Extinct even before scientific recognition: a remarkable radiation of helicinid snails (Helicinidae) on the Gambier Islands, French Polynesia

Recent literature abounds with reports of the decline and extinction of the endemic species of Achatinellidae and Partulidae in the Hawaiian and Society Islands, respectively, resulting from the introduction of the predatory snail Euglandina rosea. Here, we describe a previously unrecognised radiation of helicinid land snails from the Gambier Islands of French Polynesia, with up to seven species co-occurring in a single locality and up to eight species on a single island. This radiation had already become extinct (nine of ten species) several decades before the expansion of E. rosea in the Pacific, and even before the species were collected for scientific study. The Gambier Islands case study shows that massive extinctions of endemic land snails had already taken place in the nineteenth century, but have remained largely unrecognised and undocumented. Nine of the ten species are new to science and are described here almost entirely based on empty shells collected from the shell bank of the soil after the extinction had already taken place. This helicinid radiation alone increases the number of documented global mollusc extinctions by almost 2 %. Most of the species are minute and, at 1.5 mm, rank among the smallest, if not the smallest, species in the family. Several have apertural barriers and one has opercular apophyses—character states not previously documented in Pacific helicinids. Whereas the only surviving Gambier species belongs anatomically to the genus Sturanya, representative helicinid species from the Austral, Society and Cook Islands are not congeneric with it, and the generic name Nesiocina is here established for the latter taxa. It is hypothesised that the extinct Gambier species were also Nesiocina.     

Neuraminidase inhibitor resistance in influenza: assessing the danger of its generation and spread

Neuraminidase Inhibitors (NI) are currently the most effective drugs against influenza. Recent cases of NI resistance are a cause for concern. To assess the danger of NI resistance, a number of studies have reported the fraction of treated patients from which resistant strains could be isolated. Unfortunately, those results strongly depend on the details of the experimental protocol. Additionally, knowing the fraction of patients harboring resistance is not too useful by itself. Instead, we want to know how likely it is that an infected patient can generate a resistant infection in a secondary host, and how likely it is that the resistant strain subsequently spreads. While estimates for these parameters can often be obtained from epidemiological data, such data is lacking for NI resistance in influenza. Here, we use an approach that does not rely on epidemiological data. Instead, we combine data from influenza infections of human volunteers with a mathematical framework that allows estimation of the parameters that govern the initial generation and subsequent spread of resistance. We show how these parameters are influenced by changes in drug efficacy, timing of treatment, fitness of the resistant strain, and details of virus and immune system dynamics. Our study provides estimates for parameters that can be directly used in mathematical and computational models to study how NI usage might lead to the emergence and spread of resistance in the population. We find that the initial generation of resistant cases is most likely lower than the fraction of resistant cases reported. However, we also show that the results depend strongly on the details of the within-host dynamics of influenza infections, and most importantly, the role the immune system plays. Better knowledge of the quantitative dynamics of the immune response during influenza infections will be crucial to further improve the results.     

Methylation-Associated Partial Down-Regulation of Mesothelin Causes Resistance to Anti-Mesothelin Immunotoxins in a Pancreatic Cancer Cell Line

Anti-mesothelin Pseudomonas exotoxin A-based recombinant immunotoxins (RITs) present a potential treatment modality for pancreatic ductal adenocarcinoma (PDAC). To study mechanisms of resistance, the sensitive PDAC cell line KLM-1 was intermittently exposed to the anti-mesothelin SS1-LR-GGS RIT. Surviving cells were resistant to various anti-mesothelin RITs (IC₅₀s >1 μg/ml), including the novel de-immunized RG7787. These resistant KLM-1-R cells were equally sensitive to the anti-CD71 HB21(Fv)-PE40 RIT as KLM-1, indicating resistance was specific to anti-mesothelin RITs. Mesothelin gene expression was partially down-regulated in KLM-1-R, resulting in 5-fold lower surface protein levels and decreased cellular uptake of RG7787 compared to KLM-1. Bisulfite sequencing analysis found that the mesothelin promoter region was significantly more methylated in KLM-1-R (59 ± 3.6%) compared to KLM-1 (41 ± 4.8%), indicating hypermethylation as a mechanism of mesothelin downregulation. The DNA methyltransferase inhibitor 5-azacytidine restored original mesothelin surface expression to more than half in KLM-1-R and increased sensitivity to RG7787 (IC₅₀ = 722.4 ± 232.6 ng/ml), although cells remained significantly less sensitive compared to parental KLM-1 cells (IC₅₀ = 4.41 ± 0.38 ng/ml). Mesothelin cDNA introduction in KLM-1-R led to 5-fold higher surface protein levels and significantly higher RG7887 uptake compared to KLM-1. As a result, the original sensitivity to RG7787 was fully restored (IC₅₀ = 4.49 ± 1.11 ng/ml). A significantly higher RG7787 uptake was thus required to reach the original cytotoxicity in resistant cells, hinting that intracellular RIT trafficking is also a limiting factor. RNA deep sequencing analysis of KLM-1 and KLM-1-R cells supported our experimental findings; compared to KLM-1, resistant cells displayed differential expression of genes linked to intracellular transport and an expression pattern that matched a more general hypermethylation status. In conclusion, resistance to anti-mesothelin RITs in KLM-1 is linked to a methylation-associated down-regulation of mesothelin, while aberrations in RIT trafficking could also play a role.     

Moderate Exercise and Fibrinolytic Potential in Obese Sedentary Men with Metabolic Syndrome

Objective: To investigate the impact of 30‐minute walking exercise at 70% Vo _2max on tissue plasminogen activator (t‐PA) Ag and plasminogen activator inhibitor type 1 (PAI‐1) Ag in obese sedentary males. Research Methods and Procedures: A controlled observational study of the effect of a 30‐minute acute exercise bout at 70% Vo _2max on plasma t‐PA antigen and PAI‐1 antigen in 10 obese sedentary males matched for age, ethnic origin, and smoking status with 10 nonobese sedentary male controls. Results: The obese group remained hypofibrinolytic compared with the nonobese group at all time‐points before, during, and after exercise. t‐PA increased in both groups with exercise before returning to baseline values 30 minutes after exercise. PAI‐1 did not significantly change in either group with exercise but rose significantly 30 minutes after exercise in the obese group. Discussion: The reduction in fibrinolytic potential in the obese group represents an increase in acute thrombotic risk and could account for the increased incidence of exercise‐associated myocardial infarction observed in sedentary obese groups.     

Controlling Dengue with Vaccines in Thailand

Background

Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the foreseeable future. With four interacting dengue serotypes, the development of an effective vaccine has been a challenge. Several dengue vaccine candidates are currently being tested in clinical trials. Before the widespread introduction of a new dengue vaccine, one needs to consider how best to use limited supplies of vaccine given the complex dengue transmission dynamics and the immunological interaction among the four dengue serotypes.

Methodology/Principal Findings

We developed an individual-level (including both humans and mosquitoes), stochastic simulation model for dengue transmission and control in a semi-rural area in Thailand. We calibrated the model to dengue serotype-specific infection, illness and hospitalization data from Thailand. Our simulations show that a realistic roll-out plan, starting with young children then covering progressively older individuals in following seasons, could reduce local transmission of dengue to low levels. Simulations indicate that this strategy could avert about 7,700 uncomplicated dengue fever cases and 220 dengue hospitalizations per 100,000 people at risk over a ten-year period.

Conclusions/Significance

Vaccination will have an important role in controlling dengue. According to our modeling results, children should be prioritized to receive vaccine, but adults will also need to be vaccinated if one wants to reduce community-wide dengue transmission to low levels.     

The involvement of CD44 and its novel ligand galectin-8 in apoptotic regulation of autoimmune inflammation

The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (K(d), 6 x 10(-9) M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25-65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.     

Instabilities in multiserotype disease models with antibody-dependent enhancement

This paper investigates the complex dynamics induced by antibody-dependent enhancement (ADE) in multiserotype disease models. ADE is the increase in viral growth rate in the presence of immunity due to a previous infection of a different serotype. The increased viral growth rate is thought to increase the infectivity of the secondary infectious class. In our models, ADE induces the onset of oscillations without external forcing. The oscillations in the infectious classes represent outbreaks of the disease. In this paper, we derive approximations of the ADE parameter needed to induce oscillations and analyze the associated bifurcations that separate the types of oscillations. We then investigate the stability of these dynamics by adding stochastic perturbations to the model. We also present a preliminary analysis of the effect of a single serotype vaccination in the model.     

Ira Mellman: from endosomes to industry. Interview by William A Wells

Disease-related research requires a different kind of teamwork, says Ira Mellman. He hopes to find that team at his new home at Genentech.