Testing bias adjustment methods for regional climate change applications under observational uncertainty and resolution mismatch

Systematic biases in climate models hamper their direct use in impact studies and, as a consequence, many statistical bias adjustment methods have been developed to calibrate model outputs against observations. The application of these methods in a climate change context is problematic since there is no clear understanding on how these methods may affect key magnitudes, for example, the climate change signal or trend, under different sources of uncertainty. Two relevant sources of uncertainty, often overlooked, are the sensitivity to the observational reference used to calibrate the method and the effect of the resolution mismatch between model and observations (downscaling effect). In the present work, we assess the impact of these factors on the climate change signal of temperature and precipitation considering marginal, temporal and extreme aspects. We use eight standard and state-of-the-art bias adjustment methods (spanning a variety of methods regarding their nature—empirical or parametric—, fitted parameters and trend-preservation) for a case study in the Iberian Peninsula. The quantile trend-preserving methods (namely quantile delta mapping (QDM), scaled distribution mapping (SDM) and the method from the third phase of ISIMIP-ISIMIP3) preserve better the raw signals for the different indices and variables considered (not all preserved by construction). However, they rely largely on the reference dataset used for calibration, thus presenting a larger sensitivity to the observations, especially for precipitation intensity, spells and extreme indices. Thus, high-quality observational datasets are essential for comprehensive analyses in larger (continental) domains. Similar conclusions hold for experiments carried out at high (approximately 20 km) and low (approximately 120 km) spatial resolutions. © 2020 The Authors. Atmospheric Science Letters published by John Wiley & Sons Ltd on behalf of the Royal Meteorological Society

Testing bias adjustment methods for regional climate change applications under observational uncertainty and resolution mismatch

ABSTRACT: Systematic biases in climate models hamper their direct use in impact studies and, as a consequence, many statistical bias adjustment methods have been developed to calibrate model outputs against observations. The application of these methods in a climate change context is problematic since there is no clear understanding on how these methods may affect key magnitudes, for example, the climate change signal or trend, under different sources of uncertainty. Two relevant sources of uncertainty, often overlooked, are the sensitivity to the observational reference used to calibrate the method and the effect of the resolution mismatch between model and observations (downscaling effect). In the present work, we assess the impact of these factors on the climate change signal of temperature and precipitation considering marginal, temporal and extreme aspects. We use eight standard and state-of-the-art bias adjustment methods (spanning a variety of methods regarding their nature-empirical or parametric-, fitted parameters and tren-preservation) for a case study in the Iberian Peninsula. The quantile tren-preserving methods (namely quantile delta mapping (QDM), scaled distribution mapping (SDM) and the method from the third phase of ISIMIP-ISIMIP3) preserve better the raw signals for the different indices and variables considered (not all preserved by construction). However, they rely largely on the reference dataset used for calibration, thus presenting a larger sensitivity to the observations, especially for precipitation intensity, spells and extreme indices. Thus, high-quality observational datasets are essential for comprehensive analyses in larger (continental) domains. Similar conclusions hold for experiments carried out at high (approximately 20 km) and low (approximately 120 km) spatial resolutions.Participation of S. Herrera and J.M. Gutiérrez was partially supported by the project AfriCultuReS (European Union's Horizon 2020 program, grant agreement no, 774652). S. Lange acknowledges funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 641816 (CRESCENDO

de Branges-Rovnyak spaces: basics and theory

For $S$ a contractive analytic operator-valued function on the unit disk ${\mathbb D}$, de Branges and Rovnyak associate a Hilbert space of analytic functions ${\mathcal H}(S)$ and related extension space ${\mathcal D(S)}$ consisting of pairs of analytic functions on the unit disk ${\mathbb D}$. This survey describes three equivalent formulations (the original geometric de Branges-Rovnyak definition, the Toeplitz operator characterization, and the characterization as a reproducing kernel Hilbert space) of the de Branges-Rovnyak space ${\mathcal H}(S)$, as well as its role as the underlying Hilbert space for the modeling of completely non-isometric Hilbert-space contraction operators. Also examined is the extension of these ideas to handle the modeling of the more general class of completely nonunitary contraction operators, where the more general two-component de Branges-Rovnyak model space ${\mathcal D}(S)$ and associated overlapping spaces play key roles. Connections with other function theory problems and applications are also discussed. More recent applications to a variety of subsequent applications are given in a companion survey article

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

The effect of explicit convection on couplings between rainfall, humidity and ascent over Africa under climate change

The Hadley circulation and tropical rain belt are dominant features of African climate. Moist convection provides ascent within the rain belt, but must be parameterized in climate models, limiting predictions. Here, we use a pan-African convection-permitting model (CPM), alongside a parameterized convection model (PCM), to analyze how explicit convection affects the rain belt under climate change. Regarding changes in mean climate, both models project an increase in total column water (TCW), a widespread increase in rainfall, and slowdown of subtropical descent. Regional climate changes are similar for annual mean rainfall but regional changes of ascent typically strengthen less or weaken more in the CPM. Over a land-only meridional transect of the rain belt, the CPM mean rainfall increases less than in the PCM (5% vs 14%) but mean vertical velocity at 500 hPa weakens more (17% vs 10%). These changes mask more fundamental changes in underlying distributions. The decrease in 3-hourly rain frequency and shift from lighter to heavier rainfall are more pronounced in the CPM and accompanied by a shift from weak to strong updrafts with the enhancement of heavy rainfall largely due to these dynamic changes. The CPM has stronger coupling between intense rainfall and higher TCW. This yields a greater increase in rainfall contribution from events with greater TCW, with more rainfall for a given large-scale ascent, and so favors slowing of that ascent. These findings highlight connections between the convective-scale and larger-scale flows and emphasize that limitations of parameterized convection have major implications for planning adaptation to climate change

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference