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Im Rahmen der Pilotstudie Hip-in-Wü wurde eine der ersten Herzinsuffizienz-
Sportgruppen in Deutschland mit einem individualisierten Training über ein Jahr
entwickelt und etabliert. Den hohen Stellenwert einer Forschung auf diesem Gebiet
unterstreicht die starke Empfehlung der aktuellen Leitlinie zur sportlichen Aktivität bei
Herzinsuffizienz und das Positionspapier der DGK und DGRP von 2020 mit der
Forderung nach speziellen, in der breiten Masse zugänglichen, Herzinsuffizienz-
sportgruppen. Inhalt dieser Arbeit war die umfassende Evaluation der Studie bezüglich
ihrer Effektivität, Sicherheit und Durchführbarkeit.
Das Studienkollektiv umfasste 12 Patienten mit symptomatischer Herzinsuffizienz
(NYHA II/III) und einer linksventrikulären Ejektionsfraktion ≤45%. Alle Patienten
erhielten über die gesamte Studiendauer den Aktivitätstracker Polar M430 und wurden
dahingehend motiviert, ihre tägliche Schrittzahl und körperliche Aktivität zu steigern.
Zudem erhielten alle Patienten zu den Zeitpunkten 0, 4, 8 und 12 Monate eine
Spiroergometrie, 6-Minutengehtest, Echokardiographie und Fragebogen zur
krankheitsspezifischen Lebensqualität (KCCQ) sowie zur depressiven Verstimmung
(PHQ-9).
Die rekrutierten Patienten unseres Kollektivs waren deutlich jünger (Median 64 Jahre;
Range 38-77) und überwiegend männlich (75%) im Vergleich zum Kollektiv aller an
Herzinsuffizienz Erkrankten. Alle Patienten beendeten die Studie und nahmen im Mittel
an 76% der 36 Trainingsstunden teil. Die Polar M430 wurde mit 86% gültiger Tage
(definiert als Tage mit Tragedauer ≥1000 min.) mehrheitlich sehr zuverlässig getragen.
Während des Trainings kam es zu keinen kardiovaskulären Ereignissen. Nach 12
Monaten war die LVEF signifikant von 36% auf 41% verbessert. Die Domäne Soziale
Limitation und Körperliche Einschränkung des KCCQ waren ebenfalls signifikant und
klinisch relevant verbessert. Positive Trends zeigten sich auch in den übrigen Domänen
und Summenskalen des KCCQ. Zudem zeigten sich bei der spiroergometrisch
abgeleiteten peakVO2 und der Alltagsaktivität in den ersten 8 Monaten nominell
positive Entwicklungen.
Somit konnte die Pilotstudie Hip-in-Wü zeigen, dass ein individualisiertes und ärztliche
supervidiertes Training von Patienten mit Herzinsuffizienz und eingeschränkter
linksventrikulärer Funktion durchführbar und sicher ist. Aufgrund des kleinen
Kollektivs lassen sich noch keine belastbaren Schlussfolgerungen ziehen. Die
Erfahrungen aus der Studie lassen sich jedoch dazu nutzen, das Trainingskonzept
weiterzuentwickeln, weitere lokaler Herzinsuffizienz-Sportgruppen zu etablieren und
weitere klinische, idealerweise randomisierte Interventionsstudien zu informieren.
Limits are set on the pair production of scalar leptoquarks, where all possible decays of the leptoquark into a quark (t, b) and a lepton (, ) of the third generation are considered. The limits are presented as a function of the leptoquark mass and the branching ratio into charged leptons for up-type (LQ<sub ) and down-type (/t) leptoquarks. Many results are reinterpretations of previously published ATLAS searches. In all cases, LHC proton-proton collision data at a centre-of-mass energy of = 13 TeV recorded by the ATLAS detector in 2015 and 2016 are used, corresponding to an integrated luminosity of 36.1 fb(-1). Masses below 800 GeV are excluded for both LQu and LQd independently of the branching ratio, with masses below about 1 TeV being excluded for the limiting cases of branching ratios equal to zero or unity.
Knowledge production is inherently social, as humans interpret their environment. Scientific knowledge production differs from non-scientific ones in their systematic data collection for validation, yet both involve a social element shaping our understanding of the world. The article investigates social contestation processes as part of knowledge producing processes on a German research vessel and in German and Brazilian marine science institutes with a particular focus on the social identity markers of gender, ethnicity, and age and how they affect team-based sense-making processes. Methodologically, our research draws on participant observation of following marine scientists and associated non-scientists in their daily working routines, as well as semi-structured interviews on a research vessel in 2021 and in marine science institutes from 2022 to 2024. Conceptually, the research follows approaches of the Sociology of Knowledge (Keller et al., 2018) and intersectional approaches (Grabe &amp; Else-Quest, 2012; Patil, 2013) that integrate transnational experiences across national borders and other (physical) boundaries. Based on the empirical research, we assess transnational intersectional sense-making practices at sea. Our findings show that 1) (sexual) harassment in marine knowledge production processes occurs independent of localities, 2) intersectional discrimination at sea leads either to emancipation processes or to withdrawal, 3) tensions especially arise between scientists and non-scientists, which broadens the gap between these social groups and knowledge systems. We conclude by providing recommendations for increased intersectional and female workforce at sea and in marine sciences, so that the doing of research and work at sea can be more inclusive, equal, and safe.
Aim
Recent breakthroughs in environmental niche models (ENMs) have substantially improved our insights in niche evolution. Assuming that closely related taxa have similar niches (i.e. niche conservatism), the combination of ENMs with phylogenetic information allows the reconstruction of ancestral niches. This reconstruction helps to identify the underlying speciation processes leading to diversification (i.e. ecological speciation under niche divergence and mutation-order speciation under niche conservatism). Here, we studied the niche evolution in white-eyes (the so-called ‘great speciator’) to understand their extraordinarily fast diversification rate, wide distribution and rather conserved phenotypes. In a broader perspective, unravelling niche evolution in white-eyes can shed light on how different niche properties such as climate, habitat or trophic level may contribute to diversification.
Location
Asian-Pacific and Afrotropics.
Taxon
White-eyes (Aves, genus: Zosterops).
Methods
We selected 10 wide-ranging taxa that are equally distributed across the genus’ range and phylogeny. We studied niche evolution for a series of thermal and precipitation-related niche axes separately. We used a time-calibrated phylogeny encompassing the study taxa and estimated ancestral environmental niches in geographic and environmental niche spaces.
Results
We found that niche evolution in Zosterops is primarily driven by ecological speciation. Thermal niches, in particular, are characterized by a higher level of conservatism, as compared to precipitation-related niche axes. The fact that the youngest species diverged strongest stands in stark contrast to expectations stemming from niche conservatism.
Main conclusions
Contrasting evolutionary patterns in different niche axes suggest different underlying evolutionary pressures. Hence, future studies on niche evolution should take possible disparities between niche axes into account.
The legacy of the ‘SL > SS principle’, that a single or a few large habitat patches (SL) conserve more species than several small patches (SS), is evident in decisions to protect large patches while down-weighting small ones. However, empirical support for this principle is lacking, and most studies find either no difference or the opposite pattern (SS > SL). To resolve this dilemma, we propose a research agenda by asking, ‘are there consistent, empirically demonstrated conditions leading to SL > SS?’ We first review and summarize ‘single large or several small’ (SLOSS) theory and predictions. We found that most predictions of SL > SS assume that between-patch variation in extinction rate dominates the outcome of the extinction–colonization dynamic. This is predicted to occur when populations in separate patches are largely independent of each other due to low between-patch movements, and when species differ in minimum patch size requirements, leading to strong nestedness in species composition along the patch size gradient. However, even when between-patch variation in extinction rate dominates the outcome of the extinction–colonization dynamic, theory can predict SS > SL. This occurs if extinctions are caused by antagonistic species interactions or disturbances, leading to spreading-of-risk of landscape-scale extinction across SS. SS > SL is also predicted when variation in colonization dominates the outcome of the extinction–colonization dynamic, due to higher immigration rates for SS than SL, and larger species pools in proximity to SS than SL. Theory that considers change in species composition among patches also predicts SS > SL because of higher beta diversity across SS than SL. This results mainly from greater environmental heterogeneity in SS due to greater variation in micro-habitats within and across SS habitat patches (‘across-habitat heterogeneity’), and/or more heterogeneous successional trajectories across SS than SL. Based on our review of the relevant theory, we develop the ‘SLOSS cube hypothesis’, where the combination of three variables – between-patch movement, the role of spreading-of-risk in landscape-scale population persistence, and across-habitat heterogeneity – predict the SLOSS outcome. We use the SLOSS cube hypothesis and existing SLOSS empirical evidence, to predict SL > SS only when all of the following are true: low between-patch movement, low importance of spreading-of-risk for landscape-scale population persistence, and low across-habitat heterogeneity. Testing this prediction will be challenging, as it will require many studies of species groups and regions where these conditions hold. Each such study would compare gamma diversity across multiple landscapes varying in number and sizes of patches. If the prediction is not generally supported across such tests, then the mechanisms leading to SL > SS are extremely rare in nature and the SL > SS principle should be abandoned.
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Clinical studies suggested that endothelial dysfunction and damage could be involved in the development and severity of acute graft-versus-host disease (aGVHD). Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGVHD. In murine experimental aGVHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGVHD target organs. During intestinal aGVHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. Because recent data demonstrated an association of endothelium-related factors and steroid refractory aGVHD (SR-aGVHD), we analyzed human biopsies and murine tissues from SR-aGVHD. We found extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent SR-aGVHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGVHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGVHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGVHD complementing current anti-inflammatory treatment options.
Introduction
People living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.
Methods
Using blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1 decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.
Results
Airflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1 and FEV1/FVC, respectively. No positions were associated with FEV1 decline.
Conclusion
A large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.
Sequence-independent RNA sensing and DNA targeting by a split domain CRISPR–Cas12a gRNA switch
(2021)
CRISPR technologies increasingly require spatiotemporal and dosage control of nuclease activity. One promising strategy involves linking nuclease activity to a cell's transcriptional state by engineering guide RNAs (gRNAs) to function only after complexing with a ‘trigger’ RNA. However, standard gRNA switch designs do not allow independent selection of trigger and guide sequences, limiting gRNA switch application. Here, we demonstrate the modular design of Cas12a gRNA switches that decouples selection of these sequences. The 5′ end of the Cas12a gRNA is fused to two distinct and non-overlapping domains: one base pairs with the gRNA repeat, blocking formation of a hairpin required for Cas12a recognition; the other hybridizes to the RNA trigger, stimulating refolding of the gRNA repeat and subsequent gRNA-dependent Cas12a activity. Using a cell-free transcription-translation system and Escherichia coli, we show that designed gRNA switches can respond to different triggers and target different DNA sequences. Modulating the length and composition of the sensory domain altered gRNA switch performance. Finally, gRNA switches could be designed to sense endogenous RNAs expressed only under specific growth conditions, rendering Cas12a targeting activity dependent on cellular metabolism and stress. Our design framework thus further enables tethering of CRISPR activities to cellular states.
The ever-expanding set of CRISPR technologies and their programmable RNA-guided nucleases exhibit remarkable flexibility in DNA targeting. However, this flexibility comes with an ever-present constraint: the requirement for a protospacer adjacent motif (PAM) flanking each target. While PAMs play an essential role in self/nonself discrimination by CRISPR-Cas immune systems, this constraint has launched a far-reaching expedition for nucleases with relaxed PAM requirements. Here, we review ongoing efforts toward realizing PAM-free nucleases through natural ortholog mining and protein engineering. We also address potential consequences of fully eliminating PAM recognition and instead propose an alternative nuclease repertoire covering all possible PAM sequences.
Controls on andesitic glaciovolcanism at ice-capped volcanoes from field and experimental studies
(2021)
Glaciovolcanic deposits at Tongariro and Ruapehu volcanoes, New Zealand, represent diverse styles of interaction between wet-based glaciers and andesitic lava. There are iceconfined lavas, and also hydroclastic breccia and subaqueous pyroclastic deposits that formed during effusive and explosive eruptions into meltwater beneath the glacier; they are rare among globally reported products of andesitic glaciovolcanism. The apparent lack of hydrovolcanically fragmented andesite at ice-capped volcanoes has been attributed to a lack of meltwater at the interaction sites because either the thermal characteristics of andesite limit meltwater production or meltwater drains out through leaky glaciers and down steep volcano slopes. We used published field evidence and novel, dynamic andesite-ice experiments to show that, in some cases, meltwater accumulates under glaciers on andesitic volcanoes and that meltwater production rates increase as andesite pushes against an ice wall. We concur with models for eruptions beneath ice sheets showing that the glacial conditions and pre-eruption edifice morphology are more important controls on the style of glaciovolcanism and its products than magma composition and the thermal properties of magmas. Glaciovolcanic products can be useful proxies for paleoenvironment, and the range of andesitic products and the hydrological environments in which andesite erupts are greater than hitherto appreciated.
Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration
(2021)
Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5−/− HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence.
Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia
(2021)
The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.
Treatment of symptomatic hyponatremia with hypertonic saline: a real-life observational study
(2021)
Objective
Treatment of symptomatic hyponatremia is not well established. The European guidelines recommend bolus-wise administration of 150 mL of 3% hypertonic saline. This recommendation is, however, based on low level of evidence.
Design
Observational study.
Methods
Sixty-two consecutive hyponatremic patients admitted to the emergency department or intensive care unit of the University Hospital Wuerzburg were divided in subgroups according to treatment (150 mL bolus of 3% hypertonic saline or conventional treatment) and symptom severity. Treatment target was defined as an increase in serum sodium by 5–10 mEq/L within first 24 h and maximum 8 mEq/L during subsequent 24 h.
Results
Thirty-three out of sixty-two patients (53%) were presented with moderate symptoms and 29/62 (47%) with severe symptoms. Thirty-six were treated with hypertonic saline and 26 conventionally. In the hypertonic saline group, serum sodium increased from 116 ± 7 to 123 ± 6 (24 h) and 127 ± 6 mEq/L (48 h) and from 121 ± 6 to 126 ± 5 and 129 ± 4 mEq/L in the conventional group, respectively. Overcorrection at 24 h occurred more frequent in patients with severe symptoms than with moderate symptoms (38% vs 6%, P < 0.05). Diuresis correlated positively with the degree of sodium overcorrection at 24 h (r = 0.6, P < 0.01). Conventional therapies exposed patients to higher degrees of sodium fluctuations and an increased risk for insufficient sodium correction at 24 h compared to hypertonic saline (RR: 2.8, 95% CI: 1.4–5.5).
Conclusion
Sodium increase was more constant with hypertonic saline, but overcorrection rate was high, especially in severely symptomatic patients. Reducing bolus-volume and reevaluation before repeating bolus infusion might prevent overcorrection. Symptoms caused by hypovolemia can be misinterpreted as severely symptomatic hyponatremia and diuresis should be monitored.
Introduction
Understanding the mechanisms underlying the differences in renal decline between men and women may improve sex-specific clinical monitoring and management. To this end, we aimed to compare the slope of renal function decline in older men and women in chronic kidney disease (CKD) Stages 4 and 5, taking into account informative censoring related to the sex-specific risks of mortality and dialysis initiation.
Methods
The European QUALity Study on treatment in advanced CKD (EQUAL) study is an observational prospective cohort study in Stages 4 and 5 CKD patients ≥65 years not on dialysis. Data on clinical and demographic patient characteristics were collected between April 2012 and December 2018. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation. eGFR trajectory by sex was modelled using linear mixed models, and joint models were applied to deal with informative censoring.
Results
We included 7801 eGFR measurements in 1682 patients over a total of 2911 years of follow-up. Renal function declined by 14.0% [95% confidence interval (CI) 12.9–15.1%] on average each year. Renal function declined faster in men (16.2%/year, 95% CI 15.9–17.1%) compared with women (9.6%/year, 95% CI 6.3–12.1%), which remained largely unchanged after accounting for various mediators and for informative censoring due to mortality and dialysis initiation. Diabetes was identified as an important determinant of renal decline specifically in women.
Conclusion
In conclusion, renal function declines faster in men compared with women, which remained similar after adjustment for mediators and despite a higher risk of informative censoring in men. We demonstrate a disproportional negative impact of diabetes specifically in women.
Objective
Hypothalamic inflammation and endoplasmic reticulum (ER) stress are extensively linked to leptin resistance and overnutrition-related diseases. Surgical intervention remains the most efficient long-term weight-loss strategy for morbid obesity, but mechanisms underlying sustained feeding suppression remain largely elusive. This study investigated whether Roux-en-Y gastric bypass (RYGB) interacts with obesity-associated hypothalamic inflammation to restore central leptin signaling as a mechanistic account for post-operative appetite suppression.
Methods
RYGB or sham surgery was performed in high-fat diet-induced obese Wistar rats. Sham-operated rats were fed ad libitum or by weight matching to RYGB via calorie restriction (CR) before hypothalamic leptin signaling, microglia reactivity, and the inflammatory pathways were examined to be under the control of gut microbiota-derived circulating signaling.
Results
RYGB, other than CR-induced adiposity reduction, ameliorates hypothalamic gliosis, inflammatory signaling, and ER stress, which are linked to enhanced hypothalamic leptin signaling and responsiveness. Mechanistically, we demonstrate that RYGB interferes with hypothalamic ER stress and toll-like receptor 4 (TLR4) signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the altered gut microbial environment upon RYGB surgery.
Conclusions
Our data demonstrate that RYGB interferes with hypothalamic TLR4 signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the post-surgical altered gut microbial environment.
Purpose
Extracellular matrix remodeling is essential for extravillous trophoblast (EVT) cell migration and invasion during placental development and regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs). Sphingosine kinases (SPHK1 and SPHK2) synthesize sphingosine-1-phosphate (S1P), which works either intracellularly or extracellularly via its receptors S1PR1-5 in an autocrine or paracrine manner. The role of SPHKs/S1P in regulating the expression of MMPs and TIMPs in EVT is mostly unknown and forms the primary objective of the study.
Methods
HTR-8/SVneo cells were used as a model of EVT. To inhibit the expression of SPHKs, cells were treated with specific inhibitors, SK1-I and SKI-II, or gene-specific siRNAs. The expressions of MMPs and TIMPs were estimated by qPCR.
Results
We demonstrated that SPHK1, MMP1-3, and TIMP1-3 were highly expressed in HTR-8/SVneo cells. We found that treatment of cells with SK1-I, SKI-II, and knockdown of SPHK1 or SPHK2 increased the expression of MMP1, MMP3, and TIMP3. The addition of extracellular S1P inhibits the upregulation of MMPs and TIMPs in treated cells.
Conclusions
SPHKs negatively regulate the expression of MMP1, MMP3, and TIMP3. The level of intracellular S1P acts as a negative feedback switch for MMP1, MMP3, and TIMP3 expression in EVT cells.
High nutritional status promotes vitality of honey bees and mitigates negative effects of pesticides
(2022)
Honey bee health is affected by multiple stressors, such as the exposure to plant protection products (PPPs), dietary limitation, monofloral diets and pressure of diseases and pathogens and their interactions. Here, we analysed the interacting effects of plant protection products and low nutritional pollen source on honey bee health under semi-field conditions. We established a healthy honey bee colony in each of 24 tents, planted either with monofloral maize, maize with a diverse flower strip or with monofloral Phacelia tanacetifolia. To evaluate the interaction between exposure to PPPs and nutritional status, a mixture of the insecticide thiacloprid and the fungicide prochloraz was applied. For each colony, we investigated brood capping rate as well as adult longevity, body and head weight, and enzyme activity of acetylcholinesterase and P450 reductase of newly hatched worker bees.
We found a significant reduced capping rate in treated maize compared to flowering strips and Phacelia, but no interaction effect between pesticide treatment and nutritional status on capping rate. The response to treatment on the longevity of adults differed significantly between maize and Phacelia, with flower strips being intermediate, indicating interaction effects of PPP treatment and low pollen quality in maize compared to Phacelia and flowering strip treatments.
Head weight of newly hatched worker bees showed significant interaction of nutritional status and treatment of PPPs. PPPs slightly increased body weight in all nutritional statuses, except for Phacelia. Enzyme activity of acetylcholinesterase and P450 reductase showed significant different responses between maize and Phacelia to PPP exposure, but not between maize and flowering strip.
Our results support the hypothesis that higher pollen quality promotes development of larvae and pupae, longevity of adults and detoxification of PPPs.
In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865® exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865® significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865® on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD.
SPATS1 (spermatogenesis-associated, serine-rich 1) is an evolutionarily conserved, testis-specific protein that is differentially expressed during rat male meiotic prophase. Some reports have suggested a link between SPATS1 underexpression/mutation and human pathologies such as male infertility and testicular cancer. Given the absence of functional studies, we generated a Spats1 loss-of-function mouse model using CRISPR/Cas9 technology. The phenotypic analysis showed no overt phenotype in Spats1-/- mice, with both males and females being fertile. Flow cytometry and histological analyses did not show differences in the testicular content and histology between WT and knockout mice. Moreover, no significant differences in sperm concentration, motility, and morphology, were observed between WT and KO mice. These results were obtained both for young adults and for aged animals. Besides, although an involvement of SPATS1 in the Wnt signaling pathway has been suggested, we did not detect changes in the expression levels of typical Wnt pathway-target genes in mutant individuals. Thus, albeit Spats1 alteration might be a risk factor for male testicular health, we hereby show that this gene is not individually essential for male fertility and spermatogenesis in mouse.
Near-Infrared (NIR) phosphorescence at room temperature is challenging to achieve for organic molecules due to negligible spin–orbit coupling and a low energy gap leading to fast non-radiative transitions. Here, we show a supramolecular host–guest strategy to harvest the energy from the low-lying triplet state of C\(_{64}\) nanographene tetraimide 1. \(^1\)H NMR and X-ray analysis confirmed the 1 : 2 stoichiometric binding of a Pt(II) porphyrin on the two π-surfaces of 1. While the free 1 does not show emission in the NIR, the host–guest complex solution shows NIR phosphorescence at 77 K. Further, between 860–1100 nm, room temperature NIR phosphorescence (λ\(_{max}\)=900 nm, τ\(_{avg}\)=142 μs) was observed for a solid-state sample drop-casted from a preformed complex in solution. Theoretical calculations reveal a non-zero spin–orbit coupling between isoenergetic S\(_1\) and T\(_3\) of π-stacked [1 ⋅ Pt(II) porphyrin] complex. External heavy-atom-induced spin–orbit coupling along with rigidification and protection from oxygen in the solid-state promotes both the intersystem crossing from the first excited singlet state into the triplet manifold and the NIR phosphorescence from the lowest triplet state of 1.
Reactive electrophile species (RES), including prostaglandins, phytoprostanes and 12-oxo phytodienoic acid (OPDA), activate detoxification responses in plants and animals. However, the pathways leading to the activation of defense reactions related to abiotic or biotic stress as a function of RES formation, accumulation or treatment are poorly understood in plants. Here, the thiol-modification of proteins, including the RES-activated basic region/leucine zipper transcription factor TGA2, was studied. TGA2 contains a single cysteine residue (Cys186) that was covalently modified by reactive cyclopentenones but not required for induction of detoxification genes in response to OPDA or prostaglandin A1. Activation of the glutathione-S-transferase 6 (GST6) promoter was responsive to cyclopentenones but not to unreactive cyclopentanones, including jasmonic acid suggesting that thiol reactivity of RES is important to activate the TGA2-dependent signaling pathway resulting in GST6 activation We show that RES modify thiols in numerous proteins in vivo, however, thiol reactivity alone appears not to be sufficient for biological activity as demonstrated by the failure of several membrane permeable thiol reactive reagents to activate the GST6 promoter.
Being generally regarded as commensal bacteria, the pro-inflammatory capacity of Ureaplasma species has long been debated. Recently, we confirmed Ureaplasma–driven pro-inflammatory cytokine responses and a disturbance of cytokine equilibrium in primary human monocytes in vitro. The present study addressed the expression of CC chemokines and matrix metalloproteinase-9 (MMP-9) in purified term neonatal and adult monocytes stimulated with serovar 8 of Ureaplasma urealyticum (Uu) and serovar 3 of U. parvum (Up). Using qRT-PCR and multi-analyte immunoassay, we assessed mRNA and protein expression of the monocyte chemotactic proteins 1 and 3 (MCP-1/3), the macrophage inflammatory proteins 1α and 1β (MIP-1α/β) as well as MMP-9. For the most part, both isolates stimulated mRNA expression of all given chemokines and MMP-9 in cord blood and adult monocytes (p<0.05 and p<0.01). These results were paralleled by Uu and Up-induced secretion of MCP-1 protein in both cells (neonatal: p<0.01, adult: p<0.05 and p<0.01). Release of MCP-3, MIP-1α, MIP-1β and MMP-9 was enhanced upon exposure to Up (neonatal: p<0.05, p<0.01 and p<0.001, respectively; adult: p<0.05). Co-stimulation of LPS-primed monocytes with Up increased LPS-induced MCP-1 release in neonatal cells (p<0.05) and aggravated LPS-induced MMP-9 mRNA in both cell subsets (neonatal: p<0.05, adult: p<0.01). Our results document considerable expression of pro-inflammatory CC chemokines and MMP-9 in human monocytes in response to Ureaplasma isolates in vitro, adding to our previous data. Findings from co-stimulated cells indicate that Ureaplasma may modulate monocyte immune responses to a second stimulus.
Bactericidal materials gained interest in the health care sector as they are capable of preventing material surfaces from microbial colonization and subsequent spread of infections. However, commercialization of antimicrobial materials requires proof of their efficacy, which is usually done using in vitro methods. The ISO 22196 standard (Japanese test method JIS Z 2801) is a method for measuring the antibacterial activity of daily goods. As it was found reliable for testing the biocidal activity of antimicrobially active materials and surface coatings most of the laboratories participating in this study used this protocol. Therefore, a round robin test for evaluating antimicrobially active biomaterials had to be established. To our knowledge, this is the first report on inaugurating a round robin test for the ISO 22196 / JIS Z 2801. The first round of testing showed that analyses in the different laboratories yielded different results, especially for materials with intermediate antibacterial effects distinctly different efficacies were noted. Scrutinizing the protocols used by the different participants and identifying the factors influencing the test outcomes the approach was unified. Four critical factors influencing the outcome of antibacterial testing were identified in a series of experiments: (1) incubation time, (2) bacteria starting concentration, (3) physiological state of bacteria (stationary or exponential phase of growth), and (4) nutrient concentration. To our knowledge, this is the first time these parameters have been analyzed for their effect on the outcome of testing according to ISO 22196 / JIS Z 2801. In conclusion, to enable assessment of the results obtained it is necessary to evaluate these single parameters in the test protocol carefully. Furthermore, uniform and robust definitions of the terms antibacterial efficacy / activity, bacteriostatic effects, and bactericidal action need to be agreed upon to simplify communication of results and also regulate expectations regarding antimicrobial tests, outcomes, and materials.
The degree of conservation and evolution of cytoplasmic mRNA metabolism pathways across the eukaryotes remains incompletely resolved. In this study, we describe a comprehensive genome and transcriptome-wide analysis of proteins involved in mRNA maturation, translation, and mRNA decay across representative organisms from the six eukaryotic super-groups. We demonstrate that eukaryotes share common pathways for mRNA metabolism that were almost certainly present in the last eukaryotic common ancestor, and show for the first time a correlation between intron density and a selective absence of some Exon Junction Complex (EJC) components in eukaryotes. In addition, we identify pathways that have diversified in individual lineages, with a specific focus on the unique gene gains and losses in members of the Excavata and SAR groups that contribute to their unique gene expression pathways compared to other organisms.
Aims
To estimate the 10-year risk of fatal cardiovascular disease (CVD) in the 40 to 69 year old general population in Germany stratified by sex and to analyze differences between socio-economic status (SES), region and community size in individuals without CVD. The analysis is based on the newly recalibrated SCORE Deutschland risk charts and considered other comorbidities for the classification of the high CVD risk group according to the guidelines of the European Society of Cardiology.
Methods and results
In 3,498 participants (40–69 years) from the German Health Examination Survey for Adults 2008–2011 (DEGS1) without a history of CVD (myocardial infarction, coronary heart disease, heart failure, stroke) we estimated the proportion with a low (SCORE <1%), moderate (SCORE 1-<5%) and high 10-year CVD mortality risk (SCORE ≥5% or diabetes, renal insufficiency, SBP/DPB ≥180/110 mmHg or cholesterol >8 mmol/l). The prevalence of low, moderate and high risk was 42.8%, 38.5% and 18.8% in men and 73.7%, 18.1% and 8.2% in women. The prevalence of high risk was significantly lower in women with a high compared to a low SES (3.3% vs. 11.2%) and in communities with ≥100.000 inhabitants compared to <20.000 inhabitants (5.4% vs.10.9%). There were no significant associations between predicted CVD mortality risk and SES or community size in men and regions in men and women. Among the high risk group, 58.2% of men and 9.8% of women had SCORE ≥5%, leaving the majority of women (60.1%) classified as high risks due to diabetes and SCORE <5%.
Conclusion
Our results suggest the persistence of socioeconomic disparities in predicted cardiovascular mortality in women and support the need of large-scale prevention efforts beyond individual lifestyle modification or treatment. Furthermore, the importance of additional comorbidities for the high risk group classification is highlighted.
Pyrrolizidinalkaloide sind eine Gruppe von sekundären Pflanzenstoffen, welche durch ihre Genotoxizität und Kanzerogenität schon lange in der Kritik des Bundesinstituts für Risikobewertung (BfR) stehen. In der Leber werden diese Stoffe metabolisiert und in ihre aktive Form überführt. Als Folge eines übermäßigen Konsums von Pyrrolizidinalkaloiden wurden Fälle der venösen okklusiven Lebererkrankungen beobachtet und auch die Entstehung von Tumoren in Tiermodellen konnte auf eine Pyrrolizidinalkaloidexposition zurückgeführt werden.
Die vorliegende Arbeit verglich das genotoxische Potenzial der drei Pyrrolizidinalkaloide Lasiocarpin, Seneciphyllin und Europin in den humanen Leberzelllinien HepG2 und Huh6. Die Einschätzung erfolgte anhand der Ergebnisse der durchgeführten Mikrokerntests. Des Weiteren wurde die Rolle des metabolischen Enzyms CYP-3A4, durch Zugabe entsprechender Inhibitoren und Stimulatoren, sowie die Wirkung des intrazellulären Glutathions auf die Toxizität der Pyrrolizidinalkaloide untersucht. Zudem wurde ein Schwerpunkt auf die Analyse der Mitose von mit Pyrrolizidinalkaloiden behandelten Zellen gelegt. Hier lag die Konzentration auf der Formatierung der Mikrotubuli und auf der Entstehung der Mikrokerne. Eine abschließende Lebendzellmikroskopie visualisierte den toxischen Einfluss des Pyrrolizidinalkaloides Lasiocarpin auf die Mitose und Kernteilung der HepG2-Zellen und erlaubt einen Ausblick auf weitere Forschungshypothesen.
Das toxische Potenzial der drei untersuchten Pyrrolizidinalkaloide zeigte gleiche Tendenzen in den untersuchten toxischen Merkmalen. Bei allen verwendeten Substanzen konnte ein Anstieg der Mikrokernzahl und der apoptotischen Zellen beobachtet werden. Gegenläufig dazu zeigte sich bei allen drei Pyrrolizidinalkaloiden eine Reduktion der Mitoserate und auch ein Rückgang des Proliferationsindex. Lasiocarpin zeigte eindeutig das höchste genotoxische Potenzial.
Die Rolle des Metabolisierungsenzyms Cytochrom P450 auf den Stoffwechsel konnte anhand von klaren Ergebnissen definiert werden. Nach Hemmung des CYP-3A4-Enzyms durch das Antibiotikum Ketoconazol wurden weniger Mikrokerne durch das Pyrrolizidinalkaloid gebildet und die Zellproliferation stieg an. Die Behandlung mit Rifampicin, das eine Induktion der CYP-3A4-Expression verursachen kann, führte zu einer signifikant höheren Mikrokernzahl und einer Reduktion des Proliferationsindex im Beisein von Lasiocarpin.
Die Auswirkung einer Glutathiondepletion auf die Zyto- und Genotoxizität von Lasiocarpin wurde in dieser Studie ebenfalls untersucht. Zum einen wird klar, dass Glutathion eine Rolle in der Zytotoxizität der Pyrrolizidinalkaloiden spielt. Nach Behandlung von Gluatathion-depletierten Zellen mit Lasiocarpin sank der Proliferationsindex im Vergleich zu den Zellen, welche lediglich mit Lasiocarpin behandelt wurden. Aber auch die genotoxische Wirkung des Lasiocarpins kann durch Depletion des Glutathions verstärkt werden, was die signifikante Erhöhung der Mikrokernrate in den Huh6-Zellen belegt.
Ein großer Teil dieser Forschungsarbeit behandelt den Einfluss von Pyrrolizidinalkaloiden auf die Zellteilung. So wurde einerseits die Veränderung der Anteile der mitotischen Stadien beurteilt und die Entwicklung von mitotischen Störungen quantifiziert. Alle durchgeführten Versuche zeigten, dass die Zahl der mitotischen Zellen konzentrationsabhängig durch Lasiocarpin gesenkt wird. In der Analyse der prozentualen Verteilung der mitotischen Stadien fiel auf, dass sich durch Lasiocarpin vor allem der Anteil der Zellen in der Pro- und Metaphase verringerte. Besonders deutlich zeigte sich zudem dosisabhängig die stärkere Formatierung von fehlerhaften mitotischen Figuren. Durch die durchgeführte Kinetochor-Antikörperfärbung konnte aufgezeigt werden, dass die Mikrokerne chromosomale DNA enthalten und vermutlich durch den Verlust von vollständigen Chromosomen entstehen. Die bereits beschriebene Zunahme an gestörten mitotischen Figuren wurde ebenfalls durch die alpha-Tubulin-Antikörperfärbung bestätigt. Diese Untersuchung richtete den Fokus auf die Ausbildung der Mikrotubuli während der Mitose und den genotoxischen Einfluss des Pyrrolizidinalkaloids Lasiocarpin darauf. Durch Lasiocarpin entstanden signifikant mehr Zellen mit multiplen Spindelpolen und gleichzeitig nahm der Anteil an korrekt ausgebildeten Spindeln ab. Durch den toxischen Einfluss von Lasiocarpin bildeten sich zudem häufiger Zellen ohne erkennbaren Spindelpol mit einer deutlich gestörten Spindelorganisation. In der abschließend durchgeführten Lebendzellmikroskopie konnten die gewonnenen Ergebnisse über die genotoxische und zytotoxische Wirkung von Lasiocarpin auf die Leberzellen bestätigt und visualisiert werden. Eine neue Erkenntnis durch die Lebendzellmikroskopie ist die Zunahme der Dauer der Mitose durch Lasiocarpin. Diese Verlängerung der Zellteilung kann möglicherweise durch einen mitotischen Arrest, welcher durch Aktivierung eines Checkpoint-Signalwegs ausgelöst wird, erklärt werden. Daher sollte zukünftig die Auswirkung von Pyrrolizidinalkaloiden auf die verschiedenen Kontrollpunkte der Zellteilung untersucht werden, um die Toxizität der Pyrrolizidinalkaloide besser beurteilen zu können.
Background
Neuroblastoma (NB) is the most common, extracranial childhood solid tumor arising from neural crest progenitor cells and is a primary cause of death in pediatric patients. In solid tumors, stromal elements recruited or generated by the cancer cells favor the development of an immune-suppressive microenvironment. Herein, we investigated in NB cell lines and in NB biopsies, the presence of cancer cells with mesenchymal phenotype and determined the immune-suppressive properties of these tumor cells on natural killer (NK) cells.
Methods
We assessed the mesenchymal stromal cell (MSC)-like phenotype and function of five human NB cell lines and the presence of this particular subset of neuroblasts in NB biopsies using flow-cytometry, immunohistochemistry, RT-qPCR, cytotoxicity assays, western blot and silencing strategy. We corroborated our data consulting a public gene-expression dataset.
Results
Two NB cell lines, SK-N-AS and SK-N-BE(2)C, exhibited an unprecedented MSC phenotype (CD105+/CD90+/CD73+/CD29+/CD146+/GD2+/TAZ+). In these NB-MSCs, the ectoenzyme CD73 and the oncogenic/immune-regulatory transcriptional coactivator TAZ were peculiar markers. Their MSC-like nature was confirmed by their adipogenic and osteogenic differentiation potential. Immunohistochemical analysis confirmed the presence of neuroblasts with MSC phenotype (CD105+/CD73+/TAZ+). Moreover, a public gene-expression dataset revealed that, in stage IV NB, a higher expression of TAZ and CD105 strongly correlated with a poorer outcome.
Among the NB-cell lines analyzed, only NB-MSCs exhibited multifactorial resistance to NK-mediated lysis, inhibition of activating NK receptors, signal adaptors and of NK-cell cytotoxicity through cell-cell contact mediated mechanisms. The latter property was controlled partially by TAZ, since its silencing in NB cells efficiently rescued NK-cell cytotoxic activity, while its overexpression induced opposite effects in non-NB-MSC cells.
Conclusions
We identified a novel NB immunoregulatory subset that: (i) displayed phenotypic and functional properties of MSC, (ii) mediated multifactorial resistance to NK-cell-induced killing and (iii) efficiently inhibited, in coculture, the cytotoxic activity of NK cells against target cells through a TAZ-dependent mechanism. These findings indicate that targeting novel cellular and molecular components may disrupt the immunomodulatory milieu of the NB microenvironment ameliorating the response to conventional treatments as well as to advanced immunotherapeutic approaches, including adoptive transfer of NK cells and chimeric antigen receptor T or NK cells.
Even though automated functional annotation of genes represents a fundamental step in most genomic and metagenomic workflows, it remains challenging at large scales. Here, we describe a major upgrade to eggNOG-mapper, a tool for functional annotation based on precomputed orthology assignments, now optimized for vast (meta)genomic data sets. Improvements in version 2 include a full update of both the genomes and functional databases to those from eggNOG v5, as well as several efficiency enhancements and new features. Most notably, eggNOG-mapper v2 now allows for: 1) de novo gene prediction from raw contigs, 2) built-in pairwise orthology prediction, 3) fast protein domain discovery, and 4) automated GFF decoration. eggNOG-mapper v2 is available as a standalone tool or as an online service at http://eggnog-mapper.embl.de.
The anti-tumor response of Vγ9Vδ2 T cells requires the sensing of accumulated phosphoantigens (pAgs) bound intracellularly to butyrophilin 3A1 (BTN3A1). In this study, we show that butyrophilin 2A1 (BTN2A1) is required for BTN3A-mediated Vγ9Vδ2 T cell cytotoxicity against cancer cells, and that expression of the BTN2A1/BTN3A1 complex is sufficient to trigger Vγ9Vδ2 TCR activation. Also, BTN2A1 interacts with all isoforms of BTN3A (BTN3A1, BTN3A2, BTN3A3), which appears to be a rate-limiting factor to BTN2A1 export to the plasma membrane. BTN2A1/BTN3A1 interaction is enhanced by pAgs and, strikingly, B30.2 domains of both proteins are required for pAg responsiveness. BTN2A1 expression in cancer cells correlates with bisphosphonate-induced Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell killing of cancer cells is modulated by anti-BTN2A1 monoclonal antibodies (mAbs), whose action relies on the inhibition of BTN2A1 binding to the Vγ9Vδ2TCR. This demonstrates the potential of BTN2A1 as a therapeutic target and adds to the emerging butyrophilin-family cooperation pathway in γδ T cell activation.
CRISPR–Cas systems provide bacteria with adaptive immunity against phages and plasmids; however, pathways regulating their activity are not well defined. We recently developed a high-throughput genome-wide method (SorTn-seq) and used this to uncover CRISPR–Cas regulators. Here, we demonstrate that the widespread Rsm/Csr pathway regulates the expression of multiple CRISPR–Cas systems in Serratia (type I-E, I-F and III-A). The main pathway component, RsmA (CsrA), is an RNA-binding post-transcriptional regulator of carbon utilisation, virulence and motility. RsmA binds cas mRNAs and suppresses type I and III CRISPR–Cas interference in addition to adaptation by type I systems. Coregulation of CRISPR–Cas and flagella by the Rsm pathway allows modulation of adaptive immunity when changes in receptor availability would alter susceptibility to flagella-tropic phages. Furthermore, we show that Rsm controls CRISPR–Cas in other genera, suggesting conservation of this regulatory strategy. Finally, we identify genes encoding RsmA homologues in phages, which have the potential to manipulate the physiology of host bacteria and might provide an anti-CRISPR activity.
Heterotopic ossification (HO) represents a common problem after tendon injury with no effective treatment yet being developed. Tenomodulin (Tnmd), the best-known mature marker for tendon lineage cells, has important effects in tendon tissue aging and function. We have reported that loss of Tnmd leads to inferior early tendon repair characterized by fibrovascular scaring and therefore hypothesized that its lack will persistently cause deficient repair during later stages. Tnmd knockout (Tnmd−/−) and wild-type (WT) animals were subjected to complete Achilles tendon surgical transection followed by end-to-end suture. Lineage tracing revealed a reduction in tendon-lineage cells marked by ScleraxisGFP, but an increase in alpha smooth muscle actin myofibroblasts in Tnmd−/− tendon scars. At the proliferative stage, more pro-inflammatory M1 macrophages and larger collagen II cartilaginous template were detected in this group. At the remodeling stage, histological scoring revealed lower repair quality in the injured Tnmd−/− tendons, which was coupled with higher HO quantified by micro-CT. Tendon biomechanical properties were compromised in both groups upon injury, however we identified an abnormal stiffening of non-injured Tnmd−/− tendons, which possessed higher static and dynamic E-moduli. Pathologically thicker and abnormally shaped collagen fibrils were observed by TEM in Tnmd−/− tendons and this, together with augmented HO, resulted in diminished running capacity of Tnmd−/− mice. These novel findings demonstrate that Tnmd plays a protecting role against trauma-induced endochondral HO and can inspire the generation of novel therapeutics to accelerate repair.
Pregnancy and lactation-associated osteoporosis (PLO) is a rare skeletal disorder characterized by early-onset osteoporosis typically manifestating with vertebral compression fractures or transient osteoporosis of the hip. We hypothesized that genetic variants may play a role in the development of PLO. This study aimed to analyze the presence of genetic variants and a potential association with the clinical presentation in PLO. 42 women with PLO were included from 2013 to 2019 in a multicenter study in Germany. All cases underwent comprehensive genetic analysis based on a custom-designed gene panel including genes relevant for skeletal disorders. The skeletal status was assessed using dual-energy X-ray absorptiometry (DXA). Subgroups were further analyzed by serum bone turnover markers (n = 31) and high-resolution peripheral computed tomography (HR-pQCT; n = 23). We detected relevant genetic variants in 21 women (50%), with LRP5, WNT1 and COL1A1/A2 being the most commonly involved genes. The mean number of vertebral compression fractures was 3.3 ± 3.4 per case with a significantly higher occurrence in the subgroup with genetic variants (4.8 ± 3.7 vs. 1.8 ± 2.3, p = 0.02). Among the total cohort, DXA Z-scores were significantly lower at the lumbar spine compared to the femoral neck (p = 0.002). HR-pQCT revealed a pronounced reduction of trabecular and cortical thickness, while trabecular number was within the reference range. Eighteen women (43%) received a bone-specific therapy (primarily teriparatide). Overall, a steep increase in bone mass (+37.7%) was observed after 3 years. In conclusion, pregnancy and lactation represent skeletal risk factors, which may unmask hereditary bone disorders leading to PLO. These cases were affected more severely. Nevertheless, a timely diagnosis and adequate treatment can ensure a substantial recovery potential even without specific therapy. Patients with genetically induced low bone turnover (e.g.; LRP5, WNT1) may especially benefit from osteo-anabolic medication.
Abdominal aortic aneurysm (AAA) is a disease with high morbidity and mortality, especially when ruptured. The rationale of this study was to evaluate the repurposing of lenvatinib, a multi–tyrosine kinase inhibitor, in limiting experimental AAA growth targeting vascular smooth muscle cells (VSMCs) and angiogenesis. We applied systemic and local lenvatinib treatment to elastase-induced murine aortic aneurysms, and RNA profiling identified myosin heavy chain 11 (Myh11) as the most deregulated transcript. Daily oral treatment substantially reduced aneurysm formation in 2 independent mouse models. In addition, a large animal aneurysm model in hypercholesterolemic low-density lipoprotein receptor–knockout (LDLR–/–) Yucatan minipigs was applied to endovascularly deliver lenvatinib via drug-eluting balloons (DEBs). Here, a single local endovascular delivery blocked AAA progression successfully compared with a DEB-delivered control treatment. Reduced VSMC proliferation and a restored contractile phenotype were observed in animal tissues (murine and porcine), as well as AAA patient-derived cells. Apart from increasing MYH11 levels, lenvatinib reduced downstream ERK signaling. Hence, lenvatinib is a promising therapy to limit aortic aneurysm expansion upon local endovascular delivery. The tyrosine kinase inhibitor was able to positively affect pathways of key relevance to human AAA disease, even in a potentially new local delivery using DEBs.
Wood-living beetles make up a large proportion of forest biodiversity and contribute to important ecosystem services, including decomposition. Beetle communities in managed southern boreal forests are less species rich than in natural and near-natural forest stands. In addition, many beetle species rely primarily on specific tree species. Yet, the associations between individual beetle species, forest management category, and tree species are seldom quantified, even for red-listed beetles. We compiled a beetle capture dataset from flight intercept traps placed on Norway spruce (Picea abies), oak (Quercus sp.), and Eurasian aspen (Populus tremulae) trees in 413 sites in mature managed forest, near-natural forest, and clear-cuts in southeastern Norway. We used joint species distribution models to estimate the strength of associations for 368 saproxylic beetle species (including 20 vulnerable, endangered, or critical red-listed species) for each forest management category and tree species. Tree species on which traps were mounted had the largest effect on beetle communities; oaks had the most highly associated beetle species, including most of the red-listed species, followed by Norway spruce and Eurasian aspen. Most beetle species were more likely to be captured in near-natural than in mature managed forest. Our estimated associations were compatible – for many species – with categorical classifications found in several existing databases of saproxylic beetle preferences. These quantitative beetle-habitat associations will improve future analyses that have typically relied on categorical classifications. Our results highlight the need to prioritize conservation of near-natural forests and oak trees in Scandinavia to protect the habitat of many red-listed species in particular. Furthermore, we underline the importance of carefully considering the species of trees on which traps are mounted in order to representatively sample beetle communities in forest stands.
Antibody avidity, persistence, and response to antigen recall: comparison of vaccine adjuvants
(2021)
Differences in innate immune ‘imprinting’ between vaccine adjuvants may mediate dissimilar effects on the quantity/quality of persisting adaptive responses. We compared antibody avidity maturation, antibody/memory B cell/CD4+ T cell response durability, and recall responses to non-adjuvanted fractional-dose antigen administered 1-year post-immunization (Day [D]360), between hepatitis B vaccines containing Adjuvant System (AS)01B, AS01E, AS03, AS04, or Alum (NCT00805389). Both the antibody and B cell levels ranked similarly (AS01B/E/AS03 > AS04 > Alum) at peak response, at D360, and following their increases post-antigen recall (D390). Proportions of high-avidity antibodies increased post-dose 2 across all groups and persisted at D360, but avidity maturation appeared to be more strongly promoted by AS vs. Alum. Post-antigen recall, frequencies of subjects with high-avidity antibodies increased only markedly in the AS groups. Among the AS, total antibody responses were lowest for AS04. However, proportions of high-avidity antibodies were similar between groups, suggesting that MPL in AS04 contributes to avidity maturation. Specific combinations of immunoenhancers in the AS, regardless of their individual nature, increase antibody persistence and avidity maturation.
Background
Identifying pain-related response patterns and understanding functional mechanisms of symptom formation and recovery are important for improving treatment.
Objectives
We aimed to replicate pain-related avoidance-endurance response patterns associated with the Fear-Avoidance Model, and its extension, the Avoidance-Endurance Model, and examined their differences in secondary measures of stress, action control (i.e., dispositional action vs. state orientation), coping, and health.
Methods
Latent profile analysis (LPA) was conducted on self-report data from 536 patients with chronic non-specific low back pain at the beginning of an inpatient rehabilitation program. Measures of stress (i.e., pain, life stress) and action control were analyzed as covariates regarding their influence on the formation of different pain response profiles. Measures of coping and health were examined as dependent variables.
Results
Partially in line with our assumptions, we found three pain response profiles of distress-avoidance, eustress-endurance, and low-endurance responses that are depending on the level of perceived stress and action control. Distress-avoidance responders emerged as the most burdened, dysfunctional patient group concerning measures of stress, action control, maladaptive coping, and health. Eustress-endurance responders showed one of the highest levels of action versus state orientation, as well as the highest levels of adaptive coping and physical activity. Low-endurance responders reported lower levels of stress as well as equal levels of action versus state orientation, maladaptive coping, and health compared to eustress-endurance responders; however, equally low levels of adaptive coping and physical activity compared to distress-avoidance responders.
Conclusions
Apart from the partially supported assumptions of the Fear-Avoidance and Avoidance-Endurance Model, perceived stress and dispositional action versus state orientation may play a crucial role in the formation of pain-related avoidance-endurance response patterns that vary in degree of adaptiveness. Results suggest tailoring interventions based on behavioral and functional analysis of pain responses in order to more effectively improve patients quality of life.
The blink rate increases if a person indulges in a conversation compared to quiet rest. Since various factors were suggested to explain this increase, the present series of studies tested the influence of different motor activities, cognitive processes and auditory input on the blink behavior but at the same time minimized visual stimulation as well as social influences. Our results suggest that neither cognitive demands without verbalization, nor isolated lip, jaw or tongue movements, nor auditory input during vocalization or listening influence our blinking behavior. In three experiments, we provide evidence that complex facial movements during unvoiced speaking are the driving factors that increase blinking. If the complexity of the motor output increased such as during the verbalization of speech, the blink rate rose even more. Similarly, complex facial movements without cognitive demands, such as sucking on a lollipop, increased the blink rate. Such purely motor-related influences on blinking advise caution particularly when using blink rates assessed during patient interviews as a neurological indicator.
Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.
Studies have demonstrated an increased risk of accidents and injuries in children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about how accident risk may alter over the lifespan. Additionally, it would be important to know if the most common types of accidents and injuries differ in ADHD patients over different age groups. Furthermore, there is increasing evidence of an ameliorating effect of ADHD medication on accident risk. Lastly, the underlying risk factors and causal mechanisms behind increased accident risk remain unclear. We therefore conducted a systematic review focusing on the above described research questions. Our results suggested that accident/injury type and overall risk changes in ADHD patients over the lifespan. ADHD medication appeared to be similarly effective at reducing accident risk in all age groups. However, studies with direct comparisons of accident/injuries and effects of medication at different age groups or in old age are still missing. Finally, comorbidities associated with ADHD such as substance abuse appear to further increase the accident/injury risk.
Platinum-Templated Coupling of B=N Units: Synthesis of BNBN Analogues of 1,3-Dienes and a Butatriene
(2021)
The 1:2 reaction of [μ-(dmpm)Pt(nbe)]2 (dmpm=bis(dimethylphosphino)methane, nbe=norbornene) with Cl2BNR(SiMe3) (R=tBu, SiMe3) yields unsymmetrical (N-aminoboryl)aminoboryl PtI2 complexes by B−N coupling via ClSiMe3 elimination. A subsequent intramolecular ClSiMe3 elimination from the tBu-derivative leads to cyclization of the BNBN unit, forming a unique 1,3,2,4-diazadiboretidin-2-yl ligand. In contrast, the analogous reaction with Br2BN(SiMe3)2 leads, via a twofold BrSiMe3 elimination, to a PtII2 A-frame complex bridged by a linear BNBN isostere of butatriene. Structural and computational data confirm π electron delocalization over the entire BNBN unit.
Background
Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic.
Methods
In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed.
Findings
27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27–0·37]) and 82% at 8 weeks (0·18 [0·14–0·23]) following the week in which significant changes in population movements were recorded.
Interpretation
The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide.
A search for excited electrons produced in pp collisions at root s = 13 TeV via a contact interaction q (q) over bar -> ee* is presented. The search uses 36.1 fb(-1) of data collected in 2015 and 2016 by the ATLAS experiment at the Large Hadron Collider. Decays of the excited electron into an electron and a pair of quarks (eq (q) over bar) are targeted in final states with two electrons and two hadronic jets, and decays via a gauge interaction into a neutrino and a W boson (nu W) are probed in final states with an electron, missing transverse momentum, and a large-radius jet consistent with a hadronically decaying W boson. No significant excess is observed over the expected backgrounds. Upper limits are calculated for the pp -> ee* -> eeq (q) over bar and pp -> ee* -> e nu W production cross sections as a function of the excited electron mass m(e)* at 95% confidence level. The limits are translated into lower bounds on the compositeness scale parameter Lambda of the model as a function of m(e)*. For m(e)* < 0.5 TeV, the lower bound for Lambda is 11 TeV. In the special case of m(e)* = Lambda, the values of m(e)* < 4.8 TeV are excluded. The presented limits on Lambda are more stringent than those obtained in previous searches.
Bewegung wirkt sich in vielerlei Hinsicht positiv auf den Organismus aus. Das kann beispielsweise zu einer Verbesserung der Stoffwechselsituation und des Immunsystems führen. Außerdem kommt es zu Adaptationsprozessen im Knochen-, Knorpel- und Muskelgewebe, sowie in Sehnen, Bändern und im zentralen Nervensystem.
Die Vorgänge, die diese Änderungen bewirken sind komplex und werden durch verschiedene metabolische und molekulare Mechanismen ausgelöst. In den letzten Jahrzehnten wurden durch Sekretomanalyse eine Reihe von Myokinen entdeckt. Diese spielen eine entscheidende Rolle bei den Anpassungsprozessen des Organismus an eine sportliche Belastung. Vor allem sollen die Interleukine-6 und -8, sowie Follistatin und Follistatin-like-3 bei sportlichen Belastungen ausgeschüttet werden. Der Impuls dafür ist der muskuläre Reiz.
In dieser Gesamtstudie sollten Rückschlüsse auf die Regulation dieser Hormone erkannt werden. So wurden in der Studienreihe unterschiedliche Probandenkollektive bei der gleichen sportlichen Belastung untersucht. Im ersten Teil wurde ein Normalkollektiv als Ausgangskohorte herangezogen. In dieser Studie, dem zweiten Teil, wurden Leistungssportler betrachtet, die in Spiel- und Ausdauersportler eingeteilt werden konnten. Alle Probanden führten den gleichen Fahrradergometertest durch und es wurde zu verschiedenen Zeitpunkten (Tbaseline; T15‘post; T120‘post) Blut entnommen, um die Konzentration der Biomarker mittels ELISA zu bestimmen. Desgleichen wurden die Vitalparameter überwacht und die Serumkonzentration der Nebennierensteroide Aldosteron, Kortisol und Testosteron ausgewertet.
Es konnten einige signifikante Veränderungen der Hormone als Anpassung an einen sportlichen Reiz erkannt werden. Die Belastung führte zu einem signifikanten Anstieg der Aldosteronkonzentration und es kam zu einem signifikanten Abfall während der Regenerationszeit. Dies zeichnete sich bei den Spiel-, Ausdauersportlern und auch beim Normalkollektiv ab.
Betrachtet man die Kortisolkonzentration, so konnte wider Erwarten kein Anstieg von Kortisol als Stresshormon verzeichnet werden. Dagegen kam es in dieser Studie sogar zu einem signifikanten Abfall von Kortisol durch die Belastung. Das ist ein Hinweis auf die zu kurze und zu geringe Belastung dieses Tests. Aber dennoch waren die Kortisolwerte auch in dieser Studie bei den Sportlern nach der Regenerationszeit signifikant niedriger als vor der Belastung.
Testosteron zeichnete sich insgesamt als konstanter Parameter ab. Zudem zeigten die Sportler prozentual betrachtet einen signifikanten Anstieg der Testosteronkonzentration durch die Belastung.
Bei den FSTL-3 Konzentrationen konnte bei den Sportlern ein signifikanter Abfall durch die Belastung verzeichnet werden. Jedoch zeigten die Spielsportler nach der Belastung als auch nach der Regenerationszeit signifikant höhere Werte als die Ausdauersportler. Wider Erwarten konnten keine signifikanten Veränderungen von IL-6, IL-8 und FST nachgewiesen werden.
Es stellt sich die Frage, ob eine sportliche Belastung mit niedriger Intensität und einer Dauer von 15 Minuten überhaupt zur Ausschüttung dieser Myokine führen kann. Vermutlich wäre ein größerer Reiz notwendig gewesen um signifikantere Veränderungen zu messen. In dieser Studie kann die zu geringe Belastung subjektiv anhand den niedrigen Werten auf der Borg-Skala und objektiv anhand der geringen Veränderungen der Laktatkonzentrationen erklärt werden. So könnte die Belastung nicht ausgereicht haben, um genauere Rückschlüsse auf den Regulationsprozess verschiedener Myokine zu ziehen.
Diese Studie ist der zweite Teil einer größeren Studienreihe, bei der Unterschiede im Myokinprofil bei verschiedenen Probandengruppen gezeigt werden sollen. Es folgt eine dritte Studie mit älteren, sarkopenen Männern. Die Hoffnung liegt darin, durch Unterschiede der Myokinkonzentrationen zwischen den verschiedenen Probandenkollektiven Prognosen über das Auftreten von Muskel- und Knochenerkrankungen im Alter zu gewinnen. Dadurch könnte diesen frühzeitig durch geeignete Therapiemaßnahmen entgegenwirkt werden.
Obwohl die Prognose des MM sich die letzten Jahre signifikant verbessert hat, zeigen HR-Patienten nach wie vor ein ungünstiges Überleben. Dieses HRMM frühzeitig zu identifizieren, kann in Zukunft für die Entscheidung bezüglich der Behandlung von Vorteil sein. Allerdings fehlen Daten bezüglich der Risikostratifizierung des MM, die neben der traditionellen FISH auch andere Methoden wie SKY92 nutzen. Hierfür wurde die Studie dieser Arbeit entwickelt. Das genexpressionsbasierte Risikoklassifizierungsinstrument SKY92 konnte an der Universität Würzburg etabliert werden und dessen Vorhersagekraft getestet werden. Darüber hinaus wurde die prognostische Relevanz der Kombination von SKY92 und FISH für Patienten mit MM untersucht. Es wurden in dieser Arbeit prospektiv Knochenmarkproben und klinische Daten von 147 Patienten mit MM gesammelt. Mittels FISH wurde die Zytogenetik analysiert. Die SKY92 Risikoklassifikation und GEP-basierende IgH-Translokationen wurden mittels MMprofiler gene expression assay identifiziert. Bei 121 (82.3%) Patienten konnten wir SKY92 Daten erlangen. HR-SKY92 war bei RRMM (40/76) im Vergleich zu NDMM (6/45) (P<0.0001) deutlich erhöht. Wie erwartet war das PFS (P<0.0001) sowie auch das OS (P=0.0004) bei Patienten mit RRMM und HR SKY92 signifikant kürzer als bei SR. Auch bei Patienten mit NDMM, HR SKY92 zeigte sich ein signifikant kürzeres PFS(P=0.001) als bei Patienten mit SR. Es wurden zusätzlich bei 99 Patienten die Ergebnisse von der SKY92 Klassifikation mit zytogenetischen Analysen mittels FISH kombiniert. 30 Patienten zeigten in beiden Systemen, SKY92 und FISH, HR. Hinsichtlich des Überlebens wiesen Patienten mit double-HR sowohl bei SKY92 als auch bei FISH das schlechteste PFS (P<0.0001) und OS (P<0.0001) auf. Gleichzeitig erwies sich double-HR als negativer prognostischer Faktor für PFS bei NDMM-Patienten(P=0.01). SKY92 erwies sich in dieser Arbeit als zuverlässiges Instrument um HR-MM zu identifizieren. Des Weiteren konnte gezeigt werden, dass SKY92 und FISH, Patienten teilweise unterschiedlich klassifizieren. Auffällig war, dass die Patienten die ausschließlich SKY92 HR klassifiziert wurden, ein schlechteres PFS zeigten, als die Patienten, welche ausschließlich FISH HR aufwiesen. Dies legt die Vermutung nahe, dass SKY92 eine exaktere Klassifikation vornehmen kann als FISH alleine. Abschließend kann die Kombination aus SKY92 und FISH helfen, die Patienten mit dem höchsten Risiko zu identifizieren. In Zukunft kann die genauere Klassifizierung von MM-Patienten dazu beitragen, die Therapie zu personalisieren und das OS sowie das PFS zu verbessern.
Adipositas wurde mit erhöhtem oxidativem DNA-Schaden und verminderter DNA- Reparatur in Verbindung gebracht. Die Auswirkungen bariatrischer Chirurgie auf oxidativen DNA-Schaden sind bis heute nicht vollständig verstanden. Ziel dieser Arbeit war es, diese Fragestellung weiter zu erörtern. Die Ergebnisse zeigen eine signifikante BMI-Reduktion nach bariatrischer Operation. Unterschiedliche Operationsmethoden führten zu leicht unterschiedlichen Ergebnissen, wobei der RYGB zu einer etwas stärkeren Gewichtsreduktion führte als die SG. Eine Reduktion des DNA-Schadens wurde ebenfalls beobachtet und steht im Einklang mit früheren Ergebnissen. Der genaue Mechanismus für die Abnahme des DNA-Schadens ist nicht vollständig verstanden. Neben dem Gewichtsverlust treten komplexe metabolische Veränderungen auf, die möglicherweise eine Rolle spielen. Bei der vergleichenden Untersuchung von PBMCs vor und ein Jahr nach Operation konnte keine Verbesserung des oxidativen Status der Patienten gezeigt werden. Es wurde jedoch eine Reduktion des oxidativen Stresses nach der Operation in anderen Studien beobachtet, wobei die Datenlage sehr inkohärent ist. Des Weiteren wurde der Einfluss von Adipositas auf oxidativen DNA-Schaden in Plazentazellen untersucht. Bei adipösen Müttern wurde ein erhöhter basaler DNA- Schaden festgestellt, jedoch zeigten diese keine signifikanten Unterschiede der oxidativen DNA-Schäden im Vergleich zur Kontrollgruppe. Außerdem wurden die Reparaturaktivitäten der NER und BER in PBMCs adipöser Patienten und normalgewichtiger Kontrollen verglichen. Obwohl die PBMCs der Kontrollgruppe eine höhere Reparaturaktivität aufwiesen, war der Unterschied nicht signifikant. Weitere Untersuchungen deuten darauf hin, dass die DNA- Reparaturkapazität bei adipösen Personen verringert ist. Darüber hinaus wurden Möglichkeiten gesucht, Reparaturaktivität in kryokonservierten PBMCs nachzuweisen. Weder die Stimulation durch PHA noch die Zugabe von ATP oder längere Inkubationszeiten zur Regeneration führten zu einer nachweisbaren Reparaturaktivität. Die Herstellung von Proteinextrakten aus gefrorenen Zellen erwies sich als vielversprechende Alternative, um spezifische Reparaturwege zu untersuchen. Die Ergebnisse zeigen, dass Adipositas mit erhöhtem DNA-Schaden und oxidativem Stress assoziiert ist, eine Gewichtsabnahme nach bariatrischer Operation jedoch nicht zu der erwarteten Abnahme des oxidativen Stresses führte. Weitere Forschung ist notwendig, um die Hintergründe dieser Assoziation genauer zu verstehen.
Mixed, augmented, and virtual reality, collectively known as extended reality (XR), allows users to immerse themselves in virtual environments and engage in experiences surpassing reality's boundaries. Virtual humans are ubiquitous in such virtual environments and can be utilized for myriad purposes, offering the potential to greatly impact daily life. Through the embodiment of virtual humans, XR offers the opportunity to influence how we see ourselves and others. In this function, virtual humans serve as a predefined stimulus whose perception is elementary for researchers, application designers, and developers to understand. This dissertation aims to investigate the influence of individual-, system-, and application-related factors on the perception of virtual humans in virtual environments, focusing on their potential use as stimuli in the domain of body perception. Individual-related factors encompass influences based on the user's characteristics, such as appearance, attitudes, and concerns. System-related factors relate to the technical properties of the system that implements the virtual environment, such as the level of immersion. Application-related factors refer to design choices and specific implementations of virtual humans within virtual environments, such as their rendering or animation style. This dissertation provides a contextual framework and reviews the relevant literature on factors influencing the perception of virtual humans. To address identified research gaps, it reports on five empirical studies analyzing quantitative and qualitative data from a total of 165 participants. The studies utilized a custom-developed XR system, enabling users to embody rapidly generated, photorealistically personalized virtual humans that can be realistically altered in body weight and observed using different immersive XR displays. The dissertation's findings showed, for example, that embodiment and personalization of virtual humans serve as self-related cues and moderate the perception of their body weight based on the user's body weight. They also revealed a display bias that significantly influences the perception of virtual humans, with disparities in body weight perception of up to nine percent between different immersive XR displays. Based on all findings, implications for application design were derived, including recommendations regarding reconstruction, animation, body weight modification, and body weight estimation methods for virtual humans, but also for the general user experience. By revealing influences on the perception of virtual humans, this dissertation contributes to understanding the intricate relationship between users and virtual humans. The findings and implications presented have the potential to enhance the design and development of virtual humans, leading to improved user experiences and broader applications beyond the domain of body perception.
Postoperative Übelkeit und Erbrechen (PONV) ist eine der am häufigsten auftretenden Nebenwirkungen nach Allgemeinanästhesie. Für die Prävention von PONV stehen viele Antiemetika unterschiedlicher Substanzklassen zur Verfügung.
Ziel dieser Dissertation war die Untersuchung des Monitorings und der Berichterstattung von unerwünschten Ereignissen in Studienberichten, die in das Cochrane Review ‚Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis‘ [60] eingeschlossen wurden. Hierfür wurden nach Definition der Einschlusskriterien mithilfe des PICO-Schemas etablierte Datenbanken auf randomisierte kontrollierte Studien (RCTs) durchsucht. Literaturscreening und Datenerhebung erfolgte mit Covidence. Jede eingeschlossene Studie wurde auf ihr Risiko für Verzerrungen mithilfe des Cochrane „Risk of bias assessment tool 1.0“ untersucht. Ferner wurde das Risiko für Verzerrungen durch Monitoring und Berichterstattung jeglicher und schwerer unerwünschter Ereignisse mit einem modifizierten Tool von Tramacere et al. analysiert.
Die Anzahl eingeschlossener RCTs betrug 585 Studien mit insgesamt 97.516 Teilnehmenden. In 327 Studien wurde über relevante Sicherheitsendpunkte des Cochrane Reviews berichtet. Die Sicherheit der Evidenz wurde für die meisten Medikamente direkten Interesses lediglich als sehr niedrig bis niedrig bewertet. Der Endpunkt jegliche unerwünschten Ereignisse wurde in 61 Studien berichtet, wovon nur ein Anteil von 18% mit einem niedrigen Risiko für Verzerrung bewertet wurde. Der Endpunkt schwere unerwünschte Ereignisse wurde in 29 Studien berichtet, wovon lediglich fünf Studien als niedriges Risiko für Verzerrung eingestuft wurden.
Insgesamt sind Sicherheitsaspekte in RCTs unzureichend berichtet. Ein umfänglicheres Berichten von Monitoring und Ergebnissen von unerwünschten Ereignissen ist notwendig, um ein besseres Abwägen des Nutzen-Risiko-Verhältnisses von Interventionen zu ermöglichen. In den Ergebnissen sollte eine detaillierte Auflistung der aufgetretenen unerwünschten Ereignisse erfolgen, bei gleichzeitiger Vermeidung von allgemeinen Aussagen wie „insgesamt sicher/ gut verträglich“. Bei dem Verfassen eines Studienberichtes wird empfohlen, sich an bestehenden Standards wie die Erweiterung des CONSORT Statements für unerwünschte Ereignisse [52, 53] sowie den ICH Guidelines for Good Clinical Practice [71] zu orientieren. Zusätzlich dazu wurden im Rahmen dieser Arbeit Empfehlungen für Studienautorinnen und -autoren von RCTs für den Umgang mit unerwünschten Ereignissen erarbeitet.
In the present thesis the effect of the structure and surrounding environment on the fluorescence of merocyanine dyes was investigated. While these dyes are known to show very low fluorescence efficiencies due to the existence of conical intersections, it could be shown that different strategies to overcome this issue exist. Elongation of the polymethine bridge resulted in a slight fluorescence-enhancement and gave further insight into deactivation pathways of the excited state in these dyes. Implementation of the dyes in well-defined oligomer structures resulted in a pronounced fluorescence enhancement, which was investigated by spectroscopic and theoretical methods. Additionally, an artificial light-harvesting antenna was synthesized, which showed a strong absorption over the visible range and the most pronounced emission enhancement.