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Institute
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15–6 ng/bee) and clothianidin (0.05–2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of ≥0.5 ng/bee (clothianidin) and ≥1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.