Permafrost model sensitivity to seasonal climatic changes and extreme events in mountainous regions

Climate models project considerable ranges and uncertainties in future climatic changes. To assess the potential impacts of climatic changes on mountain permafrost within these ranges of uncertainty, this study presents a sensitivity analysis using a permafrost process model combined with climate input based on delta-change approaches. Delta values comprise a multitude of coupled air temperature and precipitation changes to analyse long-term, seasonal and seasonal extreme changes on a typical low-ice content mountain permafrost location in the Swiss Alps. The results show that seasonal changes in autumn (SON) have the largest impact on the near-surface permafrost thermal regime in the model, and lowest impacts in winter (DJF). For most of the variability, snow cover duration and timing are the most important factors, whereas maximum snow height only plays a secondary role unless maximum snow heights are very small. At least for the low-ice content site of this study, extreme events have only short-term effects and have less impact on permafrost than long-term air temperature trends

A Guide for Selection of Genetic Instruments in Mendelian Randomization Studies of Type 2 Diabetes and HbA1c: Toward an Integrated Approach

In this study we examine the instrument selection strategies currently used throughout the type 2 diabetes and HbA1c Mendelian randomization (MR) literature. We then argue for a more integrated and thorough approach, providing a framework to do this in the context of HbA1c and diabetes. We conducted a literature search for MR studies that have instrumented diabetes and/or HbA1c. We also used data from the UK Biobank (UKB) (N = 349,326) to calculate instrument strength metrics that are key in MR studies (the F statistic for average strength and R2 for total strength) with two different methods ("individual-level data regression" and Cragg-Donald formula). We used a 157-single nucleotide polymorphism (SNP) instrument for diabetes and a 51-SNP instrument (with partition into glycemic and erythrocytic as well) for HbA1c. Our literature search yielded 48 studies for diabetes and 22 for HbA1c. Our UKB empirical examples showed that irrespective of the method used to calculate metrics of strength and whether the instrument was the main one or included partition by function, the HbA1c genetic instrument is strong in terms of both average and total strength. For diabetes, a 157-SNP instrument was shown to have good average strength and total strength, but these were both substantially lesser than those of the HbA1c instrument. We provide a careful set of five recommendations to researchers who wish to genetically instrument type 2 diabetes and/or HbA1c. In MR studies of glycemia, investigators should take a more integrated approach when selecting genetic instruments, and we give specific guidance on how to do this

Semi-automated calibration method for modelling of mountain permafrost evolution in Switzerland

Permafrost is a widespread phenomenon in mountainous regions of the world such as the European Alps. Many important topics such as the future evolution of permafrost related to climate change and the detection of permafrost related to potential natural hazards sites are of major concern to our society. Numerical permafrost models are the only tools which allow for the projection of the future evolution of permafrost. Due to the complexity of the processes involved and the heterogeneity of Alpine terrain, models must be carefully calibrated, and results should be compared with observations at the site (borehole) scale. However, for large-scale applications, a site- specific model calibration for a multitude of grid points would be very time-consuming. To tackle this issue, this study presents a semi-automated calibration method using the Generalized Likelihood Uncertainty Estimation (GLUE) as implemented in a 1-D soil model (CoupModel) and applies it to six permafrost sites in the Swiss Alps. We show that this semi-automated calibration method is able to accurately reproduce the main thermal condition characteristics with some limitations at sites with unique conditions such as 3-D air or water circulation, which have to be calibrated manually. The calibration obtained was used for global and regional climate model (GCM/RCM)-based long-term climate projections under the A1B climate scenario (EU-ENSEMBLES project) specifically downscaled at each borehole site. The projection shows general permafrost degradation with thawing at 10 m, even partially reaching 20 m depth by the end of the century, but with different timing among the sites and with partly considerable uncertainties due to the spread of the applied climatic forcing

Rapid decline of snow and ice in the tropical Andes – Impacts, uncertainties and challenges ahead

Glaciers in the tropical Andes have been retreating for the past several decades, leading to a temporary increase in dry season water supply downstream. Projected future glacier shrinkage, however, will lead to a long-term reduction in dry season river discharge from glacierized catchments. This glacier retreat is closely related to the observed increase in high-elevation, surface air temperature in the region. Future projections using a simple freezing level height- equilibrium-line altitude scaling approach suggest that glaciers in the inner tropics, such as Antizana in Ecuador, may be most vulnerable to future warming while glaciers in the more arid outer tropics, such as Zongo in Bolivia, may persist, albeit in a smaller size, throughout the 21st century regardless of emission scenario. Nonetheless many uncertainties persist, most notably problems with accurate snowfall measurements in the glacier accumulation zone, uncertainties in establishing accurate thickness measurements on glaciers, unknown future changes associated with local-scale circulation and cloud cover affecting glacier energy balance, the role of aerosols and in particular black carbon deposition on Andean glaciers, and the role of groundwater and aquifers interacting with glacier meltwater.The reduction in water supply for export-oriented agriculture, mining, hydropower production and human consumption are the most commonly discussed concerns associated with glacier retreat, but many other aspects including glacial hazards, tourism and recreation, and ecosystem integrity are also affected by glacier retreat. Social and political problems surrounding water allocation for subsistence farming have led to conflicts due to lack of adequate water governance. Local water management practices in many regions reflect cultural belief systems, perceptions and spiritual values and glacier retreat in some places is seen as a threat to these local livelihoods.Comprehensive adaptation strategies, if they are to be successful, therefore need to consider science, policy, culture and practice, and involve local populations. Planning needs to be based not only on future scenarios derived from physically-based numerical models, but must also consider societal needs, economic agendas, political conflicts, socioeconomic inequality and cultural values. This review elaborates on the need for adaptation as well as the challenges and constraints many adaptation projects are faced with, and lays out future directions where opportunities exist to develop successful, culturally acceptable and sustainable adaptation strategies

Investigating the relationship between IGF-I, IGF-II, and IGFBP-3 concentrations and later-life cognition and brain volume

Background The insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized. Methods Using data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke’s Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors. Results Higher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß −0.1 (−0.21, −0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß −0.08 (−0.15, −0.02)]. Conclusions Increased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes

The role of the insulin-like growth factor pathway on later-life brain health

The Insulin-like Growth Factor (IGF)-pathway is involved in numerous biological processes, including some key to central nervous system (CNS) development and maintenance. However, the associations between circulating IGF-pathway protein concentrations and ageing brain health, and whether these are causal, remain unclear. Data collected from the National Survey of Health and Development (NSHD; n = 1,762) and UK Biobank (n = 502,411) were analysed to investigate the associations of IGF-pathway proteins with cognitive function, neuroimaging measures of brain atrophy and neurovascular health, and dementia incidence. Analytical methods included a comprehensive combination of observational epidemiology (linear and logistic regression; time-to-event analysis) and Mendelian randomisation (MR) to investigate causality. In the NSHD (age range: 53 – 73 years) and its neuroimaging sub-study, Insight-46, increased measures of IGF-pathway parameters (IGF-I, IGF-II, IGFBP-3) were associated with favourable cognitive outcomes, and some evidence of less neurovascular damage (Chapter 3). These observational findings were generally consistent in the UK Biobank (age range: 40 – 82 years) where higher IGF-I was associated with generally better performance on cognitive assessments, lower brain atrophy and neurovascular damage, and reduced risk of incident dementia (Chapter 4). In both cohorts, the magnitude of estimates varied across age groups, with association estimates for all-cause dementia models changing direction in the oldest age group (> 65 years) in the UK Biobank. These findings were, however, not reproduced in MR analyses which found no consistent associations between genetically instrumented IGF-I or IGFBP-3 and any of the brain health outcomes examined (Chapter 5). In summary, findings from observational analyses suggest generally beneficial associations between IGF-pathway proteins and brain health outcomes, but these may not be causal. Future research should aim to understand the reasons for these conflicting findings before considering interventions on the IGF-pathway as a treatment for declining brain health

A Guide for Selection of Genetic Instruments in Mendelian Randomization Studies of Type 2 Diabetes and HbA1c: Toward an Integrated Approach.

In this study we examine the instrument selection strategies currently used throughout the type 2 diabetes and HbA1c Mendelian randomization (MR) literature. We then argue for a more integrated and thorough approach, providing a framework to do this in the context of HbA1c and diabetes. We conducted a literature search for MR studies that have instrumented diabetes and/or HbA1c. We also used data from the UK Biobank (UKB) (N = 349,326) to calculate instrument strength metrics that are key in MR studies (the F statistic for average strength and R2 for total strength) with two different methods ("individual-level data regression" and Cragg-Donald formula). We used a 157-single nucleotide polymorphism (SNP) instrument for diabetes and a 51-SNP instrument (with partition into glycemic and erythrocytic as well) for HbA1c. Our literature search yielded 48 studies for diabetes and 22 for HbA1c. Our UKB empirical examples showed that irrespective of the method used to calculate metrics of strength and whether the instrument was the main one or included partition by function, the HbA1c genetic instrument is strong in terms of both average and total strength. For diabetes, a 157-SNP instrument was shown to have good average strength and total strength, but these were both substantially lesser than those of the HbA1c instrument. We provide a careful set of five recommendations to researchers who wish to genetically instrument type 2 diabetes and/or HbA1c. In MR studies of glycemia, investigators should take a more integrated approach when selecting genetic instruments, and we give specific guidance on how to do this

A new phenylacetate-bisphosphonate inhibits breast cancer cell growth by proapoptotic and antiangiogenic effects.

International audienceSodium phenylacetate (NaPa) and some bisphosphonates demonstrated antiproliferative and proapoptotic properties against cancer. We have previously shown that NaPa inhibited cell proliferation of MCF7-ras tumor breast cells both in vitro and in vivo. On the other hand, bisphosphonate activities have only been demonstrated in vitro. Here we evaluated the antitumor effects of a new bisphosphonate, the phenylacetate-bisphosphonate (PaBp), on human breast cancer MCF7 and MCF7-ras cell lines, both in vitro and in vivo. To our knowledge, this is the first report indicating the use of a bisphosphonate derivative as a powerful cytostatic and cytotoxic agent, with proapoptotic and antiangiogenic properties on human breast cancer cells lines, with no animal toxicity

A new phenylacetate-bisphosphonate inhibits breast cancer cell growth by proapoptotic and antiangiogenic effects.

International audienceSodium phenylacetate (NaPa) and some bisphosphonates demonstrated antiproliferative and proapoptotic properties against cancer. We have previously shown that NaPa inhibited cell proliferation of MCF7-ras tumor breast cells both in vitro and in vivo. On the other hand, bisphosphonate activities have only been demonstrated in vitro. Here we evaluated the antitumor effects of a new bisphosphonate, the phenylacetate-bisphosphonate (PaBp), on human breast cancer MCF7 and MCF7-ras cell lines, both in vitro and in vivo. To our knowledge, this is the first report indicating the use of a bisphosphonate derivative as a powerful cytostatic and cytotoxic agent, with proapoptotic and antiangiogenic properties on human breast cancer cells lines, with no animal toxicity