Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant

Age-related macular degeneration is a leading form of blindness in Western countries and is associated with a common SNP (rs 1061170/Y402H) in the Factor H gene, which encodes the two complement inhibitors Factor H and FHL1. However, the functional consequences of this Tyr(402) His exchange in domain 7 are not precisely defined. In this study, we show that the Tyr(402) His sequence variation affects Factor H surface recruitment by monomeric C-reactive protein (mCRP) to specific patches on the surface of necrotic retinal pigment epithelial cells. Enhanced attachment of the protective Tyr(402) variants of both Factor H and FHL1 by mCRP results in more efficient complement control and further provides an anti-inflammatory environment. In addition, we demonstrate that mCRP is generated on the surface of necrotic retinal pigment epithelial cells and that this newly formed mCRP colocalizes with the cell damage marker annexin V. Bound to the cell surface, Factor H-mCRP complexes allow complement inactivation and reduce the release of the proinflammatory cytokine TNF-α. This mCRP-mediated complement inhibitory and anti-inflammatory activity at necrotic membrane lesions is affected by residue 402 of Factor H and defines a new role for mCRP, for Factor H, and also for the mCRP-Factor H complex. The increased protective capacity of the Tyr(402) Factor H variant allows better and more efficient clearance and removal of cellular debris and reduces inflammation and pathology.     

Quantifying the response of free-ranging mammalian herbivores to the interplay between plant defense and nutrient concentrations

While trying to achieve their nutritional requirements, foraging herbivores face the costs of plant defenses, such as toxins. Teasing apart the costs and benefits of various chemical constituents in plants is difficult because their chemical defenses and nutrient concentrations often co-vary. We used an approach derived from predator–prey studies to quantitatively compare the foraging response of a free-ranging mammalian herbivore, the swamp wallaby (Wallabia bicolor), through three feeding trials with artificial diets that differed in their concentrations of (1) the terpene 1,8-cineole, (2) primary constituents (including nitrogen and fiber), and (3) both the terpene and the primary constituents. Applying the giving-up density (GUD) framework, we demonstrated that the foraging cost of food patches increases with higher dietary cineole concentration and decreases with higher dietary nutrient concentration. The effect of combined differences in nutrients and cineole concentrations on GUD was interactive, and high nutrient food required more cineole to achieve the same patch value as low nutrient food. Our results indicate that swamp wallabies equate low nutrient, poorly defended food with high nutrient, highly defended food, providing two contrasting diets with similar cost–benefit outcomes. This behavior suggests that equal concentrations of chemical defenses provide nutrient-poor plants with relatively greater protection as nutrient-rich plants. Nutrient-rich plants may therefore face the exacerbated problem of being preferred by herbivores and therefore need to produce more defense compounds to achieve the same level of defense as nutrient-poor plants. Our findings help explain the difference in anti-herbivore strategy of nutrient-poor and rich plants, i.e., tolerance versus defense.     

Shifts in Geographic Distribution and Antimicrobial Resistance during a Prolonged Typhoid Fever Outbreak — Bundibugyo and Kasese Districts,Uganda, 2009–2011

Background

Salmonella enterica serovar Typhi is transmitted by fecally contaminated food and water and causes approximately 22 million typhoid fever infections worldwide each year. Most cases occur in developing countries, where approximately 4% of patients develop intestinal perforation (IP). In Kasese District, Uganda, a typhoid fever outbreak notable for a high IP rate began in 2008. We report that this outbreak continued through 2011, when it spread to the neighboring district of Bundibugyo.

Methodology/Principal Findings

A suspected typhoid fever case was defined as IP or symptoms of fever, abdominal pain, and ≥1 of the following: gastrointestinal disruptions, body weakness, joint pain, headache, clinically suspected IP, or non-responsiveness to antimalarial medications. Cases were identified retrospectively via medical record reviews and prospectively through laboratory-enhanced case finding. Among Kasese residents, 709 cases were identified from August 1, 2009–December 31, 2011; of these, 149 were identified during the prospective period beginning November 1, 2011. Among Bundibugyo residents, 333 cases were identified from January 1–December 31, 2011, including 128 cases identified during the prospective period beginning October 28, 2011. IP was reported for 507 (82%) and 59 (20%) of Kasese and Bundibugyo cases, respectively. Blood and stool cultures performed for 154 patients during the prospective period yielded isolates from 24 (16%) patients. Three pulsed-field gel electrophoresis pattern combinations, including one observed in a Kasese isolate in 2009, were shared among Kasese and Bundibugyo isolates. Antimicrobial susceptibility was assessed for 18 isolates; among these 15 (83%) were multidrug-resistant (MDR), compared to 5% of 2009 isolates.

Conclusions/Significance

Molecular and epidemiological evidence suggest that during a prolonged outbreak, typhoid spread from Kasese to Bundibugyo. MDR strains became prevalent. Lasting interventions, such as typhoid vaccination and improvements in drinking water infrastructure, should be considered to minimize the risk of prolonged outbreaks in the future.     

Comparative Genomics Elucidates the Origin of a Supergene Controlling Floral Heteromorphism

Supergenes are nonrecombining genomic regions ensuring the coinheritance of multiple, coadapted genes. Despite the importance of supergenes in adaptation, little is known on how they originate. A classic example of supergene is the S locus controlling heterostyly, a floral heteromorphism occurring in 28 angiosperm families. In Primula, heterostyly is characterized by the cooccurrence of two complementary, self-incompatible floral morphs and is controlled by five genes clustered in the hemizygous, ca. 300-kb S locus. Here, we present the first chromosome-scale genome assembly of any heterostylous species, that of Primula veris (cowslip). By leveraging the high contiguity of the P. veris assembly and comparative genomic analyses, we demonstrated that the S-locus evolved via multiple, asynchronous gene duplications and independent gene translocations. Furthermore, we discovered a new whole-genome duplication in Ericales that is specific to the Primula lineage. We also propose a mechanism for the origin of S-locus hemizygosity via nonhomologous recombination involving the newly discovered two pairs of CFB genes flanking the S locus. Finally, we detected only weak signatures of degeneration in the S locus, as predicted for hemizygous supergenes. The present study provides a useful resource for future research addressing key questions on the evolution of supergenes in general and the S locus in particular: How do supergenes arise? What is the role of genome architecture in the evolution of complex adaptations? Is the molecular architecture of heterostyly supergenes across angiosperms similar to that of Primula?     

Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells

Although testosterone deficiency (TD) may be present in one out of five men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that the TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs, and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of the TME (Sertoli and PMC). The results demonstrated that TME secretes leptin, which induces LSC differentiation and increases testosterone production. Leptin’s effects on LSC differentiation and testosterone production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin binds to the leptin receptor on LSCs and induces DHH signaling to modulate LSC differentiation. Leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effect on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.Subject terms: Stem-cell differentiation, Translational research     

Maternal dopamine exposure provides offspring starvation resistance in Daphnia

The neurotransmitter dopamine has been shown to play an important role in modulating behavioral, morphological, and life history responses to food abundance. However, costs of expressing high dopamine levels remain poorly studied and are essential for understanding the evolution of the dopamine system. Negative maternal effects on offspring size from enhanced maternal dopamine levels have previously been documented in Daphnia. Here, we tested whether this translates into fitness costs in terms of lower starvation resistance in offspring. We exposed Daphnia magna mothers to aqueous dopamine (2.3 or 0 mg/L for the control) at two food levels (ad libitum vs. 30% ad libitum) and recorded a range of maternal life history traits. The longevity of their offspring was then quantified in the absence of food. In both control and dopamine treatments, mothers that experienced restricted food ration had lower somatic growth rates and higher age at maturation. Maternal food restriction also resulted in production of larger offspring that had a superior starvation resistance compared to ad libitum groups. However, although dopamine exposed mothers produced smaller offspring than controls at restricted food ration, these smaller offspring survived longer under starvation. Hence, maternal dopamine exposure provided an improved offspring starvation resistance. We discuss the relative importance of proximate and ultimate causes for why D. magna may not evolve toward higher endogenous dopamine levels despite the fitness benefits this appears to have.     

Mapping stakeholder viewpoints in biodiversity management: an application in Niger using Q methodology

The purpose of this paper is to examine the viewpoints of stakeholders in the management and conservation of farm animal biodiversity in Niger. The research applies Q methodology in order to reveal consensual and divergent discourses. After the development of the set of items on the topic of biodiversity (Q sample), the statements were sorted by the respondents through a 7-grade scale, from ?3 to +3. The analysis of Q-sort data with the qmethod package under the R software highlighted three distinct stakeholder viewpoints on the importance of biodiversity in agriculture and animal husbandry, the balance between progress and preservation and the effectiveness of different methods of conservation. The study shows an apparent consensus on the importance of biodiversity that is obviously a promoted topic in the country. Behind the consensus, different discourses are defined that all appear divided by the same dilemma between conservation and economic development. Understanding the different answers and weight attributed to each of the components of the dilemma will guide awareness-raising campaigns and help to pinpoint divergent interests among stakeholders.     

Transmission of molecularly undetectable circulating parasite clones leads to high infection complexity in mosquitoes post feeding

Plasmodium falciparum malaria infections often comprise multiple distinct parasite clones. Few datasets have directly assessed infection complexity in humans and mosquitoes they infect. Examining parasites using molecular tools may provide insights into the selective transmissibility of isolates. Using capillary electrophoresis genotyping and next generation amplicon sequencing, we analysed complexity of parasite infections in human blood and in the midguts of mosquitoes that became infected in membrane feeding experiments using the same blood material in two West African settings. Median numbers of clones in humans and mosquitoes were higher in samples from Burkina Faso (4.5, interquartile range 2–8 for humans; and 2, interquartile range 1–3 for mosquitoes) than in The Gambia (2, interquartile range 1–3 and 1, interquartile range 1–3, for humans and mosquitoes, respectively). Whilst the median number of clones was commonly higher in human blood samples, not all transmitted alleles were detectable in the human peripheral blood. In both study sample sets, additional parasite alleles were identified in mosquitoes compared with the matched human samples (10–88.9% of all clones/feeding assay, n?=?73 feeding assays). The results are likely due to preferential amplification of the most abundant clones in peripheral blood but confirm the presence of low density clones that produce transmissible sexual stage parasites.