The cGAS-STING signaling pathway is modulated by urolithin A.

During aging, general cellular processes, including autophagic clearance and immunological responses become compromised; therefore, identifying compounds that target these cellular processes is an important approach to improve our health span. The innate immune cGAS-STING pathway has emerged as an important signaling system in the organismal defense against viral and bacterial infections, inflammatory responses to cellular damage, regulation of autophagy, and tumor immunosurveillance. These key functions of the cGAS-STING pathway make it an attractive target for pharmacological intervention in disease treatments and in controlling inflammation and immunity. Here, we show that urolithin A (UA), an ellagic acid metabolite, exerts a profound effect on the expression of STING and enhances cGAS-STING activation and cytosolic DNA clearance in human cell lines. Animal laboratory models and limited human trials have reported no obvious adverse effects of UA administration. Thus, the use of UA alone or in combination with other pharmacological compounds may present a potential therapeutic approach in the treatment of human diseases that involves aberrant activation of the cGAS-STING pathway or accumulation of cytosolic DNA and this warrants further investigation in relevant transgenic animal models.

The KMT2A recombinome of acute leukemias in 2023.

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Factors related to self-rated health: a survey among patients and their general practitioners.

OBJECTIVE: To explore associations between general practice patients' SRH and symptoms, diagnoses, chronic conditions, unexplained conditions, and life stressors. DESIGN: A cross-sectional study. Data were collected from GP and patient questionnaires. SETTING: General practices in Southeast Norway. SUBJECTS: 47 general practitioners (GPs) who included 866 consecutive patients. MAIN OUTCOME MEASURES: SRH was measured with a single question from the COOP-WONCA overall health chart and dichotomized into good/poor SRH. Binary logistic regression models were used in the analyses. RESULTS: Poor SRH was reported by 48% of the patients in the past week. A higher prevalence of poor SRH was found for women, middle-aged, recipients of social security grants, patients diagnosed with asthenia, lower back pain, and depression/anxiety, and for patients with reported life stressors and unexplained conditions. We found an almost linear association between the number of symptoms and the likelihood of reporting poor SRH. The probability of reporting poor SRH increased along with an increasing number of symptoms for common diagnoses. In a multivariate analysis, the only number of symptoms, being in receipt of social security grants and being retired was associated with poor SRH. CONCLUSION: The likelihood of reporting poor SRH increased with an increasing number of symptoms, partly independent of the diagnosis given by GPs. This result coincides with our previous findings of a strong association between the number of symptoms, function, and health. The symptom burden thus appears to be an important factor for SRH among patients in general practice.KEY POINTSThere is a high prevalence of poor SRH in general practice patients.The likelihood of reporting poor SRH is partly independent of the diagnosis given.The number of symptoms was the factor strongest associated with poor SRH.

Prioritize effluent quality, operational costs or global warming? - Using predictive control of wastewater aeration for flexible management of objectives in WRRFs.

This study presents a general model predictive control (MPC) algorithm for optimizing wastewater aeration in Water Resource Recovery Facilities (WRRF) under different management objectives. The flexibility of the MPC is demonstrated by controlling a WRRF under four management objectives, aiming at minimizing: (A) effluent concentrations, (B) electricity consumption, (C) total operations costs (sum electricity costs and discharge effluent tax) or (D) global warming potential (direct and indirect nitrous oxide emissions, and indirect from electricity production) . The MPC is tested with data from the alternating WRRF in Nørre Snede (Denmark) and from the Danish electricity grid. Results showed how the four control objectives resulted in important differences in aeration patterns and in the concentration dynamics over a day. Controls B and C showed similarities when looking at total costs, while similarities in global warming potential for controls A and D suggest that improving effluent quality also reduced greenhouse gasses emissions. The MPC flexibility in handling different objectives is shown by using a combined objective function, optimizing both cost and greenhouse emissions. This shows the trade-off between the two objectives, enabling the calculation of marginal costs and thus allowing WRRF operators to carefully evaluate prioritization of management objectives. The long-term MPC performance is evaluated over 51 days covering seasonal and inter-weekly variations. On a daily basis, control A was 9-30% cheaper on average compared to controls A, D and to the current rule-based control. Similarly, control D resulted on average in 35-43% lower greenhouse gasses daily emission compared to the other controls. Difference between control performance increased for days with greater inter-diurnal variations in electricity price or greenhouse emissions from electricity production, i.e. when MPC has greater possibilities for exploiting input variations. The flexibility of the proposed MPC can easily accommodate for additional control objectives, allowing WRRF operators to quickly adapt the plant operation to new management objectives and to face new performance requirements.

Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.

PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p < 0.0001), 29 (HzR 2.7, p < 0.0001), and 79 (HzR 3.5, p < 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10-2 versus 5.2 × 10-3, p < 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD > 10-4 associated with a CIR5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.

Integrated model predictive control of water resource recovery facilities and sewer systems in a smart grid: example of full-scale implementation in Kolding.

An integrated model predictive control (MPC) strategy to control the power consumption and the effluent quality of a water resource recovery facility (WRRF) by utilizing the storage capacity from the sewer system was implemented and put into operation for a 7-day trial period. This price-based MPC reacted to electricity prices and forecasted pollutant loads 24 hours ahead. The large storage capacity available in the sewer system directly upstream from the plant was used to control the incoming loads and, indirectly, the power consumption of the WRRF during dry weather operations. The MPC balances electricity costs and treatment quality based on linear dynamical models and predictions of storage capacity and effluent concentrations. This article first shows the modelling results involved in the design of this MPC. Secondly, results from full-scale MPC operation of the WRRF are shown. The monetary savings of the MPC strategy for the specific plant were quantified around approximately 200 DKK per day when fully exploiting the allowed storage capacity. The developed MPC strategy provides a new option for linking WRRFs to smart grid electricity systems.

Correction: Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.

Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

The MLL recombinome of acute leukemias in 2017.

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

Quantification and phenotypic characterisation of peripheral IFN-γ producing leucocytes in chickens vaccinated against Newcastle disease.

The aim of this study was to optimise and evaluate an intracellular cytokine staining (ICS) assay for assessment of T cell IFN-γ responses in chickens vaccinated against Newcastle disease (ND). We aimed to validate currently available antibodies to chicken IFN-γ using transfected CHO cells. Moreover, this ICS assay was evaluated for use to detect mitogen and antigen induced IFN-γ production in chicken peripheral blood leucocytes. Chickens from an inbred white leghorn line containing two MHC haplotypes, B19 and B21, were divided into three experimental groups; one group was kept as naive controls, one group was vaccinated intramuscularly twice with a commercial inactivated ND virus (NDV) vaccine, and the last group was vaccinated orally twice with a commercial live attenuated NDV vaccine. PBMC were ex vivo stimulated with ConA or with NDV antigen. The ICS assay was used to determine the phenotype and frequency of IFN-γ positive cells. ConA stimulation induced extensive IFN-γ production in both CD3+TCRγδ+ (γδ T cells) cells and CD3+TCRγδ- cells (αß T cells), but no significant differences were observed between the experimental groups. Furthermore, a large proportion of the IFN-γ producing cells were CD3- indicating that other cells than classic T cells, secreted this cytokine. NDV antigen stimulation induced IFN-γ production but to a lower extent than ConA and with a large variation between individuals. The CD3+TCR1γδ-CD8α+ (CTL) population produced the highest NDV specific IFN-γ responses, with significantly elevated levels of IFN-γ producing cells in the B19 chickens vaccinated orally with live attenuated NDV vaccine. This was not the case in the B21 animals, indicating a haplotype restricted variation. In contrast, the CD3+TCR1γδ-CD4+ (Th) population did not show a significant increase in IFN-γ production in NDV stimulated samples which was in part due to a high number of IFN-γ producing cells after incubation with medium alone. In conclusion, an ICS assay for phenotyping of IFN-γ producing chicken leukocytes was set up that proved useful in identifying cytokine producing cells upon either mitogen or antigen-specific stimulation.

Comparison of growth performance and immune parameters of three commercial chicken lines used in organic production.

Owing to the higher demands for avoiding medication and antibiotics, health status of the production animals plays an important role in the poultry industry, especially in organic poultry systems. Immunity plays a major role in keeping the host free from disease, and it is evident that the host's genetic make-up influences immunity and disease resistance/susceptibility in chickens. Previously, breeding strategies aimed at selection for resistance against specific diseases with the risk of creating less disease resistance against other pathogens. Changing breeding strategies towards selection of chickens with a more general and broad disease resistance or robustness may therefore improve the overall health status, animal welfare, and food security in the poultry production. The aim of this study was therefore to compare the immunocompetence of the presumed "robust" Hellevad chickens with two chicken lines widely used in organic production, Bovans Brown (Bovans) and Hisex White (Hisex). The chickens were subjected to a routine vaccination program comprising one parasite and four viral vaccines. The current study indicates that considerable differences in immunocompetence may exist between commercial layer lines used in organic production. The Hellevad chickens were found to have higher body weight at the end of the experiment (17 weeks of age) than the other two lines. Furthermore, Hellevad and Hisex chickens were found to have higher levels of humoral innate immunity with regard to sample to positive ratio of natural antibodies in serum and concentration of mannose-binding lectin in serum as compared to Bovans. Moreover, indications of an inflammatory response were observed in the Bovans at week 5, corresponding to 1 week after vaccination with live infectious bursal disease virus. With regard to adaptive immune parameters such as IgY concentration in blood and infectious bursal disease virus (IBDV)-specific antibody titres, the Hellevad and Hisex chickens had lower levels than the Bovans. How the differences observed in growth and immune parameters in the three chicken lines influence the immune protection against infection needs to be studied further.

Regional frequency analysis of short duration rainfall extremes using gridded daily rainfall data as co-variate.

A regional partial duration series (PDS) model is applied for estimation of intensity duration frequency relationships of extreme rainfalls in Denmark. The model uses generalised least squares regression to relate the PDS parameters to gridded rainfall statistics from a dense network of rain gauges with daily measurements. The Poisson rate is positively correlated to the mean annual precipitation for all durations considered (1 min to 48 hours). The mean intensity can be assumed constant over Denmark for durations up to 1 hour. For durations larger than 1 hour, the mean intensity is significantly correlated to the mean extreme daily precipitation. A Generalised Pareto distribution with a regional constant shape parameter is adopted. Compared to previous regional studies in Denmark, a general increase in extreme rainfall intensity for durations up to 1 hour is found, whereas for larger durations both increases and decreases are seen. A subsample analysis is conducted to evaluate the impacts of non-stationarities in the rainfall data. The regional model includes the non-stationarities as an additional source of uncertainty, together with sampling uncertainty and uncertainty caused by spatial variability.

Biology and Control of Snail Intermediate Host of Schistosoma japonicum in The People's Republic of China.

Schistosomiasis caused by Schistosoma japonicum is a severe parasitic disease in The People's Republic of China and imposed considerable burden on human and domestic animal health and socioeconomic development. The significant achievement in schistosomiasis control has been made in last 60years. Oncomelania hupensis as the only intermediate host of S. japonicum plays a key role in disease transmission. The habitat complexity of the snails challenges to effective control. In this review we share the experiences in control and research of O. hupensis.

Two-year intervention trial to control of fish-borne zoonotic trematodes in giant gourami (Osphronemus goramy) and striped catfish (Pangasianodon hypophthalmus) in nursery ponds in the Mekong Delta, Vietnam.

Fish-borne zoonotic trematode parasites (FZT) pose a food safety and public health problem in Vietnam. The transmission cycle is complex as domestic animals, especially dogs, cats, fish-eating birds and pigs together with humans serve as reservoir hosts and contribute to FZT egg contamination of aquaculture ponds and the environment. This intervention trial was conducted to determine the effectiveness of various on-farm interventions, including reduction in FZT egg contamination through treatment of infected people and domestic animals, reduction in snail density through mud removal from aquaculture ponds prior to fish stocking, and various other measures in reducing FZT infection in juvenile striped catfish (Pangasianodon hypophthalmus) and giant gourami (Osphronemus goramy). Interventions were implemented on 5 farms for each fish species during production cycles in 2009 and 2010 while 5 similar farms for each species served as control. For both fish species, both prevalence and intensity of infection did not differ significantly between intervention and non-intervention farms prior to the interventions. The interventions significantly reduced both prevalence and intensity of FZT infection in the juvenile fish compared to control ponds. For giant gourami, odds of infection in intervention ponds was 0.13 (95% CL: 0.09-0.20; p<0.001) of that in non-intervention ponds after the 2009 trial and 0.07 (0.03-0.14; p<0.001) after the 2010 trial. For striped catfish, these figures were 0.17 (0.08-0.35; p<0.001) after the 2009 trial while after the 2010 trial all ponds with interventions were free from infection. Metacercariae intensity (no. of metacercariae/fish) in giant gourami from intervention ponds was 0.16 (0.11-0.23; p<0.001) of that in fish from non-intervention ponds after the 2009 trial and 0.07 (0.04-0.15; p<0.001) after the 2010 trial; for striped catfish these figures were 0.18 (0.09-0.36; p<0.001) and 0.00 (confidence limits not estimated), respectively. The aquaculture farm pond intervention approaches taken in this trial have the potential to reduce or eliminate FZT infections in fish and may be implemented across the entire region if adjusted to local conditions and fish species.

Effect of pond water depth on snail populations and fish-borne zoonotic trematode transmission in juvenile giant gourami (Osphronemus goramy) aquaculture nurseries.

Infection with fish-borne zoonotic trematodes (FZT) is an important public health problem in many parts of Southeast Asia. People become infected with FZT when eating raw or undercooked fish that contain the infective stage (metacercariae) of FZT. The parasites require specific freshwater snails as first intermediate host and a variety of fish species, both wild caught and cultured, as second intermediate host. Aquaculture production has grown almost exponentially in SE Asia and in order to produce fish free from FZT metacercariae, it is important to mitigate factors promoting transmission to fish. Here we report results from a cross-sectional study to look at the association between pond depth and infection with FZT in giant gourami nursery ponds. Density of intermediate host snails was positively associated with pond depth (count ratio associated with a 1m increase in pond depth was 10.4 (95% C.L.: 1.61-67.1, p<0.5)) and this may partly explain the higher prevalence and intensity of FZT infection in juvenile fish. High fry stocking density (>200 fry m(-3)) was associated with lower host snail density (count ratio=0.15) than low stocking density (<100 fry m(3)). Ponds stocked with 100-200 fry m(-3) had snail counts 0.76 (95% C.L.: 0.33-1.75, p n.s.) of those in ponds stocked with fry density of <100 fry m(-3). Since density of intermediate snail hosts was associated with FZT transmission to fish, effort should be taken to reduce snail density prior to stocking the fry, but focus should also be on habitats surrounding ponds as transmission may occur through cercariae produced outside ponds and carried into ponds with water pumped into ponds.

Wild boars from Sweden, Austria, the Czech Republic and Japan possess intact mannose-binding lectin 2 (MBL2) genes.

The two-nucleotide deletion recently detected in the mannose-binding lectin 2 gene in purebred and crossbred domestic pigs was not found among 68 wild boars representing 4 populations from Europe and Asia. This suggests that the deletion is a result of breeding and/or genetic drift/bottle necks.

Identifying climate analogues for precipitation extremes for Denmark based on RCM simulations from the ENSEMBLES database.

Climate analogues, also denoted Space-For-Time, may be used to identify regions where the present climatic conditions resemble conditions of a past or future state of another location or region based on robust climate variable statistics in combination with projections of how these statistics change over time. The study focuses on assessing climate analogues for Denmark based on current climate data set (E-OBS) observations as well as the ENSEMBLES database of future climates with the aim of projecting future precipitation extremes. The local present precipitation extremes are assessed by means of intensity-duration-frequency curves for urban drainage design for the relevant locations being France, the Netherlands, Belgium, Germany, the United Kingdom, and Denmark. Based on this approach projected increases of extreme precipitation by 2100 of 9 and 21% are expected for 2 and 10 year return periods, respectively. The results should be interpreted with caution as the best region to represent future conditions for Denmark is the coastal areas of Northern France, for which only little information is available with respect to present precipitation extremes.

Interactions between smoking, increased serum levels of anti-CCP antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis.

OBJECTIVES: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset. METHOD: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity. RESULTS: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes. CONCLUSIONS: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.