Transgenic Overexpression of Active Calcineurin in β-Cells Results in Decreased β-Cell Mass and Hyperglycemia

Background

Glucose modulates β-cell mass and function through an initial depolarization and Ca²⁺ influx, which then triggers a number of growth regulating signaling pathways. One of the most important downstream effectors in Ca²⁺ signaling is the calcium/Calmodulin activated serine threonine phosphatase, calcineurin. Recent evidence suggests that calcineurin/NFAT is essential for β-cell proliferation, and that in its absence loss of β-cells results in diabetes. We hypothesized that in contrast, activation of calcineurin might result in expansion of β-cell mass and resistance to diabetes.

Methodology/Principal Findings

To determine the role of activation of calcineurin signaling in the regulation of pancreatic β-cell mass and proliferation, we created mice that expressed a constitutively active form of calcineurin under the insulin gene promoter (caCn^RIP). To our surprise, these mice exhibited glucose intolerance. In vitro studies demonstrated that while the second phase of Insulin secretion is enhanced, the overall insulin secretory response was conserved. Islet morphometric studies demonstrated decreased β-cell mass suggesting that this was a major component responsible for altered Insulin secretion and glucose intolerance in caCn^RIP mice. The reduced β-cell mass was accompanied by decreased proliferation and enhanced apoptosis.

Conclusions

Our studies identify calcineurin as an important factor in controlling glucose homeostasis and indicate that chronic depolarization leading to increased calcineurin activity may contribute, along with other genetic and environmental factors, to β-cell dysfunction and diabetes.     

Virus mediated trophic interactions between aphids and their natural enemies

Microbial endosymbionts alter the phenotype of their host which may have cascading effects at both population and community levels. However, we currently lack information on whether the effects of viruses on both host phenotypic traits and host population demography can modify interactions with upper trophic levels. To fill this gap, we investigated whether a prevalent densovirus infecting the aphid Myzus persicae (i.e. MpDNV) can modify trophic interactions between host aphids and their natural enemies (i.e. predators and parasitoids) by influencing aphid phenotypic traits (i.e. body mass and defensive behaviours), population demography (i.e. density and age-structure) and susceptibility towards both predation and parasitism. We found that the virus decreased aphid body mass but did not influence their behavioural defences. At the population level, the virus had a minor effect on aphid adult mortality whereas it strongly reduced the density of nymphs and influenced the stage structure of aphid populations. In addition, the virus enhanced the susceptibility of aphids to parasitism regardless of the parasitoid species. Predation rate on adult aphids was not influenced by the virus but ladybeetle predators strongly decreased the number of aphid nymphs, especially for uninfected ones compared to infected ones. As a result, the virus decreased predator effect on aphid populations. By reducing both aphid quality and availability, increasing their susceptibility to parasitism, and modulating predator effect on aphid populations, we highlighted that viral endosymbionts can be prevalent drivers of their host ecology as they modify their phenotypes and interspecific interactions. These virus-mediated ecological effects may have consequences on enemies foraging strategies as well as trophic webs dynamics and structure.     

Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC

Background

Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT).

Methods

We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors.

Results

Two-year overall survival estimate was 69.9% (95% CI, 58.5–69.4) in the ATG group and 67.6% (95% CI, 60.3–74.9) in the CD34+ group (p?=?0.31). The cumulative incidence of grade II–IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1–3.7), p?=?0.02; HR 15.1 (95% CI 5.3–42.2), p?<?0.0001]. Parameters associated with a lower GVHD-free relapse-free survival (GRFS) were ATG [HR 1.6 (95% CI 1.1–2.2), p?=?0.006], adverse cytogenetic [HR 1.7 (95% CI 1.3–2.2), p?=?0.0004], and the use of an unrelated donor [HR 1.4 (95% CI 1.0–1.9), p?=?0.02]. There were no statistical differences between ATG and CD34+ in terms of relapse [HR 1.52 (95% CI 0.96–2.42), p?=?0.07], non-relapse mortality [HR 0.96 (95% CI 0.54–1.74), p?=?0.90], overall survival [HR 1.43 (95% CI 0.97–2.11), p?=?0.07], and leukemia-free survival [HR 1.25 (95% CI 0.88–1.78), p?=?0.21]. Significantly, more deaths related to infection occurred in the CD34+ group (16/52 vs. 19/112, p?=?0.04).

Conclusions

These data suggest that both ex vivo CD34-selected and in vivo ATG T cell depletion are associated with a rather high OS and should be compared in a prospective randomized trial.

     

Two‐scale dispersal estimation for biological invasions via synthetic likelihood

Biological invasions reshape environments and affect the ecological and economic welfare of states and communities. Such invasions advance on multiple spatial scales, complicating their control. When modeling stochastic dispersal processes, intractable likelihoods and autocorrelated data complicate parameter estimation. As with other approaches, the recent synthetic likelihood framework for stochastic models uses summary statistics to reduce this complexity; however, it additionally provides usable likelihoods, facilitating the use of existing likelihood‐based machinery. Here, we extend this framework to parameterize multi‐scale spatio‐temporal dispersal models and compare existing and newly developed spatial summary statistics to characterize dispersal patterns. We provide general methods to evaluate potential summary statistics and present a fitting procedure that accurately estimates dispersal parameters on simulated data. Finally, we apply our methods to quantify the short and long range dispersal of Chagas disease vectors in urban Arequipa, Peru, and assess the feasibility of a purely reactive strategy to contain the invasion.     

Soil fauna responses to invasive alien plants are determined by trophic groups and habitat structure: a global meta‐analysis

Despite increasing frequency of invasions by alien plant species with widespread ecological and economic consequences, it remains unclear how belowground compartments of ecosystems are impacted. In order to synthetize current knowledge and provide future directions for research we performed a meta‐analysis assessing the impact of invasive alien plant species on soil fauna abundance. Compared to previous synthesis on this topic, we included together in our model the trophic group of each soil faunal taxa (from herbivores to predators) and habitat structure, namely open and closed habitats (i.e. grass and shrub dominated areas versus forested areas). In doing so, we highlighted that both moderators strongly interact to determine the response of soil fauna to the presence of invasive alien plants. Soil fauna abundance increase in the presence of invasive species only in closed habitats (+18.2%). This pattern of habitat‐dependent response (positive effect in closed habitats) was only found for primary consumers (i.e. herbivores +29.1% and detritivores +66.7%) within both detritus‐based and live root‐based trophic pathways. Abundances of predators and microbivores did not respond to the presence of IAS irrespective of habitat structure. For several groups, the habitat structure (open or closed) significantly drove their responses to the presence of invasive alien species. In addition, we carefully considered potential sources of bias (e.g. geographic, taxonomic and functional) within the collected data in an attempt to highlight gaps in available knowledge on the subject. Our findings support the conclusions of previous studies on the subject by demonstrating 1) that soil fauna abundance is impacted by biological invasions, 2) that initial habitat structure has a strong influence on the outcome and 3) that responses within the soil fauna differ between trophic levels with a stronger response of primary consumers.     

A perspective on insect–microbe holobionts facing thermal fluctuations in a climate-change context

Temperature influences the ecology and evolution of insects and their symbionts by impacting each partner independently and their interactions, considering the holobiont as a primary unit of selection. There are sound data about the responses of these partnerships to constant temperatures and sporadic thermal stress (mostly heat shock). However, the current understanding of the thermal ecology of insect–microbe holobionts remains patchy because the complex thermal fluctuations (at different spatial and temporal scales) experienced by these organisms in nature have often been overlooked experimentally. This may drastically constrain our ability to predict the fate of mutualistic interactions under climate change, which will alter both mean temperatures and thermal variability. Here, we tackle down these issues by focusing on the effects of temperature fluctuations on the evolutionary ecology of insect–microbe holobionts. We propose potentially worth-investigating research avenues to (i) evaluate the relevance of theoretical concepts used to predict the biological impacts of temperature fluctuations when applied to holobionts; (ii) acknowledge the plastic (behavioural thermoregulation, physiological acclimation) and genetic responses (evolution) expressed by holobionts in fluctuating thermal environments; and (iii) explore the potential impacts of previously unconsidered patterns of temperature fluctuations on the outcomes and the dynamic of these insect–microbe associations.     

Genetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistance

Despite treatment with agents that enhance β-cell function and insulin action, reduction in β-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3β (Gsk-3β). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3β to regulation of β-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir^+/−) exhibit insulin resistance and a doubling of β-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3β (Gsk-3β^+/−) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced β-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2^−/−), like the Ir^+/− mice, are insulin resistant, but develop profound β-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3β activity associated with a marked reduction of β-cell proliferation and increased apoptosis. Irs2^−/− mice crossed with Gsk-3β^+/− mice preserved β-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2^−/− mice had increased cyclin-dependent kinase inhibitor p27^kip1 that was limiting for β-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of β-cell mass in Gsk-3β^+/−Irs2^−/− mice was accompanied by suppressed p27^kip1 levels and increased Pdx1 levels. To separate peripheral versus β-cell–specific effects of reduction of Gsk3β activity on preservation of β-cell mass, mice homozygous for a floxed Gsk-3β allele (Gsk-3^F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce β-cell–specific knockout of Gsk-3β (βGsk-3β^−/−). Like Gsk-3β^+/− mice, βGsk-3β^−/− mice also prevented the diabetes of the Irs2^−/− mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within β-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of β-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve β-cells and prevent diabetes onset.     

FGFR1-IIIb is a putative marker of pancreatic progenitor cells

The pancreas develops from buds that derive from the endodermal epithelium of the digestive tract. The progenitor cells that will give rise to the mature pancreatic cells reside within this epithelium. However, their exact identity remains unknown. In the present study, we searched for genes expressed by pancreatic progenitor cells. We focused our search on receptor tyrosine kinases. We found that fibroblast growth factor-IIIb (FGFR1-IIIb) expression is high in pancreatic epithelium enriched in progenitor cells. We next investigated FGFR1-IIIb expression throughout pancreatic development. At early stages of pancreas development, FGFR1-IIIb is expressed by pancreatic epithelial cells that resemble undifferentiated cells, while at later stages of development, FGFR1-IIIb expression decreases, concomitant with the expected decrease in the number of progenitor cells.     

Interleukin-7 regulates adipose tissue mass and insulin sensitivity in high-fat diet-fed mice through lymphocyte-dependent and independent mechanisms

Although interleukin (IL)-7 is mostly known as a key regulator of lymphocyte homeostasis, we recently demonstrated that it also contributes to body weight regulation through a hypothalamic control. Previous studies have shown that IL-7 is produced by the human obese white adipose tissue (WAT) yet its potential role on WAT development and function in obesity remains unknown. Here, we first show that transgenic mice overexpressing IL-7 have reduced adipose tissue mass associated with glucose and insulin resistance. Moreover, in the high-fat diet (HFD)-induced obesity model, a single administration of IL-7 to C57BL/6 mice is sufficient to prevent HFD-induced WAT mass increase and glucose intolerance. This metabolic protective effect is accompanied by a significant decreased inflammation in WAT. In lymphocyte-deficient HFD-fed SCID mice, IL-7 injection still protects from WAT mass gain. However, IL-7-triggered resistance against WAT inflammation and glucose intolerance is lost in SCID mice. These results suggest that IL-7 regulates adipose tissue mass through a lymphocyte-independent mechanism while its protective role on glucose homeostasis would be relayed by immune cells that participate to WAT inflammation. Our observations establish a key role for IL-7 in the complex mechanisms by which immune mediators modulate metabolic functions.