Simulating model uncertainty of subgrid-scale processes by sampling model errors at convective scales

Ideally, perturbation schemes in ensemble forecasts should be based on the statistical properties of the model errors. Often, however, the statistical properties of these model errors are unknown. In practice, the perturbations are pragmatically modelled and tuned to maximize the skill of the ensemble forecast. In this paper a general methodology is developed to diagnose the model error, linked to a specific physical process, based on a comparison between a target and a reference model. Here, the reference model is a configuration of the ALADIN (Aire Limitée Adaptation Dynamique Développement International) model with a parameterization of deep convection. This configuration is also run with the deep-convection parameterization scheme switched off, degrading the forecast skill. The model error is then defined as the difference of the energy and mass fluxes between the reference model with scale-aware deep-convection parameterization and the target model without deep-convection parameterization. In the second part of the paper, the diagnosed model-error characteristics are used to stochastically perturb the fluxes of the target model by sampling the model errors from a training period in such a way that the distribution and the vertical and multivariate correlation within a grid column are preserved. By perturbing the fluxes it is guaranteed that the total mass, heat and momentum are conserved. The tests, performed over the period 11–20 April 2009, show that the ensemble system with the stochastic flux perturbations combined with the initial condition perturbations not only outperforms the target ensemble, where deep convection is not parameterized, but for many variables it even performs better than the reference ensemble (with scale-aware deep-convection scheme). The introduction of the stochastic flux perturbations reduces the small-scale erroneous spread while increasing the overall spread, leading to a more skillful ensemble. The impact is largest in the upper troposphere with substantial improvements compared to other state-of-the-art stochastic perturbation schemes. At lower levels the improvements are smaller or neutral, except for temperature where the forecast skill is degraded

Porous stones increase the noise shielding of a gabion

Gabions - metal-wired cages filled up with stones - are increasingly becoming popular as decorative elements and land property boundaries. It has been shown before that such structures can be used as road traffic noise barriers as well. However, the types of stones used in gabions have not been experimentally studied so far. Exploratory measurements at full scale in a semi-anechoic room were performed to study the effect of both porous and rigid stones on their noise reducing potential. At the 1/3 octave bands below 1 kHz, low-height gabions (with depths of 20 cm and 30 cm) hardly provide any sound pressure level reduction. At higher sound frequencies, in contrast, the shielding rapidly increases. Porous lava stones were found to significantly increase the shielding compared to rigid stones. Reflections on such nondeep low-height barriers towards the source side were found to be of minor importance when considering a standardized A-weighted road traffic noise spectrum. (C) 2018 Elsevier Ltd. All rights reserved

Nanobodies as tools to understand, diagnose, and treat African trypanosomiasis

African trypanosomes are strictly extracellular protozoan parasites that cause diseases in humans and livestock and significantly affect the economic development of sub-Saharan Africa. Due to an elaborate and efficient (vector)-parasite-host interplay, required to complete their life cycle/transmission, trypanosomes have evolved efficient immune escape mechanisms that manipulate the entire host immune response. So far, not a single field applicable vaccine exists, and chemotherapy is the only strategy available to treat the disease. Current therapies, however, exhibit high drug toxicity and an increased drug resistance is being reported. In addition, diagnosis is often hampered due to the inadequacy of current diagnostic procedures. In the context of tackling the shortcomings of current treatment and diagnostic approaches, nanobodies (Nbs, derived from the heavy chain-only antibodies of camels and llamas) might represent unmet advantages compared to conventional tools. Indeed, the combination of their small size, high stability, high affinity, and specificity for their target and tailorability represents a unique advantage, which is reflected by their broad use in basic and clinical research to date. In this article, we will review and discuss (i) diagnostic and therapeutic applications of Nbs that are being evaluated in the context of African trypanosomiasis, (ii) summarize new strategies that are being developed to optimize their potency for advancing their use, and (iii) document on unexpected properties of Nbs, such as inherent trypanolytic activities, that besides opening new therapeutic avenues, might offer new insight in hidden biological activities of conventional antibodies

Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

Bovine African Trypanosomosis is an infectious parasitic disease affecting livestock productivity and thereby impairing the economic development of Sub-Saharan Africa. The most important trypanosome species implicated is T. congolense, causing anemia as most important pathological feature. Using murine models, it was shown that due to the parasite's efficient immune evasion mechanisms, including (i) antigenic variation of the variable surface glycoprotein (VSG) coat, (ii) induction of polyclonal B cell activation, (iii) loss of B cell memory and (iv) T cell mediated immunosuppression, disease prevention through vaccination has so far been impossible. In trypanotolerant models a strong, early pro-inflammatory immune response involving IFN-gamma, TNF and NO, combined with a strong humoral anti-VSG response, ensures early parasitemia control. This potent protective inflammatory response is counterbalanced by the production of the anti-inflammatory cytokine IL-10, which in turn prevents early death of the host from uncontrolled hyper-inflammation-mediated immunopathologies. Though at this stage different hematopoietic cells, such as NK cells, T cells and B cells as well as myeloid cells (i.e. alternatively activated myeloid cells (M2) or Ly6c(-) monocytes), were found to produce IL-10, the contribution of non-hematopoietic cells as potential IL-10 source during experimental T. congolense infection has not been addressed. Here, we report for the first time that during the chronic stage of T. congolense infection non-hematopoietic cells constitute an important source of IL-10. Our data shows that hepatocyte-derived IL-10 is mandatory for host survival and is crucial for the control of trypanosomosis-induced inflammation and associated immunopathologies such as anemia, hepatosplenomegaly and excessive tissue injury. Author summary Bovine African Trypanosomosis is a parasitic disease of veterinary importance that adversely affects the public health and economic development of sub-Saharan Africa. The most important trypanosome species implicated is T. congolense, causing anemia as most important pathological feature and major cause of death. Using murine models, it was shown that the disease is characterized by a well-timed and balanced production of pro-inflammatory cytokine promoting factors followed by an anti-inflammatory response, involving IL-10. The latter is required to attenuate infection-associated pathogenicity and to prevent early host death from uncontrolled hyper-inflammation mediated immunopathologies. However, the cellular source of IL-10 in vivo and the window within which these cells exert their function during the course of African trypanosomiasis remain poorly understood, which hampers the design of effective therapeutic strategies. Using a T. congolense infection mouse model, relevant for bovine trypanosomosis, we demonstrate that during the chronic stage of infection hepatocyte-derived IL-10, but not myeloid cell-derived IL-10, regulates the main infection-associated immunopathologies and ultimately mediates host survival. Hence, strategies that tilt the balance of hepatocyte cytokine production in favor of IL-10 could majorly impact the wellbeing and survival of T. congolense-infected animals. Given the unmet medical need for this parasite infection, our findings offer promise for improved treatment protocols in the field

Mechanisms Driving Macrophage Diversity and Specialization in Distinct Tumor Microenvironments and Parallelisms with Other Tissues

Macrophages are extremely versatile cells that adopt a distinct phenotype in response to a changing microenvironment. Consequently, macrophages are involved in diverse functions, ranging from organogenesis and tissue homeostasis to recognition and destruction of invading pathogens. In cancer, tumor-associated macrophages (TAM) often contribute to tumor progression by increasing cancer cell migration and invasiveness, stimulating angiogenesis, and suppressing anti-tumor immunity. Accumulating evidence suggests that these different functions could be exerted by specialized TAM subpopulations. Here, we discuss the potential underlying mechanisms regulating TAM specialization and elaborate on TAM heterogeneity in terms of their ontogeny, activation state, and intra-tumoral localization. In addition, parallels are drawn between TAM and macrophages in other tissues. Together, a better understanding of TAM diversity could provide a rationale for novel strategies aimed at targeting the most potent tumor-supporting macrophages

Expression of the inhibitory Ly49E receptor is not critically involved in the immune response against cutaneous, pulmonary or liver tumours

Natural killer (NK) lymphocytes are part of the innate immune system and are important in immune protection against tumourigenesis. NK cells display a broad repertoire of activating and inhibitory cell surface receptors that regulate NK cell activity. The Ly49 family of NK receptors is composed of several members that recognize major histocompatibility complex class I (MHC-I) or MHC-I-related molecules. Ly49E is a unique inhibitory member, being triggered by the non-MHC-I-related protein urokinase plasminogen activator (uPA) in contrast to the known MHC-I-triggering of the other inhibitory Ly49 receptors. Ly49E also has an uncommon expression pattern on NK cells, including high expression on liver DX5-NK cells. Furthermore, Ly49E is the only Ly49 member expressed by epidermal gamma delta T cells. As gamma delta T cells and/or NK cells have been shown to be involved in the regulation of cutaneous, pulmonary and liver malignancies, and as uPA is involved in tumourigenesis, we investigated the role of the inhibitory Ly49E receptor in the anti-tumour immune response. We demonstrate that, although Ly49E is highly expressed on epidermal gamma delta T cells and liver NK cells, this receptor does not play a major role in the control of skin tumour formation or in lung and liver tumour development