming from increased reproductive activity and greater genetic variability caused by outcrossing. We aimed to determine if stand reproduction and % outcrossing were affected by cold stress (stress increases with latitude), anthropogenic stress (human population density as a proxy), and years since a major hurricane. Further, we wished to determine if mutation rate varied with the stressors and if that affected stand reproduction. Both coasts of Florida from the southern Florida Keys to Tampa Bay on the Gulf of Mexico coast, and Merritt Island on the Atlantic coast. We conducted field surveys of frequency of reproducing trees (104,211 trees surveyed in 102 forested stands), incidence of trees showing albinism in propagules, and% outcrossing estimated from the ratio of albino:normal propagules. Structural equation modeling (SEM) was used to test a conceptual model that served as a multivariate hypothesis. Reproductive frequencies varied by site and increased with latitude although more strongly on the Gulf coast. Our SEM results indicate that outcrossing increases in this predominately selfing species under conditions of cold and anthropogenic stress, and that this increases reproductive output in the population. Further, we find that increased mutation rates suppress stand reproductive output but there is no significant relationship between outcrossing and mutation rate. Tree size responded to stressors but did not affect stand reproduction. Reproduction increased with years since major hurricane. Potential for colonization of northern Florida salt marshes by mangroves is enhanced by increased reproductive rates that provides more propagules and outcrossing that should enhance genetic variation thereby promoting adaptation to novel environmental conditions. Natural (cold) stress reduced mutation rate and increased stand reproductive output but anthropogenic stress did the opposite.     

Cologastric fistula with a foreign body in a patient with Crohn's disease

Although the medical management of fistulizing Crohn's disease is improving, a subset of patients does not respond to maximal medical therapy and is referred for surgical consultation. We report a case of Crohn's colitis with an ingested foreign body resulting in a cologastric fistula. The patient underwent segmental colectomy and takedown of the cologastric fistula. At the time of laparotomy, the foreign body was found in the fistulous colonic segment. The presence of an ingested foreign body likely contributed to a rare fistula that was refractory to medical management.     

Differential role of the alpha1C subunit tails in regulation of the Cav1.2 channel by membrane potential, beta subunits, and Ca2+ ions

Voltage-gated Ca(v)1.2 channels are composed of the pore-forming alpha1C and auxiliary beta and alpha2delta subunits. Voltage-dependent conformational rearrangements of the alpha1C subunit C-tail have been implicated in Ca2+ signal transduction. In contrast, the alpha1C N-tail demonstrates limited voltage-gated mobility. We have asked whether these properties are critical for the channel function. Here we report that transient anchoring of the alpha1C subunit C-tail in the plasma membrane inhibits Ca2+-dependent and slow voltage-dependent inactivation. Both alpha2delta and beta subunits remain essential for the functional channel. In contrast, if alpha1C subunits with are expressed alpha2delta but in the absence of a beta subunit, plasma membrane anchoring of the alpha1C N terminus or its deletion inhibit both voltage- and Ca2+-dependent inactivation of the current. The following findings all corroborate the importance of the alpha1C N-tail/beta interaction: (i) co-expression of beta restores inactivation properties, (ii) release of the alpha1C N terminus inhibits the beta-deficient channel, and (iii) voltage-gated mobility of the alpha1C N-tail vis a vis the plasma membrane is increased in the beta-deficient (silent) channel. Together, these data argue that both the alpha1C N- and C-tails have important but different roles in the voltage- and Ca2+-dependent inactivation, as well as beta subunit modulation of the channel. The alpha1C N-tail may have a role in the channel trafficking and is a target of the beta subunit modulation. The beta subunit facilitates voltage gating by competing with the N-tail and constraining its voltage-dependent rearrangements. Thus, cross-talk between the alpha1C C and N termini, beta subunit, and the cytoplasmic pore region confers the multifactorial regulation of Ca(v)1.2 channels.     

hunchback and Ikaros-like zinc finger genes control reproductive system development in Caenorhabditis elegans

Here we provide evidence for a C2H2 zinc finger gene family with similarity to Ikaros and hunchback. The founding member of this family is Caenorhabditis elegans ehn-3, which has important and poorly understood functions in somatic gonad development. We examined the expression and function of four additional hunchback/Ikaros-like (HIL) genes in C. elegans reproductive system development. Two genes, ehn-3 and R08E3.4, are expressed in somatic gonadal precursors (SGPs) and have overlapping functions in their development. In ehn-3; R08E3.4 double mutants, we find defects in the generation of distal tip cells, anchor cells, and spermatheca; three of the five tissues derived from the SGPs. We provide in vivo evidence that C. elegans HIL proteins have functionally distinct zinc finger domains, with specificity residing in the N-terminal set of four zinc fingers and a likely protein-protein interaction domain provided by the C-terminal pair of zinc fingers. In addition, we find that a chimeric human Ikaros protein containing the N-terminal zinc fingers of EHN-3 functions in C. elegans. Together, these results lend support to the idea that the C. elegans HIL genes and Ikaros have similar functional domains. We propose that hunchback, Ikaros, and the HIL genes arose from a common ancestor that was present prior to the divergence of protostomes and deuterostomes.