Regulation of Gene Expression in Protozoa Parasites

Infections with protozoa parasites are associated with high burdens of morbidity and mortality across the developing world. Despite extensive efforts to control the transmission of these parasites, the spread of populations resistant to drugs and the lack of effective vaccines against them contribute to their persistence as major public health problems. Parasites should perform a strict control on the expression of genes involved in their pathogenicity, differentiation, immune evasion, or drug resistance, and the comprehension of the mechanisms implicated in that control could help to develop novel therapeutic strategies. However, until now these mechanisms are poorly understood in protozoa. Recent investigations into gene expression in protozoa parasites suggest that they possess many of the canonical machineries employed by higher eukaryotes for the control of gene expression at transcriptional, posttranscriptional, and epigenetic levels, but they also contain exclusive mechanisms. Here, we review the current understanding about the regulation of gene expression in Plasmodium sp., Trypanosomatids, Entamoeba histolytica and Trichomonas vaginalis

POS1247 CLINICAL FEATURES AND OUTCOMES OF COVID-19 IN PATIENTS WITH IGG4-RELATED DISEASE. A COLLABORATIVE EUROPEAN MULTI-CENTRE STUDY

Background:Coronavirus disease 2019 (COVID-19) is a pandemic-spread systemic infectious disease with prominent respiratory manifestations and significant associated morbidity and mortality. Elderly people are most significantly affected with mortality ranging from 2.4% (age 60-69) to 19.6% (age>80) in European Countries. The prevalence of COVID-19 and of its complications in patients with immune-mediated disorders, remains unclear. The frequency and impact of COVID-19 on patients with IgG4-related diease (IgG4-RD), many of whom are on concurrent immunosuppression has not been addressed.Objectives:To assess the epidemiological and clinical relevance of COVID-19 in patients with IgG4-RD.Methods:This is a multi-centre retrospective observational study of IgG4-RD patients from France, Italy, Spain and the United Kingdom. Demographics, comorbidities, IgG4-RD features, current and past treatment along with COVID-19-suggestive symptoms and COVID-19 diagnoses from February 2020 to January 2021 were recorded by means of direct or phone interviews. Patients with reverse-transcriptase polymerase chain reaction-confirmed (cCOVID) or presumed COVID-19 based on clinical, serological or imaging features (pCOVID) were pooled for analysis (totCOVID) and compared to patients who were not diagnosed with COVID-19. Inter-group comparison of categorical and quantitative variables were performed by using the chi-square test with Fisher's correction and the Mann-Whitney's test respectively. Data are expressed as median (interquartile range) unless otherwise specified.Results:A total of 305 patients [71% males, median age 64 (54-74) years] were studied. Pancreato-biliary disease was the most frequently observed IgG4-RD phenotype (39%). Fifty-one percent of patients were taking corticosteroids at time of interview and 30% were on biological or conventional immunosuppressants. Thirty-two totCOVID cases (23 cCOVID, nine pCOVID) were identified: 11/32 were hospitalised, two needed intensive care and four (13%; 3/4 aged >80 years) died. Having one or more infected family members was a risk factor for COVID-19 in patients with IgG4-RD (OR=19.9; p20mg) or rituximab administration.Conclusion:The prevalence and course of COVID-19 in IgG4-RD patients are similar to those of the general population of the same age, with no evident impact of disease- or treatment-related factors to the basal infectious risk. Effective public health countermeasures might be beneficial for patients with IgG4RD.References:[1]European Centre for Disease Prevention and Control (ECDC): https://covid19-surveillance-report.ecdc.europa.eu/[2]Yang H, Ann Rheum Dis, 2021Disclosure of Interests:Giuseppe Alvise Ramirez: None declared, Marco Lanzillotta: None declared, Mikael Ebbo: None declared, Andreu Fernandez-Codina Consultant of: consulting fees from Atheneum Consulting, Gaia Mancuso: None declared, Fernando Martínez-Valle: None declared, Olimpia Orozco-Galvez: None declared, Nicolas Schleinitz: None declared, Lorenzo Dagna Consultant of: Abbvie, Amgen, Biogen, BristolMyers Squibb, Celltrion, Galapagos, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI, Grant/research support from: The Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) received unresctricted research/educational grants from Abbvie, Bristol-Myers Squibb, Celgene, GlaxoSmithKline,Janssen, Merk Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi Genzyme, and SOBI, Emma L. Culver: None declared, Emanuel Della Torre: None declare

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFa. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology

Development of a T cell-based immunodiagnostic system to effectively distinguish SARS-CoV-2 infection and COVID-19 vaccination status

Both SARS-CoV-2 infections and COVID-19 vaccines elicit memory T cell responses. Here, we report the development of 2 pools of experimentally defined SARS-CoV-2 T cell epitopes that, in combination with spike, were used to discriminate 4 groups of subjects with different SARS-CoV-2 infection and COVID-19 vaccine status. The overall T cell-based classification accuracy was 89.2% and 88.5% in the experimental and validation cohorts. This scheme was applicable to different mRNA vaccines and different lengths of time post infection/post vaccination and yielded increased accuracy when compared to serological readouts. T cell responses from breakthrough infections were also studied and effectively segregated from vaccine responses, with a combined performance of 86.6% across all 239 subjects from the 5 groups. We anticipate that a T cell-based immunodiagnostic scheme to classify subjects based on their vaccination and natural infection history will be an important tool for longitudinal monitoring of vaccinations and for establishing SARS-CoV-2 correlates of protection

Shake-table testing of a stone masonry building aggregate: overview of blind prediction study

City centres of Europe are often composed of unreinforced masonry structural aggregates, whose seismic response is challenging to predict. To advance the state of the art on the seismic response of these aggregates, the Adjacent Interacting Masonry Structures (AIMS) subproject from Horizon 2020 project Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe (SERA) provides shake-table test data of a two-unit, double-leaf stone masonry aggregate subjected to two horizontal components of dynamic excitation. A blind prediction was organized with participants from academia and industry to test modelling approaches and assumptions and to learn about the extent of uncertainty in modelling for such masonry aggregates. The participants were provided with the full set of material and geometrical data, construction details and original seismic input and asked to predict prior to the test the expected seismic response in terms of damage mechanisms, base-shear forces, and roof displacements. The modelling approaches used differ significantly in the level of detail and the modelling assumptions. This paper provides an overview of the adopted modelling approaches and their subsequent predictions. It further discusses the range of assumptions made when modelling masonry walls, floors and connections, and aims at discovering how the common solutions regarding modelling masonry in general, and masonry aggregates in particular, affect the results. The results are evaluated both in terms of damage mechanisms, base shear forces, displacements and interface openings in both directions, and then compared with the experimental results. The modelling approaches featuring Discrete Element Method (DEM) led to the best predictions in terms of displacements, while a submission using rigid block limit analysis led to the best prediction in terms of damage mechanisms. Large coefficients of variation of predicted displacements and general underestimation of displacements in comparison with experimental results, except for DEM models, highlight the need for further consensus building on suitable modelling assumptions for such masonry aggregates

Effectiveness of an mHealth intervention combining a smartphone app and smart band on body composition in an overweight and obese population: Randomized controlled trial (EVIDENT 3 study)

Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]