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"Mueller, F"
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Benchmarking atlas-level data integration in single-cell genomics
Single-cell atlases often include samples that span locations, laboratories and conditions, leading to complex, nested batch effects in data. Thus, joint analysis of atlas datasets requires reliable data integration. To guide integration method choice, we benchmarked 68 method and preprocessing combinations on 85 batches of gene expression, chromatin accessibility and simulation data from 23 publications, altogether representing >1.2 million cells distributed in 13 atlas-level integration tasks. We evaluated methods according to scalability, usability and their ability to remove batch effects while retaining biological variation using 14 evaluation metrics. We show that highly variable gene selection improves the performance of data integration methods, whereas scaling pushes methods to prioritize batch removal over conservation of biological variation. Overall, scANVI, Scanorama, scVI and scGen perform well, particularly on complex integration tasks, while single-cell ATAC-sequencing integration performance is strongly affected by choice of feature space. Our freely available Python module and benchmarking pipeline can identify optimal data integration methods for new data, benchmark new methods and improve method development.
This benchmarking study compares 16 methods for integrating complex single-cell RNA and ATAC datasets and provides a guide to method choice.
Journal Article
Social, demographic, and economic correlates of food and chemical consumption measured by wastewater-based epidemiology
Wastewater is a potential treasure trove of chemicals that reflects population behavior and health status. Wastewater-based epidemiology has been employed to determine population-scale consumption of chemicals, particularly illicit drugs, across different communities and over time. However, the sociodemographic or socioeconomic correlates of chemical consumption and exposure are unclear. This study explores the relationships between catchment specific sociodemographic parameters and biomarkers in wastewater generated by the respective catchments. Domestic wastewater influent samples taken during the 2016 Australian census week were analyzed for a range of diet, drug, pharmaceutical, and lifestyle biomarkers. We present both linear and rank-order (i.e., Pearson and Spearman) correlations between loads of 42 biomarkers and census-derived metrics, index of relative socioeconomic advantage and disadvantage (IRSAD), median age, and 40 socioeconomic index for area (SEIFA) descriptors. Biomarkers of caffeine, citrus, and dietary fiber consumption had strong positive correlations with IRSAD, while tramadol, atenolol, and pregabalin had strong negative correlation with IRSAD. As expected, atenolol and hydrochlorothiazide correlated positively with median age. We also found specific SEIFA descriptors such as occupation and educational attainment correlating with each biomarker. Our study demonstrates that wastewater-based epidemiology can be used to study sociodemographic influences and disparities in chemical consumption.
Journal Article
Isotonitazene: Fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland
•Isotonitazene quantification in human post-mortem tissues, blood and hair.•Isotonitazene accumulation in brain and hearth and very low concentration in liver.•Isotonitazene powder determination using GC-MS, NMR.•Very low isotonitazene concentration in blood can be fatal.
The paper describes the first three deaths reported in Europe involved in isotonitazene consumption, a potent benzimidazole derivate opioid consumed in the recreational drug scene. Isotonitazene powder and purity determination was performed on the sample collected in the first death scene by NMR, HRMS, GC-FTIR, ATR-FTIR and GC–MS. Isotonitazene purity was determined by GC–MS analysis and proton NMR, and was defined to be above 95 % and 98 %, respectively.
Quantification of isotonitazene in biological samples was performed using a targeted analysis based on SPE extraction and ultra-high performance liquid chromatography tandem mass spectrometry.
The isotonitazene median concentration in femoral whole blood was 1.20ng/mL. Isotonitazene concentration in hair was similar or even lower compared to that seen in fentanyl abusers. Isotonitazene distribution in tissues converges in the brain, lungs and heart, respectively. Surprisingly, isotonitazene concentration in liver is the lowest measured for all tissues and fluids analyzed.
Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of all three deaths was an acute intoxication with isotonitazene.
Since isotonitazene toxic concentration levels are very low, the consumption of this new psychoactive drug is a real hazard for human health.
Journal Article
Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila
Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of
Drosophila N
-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of
Pngl
in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of
Pngl
mutants rescued their developmental delay but not lethality. However, raising
Pngl
mutants on isocaloric, fat-rich diets partially rescued lethality. Our data indicate that Pngl functions in
Drosophila
larvae to establish the gut barrier, and that the lethality caused by loss of
Pngl
is primarily mediated through non-bacterial induction of immune and metabolic abnormalities.
NGLY1 mutations cause a multisystem developmental disorder. Here they show that this enzyme is required for normal gut barrier function, and when mutated, causes immune and metabolic abnormalities, contributing to lethality.
Journal Article
Degradation of Herbicides in the Tropical Marine Environment: Influence of Light and Sediment
Widespread contamination of nearshore marine systems, including the Great Barrier Reef (GBR) lagoon, with agricultural herbicides has long been recognised. The fate of these contaminants in the marine environment is poorly understood but the detection of photosystem II (PSII) herbicides in the GBR year-round suggests very slow degradation rates. Here, we evaluated the persistence of a range of commonly detected herbicides in marine water under field-relevant concentrations and conditions. Twelve-month degradation experiments were conducted in large open tanks, under different light scenarios and in the presence and absence of natural sediments. All PSII herbicides were persistent under control conditions (dark, no sediments) with half-lives of 300 d for atrazine, 499 d diuron, 1994 d hexazinone, 1766 d tebuthiuron, while the non-PSII herbicides were less persistent at 147 d for metolachlor and 59 d for 2,4-D. The degradation of herbicides was 2-10 fold more rapid in the presence of a diurnal light cycle and coastal sediments; apart from 2,4-D which degraded more slowly in the presence of light. Despite the more rapid degradation observed for most herbicides in the presence of light and sediments, the half-lives remained > 100 d for the PS II herbicides. The effects of light and sediments on herbicide persistence were likely due to their influence on microbial community composition and its ability to utilise the herbicides as a carbon source. These results help explain the year-round presence of PSII herbicides in marine systems, including the GBR, but more research on the transport, degradation and toxicity on a wider range of pesticides and their transformation products is needed to improve their regulation in sensitive environments.
Journal Article
High PIRCHE Scores May Allow Risk Stratification of Borderline Rejection in Kidney Transplant Recipients
The diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury.
We identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection,
DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes.
Total PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of
DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop
DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003).
High PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.
Journal Article
Herbicide Persistence in Seawater Simulation Experiments
Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR). The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities). Very little degradation was recorded over the standard 60 d period (Experiment 1) so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated flood plumes transporting a high proportion of the original herbicide from rivers into the GBR lagoon.
Journal Article
Assessment of Organ Quality in Kidney Transplantation by Molecular Analysis and Why It May Not Have Been Achieved, Yet
Donor organ shortage, growing waiting lists and substantial organ discard rates are key problems in transplantation. The critical importance of organ quality in determining long-term function is becoming increasingly clear. However, organ quality is difficult to predict. The lack of good measures of organ quality is a serious challenge in terms of acceptance and allocation of an organ. The underlying review summarizes currently available methods used to assess donor organ quality such as histopathology, clinical scores and machine perfusion characteristics with special focus on molecular analyses of kidney quality. The majority of studies testing molecular markers of organ quality focused on identifying organs at risk for delayed graft function, yet without prediction of long-term graft outcome. Recently, interest has emerged in looking for molecular markers associated with biological age to predict organ quality. However, molecular gene sets have not entered the clinical routine or impacted discard rates so far. The current review critically discusses the potential reasons why clinically applicable molecular quality assessment using early kidney biopsies might not have been achieved yet. Besides a critical analysis of the inherent limitations of surrogate markers used for organ quality, i.e., delayed graft function, the intrinsic methodological limitations of studies assessing organ quality will be discussed. These comprise the multitude of unpredictable hits as well as lack of markers of nephron mass, functional reserve and regenerative capacity.
Journal Article
Clinical progression parameters associated with SARS-CoV-2, influenza, and respiratory syncytial virus infections in a large US integrated healthcare population
Mathematical and computational models are often used to forecast respiratory infectious disease burden, including to inform healthcare capacity. We aimed to characterize pathways of clinical progression associated with SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) infections using data from patients aged 0 to >90 years in an integrated healthcare system, whose encounters were monitored across all levels of acuity spanning virtual, ambulatory, and inpatient care settings. Using parametric survival models, we estimated probabilities of progression and distributions of time to progression from each setting to all higher-acuity settings on a cascade encompassing the following classes of events or encounters: symptoms onset; diagnostic testing; telehealth or other virtual care appointment; outpatient physician office visit; urgent care presentation; emergency department presentation; hospital admission; mechanical ventilation; and death. Our analyses included data from 59,668, 22,705, and 1,668 episodes associated with positive SARS-CoV-2, influenza, and RSV tests, respectively, between 1 April 2023 and 31 March 2024. First clinical encounters occurred in inpatient settings for only 4.7%, 3.4%, and 18.7% of SARS-CoV-2, influenza, and RSV episodes, respectively, with median times (interquartile range) of 6.8 (3.6-13.2), 6.6 (3.5-12.1), and 6.4 (3.8-10.6) days from symptoms onset to admission. Overall, 7.9% of SARS-CoV-2 episodes, 5.8% of influenza episodes, and 33.8% of RSV episodes resulted in inpatient admission, ventilation, or death. Between 40.4-62.1%, 71.6-87.3%, and 47.9-58.7% of SARS-CoV-2, influenza, and RSV infections, respectively, had encounters in lower-acuity virtual care, outpatient, or urgent care settings. For all three viruses, the proportions of cases receiving care at each level of acuity increased with older age and greater numbers of comorbid conditions. Median durations of hospital stay were 4.2 (2.6, 7.3), 4.0 (2.3, 6.8), and 4.3 (2.5, 7.4) days for SARS-CoV-2, influenza, and RSV episodes resulting in admission. These estimates provide a basis for modeling real-world clinical care requirements and the progression of respiratory viral infections.
Journal Article