Abstract
The migration of many cell types relies on the formation of actomyosin-dependent protrusions called blebs, but the mechanisms responsible for focusing this kind of protrusive activity to the ...cell front are largely unknown. Here, we employ zebrafish primordial germ cells (PGCs) as a model to study the role of cell-cell adhesion in bleb-driven single-cell migration in vivo. Utilizing a range of genetic, reverse genetic and mathematical tools, we define a previously unknown role for E-cadherin in confining bleb-type protrusions to the leading edge of the cell. We show that E-cadherin-mediated frictional forces impede the backwards flow of actomyosin-rich structures that define the domain where protrusions are preferentially generated. In this way, E-cadherin confines the bleb-forming region to a restricted area at the cell front and reinforces the front-rear axis of migrating cells. Accordingly, when E-cadherin activity is reduced, the bleb-forming area expands, thus compromising the directional persistence of the cells.
Plant cells are encapsulated by cell walls whose properties largely determine cell growth. We have previously identified the
mutant, which shows defects in seedling root and shoot development.
is ...affected in the
(
) and shows alterations in the structures of Rhamnogalacturonan I (RG I) and RG II, two rhamnose-containing pectins. The data presented here shows that root tissue of the
mutant fails to properly differentiate the cell wall in cell corners and accumulates excessive amounts of callose, both of which likely alter the physical properties of cells. A
(
) mutant was identified that alleviates the cell growth defects in
. The cell wall differentiation defect is re-established in the
mutant and callose accumulation is reduced compared to
. The
mutation is an allele of the
(
), which encodes a component of the mediator complex that influences processes central to plant growth and development. Together, the identification of the
mutant suggests that changes in cell wall composition and turnover in the
mutant have a significant impact on cell growth and reveals a function of CDK8 in cell wall architecture and composition.
SUMMARY
Colonization of land by green plants (Viridiplantae) some 500 million years ago was made possible by large metabolic and biochemical adaptations. Chlorophyll, the central pigment of ...photosynthesis, is highly photo‐active. In order to mitigate deleterious effects of pigment accumulation, some plants have evolved a coordinated pathway to deal with chlorophyll degradation end‐products, so‐called phyllobilins. This pathway has been so far mostly unravelled in Arabidopsis thaliana. Here, large‐scale comparative phylogenomic coupled to an innovative biochemical characterization strategy of phyllobilins allow a better understanding of how such a pathway appeared in Viridiplantae. Our analysis reveals a stepwise evolution of the canonical pheophorbide a monooxygenase/phyllobilin pathway. It appears to have evolved gradually, first in chlorophyte's chloroplasts, to ensure multicellularity by detoxifying chlorophyll catabolites, and in charophytes outside chloroplasts to allow adaptation of embryophytes to land. At least six out of the eight genes involved in the pathway were already present in the last common ancestor of green plants. This strongly suggests parallel evolution of distinct enzymes catalysing similar reactions in various lineages, particularly for the dephytylation step. Together, our study suggests that chlorophyll detoxification accompanied the transition from water to land, and was therefore of great importance for plant diversification.
Significance Statement
Chlorophyll, the central pigment of photosynthesis, is highly photo‐active and degraded enzymatically during leaf senescence. Merging comparative genomics and metabolomics, we evaluate the extent to which the chlorophyll detoxification pathway has evolved in Viridiplantae. We argue that cytosolic detoxification of phyllobilins in particular was a critical process to the green lineage’s transition to land.
Geological maps are available for almost every region of the world and, therefore, represent the most commonly used source of information for earth scientists. Advances in computing power and the ...availability of digital elevation data have opened new possibilities to automatically extract quantitative information from geological maps, especially in regions with topographic relief and good bedrock exposure. We present an innovative approach to automatically extract orientation (dip direction/dip) and stratigraphic thickness from a 1:25′000 geological map vector data set of the Swiss Alps. The approach allows a rapid spatial overview on the orientation and thickness of a given geological unit over large areas. Key improvements of the approach with respect to commonly used 3D modelling approaches are its objectivity, rapidity and the possibility to classify and/or filter orientation and thickness model output after five numeric reliability parameters. The approach is designed to support authorities and the industry in performing a rapid screening of a given region and to early identify promising areas for potential mineral extraction projects. Large-scale spatial overviews on the orientation and thickness of geological units are of large interest in many other disciplines such as tectonic and stratigraphic reconstruction, hydrogeological or geotechnical analyses. Therefore, the approach will be widely applicable also beyond the evaluation of potential mineral resources.
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•Automated extraction of orientation (dip direction/dip) and stratigraphic thickness from geological maps.•Independent thickness data from published cross sections are used to validate the model output.•Numeric parameters are used to evaluate the reliability and allow flexible filtering of the model output.•The approach allows a rapid spatial overview on the orientation and thickness of a given target unit.•No manual digitisation or interpretation steps are involved so that the approach produces objective results.
The connection between Pediatric Inflammatory Multisystem Syndrome (PIMS) and Kawasaki Disease (KD) is not yet fully understood. Using the same national registry, clinical features and outcome of ...children hospitalized in Germany, and Innsbruck (Austria) were compared. Reported to the registry were 395 PIMS and 69 KD hospitalized patients. Patient age in PIMS cases was higher than in KD cases (median 7 IQR 4-11 vs. 3 IQR 1-4 years). A majority of both PIMS and KD patients were male and without comorbidities. PIMS patients more frequently presented with organ dysfunction, with the gastrointestinal (80%), cardiovascular (74%), and respiratory (52%) systems being most commonly affected. By contrast, KD patients more often displayed dermatological (99% vs. 68%) and mucosal changes (94% vs. 64%), plus cervical lymph node swelling (51% vs. 34%). Intensive care admission (48% vs. 19%), pulmonary support (32% vs. 10%), and use of inotropes/vasodilators (28% vs. 3%) were higher among PIMS cases. No patients died. Upon patient discharge, potentially irreversible sequelae-mainly cardiovascular-were reported (7% PIMS vs. 12% KD). Despite differences in age distribution and disease severity, PIMS and KD cases shared many common clinical and prognostic characteristics. This supports the hypothesis that the two entities represent a syndrome continuum.
The reported outcomes of central retinal artery occlusion (CRAO) with or without treatment vary considerably. Although local intra-arterial fibrinolysis (LIF) using recombinant tissue plasminogen ...activator (rtPA) is a promising treatment, outcomes have not been compared in randomized trials.
Prospective randomized multicenter clinical trial (the European Assessment Group for Lysis in the Eye Study) to compare treatment outcome after conservative standard treatment (CST) and LIF for acute nonarteritic CRAO.
Between 2002 and 2007, 9 centers in Austria and Germany recruited 84 patients (40 received CST, 44 received LIF), and data for 82 patients were analyzed.
Patients (age 18-75 years) with CRAO, symptoms for 20 hours or less, and best-corrected visual acuity (BCVA) <0.5 logarithm of the minimum angle of resolution (logMAR) were randomized to the CST or LIF group.
The primary end point was BCVA after 1 month; the secondary end point was safety.
The mean interval between first symptoms and therapy was 10.99+/-5.49 hours (CST) and 12.78+/-5.77 hours (LIF). The mean BCVA (logMAR) improved significantly in both groups (CST: -0.44 standard deviation 0.55; LIF: -0.45 standard deviation 0.55; both P < 0.0001) and did not differ between groups (P=0.69). Clinically significant visual improvement (> or = 0.3 logMAR) was noted in 60.0% (CST) and 57.1% (LIF) of patients. Two patients in the CST group (4.3%) and 13 patients in the LIF group (37.1%) had adverse reactions. Because of apparently similar efficacy and the higher rate of adverse reactions in the LIF group, the study was stopped after the first interim analysis at the recommendation of the data and safety monitoring committee.
In light of these 2 therapies' similar outcomes and the higher rate of adverse reactions associated with LIF, we cannot recommend LIF for the management of acute CRAO.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Abstract Objective We aimed to prospectively derive and validate a novel 1h-algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for early rule-out and rule-in of acute myocardial ...infarction. Methods We performed a prospective multicenter diagnostic study enrolling 1811 patients with suspected acute myocardial infarction. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography, echocardiography, follow-up data, and serial measurements of hs-cTnT (but not hs-cTnI). The hs-cTnI 1h-algorithm, incorporating measurements performed at baseline and absolute changes within 1 hour, was derived in a randomly selected sample of 906 patients (derivation cohort), and then validated in the remaining 905 patients (validation cohort). Results Acute myocardial infarction was the final diagnosis in 18% of patients. After applying the hs-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 50.5% of patients could be classified as “rule-out,” 19% as “rule-in,” 30.5% as “observe.” In the validation cohort, the negative predictive value for acute myocardial infarction in the “rule-out” zone was 99.6% (95% confidence interval, 98.4%-100%), and the positive predictive value for acute myocardial infarction in the “rule-in” zone was 73.9% (95% confidence interval, 66.7%-80.2%). Negative predictive value of the 1h-algorithm was higher compared with the classical dichotomous interpretation of hs-cTnI and to the standard of care combining hs-cTnI with the electrocardiogram (both P < .001). Positive predictive value also was higher compared with the standard of care ( P < .001). Conclusion Using a simple algorithm incorporating baseline hs-cTnI values and the absolute change within the first hour allows safe rule-out as well as accurate rule-in of acute myocardial infarction in 70% of patients presenting with suspected acute myocardial infarction.
Summary Background Only 2–5% of patients who have a stroke receive thrombolytic treatment, mainly because of delay in reaching the hospital. We aimed to assess the efficacy of a new approach of ...diagnosis and treatment starting at the emergency site, rather than after hospital arrival, in reducing delay in stroke therapy. Methods We did a randomised single-centre controlled trial to compare the time from alarm (emergency call) to therapy decision between mobile stroke unit (MSU) and hospital intervention. For inclusion in our study patients needed to be aged 18–80 years and have one or more stroke symptoms that started within the previous 2·5 h. In accordance with our week-wise randomisation plan, patients received either prehospital stroke treatment in a specialised ambulance (equipped with a CT scanner, point-of-care laboratory, and telemedicine connection) or optimised conventional hospital-based stroke treatment (control group) with a 7 day follow-up. Allocation was not masked from patients and investigators. Our primary endpoint was time from alarm to therapy decision, which was analysed with the Mann-Whitney U test. Our secondary endpoints included times from alarm to end of CT and to end of laboratory analysis, number of patients receiving intravenous thrombolysis, time from alarm to intravenous thrombolysis, and neurological outcome. We also assessed safety endpoints. This study is registered with ClinicalTrials.gov , number NCT00792220. Findings We stopped the trial after our planned interim analysis at 100 of 200 planned patients (53 in the prehospital stroke treatment group, 47 in the control group), because we had met our prespecified criteria for study termination. Prehospital stroke treatment reduced the median time from alarm to therapy decision substantially: 35 min (IQR 31–39) versus 76 min (63–94), p<0·0001; median difference 41 min (95% CI 36–48 min). We also detected similar gains regarding times from alarm to end of CT, and alarm to end of laboratory analysis, and to intravenous thrombolysis for eligible ischaemic stroke patients, although there was no substantial difference in number of patients who received intravenous thrombolysis or in neurological outcome. Safety endpoints seemed similar across the groups. Interpretation For patients with suspected stroke, treatment by the MSU substantially reduced median time from alarm to therapy decision. The MSU strategy offers a potential solution to the medical problem of the arrival of most stroke patients at the hospital too late for treatment. Funding Ministry of Health of the Saarland, Germany, the Werner-Jackstädt Foundation, the Else-Kröner-Fresenius Foundation, and the Rettungsstiftung Saar.
Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular ...processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
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