Habitat use by smooth snakes on lowland heath managed using 'conservation grazing'

Heathland in the UK, and parts of mainland Europe, is being managed increasingly by landowners and statutory conservation bodies e.g., Natural England, using cattle grazing which is often referred to as 'conservation grazing' in an attempt to justify its use in the absence of any detailed prior research into its actual benefits for wildlife species whose individual habitat requirements are likely to vary. Over four years, between 2010 and 2013, cattle were excluded from six hectares of lowland heath that had been subject to annual summer cattle grazing between May 1997 and autumn 2009 and in which reptile numbers had been monitored annually since 1997. Changes in smooth snake (Coronella austriaca) numbers were recorded annually in the ungrazed area and in a four hectare area of heathland adjacent to it that continued to be grazed. The number of individual smooth snakes, and the total number of smooth snake captures, were significantly higher in the ungrazed heath than the grazed heath and were associated with increased habitat structure, resulting principally from tall heathers and grasses. The results of the study suggest that the use of cattle grazing as a management tool on lowland heath is detrimental to smooth snake populations and that their recovery, following the cessation of grazing, may take many years

The relative performance of smooth snakes inhabiting open heathland and conifer plantations

Different habitat types that support similar densities of a particular species may not be equally suitable for that species and this may impact on the ability of that species to grow, reproduce, and survive. Here we investigate the impact of habitat quality on the performance of the UK’s rarest snake which inhabits both lowland heath and adjacent areas of managed conifer plantation located on former lowland heath. Annually, over an 8 year period (2009–2016), we recaptured known individual smooth snakes (Coronella austriaca) in these two habitat types and compared their survivorship, using Program MARK, and growth rates, estimated ages, reproductive outputs, emigration/immigration, and body condition, using regression analysis and GLM. When compared with snakes from plantations those inhabiting open heathland had higher growth rates, were larger for any given age, had a higher body condition and females produced more embryos for a given body size. Smooth snake survivorship rates within the two habitats were similar. Whilst the body condition of snakes in heathland did not change during the study it declined in plantations and this decline was correlated with increasing plantation age and tree canopy cover. Our data show that although smooth snakes occur in both habitat types the overall quality of open heathland is superior to that of plantations, particularly in the long term. This study has potentially important implications for the conservation of smooth snakes and other reptile and vertebrate species inhabiting coniferous plantations, where management practices aimed at reducing ground vegetation cover, such as cattle grazing and the use of herbicides, are also used. The combination of increasing canopy cover and these additional ground vegetation control measures are likely to significantly reduce further the time period over which plantations can be utilised by these taxa

Habitat use by grass snakes and three sympatric lizard species on lowland heath managed using ‘conservation grazing’

Cattle grazing is being used increasingly by landowners and statutory conservation bodies to manage heathlands in parts of mainland Europe and in the UK, where it is called 'conservation grazing'. Between 2010 and 2013, cattle were excluded from six hectares of lowland heath, in southern England, that had been subject to annual summer cattle grazing between May 1997 and autumn 2009. Changes in grass snake Natrix natrix, common lizard Zootoca vivipara, slow worm Anguis fragilis and sand lizard Lacerta agilis numbers were recorded annually in the ungrazed area and in a four hectare area of heathland adjacent to it that continued to be grazed. The number of grass snake, common lizard and slow worm sightings were significantly higher in the ungrazed heath than the grazed heath and were associated with increased habitat structure, resulting principally from increased height and cover of grasses, particularly Molinia caerulea. Conversely, there was no significant difference in the number of adult sand lizard sightings between the grazed and ungrazed heath though sighting frequency was inversely correlated with both grass and grass litter cover. Our results suggest that the use of cattle grazing as a management tool on lowland heath is detrimental to grass snake, slow worm and common lizard populations but may be less so to adult sand lizards. Although newborn slow worms and common lizards were observed throughout the study area, significantly fewer were found in the grazed areas than the ungrazed areas. The absence of newborn grass snakes and sand lizards in the grazed areas suggests that successful breeding had not occurred in these areas

The role of managed coniferous forest in the conservation of reptiles

Commercially managed coniferous forest is often considered detrimental to wildlife despite their early developmental growth stages being well utilised by some species from a number of different taxa. Our study investigated the use of different aged conifer plantations by reptiles in southern England using arrays of artificial refuges, placed within 20 plantations of varying age, to determine the presence of reptiles annually within each between 2009 and 2013. All six native British reptile species (adder Vipera berus, grass snake Natrix natrix, smooth snake Coronella austriaca, common lizard Zootoca vivipara, sand lizard Lacerta agilis, slow worm Anguis fragilis) occurred in conifer plantations. Excluding the slow worm, which occurred in plantations of all ages, the majority of reptile observations occurred in plantations up to 20 years old and where tree canopy cover was below 65% with the highest numbers occurring in 3–12 year old plantations with a canopy cover below 50%. The early stages of plantation growth are utilised well by reptiles but become increasingly unsuitable over time. Furthermore, the availability of suitable reptile habitat is transient, depending on the rate of tree growth, the timing and extent of tree thinning and felling operations, the size of the plantation units and their proximity to adjacent areas inhabited by reptiles. Our study shows that coniferous forests can be managed so that both timber production and biodiversity conservation can be achieved through the formation of a mosaic of relatively small, multi-aged plantations and that small changes in ground preparation and habitat management practices may further enhance its suitability for reptiles and, by implication, for species from other taxa. The results of our study also have pertinence for species conservation and biodiversity within similar managed forestry throughout the world

17α-Ethynyl-5α-androstane-3α, 17β-diol Treatment of MNU-Induced Mammary Cancer in Rats

N-methyl-N-nitrosourea (MNU) induces estrogen-dependent mammary tumors in female Lewis rats. We explored the antineoplastic activity of a synthetic androstane derivative, 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235), as a single agent or in combination with docetaxel compared to tamoxifen, anastrazole, and docetaxel monotherapies against MNU-induced mammary tumors in female Lewis rats. Treatment with HE3235 alone rapidly reduced tumor burden, similar in effect to tamoxifen and anastrozole. The combination of HE3235 with docetaxel was more effective than any single agent, although without apparent toxicity. Only HE3235 or HE3235 plus docetaxel continued to suppress tumor growth after cessation of treatment. HE3235 treatment increased immunohistochemical markers of apoptosis and expression of proapoptotic genes and estrogen receptor beta and decreased expression of antiapoptotic genes, androgen receptor, and estrogen receptor alpha. These data warrant clinical investigation of HE3235 for breast cancer treatment

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.This work was supported by the JDRF UK Centre for Diabetes Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003), the Wellcome Trust (WT061858/091157) and the NIHR Cambridge Biomedical Research Centre (CBRC). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/db15-051

The diversity of population responses to environmental change

This is the final version. Available from Wiley via the DOI in this record.Data available from the Dryad Digital Repository: https:// doi.org/10.5061/dryad.d5f54s7The current extinction and climate change crises pressure us to predict population dynamics with ever-greater accuracy. Although predictions rest on the well-advanced theory of age-structured populations, two key issues remain poorly explored. Specifically, how the age-dependency in demographic rates and the year-to-year interactions between survival and fecundity affect stochastic population growth rates. We use inference, simulations and mathematical derivations to explore how environmental perturbations determine population growth rates for populations with different age-specific demographic rates and when ages are reduced to stages. We find that stage- vs. age-based models can produce markedly divergent stochastic population growth rates. The differences are most pronounced when there are survival-fecundity-trade-offs, which reduce the variance in the population growth rate. Finally, the expected value and variance of the stochastic growth rates of populations with different age-specific demographic rates can diverge to the extent that, while some populations may thrive, others will inevitably go extinct.Max Planck Society, Marie Curie FellowshipERCGerman Research FoundationSwiss National Science FoundationNational Science FoundationNational Institute of AgingRamon y Cajal Research GrantWenner-Gren FoundationLeakey FoundationNational Geographic SocietyZoological Society of San DiegoUniversity of PennsylvaniaArgentinean National Council of Researc

Molecular Targets for 17α-Ethynyl-5-Androstene-3β,7β,17β-Triol, an Anti-Inflammatory Agent Derived from the Human Metabolome

HE3286, 17α-ethynyl-5-androstene-3β, 7β, 17β-triol, is a novel synthetic compound related to the endogenous sterol 5-androstene-3β, 7β, 17β-triol (β-AET), a metabolite of the abundant adrenal steroid dehydroepiandrosterone (DHEA). HE3286 has shown efficacy in clinical studies in impaired glucose tolerance and type 2 diabetes, and in vivo models of types 1 and 2 diabetes, autoimmunity, and inflammation. Proteomic analysis of solid-phase HE3286-bound bead affinity experiments, using extracts from RAW 264.7 mouse macrophage cells, identified 26 binding partners. Network analysis revealed associations of these HE3286 target proteins with nodes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for type 2 diabetes, insulin, adipokine, and adipocyte signaling. Binding partners included low density lipoprotein receptor-related protein (Lrp1), an endocytic receptor; mitogen activated protein kinases 1 and 3 (Mapk1, Mapk3), protein kinases involved in inflammation signaling pathways; ribosomal protein S6 kinase alpha-3 (Rsp6ka3), an intracellular regulatory protein; sirtuin-2 (Sirt2); and 17β-hydroxysteroid dehydrogenase 1 (Hsd17β4), a sterol metabolizing enzyme

Antigen-driven EGR2 expression is required for exhausted CD8 + T cell stability and maintenance

Chronic stimulation of CD8 T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells. +This work was funded by National Institutes of Health Grant U19-AI100627, the Swiss National Science Foundation and the Novartis Foundation for Medical-Biological Research (S.S.G.), the Australian Cancer Research Foundation (for the Peter Mac Flow Cytometry and Molecular Genomics facilities) and by the National Health and Medical Research Council (NHMRC) through Program Grants 1016953 & 1113904, Ideas Grant APP2001719, Australia Fellowship 585490 (C.C.G.), Senior Principal Research Fellowships (1081858, C.C.G., 1139607, A.K.), and CJ Martin Early Career Fellowship 585518 (I.A.P.)