Ein langer Atem zahlt sich aus

Um das Grundwasser hinreichend zu schützen, müssen Landwirte, Erzeuger und Konsumenten an einem Strang ziehen. Nur dann können Schutzmaßnahmen greifen und zum langfristigen Erfolg führen. In Unterfranken hat das FiBL entsprechende Instrumente erarbeitet. Ein Blick auf den Status quo

A preliminary investigation on the influence of flavonoids on ethyl glucuronide formation

Abstract Aims: A large variation of the formation of ethyl glucuronide (EtG) which is a minor metabolite of ethanol has been observed in man. At present there is only a single investigation on glucuronosyltransferases (UGT) responsible for catalyzing EtG formation whereas a possible influence of nutritional components on EtG formation has not been addressed at all. Methods: Following optimization of the substrate concentration, incubation conditions such as buffer and time, as well as isolation of EtG from the incubation mixture, recombinant UGT enzymes (UGT 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B10, 2B15) were screened for their activity towards ethanol. Subsequently, quercetin and kaempferol were chosen to study their possible influence on the glucuronidation of ethanol for UGT1A1, 1A3 and UGT1A9. Analysis of EtG formation was performed by LC-MS/MS following solid phase extraction. EtG-d 5 was used as the internal standard. For inhibition experiments, EtG formation was determined after addition of kaempferol and quercetin in different concentrations to the incubation mixture to determine the half maximum inhibitory constants (IC 50 ). Results: Optimization of both, the incubation and isolation procedures resulted in a significant decrease of matrix effects. EtG was formed by all enzymes under investigation at variable rates ranging from 0.79 -10.41 pmol/min/mg at 50 mM ethanol and 0.95-12.9 pmol/mg/min at 200 mM ethanol. Respective kinetics followed the Michaelis-Menten model so that the Michaelis-Menten constant K m and the maximum velocity V max values could be calculated. Both flavonoids reduced formation of EtG, irrespective of the enzyme involved. The IC 50 -values ranged from 3.04 µM quercetin for UGT1A1 to 38.47 µM kaempferol for UGT1A9. Conclusions: Formation of EtG from ethanol is catalyzed by multiple UGT isoforms. In addition, co-incubation affected the glucuronidation rate, irrespective of the particular enzyme. It seems that nutritional components will influence conversion of ethanol to EtG which may partly explain its variable formation in man

Judge-Jury Agreement in Criminal Cases: A Partial Replication of Kalven and Zeisel\u27s The American Jury

This study uses a new criminal case data set to partially replicate Kalven and Zeisel\u27s classic study of judge-jury agreement. The data show essentially the same rate of judge-jury agreement as did Kalven and Zeisel for cases tried almost 50 years ago. This study also explores judge-jury agreement as a function of evidentiary strength (as reported by both judges and juries), evidentiary complexity (as reported by both judges and juries), legal complexity (as reported by judges), and locale. Regardless of which adjudicator\u27s view of evidentiary strength is used, judges tend to convict more than juries in cases of middle evidentiary strength. Judges tend to acquit more than juries in cases in which judges regard the evidence favoring the prosecution as weak. Judges tend to convict more than juries in cases in which judges regard the evidence favoring the prosecution as strong. Rates of adjudicator agreement are thus partly a function of which adjudicator\u27s view of evidentiary strength is used, a result not available to Kalven and Zeisel, who were limited to judges\u27 views of the evidence. We find little evidence that evidentiary complexity or legal complexity help explain rates of judge-jury disagreement. Rather, the data support the view that judges have a lower conviction threshold than juries. Local variation exists among the sites studied. The influences of juror race, sex, and education are also considered

CLEMSite, a software for automated phenotypic screens using light microscopy and FIB-SEM

This work was supported by EMBL funds and by by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project number 240245660 – SFB 1129 (project Z2).In recent years, Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) has emerged as a flexible method that enables semi-automated volume ultrastructural imaging. We present a toolset for adherent cells that enables tracking and finding cells, previously identified in light microscopy (LM), in the FIB-SEM, along with the automatic acquisition of high-resolution volume datasets. We detect the underlying grid pattern in both modalities (LM and EM), to identify common reference points. A combination of computer vision techniques enables complete automation of the workflow. This includes setting the coincidence point of both ion and electron beams, automated evaluation of the image quality and constantly tracking the sample position with the microscope’s field of view reducing or even eliminating operator supervision. We show the ability to target the regions of interest in EM within 5 µm accuracy while iterating between different targets and implementing unattended data acquisition. Our results demonstrate that executing volume acquisition in multiple locations autonomously is possible in EM.Publisher PDFPeer reviewe

Pre-assembled Nuclear Pores Insert into the Nuclear Envelope during Early Development

SummaryNuclear pore complexes (NPCs) span the nuclear envelope (NE) and mediate nucleocytoplasmic transport. In metazoan oocytes and early embryos, NPCs reside not only within the NE, but also at some endoplasmic reticulum (ER) membrane sheets, termed annulate lamellae (AL). Although a role for AL as NPC storage pools has been discussed, it remains controversial whether and how they contribute to the NPC density at the NE. Here, we show that AL insert into the NE as the ER feeds rapid nuclear expansion in Drosophila blastoderm embryos. We demonstrate that NPCs within AL resemble pore scaffolds that mature only upon insertion into the NE. We delineate a topological model in which NE openings are critical for AL uptake that nevertheless occurs without compromising the permeability barrier of the NE. We finally show that this unanticipated mode of pore insertion is developmentally regulated and operates prior to gastrulation

Impact of breast cancer family history on tumor detection and tumor size in women newly-diagnosed with invasive breast cancer

This study evaluated the impact of family history (FH) on tumor detection, the patient's age and tumor size at diagnosis in breast cancer (BC). Furthermore, we investigated whether the impact of FH on these features was dependent on degree of relationship, number of relatives with a BC history, or the age of the affected relative at the time that her BC was diagnosed. Out of the entire cohort (n=1,037), 244 patients (23.5%) had a positive FH; 159 (15.3%) had first-degree relatives affected with BC and 85 patients (8.2%) had second-degree affected relatives. Compared to women who had no BC-affected relatives, the tumors of women who had positive FH were more often found by radiological breast examination (RBE: 31.7%/27.2%, p=0.008), and they were smaller (general tumor size: 21.8mm/26.4mm, p=0.003; size of tumors found by breast self-examination (BSE): 26.1mm/30.6mm, p=0.041). However, this positive effect of increased use of BC screening and smaller tumor sizes was only observed in patients whose first-degree relatives were affected (comparison with second-degree affected relatives: RBE: 43.8%/24.7%; odds ratio 2.38, p=0.007; general tumor size: 19.3mm/26.3mm; mean difference (MD) −6.9, p=0.025; tumor size found by BSE: 22.5mm/31.0mm; MD −8.5, p=0.044). When more second-degree relatives or older relatives were diagnosed with BC, the tumors of these patients were similarly often detected by RBE (relationship: 24.7%/27.2%, p=0.641; age: 33.7%/27.2%, p=0.177) and had similar tumor sizes (general size: 26.3mm/26.4mm, p=0.960; BSE: 31.0mm/30.6mm, p=0.902) as those of women without a FH. Women with a positive FH generally use mammography screening more often and perceive changes in the breast earlier than women without such history. The increased awareness of BC risk decreases if the relationship is more distant

Can We Geographically Validate a Natural Language Processing Algorithm for Automated Detection of Incidental Durotomy Across Three Independent Cohorts From Two Continents?

Background Incidental durotomy is an intraoperative complication in spine surgery that can lead to postoperative complications, increased length of stay, and higher healthcare costs. Natural language processing (NLP) is an artificial intelligence method that assists in understanding free-text notes that may be useful in the automated surveillance of adverse events in orthopaedic surgery. A previously developed NLP algorithm is highly accurate in the detection of incidental durotomy on internal validation and external validation in an independent cohort from the same country. External validation in a cohort with linguistic differences is required to assess the transportability of the developed algorithm, referred to geographical validation. Ideally, the performance of a prediction model, the NLP algorithm, is constant across geographic regions to ensure reproducibility and model validity. Question/purpose Can we geographically validate an NLP algorithm for the automated detection of incidental durotomy across three independent cohorts from two continents? Methods Patients 18 years or older undergoing a primary procedure of (thoraco)lumbar spine surgery were included. In Massachusetts, between January 2000 and June 2018, 1000 patients were included from two academic and three community medical centers. In Maryland, between July 2016 and November 2018, 1279 patients were included from one academic center, and in Australia, between January 2010 and December 2019, 944 patients were included from one academic center. The authors retrospectively studied the free-text operative notes of included patients for the primary outcome that was defined as intraoperative durotomy. Incidental durotomy occurred in 9% (93 of 1000), 8% (108 of 1279), and 6% (58 of 944) of the patients, respectively, in the Massachusetts, Maryland, and Australia cohorts. No missing reports were observed. Three datasets (Massachusetts, Australian, and combined Massachusetts and Australian) were divided into training and holdout test sets in an 80:20 ratio. An extreme gradient boosting (an efficient and flexible tree-based algorithm) NLP algorithm was individually trained on each training set, and the performance of the three NLP algorithms (respectively American, Australian, and combined) was assessed by discrimination via area under the receiver operating characteristic curves (AUC-ROC; this measures the model's ability to distinguish patients who obtained the outcomes from those who did not), calibration metrics (which plot the predicted and the observed probabilities) and Brier score (a composite of discrimination and calibration). In addition, the sensitivity (true positives, recall), specificity (true negatives), positive predictive value (also known as precision), negative predictive value, Fl-score (composite of precision and recall), positive likelihood ratio, and negative likelihood ratio were calculated. Results The combined NLP algorithm (the combined Massachusetts and Australian data) achieved excellent performance on independent testing data from Australia (AUC-ROC 0.97 [95% confidence interval 0.87 to 0.99]), Massachusetts (AUC-ROC 0.99 [95% CI 0.80 to 0.99]) and Maryland (AUC-ROC 0.95 [95% CI 0.93 to 0.97]). The NLP developed based on the Massachusetts cohort had excellent performance in the Maryland cohort (AUC-ROC 0.97 [95% CI 0.95 to 0.99]) but worse performance in the Australian cohort (AUC-ROC 0.74 [95% CI 0.70 to 0.77]). Conclusion We demonstrated the clinical utility and reproducibility of an NLP algorithm with combined datasets retaining excellent performance in individual countries relative to algorithms developed in the same country alone for detection of incidental durotomy. Further multi-institutional, international collaborations can facilitate the creation of universal NLP algorithms that improve the quality and safety of orthopaedic surgery globally. The combined NLP algorithm has been incorporated into a freely accessible web application that can be found at https://sorg-apps.shinyapps.io/nlp_incidental_durotomy/. Clinicians and researchers can use the tool to help incorporate the model in evaluating spine registries or quality and safety departments to automate detection of incidental durotomy and optimize prevention efforts

Personal factors understood through the Ecological-Enactive Model of Disability and implications for rehabilitation research

The International Classification of Functioning, Disability and Health (ICF) recognizes that disability arises from the interaction between an individual with a medical condition and the context in which they are embedded. Context in the ICF is comprised of environmental and personal factors. Personal factors, the background life and lifestyle of an individual, are poorly understood in rehabilitation. There is limited knowledge about how personal and environmental factors interact to shape the contextual conditions critical for explaining functioning and disability. In this paper, we explore how a newly proposed model of disability, the Ecological-Enactive Model of Disability, can enhance understanding of personal factors across multiple rehabilitation disciplines. We draw from a review of evidence and phenomenological interviews of individuals with Friedreich's Ataxia. We consider the practical impact of this understanding on disability and rehabilitation research and pathways for the future focusing on representative design

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability

Cytoklepty in the plankton: A host strategy to optimize the bioenergetic machinery of endosymbiotic algae

Endosymbioses have shaped the evolutionary trajectory of life and remain ecologically important. Investigating oceanic photosymbioses can illuminate how algal endosymbionts are energetically exploited by their heterotrophic hosts and inform on putative initial steps of plastid acquisition in eukaryotes. By combining three-dimensional subcellular imaging with photophysiology, carbon flux imaging, and transcriptomics, we show that cell division of endosymbionts (Phaeocystis) is blocked within hosts (Acantharia) and that their cellular architecture and bioenergetic machinery are radically altered. Transcriptional evidence indicates that a nutrient-independent mechanism prevents symbiont cell division and decouples nuclear and plastid division. As endosymbiont plastids proliferate, the volume of the photosynthetic machinery volume increases 100-fold in correlation with the expansion of a reticular mitochondrial network in close proximity to plastids. Photosynthetic efficiency tends to increase with cell size, and photon propagation modeling indicates that the networked mitochondrial architecture enhances light capture. This is accompanied by 150-fold higher carbon uptake and up-regulation of genes involved in photosynthesis and carbon fixation, which, in conjunction with a ca.15-fold size increase of pyrenoids demonstrates enhanced primary production in symbiosis. Mass spectrometry imaging revealed major carbon allocation to plastids and transfer to the host cell. As in most photosymbioses, microalgae are contained within a host phagosome (symbiosome), but here, the phagosome invaginates into enlarged microalgal cells, perhaps to optimize metabolic exchange. This observation adds evidence that the algal metamorphosis is irreversible. Hosts, therefore, trigger and benefit from major bioenergetic remodeling of symbiotic microalgae with potential consequences for the oceanic carbon cycle. Unlike other photosymbioses, this interaction represents a so-called cytoklepty, which is a putative initial step toward plastid acquisition