Pemafibrate abrogates SLD in a rat experimental dietary model, inducing a shift in fecal bile acids and microbiota composition.

BACKGROUND AND AIMS: Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only efficacy, but also a high safety profile. Repurposing of drugs in clinical use, such as pemafibrate and mirabegron, could facilitate the finding of an effective and safe drug-treatment for SLD. APPROACH AND RESULTS: The SLD High Fat High Fructose (HFHFr) rat model develops steatosis without the influence of other metabolic disturbances, such as obesity, inflammation, or type 2 diabetes. Further, liver fatty acids are provided, as in human pathology, both from dietary origin and de novo lipid synthesis. We used the HFHFr model to evaluate the efficacy of pemafibrate and mirabegron, alone or in combination, in the resolution of SLD, analyzing zoometric, biochemical, histological, transcriptomic, fecal metabolomic and microbiome data. We provide evidence showing that pemafibrate, but not mirabegron, completely reverted liver steatosis, due to a direct effect on liver PPARα-driven fatty acid catabolism, without changes in total energy consumption, subcutaneous, perigonadal and brown fat, blood lipids and body weight. Moreover, pemafibrate treatment showed a neutral effect on whole-body glucose metabolism, but deeply modified fecal bile acid composition and microbiota. CONCLUSIONS: Pemafibrate administration reverts liver steatosis in the HFHFr dietary rat SLD model without altering parameters related to metabolic or organ toxicity. Our results strongly support further clinical research to reposition pemafibrate for the treatment of SLD/MASLD.

The wildcat (Felis s. silvestris) in the Mediterranean forest: sighting through photo-trapping and non-invasive hair collection for genetic purposes.

The European wildcat (Felis silvestris silvestris) is a mesocarnivore species widely distributed in Europe, from Eastern Europe to Portugal and from Scotland to Italy. Recent biogeographical studies of wildcat populations have endeavoured to assess in detail the various issues that pose a threat to this species, including hybridization with domestic cats. The use of non-invasive sampling methods supported by photo-trapping and some attractants has made it possible to gather genetic material for the detection of native wildcats in locally threatened populations, some of which live in the Iberian Peninsula. Testimonies of naturalists, hunters and farm workers led our team to choose specific areas in two large territories of Mediterranean forests where the presence of wildcats has been historically attested: the Almonte River basin and the Sierra de San Pedro Mountains. Between 2014 and 2018, non-invasive hair sampling was performed using valerian (Valeriana officinalis) as an attractant and supported by photo-trapping to guarantee the collection of genuine biological material (hair samples). The hair samples were genetically assessed by sequencing the nuclear gene IRBP (interphotoreceptor retinoid-binding protein) and the mtDNA gene ND4 (NADH dehydrogenase subunit 4). Despite the low density of wildcats, this combined protocol proved to be an applicable tool for detecting the presence of elusive wildcats and other mesocarnivore species in this remote region of southern Europe. In addition, non-invasive hair trapping contributes to the collection of genetic material from current wildcat populations. This procedure could enhance future management actions focused on collecting quality individualized biological material.

Bioaccessibility, Intestinal Absorption and Anti-Inflammatory Activity of Curcuminoids Incorporated in Avocado, Sunflower, and Linseed Beeswax Oleogels.

Beeswax oleogels (OGs), with a mechanical strength similar to pork backfat, were formulated with avocado (A), sunflower (S), and linseed (L) oils, applying a central composite design plus star point, and were evaluated as oral delivery vehicles of curcuminoids (OGACur, OGSCur, OGLCur). The incorporation of curcumin into the OG matrix significantly delayed both the formation of peroxides and conjugated trienes (K268 values), and the degradation rate of curcumin decreased with the increase of the oil polyunsaturated fatty acids (PUFA) content. The oil structuring did not affect the bioaccessibility of curcuminoids (>55% in all the OGs, regardless of the oil type), but it did reduce the release of fatty acids (~10%) during in vitro gastrointestinal digestion. The intestinal absorption, evaluated in Caco-2 cell monolayers, was higher for the micelle-solubilized curcumin from the digested OG than from unstructured oils, and it showed high anti-inflammatory potential by inhibiting the tumor necrosis factor-α (TNF-α) production compared to the positive control, both before and after the stimulation of ThP-1 cells with LPS. Regardless of the oil type, these beeswax-based OGs with gel-like behavior designed as fat replacers may be promising vehicles for the oral delivery of curcuminoids.

Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients.

BACKGROUND: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission. OBJECTIVES: To ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission. METHODS: A multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria. RESULTS: The study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06-1.23; p<0.001), admissions at ICU (2.69; 1.30-5.56; p=0.01), high count of SAE (1.21; 1.03-1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95-0.98; p<0.001), a high ACT score (0.93; 0.88-0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29-0.91; p=0.02) showed strong associations with achieving clinical remission. CONCLUSION: A substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons.

Bos d 13, A Novel Heat-Stable Beef Allergen.

SCOPE: Red meat, a staple food of Western diets, can also induce IgE-mediated allergic reactions. Yet, apart from the heat-labile protein serum albumin and the carbohydrate α-Gal, the molecules causing allergic reactions to red meat remain unknown. METHODS AND RESULTS: IgE reactivity profiles of beef-sensitized individuals are analyzed by IgE-immunoblotting with protein extracts from raw and cooked beef. Two IgE-reactive proteins are identified by peptide mass fingerprinting as myosinlight chain 1 (MYL1) and myosin light chain 3 (MYL3) in cooked beef extract and are designated Bos d 13 isoallergens. MYL1 and MYL3 are produced recombinantly in Escherichia coli. ELISAs proved their IgE reactivity and circular dichroism analysis showed that they represent folded molecules with remarkable thermal stability. In vitro gastrointestinal digestion experiments showed the higher stability of rMYL1 as compared to rMYL3. Exposure of a monolayer of Caco-2 cells to rMYL1 indicated that the molecule is able to cross intestinal epithelial cells without disturbing the integrity of the tight junctions, suggesting the sensitizing capacity of MYL1. CONCLUSION: MYLs are identified as novel heat-stable bovine meat allergens.

Soybean oil organogelled emulsions as oral delivery systems of hydroxytyrosol and hydroxytyrosol alkyl esters.

Water-in-soybean oil organogelled emulsions (OGEs) were formulated as fat replacers and evaluated as delivery systems of hydroxytyrosol (HT, hydrophilic compound), hydroxytyrosol octanoate (HTC18, hydrophobic compound) and hydroxytyrosol decanoate (HTC10, with intermediate hydrophobicity and the highest antioxidant activity measured by conjugated autoxidizable triene assay). OGEs formulated with 55% of water and a ternary blend of candelilla wax, fully hydrogenated palm oil and monoacylglycerols showed mechanical properties similar to lard and solid-like behavior. The increase in the water content, together with a higher concentration of structuring agents in the oil phase, led to an increase in oil retention capacity and texture parameters. A slight desesterification of HTC10 and HTC18 was found during in vitro gastrointestinal digestion. The three bioactive compounds loaded in OGEs showed high bioaccessibility values (∼84%) at the end of digestion, regardless their chain length and hydrophobicity. These OGEs designed as fat replacers showed a great potential for vehiculation of both hydrophilic and lipophilic compounds.

Effects of air pollution on dementia over Europe for present and future climate change scenarios.

The scientific literature is scarce when referring to the influence of atmospheric pollutants on neurodegenerative diseases for present and future climate change scenarios. In this sense, this contribution evaluates the incidence of dementia (Alzheimer's disease, AD, and dementia from unspecified cause, DU) occurring in Europe associated with the exposure to air pollution (essentially NO2 and PM2.5) for the present climatic period (1991-2010) and for a future climate change scenario (RCP8.5, 2031-2050). The GEMM methodology has been applied to air pollution simulations using the chemistry/climate regional model WRF-Chem. Present population data were obtained from NASA's Center for Socioeconomic Data and Applications (SEDAC); while future population projections for the year 2050 were derived from the United Nations (UN) Department of Economic and Social Affairs-Population Dynamics. Overall, the estimated incidence rate (cases per year) of AD and DU associated with exposure to air pollution over Europe is 498,000 [95% confidence interval (95% CI) 348,600-647,400] and 314,000 (95% CI 257,500-401,900), respectively. An important increase in the future incidence rate is projected (around 72% for both types of dementia) when considering the effect of climate change together with the foreseen changes in the future population, because of the expected aging of European population. The climate penalty (impacts of future climate change alone on air quality) has a limited effect on the total changes of dementia (approx. 0.5%), because the large increase in the incidence rate over southern Europe is offset by its decrease over more northern countries, favored by an improvement of air pollution caused by the projected enhancement of rainfall.

Impacto sobre el riesgo de malnutrición y depresión en un ensayo clínico con intervención educativa nutricional en adultos mayores no institucionalizados, receptores de un servicio de teleasistencia en la ciudad de Tarrasa (España) / Impact on the risk of malnutrition and depression of a clinical trial with nutritional educational intervention in non-institutionalized elderly subjects receiving a telecare service in Terrassa (Spain)

INTRODUCCIÓN: los adultos mayores son una población creciente y vulnerable. La existencia de depresión y malnutrición es frecuente y parecen estar asociados. OBJETIVOS: evaluar el impacto de una intervención educativa nutricional sobre el riesgo de malnutrición y depresión en adultos mayores. MÉTODOS: estudio analítico, experimental y longitudinal aleatorizado en 38 adultos mayores, autónomos y no institucionalizados. El riesgo nutricional y el grado de depresión se midieron mediante la Evaluación Mínima Nutricional (MNA) y la Escala de Depresión Geriátrica de Yesavage (GDS-SF), respectivamente. El grupo de intervención recibió formación mediante educación nutricional con refuerzo telefónico. El impacto de la intervención se midió con cuestionarios de conocimientos de nutrición y seguridad alimentaria. Se realizó una estadística descriptiva, se calculó el coeficiente de correlación de Spearman y la comparación entre medias se efectuó con la prueba t de Student. Se consideró una p < 0,05 como significativa. RESULTADOS: el 63,2 % de la muestra presentaban un estado nutricional normal, el 28,9 % riesgo de malnutrición y el 7,9 % malnutrición. Del total de sujetos, el 28,9 % presentaban depresión. Se encontró una relación lineal estadísticamente significativa, moderada y negativa entre el grado de depresión y el riesgo nutricional (rho = -0,489; p < 0,01). La intervención educativa nutricional produjo un incremento significativo de los conocimientos de seguridad alimentaria (2,95 ± 2,53 frente a 0,37 ± 1,46; p < 0,0005). CONCLUSIONES: el riesgo de malnutrición y el de depresión se asocian significativamente en los adultos mayores. Además, la intervención educativa nutricional mejoró los conocimientos de seguridad alimentaria, aunque no produjo una mejora del estado nutricional ni del grado de depresión

INTRODUCTION: the elderly are a growing and vulnerable population. Depression and malnutrition are frequent and there seems to be associated. OBJECTIVES: to assess the impact of a nutritional educational intervention on the risk of malnutrition and depression in elderly subjects. METHODS: Analytical, experimental, randomized longitudinal study in 38 autonomous, non-institutionalized elderly subjects. Nutritional and depression risk were measured using the Mini Nutritional Assessment (MNA) and the Yesavage Geriatric Depression Scale (GDS-SF), respectively. The impact of the intervention was measured with nutrition and food security questionnaires. Statistics were performed with Spearman's correlation coefficient, and comparisons between means with the Student's t-test. A p-value < 0.05 was considered significant. RESULTS: 63.2 % of the sample had a good nutritional status, 28,9 % were at risk of malnutrition, and 7.9 % had malnutrition. Of the total of participants, 28.9 % had depression. A statistically significant, moderate and negative linear relationship was found between depression and nutritional risk (rho = -0.489; p < 0.01). The nutritional educational intervention produced a significant increase in knowledge of food security (2.95 ± 2.53 compared to 0.37 ± 1.46; p < 0.0005). CONCLUSIONS: the risks of malnutrition and depression are significantly associated in older adults. Furthermore, the nutritional educational intervention improved knowledge of food safety, but did not improve nutritional status or in the degree of depression

Contribution of fine particulate matter to present and future premature mortality over Europe: A non-linear response.

The World Health Organization estimates that around 7 million people die every year from exposure to fine particles (PM2.5) inpolluted air. Here, the number of premature deaths in Europe from different diseases associated to the ambient exposure to PM2.5 have here been studied both for present (1991-2010) and future periods (2031-2050, RCP8.5 scenario). This contribution combines different state-of-the-art approaches (use of high-resolution climate/chemistry simulations over Europe for providing air quality data; use of different baseline mortality data for specific European regions; inclusion of future population projections and dynamical changes for 2050 obtained from the United Nations (UN) Population Projections or use of non-linear exposure-response functions) to estimate the premature mortality due to PM2.5. The mortality endpoints included in this study are Lung Cancer (LC), Chronic Obstructive Pulmonary Disease (COPD), Cerebrovascular Disease (CEV), Ischemic Heart Disease (IHD), Lower Respiratory Infection (LRI) and other Non-Communicable Diseases (other NCDs). Different risk ratio and baseline mortalities for each disease end each age range have been estimated individually. The results indicate that the annual excess mortality rate from fine particulate matter in Europe is 904,000 [95% confidence interval (95% CI) 733,100-1,067,800], increasing by 73% in 2050s (1,560,000; 95% CI 1,260,000-1,840,000); meanwhile population decreases from 808 to 806 million according to the UN estimations. The results show that IHD is the main cause of premature mortality in Europe associated to PM2.5 (around 48%) both for the present and future periods. Despite several marked regional differences, premature deaths associated to all the endpoints included in this study will increase in the future period due to the climate penalty but especially because of changes in the population projected and its aging.

[Impact on the risk of malnutrition and depression of a clinical trial with nutritional educational intervention in non-institutionalized elderly subjects receiving a telecare service in Terrassa (Spain)]. / Impacto sobre el riesgo de malnutrición y depresión en un ensayo clínico con intervención educativa nutricional en adultos mayores no institucionalizados, receptores de un servicio de teleasistencia en la ciudad de Tarrasa (España).

INTRODUCTION: Introduction: the elderly are a growing and vulnerable population. Depression and malnutrition are frequent, and there seems to be associated. Objectives: to assess the impact of a nutritional educational intervention on the risk of malnutrition and depression in elderly subjects. Methods: Analytical, experimental, randomized longitudinal study in 38 autonomous, non-institutionalized elderly subjects. Nutritional and depression risk were measured using the Mini Nutritional Assessment (MNA) and the Yesavage Geriatric Depression Scale (GDS-SF), respectively. The impact of the intervention was measured with nutrition and food security questionnaires. Statistics were performed with Spearman's correlation coefficient, and comparisons between means with the Student's t-test. A p-value  0.05 was considered significant. Results: 63.2 % of the sample had a good nutritional status, 28,9 % were at risk of malnutrition, and 7.9 % had malnutrition. Of the total of participants, 28.9 % had depression. A statistically significant, moderate and negative linear relationship was found between depression and nutritional risk (rho = -0.489; p  0.01). The nutritional educational intervention produced a significant increase in knowledge of food security (2.95 ± 2.53 compared to 0.37 ± 1.46; p  0.0005). Conclusions: the risks of malnutrition and depression are significantly associated in older adults. Furthermore, the nutritional educational intervention improved knowledge of food safety, but did not improve nutritional status or in the degree of depression.

INTRODUCCIÓN: Introducción: los adultos mayores son una población creciente y vulnerable. La existencia de depresión y malnutrición es frecuente y parecen estar asociados. Objetivos: evaluar el impacto de una intervención educativa nutricional sobre el riesgo de malnutrición y depresión en adultos mayores. Métodos: estudio analítico, experimental y longitudinal aleatorizado en 38 adultos mayores, autónomos y no institucionalizados. El riesgo nutricional y el grado de depresión se midieron mediante la Evaluación Mínima Nutricional (MNA) y la Escala de Depresión Geriátrica de Yesavage (GDS-SF), respectivamente. El grupo de intervención recibió formación mediante educación nutricional con refuerzo telefónico. El impacto de la intervención se midió con cuestionarios de conocimientos de nutrición y seguridad alimentaria. Se realizó una estadística descriptiva, se calculó el coeficiente de correlación de Spearman y la comparación entre medias se efectuó con la prueba t de Student. Se consideró una p  0,05 como significativa. Resultados: el 63,2 % de la muestra presentaban un estado nutricional normal, el 28,9 % riesgo de malnutrición y el 7,9 % malnutrición. Del total de sujetos, el 28,9 % presentaban depresión. Se encontró una relación lineal estadísticamente significativa, moderada y negativa entre el grado de depresión y el riesgo nutricional (rho = -0,489; p  0,01). La intervención educativa nutricional produjo un incremento significativo de los conocimientos de seguridad alimentaria (2,95 ± 2,53 frente a 0,37 ± 1,46; p  0,0005). Conclusiones: el riesgo de malnutrición y el de depresión se asocian significativamente en los adultos mayores. Además, la intervención educativa nutricional mejoró los conocimientos de seguridad alimentaria, aunque no produjo una mejora del estado nutricional ni del grado de depresión.

The α-Gal Syndrome and Potential Mechanisms.

The α-Gal syndrome is a complex allergic disease characterized by the development of specific IgE antibodies against the carbohydrate galactose-α-1,3-galactose (α-Gal), an oligosaccharide present in cells and tissues of non-primate mammals. Individuals with IgE antibodies to α-Gal suffer from a delayed form of anaphylaxis following red meat consumption. There are several features that make the α-Gal syndrome such a unique allergic disease and distinguish it from other food allergies: (1) symptoms causing IgE antibodies are directed against a carbohydrate moiety, (2) the unusual delay between the consumption of the food and the onset of the symptoms, and (3) the fact that primary sensitization to α-Gal occurs via tick bites. This review takes a closer look at the immune response against α-Gal, in healthy and in α-Gal allergic individuals. Furthermore, the similarities and differences between immune response against α-Gal and against the other important glycan moieties associated with allergies, namely cross-reactive carbohydrate determinants (CCDs), are discussed. Then different mechanisms are discussed that could contribute to the delayed onset of symptoms after consumption of mammalian meat. Moreover, our current knowledge on the role of tick bites in the sensitization process is summarized. The tick saliva has been shown to contain proteins carrying α-Gal, but also bioactive molecules, such as prostaglandin E2, which is capable of stimulating an increased expression of anti-inflammatory cytokines while promoting a decrease in the production of proinflammatory mediators. Together these components might promote Th2-related immunity and trigger a class switch to IgE antibodies directed against the oligosaccharide α-Gal. The review also points to open research questions that remain to be answered and proposes future research directions, which will help to get a better understanding and lead to a better management of the disease.

Population exposure to particulate-matter and related mortality due to the Portuguese wildfires in October 2017 driven by storm Ophelia.

In October 2017, hundreds of wildfires ravaged the forests of the north and centre of Portugal. The fires were fanned by strong winds as tropical storm Ophelia swept the Iberian coast, dragging up smoke (together with Saharan dust from north-western Africa) into higher western European latitudes. Here we analyse the long-range transport of particulate matter (PM10) and study associations between PM10 and short-term mortality in the Portuguese population exposed to PM10 due to the October 2017 wildfires, the worst fire sequence in the country over the last decades. We analysed space- and ground-level observations to track the smoke plume and dust trajectory over Portugal and Europe, and to access PM10 concentrations during the wildfires. The effects of PM10 on mortality were evaluated using satellite data for exposure and Poisson regression models. The smoke plume covered most western European countries (including Spain, France, Belgium and the Netherlands), and reached the United Kingdom, where the population was exposed in average to an additional PM10 level of 11.7 µg/m3 during seven smoky days (three with dust) in relation to the reference days (days without smoke or dust), revealing the impact of the wildfires on distant populations. In Portugal, the population was exposed in average to additional PM10 levels that varied from 16.2 to 120.6 µg/m3 in smoky days with dust and from 6.1 to 20.9 µg/m3 in dust-free smoky days. Results suggest that PM10 had a significant effect on the same day natural and cardiorespiratory mortalities during the month of October 2017. For every additional 10 µg/m3 of PM10, there was a 0.89% (95% confidence interval, CI, 0-1.77%) increase in the number of natural deaths and a 2.34% (95% CI, 0.99-3.66%) increase in the number of cardiorespiratory-related deaths. With rising temperatures and a higher frequency of storms due to climate change, PM from Iberian wildfires together with NW African dust will tend to be more often transported into Northern European countries, which may carry health threats to areas far from the ignition sites.

Effect of Adding Curcumin on the Properties of Linseed Oil Organogels Used as Fat Replacers in Pâtés.

Beeswax-based organogels were formulated with linseed oil and curcumin according to a statistical design to increase the oxidative stability of spreadable meat products (pâté) where these organogels (OGCur) were incorporated as fat substitutes. The organogels obtained under optimal conditions (9.12% beeswax, 0.54% curcumin) showed a mechanical strength similar to pork backfat determined by back extrusion and high oil binding capacity (OBC; over 90%). The incorporation of curcumin at this concentration did not lead to any change in the arrangement of the crystal network, OBC, and mechanical, thermal, or rheological properties of the organogels. Beeswax organogels with and without curcumin, with a ß' orthorhombic subcell structure, showed a predominant elastic behavior and a melting event wider and shifted to lower temperatures than pure beeswax, suggesting a plasticizer effect of the oil in the wax crystals. The oxidative stability of the organogels under accelerated oxidation conditions increased due to the incorporation of curcumin. A decrease in the curcumin content was found from day 4 at 60 °C, together with a significantly lower formation of both peroxides and malonaldehyde. When pork backfat was partially or totally replaced by OGCur in pâtés, a noticeable protective effect of curcumin against lipid oxidation was found during chilled storage.

Infection with Toxocara canis Inhibits the Production of IgE Antibodies to α-Gal in Humans: Towards a Conceptual Framework of the Hygiene Hypothesis?

α-Gal syndrome (AGS) is a type of anaphylactic reaction to mammalian meat characterized by an immunoglobulin (Ig)E immune response to the oligosaccharide α-Gal (Galα1-3Galß1-4GlcNAc-R). Tick bites seems to be a prerequisite for the onset of the allergic disease in humans, but the implication of non-tick parasites in α-Gal sensitization has also been deliberated. In the present study, we therefore evaluated the capacity of helminths (Toxocara canis, Ascaris suum, Schistosoma mansoni), protozoa (Toxoplasma gondii), and parasitic fungi (Aspergillus fumigatus) to induce an immune response to α-Gal. For this, different developmental stages of the infectious agents were tested for the presence of α-Gal. Next, the potential correlation between immune responses to α-Gal and the parasite infections was investigated by testing sera collected from patients with AGS and those infected with the parasites. Our results showed that S. mansoni and A. fumigatus produce the terminal α-Gal moieties, but they were not able to induce the production of specific antibodies. By contrast, T. canis, A. suum and T. gondii lack the α-Gal epitope. Furthermore, the patients with T. canis infection had significantly decreased anti-α-Gal IgE levels when compared to the healthy controls, suggesting the potential role of this nematode parasite in suppressing the allergic response to the glycan molecule. This rather intriguing observation is discussed in the context of the 'hygiene hypothesis'. Taken together, our study provides new insights into the relationships between immune responses to α-Gal and parasitic infections. However, further investigations should be undertaken to identify T. canis components with potent immunomodulatory properties and to assess their potential to be used in immunotherapy and control of AGS.

Gal d 7-a major allergen in primary chicken meat allergy.

BACKGROUND: Poultry meat can induce severe allergic reactions. So far, the molecules causing poultry meat allergy are largely unknown. OBJECTIVE: Our aim was to identify and characterize poultry meat allergens. METHODS: Profiles of patients' IgE reactivity to chicken muscle were analyzed in immunoblots, and proteins recognized by the majority of patients were subjected to peptide mass fingerprinting. A 23-kDa IgE-reactive protein was identified as myosin light chain 1, designated Gallus domesticus 7 (Gal d 7). Recombinant Gal d 7 was produced in Escherichia coli. The protein's IgE reactivity was analyzed in ELISA experiments, and cross-reactivity with allergens of other poultry species was assessed in inhibition immunoblots. Fold and thermal stability were evaluated by circular dichroism analysis, and enzymatic stability was investigated using in vitro gastrointestinal digestion assays. RESULTS: Recombinant Gal d 7 represents a properly folded, predominantly α-helical protein and displays IgE-binding activity comparable to that of its natural counterpart. IgE reactivity analysis in 28 patients allergic to chicken meat revealed that Gal d 7 is a major allergen for patients primarily sensitized to chicken meat. Furthermore, Gal d 7-cross-reactive allergens were also detected in other poultry species, suggesting that recombinant Gal d 7 can be used as a diagnostic marker allergen for poultry meat allergy. The high thermal stability, refolding capacity, and resistance to gastrointestinal enzymes might explain why Gal d 7 can act as a potent sensitizing agent. CONCLUSION: Gal d 7 represents a novel major chicken meat allergen. Recombinant Gal d 7 could be used for diagnosis of genuine poultry meat sensitization.

Climate drivers of the 2017 devastating fires in Portugal.

A record 500,000 hectares burned in Portugal during the extreme wildfire season of 2017, with more than 120 human lives lost. Here we analyse the climatic factors responsible for the burned area (BA) from June to October series in Portugal for the period 1980-2017. Superposed onto a substantially stationary trend on BA data, strong oscillations on shorter time scales were detected. Here we show that they are significantly affected by the compound effect of summer (June-July-August) drought and high temperature conditions during the fire season. Drought conditions were calculated using the Standardized Precipitation Evapotranspiration Index (SPEI), the Standardized Precipitation Index (SPI) and the Standardized Soil Moisture Index (SSI). Then the extent to which the burned area has diverged from climate-expected trends was assessed. Our results indicate that in the absence of other drivers, climate change would have led to higher BA values. In addition, the 2017 extreme fire season is well captured with the model forced with climate drivers only, suggesting that the extreme fire season of 2017 could be a prelude to future conditions and likewise events. Indeed, the expected further increase of drought and high temperature conditions in forthcoming decades, point at a potential increase of fire risk in this region. The climate-fire model developed in this study could be useful to develop more skilled seasonal predictions capable of anticipating potentially hazardous conditions.

Environmental and Molecular Drivers of the α-Gal Syndrome.

The α-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody (Ab) response against the carbohydrate Galα1-3Galß1-4GlcNAc-R (α-Gal), which is present in glycoproteins from tick saliva and tissues of non-catarrhine mammals. Recurrent tick bites induce high levels of anti-α-Gal IgE Abs that mediate delayed hypersensitivity to consumed red meat products in humans. This was the first evidence that tick glycoproteins play a major role in allergy development with the potential to cause fatal delayed anaphylaxis to α-Gal-containing foods and drugs and immediate anaphylaxis to tick bites. Initially, it was thought that the origin of tick-derived α-Gal was either residual blood meal mammalian glycoproteins containing α-Gal or tick gut bacteria producing this glycan. However, recently tick galactosyltransferases were shown to be involved in α-Gal synthesis with a role in tick and tick-borne pathogen life cycles. The tick-borne pathogen Anaplasma phagocytophilum increases the level of tick α-Gal, which potentially increases the risk of developing AGS after a bite by a pathogen-infected tick. Two mechanisms might explain the production of anti-α-Gal IgE Abs after tick bites. The first mechanism proposes that the α-Gal antigen on tick salivary proteins is presented to antigen-presenting cells and B-lymphocytes in the context of Th2 cell-mediated immunity induced by tick saliva. The second mechanism is based on the possibility that tick salivary prostaglandin E2 triggers Immunoglobulin class switching to anti-α-Gal IgE-producing B cells from preexisting mature B cells clones producing anti-α-Gal IgM and/or IgG. Importantly, blood group antigens influence the capacity of the immune system to produce anti-α-Gal Abs which in turn impacts individual susceptibility to AGS. The presence of blood type B reduces the capacity of the immune system to produce anti-α-Gal Abs, presumably due to tolerance to α-Gal, which is very similar in structure to blood group B antigen. Therefore, individuals with blood group B and reduced levels of anti-α-Gal Abs have lower risk to develop AGS. Specific immunity to tick α-Gal is linked to host immunity to tick bites. Basophil activation and release of histamine have been implicated in IgE-mediated acquired protective immunity to tick infestations and chronic itch. Basophil reactivity was also found to be higher in patients with AGS when compared to asymptomatic α-Gal sensitized individuals. In addition, host resistance to tick infestation is associated with resistance to tick-borne pathogen infection. Anti-α-Gal IgM and IgG Abs protect humans against vector-borne pathogens and blood group B individuals seem to be more susceptible to vector-borne diseases. The link between blood groups and anti-α-Gal immunity which in turn affects resistance to vector-borne pathogens and susceptibility to AGS, suggests a trade-off between susceptibility to AGS and protection to some infectious diseases. The understanding of the environmental and molecular drivers of the immune mechanisms involved in AGS is essential to developing tools for the diagnosis, control, and prevention of this growing health problem.

Antitumor Effects of Anti-Semaphorin 4D Antibody Unravel a Novel Proinvasive Mechanism of Vascular-Targeting Agents.

One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular-targeting agent targeting semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases was comparable with the one produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving platelet-derived growth factor B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement, which induced their recruitment to the tumor invasive fronts and secretion of stromal cell-derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial antitumor and prosurvival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D-positive macrophages to invasive fronts and their secretion of proinvasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs. SIGNIFICANCE: An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5328/F1.large.jpg.See related commentary by Tamagnone and Franzolin, p. 5146.

Only α-Gal bound to lipids, but not to proteins, is transported across enterocytes as an IgE-reactive molecule that can induce effector cell activation.

BACKGROUND: The oligosaccharide galactose-α-1,3-galactose (α-Gal), present in mammalian proteins and lipids, causes an unusual delayed allergic reaction 3 to 6 hours after ingestion of mammalian meat in individuals with IgE antibodies against α-Gal. To better understand the delayed onset of allergic symptoms and investigate whether protein-bound or lipid-bound α-Gal causes these symptoms, we analyzed the capacity of α-Gal conjugated proteins and lipids to cross a monolayer of intestinal cells. METHODS: Extracts of proteins and lipids from beef were prepared, subjected to in vitro digestions, and added to Caco-2 cells grown on permeable supports. The presence of α-Gal in the basolateral medium was investigated by immunoblotting, thin-layer chromatography with immunostaining and ELISA, and its allergenic activity was analyzed in a basophil activation test. RESULTS: After addition of beef proteins to the apical side of Caco-2 cells, α-Gal containing peptides were not detected in the basolateral medium. Those peptides that crossed the Caco-2 monolayer did not activate basophils from an α-Gal allergic patient. Instead, when Caco-2 cells were incubated with lipids extracted from beef, α-Gal was detected in the basolateral medium. Furthermore, these α-Gal lipids were able to activate the basophils of an α-Gal allergic patient in a dose-dependent manner. CONCLUSION: Only α-Gal bound to lipids, but not to proteins, is able to cross the intestinal monolayer and trigger an allergic reaction. This suggests that the slower digestion and absorption of lipids might be responsible for the unusual delayed allergic reactions in α-Gal allergic patients and identifies glycolipids as potential allergenic molecules.