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Abstract
Background
Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin–glycoprotein‐complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para‐clinical parameters in the early disease phase in the well‐established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long‐term pre‐clinical study in mdx mice.
Methods
IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology.
Results
IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, (P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening (P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells (P = 0.0002) and macrophages (P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells (P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages (P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps (P ≤ 0.002 in all).
Conclusions
The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long‐term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. The data call for a clinical trial with IgG in DMD.
Background
We investigated the association between low cardiorespiratory fitness and liver fat content (LFC) in the general population.
Materials and Methods
We evaluated data from 2151 adults (51.1% women) from two population-based cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analysed the cross-sectional associations of peak oxygen uptake (VO2peak) with LFC, assessed by magnetic resonance imaging proton density fat fraction, as well as serum gamma-glutamyltransferase (GGT) and aminotransferase concentrations by multivariable regression models.
Results
We observed significant inverse associations of VO2peak with LFC and serum GGT, but not with serum aminotransferase levels. Specifically, a 1 L/min lower VO2peak was associated with a 1.09% (95% confidence interval [CI]: 0.45-1.73; P = .002) higher LFC and a 0.18 μkatal/L (95% CI: 0.09-0.26; P < .001) higher GGT levels. The adjusted odds ratio (OR) for the risk of prevalent hepatic steatosis (HS) by a 1 L/min decrease in VO2peak was 1.61 (95% CI: 1.22-2.13; P = .001). Compared to subjects with high VO2peak, obese and overweight individuals with low VO2peak had 1.78% (95% CI: 0.32-3.25; P = .017) and 0.94% (95% CI: 0.15-1.74; P = .021) higher mean LFC, respectively. Compared to those with high VO2peak, low VO2peak was independently associated with a higher risk of prevalent HS in the obese (adjusted-OR 2.29, 95% CI=1.48-3.56; P < .001) and overweight (adjusted OR 1.57, 95% CI=1.16-2.14; P = .04) groups.
Conclusions
Lower VO2peak was significantly associated with greater LFC and higher serum GGT levels in a population-based cohort of adult individuals. Our results suggest that low VO2peak might be a risk factor for HS.
The vast majority of RNA splicing in today‘s organisms is achieved by the highly regulated and precise removal of introns from pre-mRNAs via the spliceosome. Here we present a model of how RNA splicing may have occurred in earlier life forms. We have designed a hairpin ribozyme derived spliceozyme that mediates two RNA cleavages and one ligation event at specific positions and thus cuts a segment (intron) out of a parent RNA and ligates the remaining fragments (exons). The cut-out intron then performs a downstream function, acting as a positive regulator of the activity of a bipartite DNAzyme. This simple scenario shows how small RNAs can perform complex RNA processing dynamics, involving the generation of new phenotypes by restructuring segments of given RNA species, as well as delivering small RNAs that may play a functional role in downstream processes.
Abstract
Climate change is increasing the frequency and intensity of drought events in many boreal forests. Trees are sessile organisms with a long generation time, which makes them vulnerable to fast climate change and hinders fast adaptations. Therefore, it is important to know how forests cope with drought stress and to explore the genetic basis of these reactions. We investigated three natural populations of white spruce (Picea glauca) in Alaska, located at one drought‐limited and two cold‐limited treelines with a paired plot design of one forest and one treeline plot. We obtained individual increment cores from 458 trees and climate data to assess dendrophenotypes, in particular the growth reaction to drought stress. To explore the genetic basis of these dendrophenotypes, we genotyped the individual trees at 3000 single nucleotide polymorphisms in candidate genes and performed genotype–phenotype association analysis using linear mixed models and Bayesian sparse linear mixed models. Growth reaction to drought stress differed in contrasting treeline populations. Therefore, the populations are likely to be unevenly affected by climate change. We identified 40 genes associated with dendrophenotypic traits that differed among the treeline populations. Most genes were identified in the drought‐limited site, indicating comparatively strong selection pressure of drought‐tolerant phenotypes. Contrasting patterns of drought‐associated genes among sampled sites and in comparison to Canadian populations in a previous study suggest that drought adaptation acts on a local scale. Our results highlight genes that are associated with wood traits which in turn are critical for the establishment and persistence of future forests under climate change.
Abstract
The KV7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine‐induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. KV7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand‐based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved KV7.2/3 channel opening activity, indicated by an up to 13‐fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.
KV7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued KV7 channel openers flupirtine and retigabine bear an oxidation‐sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent KV7.2/3 opening activity, as evidenced by EC50 values approaching the single‐digit nanomolar range. On the other hand, weighted KV7.2/3 opening activity data including inactive compounds allowed for the establishment of structure–activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.
Abstract
Biocatalysis has found numerous applications in various fields as an alternative to chemical catalysis. The use of enzymes in organic synthesis, especially to make chiral compounds for pharmaceuticals as well for the flavors and fragrance industry, are the most prominent examples. In addition, biocatalysts are used on a large scale to make specialty and even bulk chemicals. This review intends to give illustrative examples in this field with a special focus on scalable chemical production using enzymes. It also discusses the opportunities and limitations of enzymatic syntheses using distinct examples and provides an outlook on emerging enzyme classes.
Introduction
Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD).
Methods
Data from 659 participants (age range: 21–81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]).
Results
Higher spermidine levels were significantly associated with lower hippocampal volume (ß = −0.076; 95% confidence interval [CI]: −0.13 to −0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = −0.104; 95% CI: −0.17 to −0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis.
Discussion
Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.
Abstract
Background
Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)‐cohort. We aimed to investigate clinical and molecular benefits or detriments of early mobilization and muscle activating measures in a high‐risk ICU‐acquired weakness cohort.
Methods
Fifty patients with a SOFA score ≥9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole‐body vibration in addition to early protocol‐based physiotherapy (intervention) or early protocol‐based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow‐up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol‐based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU‐acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier.
Results
ICU‐acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median [IQR]: CPP 3.3 [3.0–4.3]; control 3.0 [2.7–3.4]; intervention 3.0 [2.1–3.8]; P > 0.05 for all), ICU discharge (MRC median [IQR]: CPP 3.8 [3.4–4.4]; control 3.9 [3.3–4.0]; intervention 3.6 [2.8–4.0]; P > 0.05 for all), and 12 month follow‐up (MRC median [IQR]: control 5.0 [4.3–5.0]; intervention 4.8 [4.3–5.0]; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross‐sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up‐regulated gene expression for myosin heavy chains (fold change median [IQR]: MYH1 2.3 [1.1–2.7]; MYH2 0.7 [0.2–1.8]; MYH4 5.1 [2.2–15.3]) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32.
Conclusions
In our patients with sepsis syndrome at high risk for ICU‐acquired weakness muscle activating measures in addition to early protocol‐based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow‐up. Yet it prevented muscle atrophy.
Abstract
Background
Heparin induced thrombocytopenia (HIT) is likely a misdirected bacterial host defense mechanism. Platelet factor 4 (PF4) binds to polyanions on bacterial surfaces exposing neo‐epitopes to which HIT antibodies bind. Platelets are activated by the resulting immune complexes via FcγRIIA, release bactericidal substances, and kill Gram‐negative Escherichia coli.
Objectives
To assess the role of PF4, anti‐PF4/H antibodies and FcγRIIa in killing of Gram‐positive bacteria by platelets.
Methods
Binding of PF4 to protein‐A deficient Staphylococcus aureus (SA113Δspa) and non‐encapsulated Streptococcus pneumoniae (D39Δcps) and its conformational change were assessed by flow cytometry using monoclonal (KKO,5B9) and patient derived anti‐PF4/H antibodies. Killing of bacteria was quantified by counting colony forming units (cfu) after incubation with platelets or platelet releasate. Using flow cytometry, platelet activation (CD62P‐expression, PAC‐1 binding) and phosphatidylserine (PS)‐exposure were analyzed.
Results
Monoclonal and patient‐derived anti‐PF4/H antibodies bound in the presence of PF4 to both S. aureus and S. pneumoniae (1.6‐fold increased fluorescence signal for human anti‐PF4/H antibodies to 24.0‐fold increase for KKO). Staphylococcus aureus (5.5 × 104cfu/mL) was efficiently killed by platelets (2.7 × 104cfu/mL) or their releasate (2.9 × 104cfu/mL). Killing was not further enhanced by PF4 or anti‐PF4/H antibodies. Blocking FcγRIIa had no impact on killing of S. aureus by platelets. In contrast, S. pneumoniae was not killed by platelets or releasate. Instead, after incubation with pneumococci platelets were unresponsive to TRAP‐6 stimulation and exposed high levels of PS.
Conclusions
Anti‐PF4/H antibodies seem to have only a minor role for direct killing of Gram‐positive bacteria by platelets. Staphylococcus aureus is killed by platelets or platelet releasate. In contrast, S. pneumoniae affects platelet viability.
Urbanization is a major contributor to the loss of biodiversity. Its rapid progress is mostly at the expense of natural ecosystems and the species inhabiting them. While some species can adjust quickly and thrive in cities, many others cannot. To support biodiversity conservation and guide management decisions in urban areas, it is important to find robust methods to estimate the urban affinity of species (i.e. their tendency to live in urban areas) and understand how it is associated with their traits. Since previous studies mainly relied on discrete classifications of species' urban affinity, often involving inconsistent assessments or variable parameters, their results were difficult to compare. To address this issue, we developed and evaluated a set of continuous indices that quantify species' urban affinity based on publicly available occurrence data. We investigated the extent to which a species' position along the urban affinity gradient depends on the chosen index and how this choice affects inferences about the relationship between urban affinity and a set of morphological, sensory and functional traits. While these indices are applicable to a wide range of taxonomic groups, we examined their performance using a global set of 356 bat species. As bats vary in sensitivity to anthropogenic disturbances, they provide an interesting case study. We found that different types of indices resulted in different rankings of species on the urban affinity spectrum, but this had little effect on the association of traits with urban affinity. Our results suggest that bat species predisposed to urban life are characterized by low echolocation call frequencies, relatively long call durations, small body size and flexibility in the selection of the roost type. We conclude that simple indices are appropriate and practical, and propose to apply them to more taxa to improve our understanding of how urbanization favours or filters species with particular traits.
Background and purpose
The insula has important functions in monitoring and integrating physiological responses to a personal experience of multimodal input. The experience of chills in response to auditory stimuli is an important example for a relevant arousing experience coupled with bodily response. A group study about altered chill experiences in patients with insula lesions is lacking.
Methods
Twenty-eight stroke patients with predominantly insula lesions in the chronic stage and 14 age-matched controls were investigated using chill stimuli of both valences (music, harsh sounds). Group differences were analyzed in subjective chill reports, associated bodily responses (skin conductance response), lesion mapping, diffusion-weighted imaging and functional magnetic resonance imaging. Other neuropsychological deficits were excluded by comprehensive testing. Diffusion-weighted imaging was quantified for four insula tracts using fractional anisotropy.
Results
The frequency of chill experiences was comparable between participant groups. However, bodily responses were decreased for the stroke group. Whereas there was no association of lesion location, a positive association was found for the skin conductance response during aversive sounds and the tract connecting anterior inferior insula and left temporal pole in the stroke group. Similarly, functional magnetic resonance imaging activation in areas hypothesized to compensate for damage was increased with bodily response.
Conclusions
A decoupling of felt arousal and bodily response after insula lesion was observed. Impaired bodily response was related to an impaired interaction of the left anterior insula and the temporal pole.
Purpose
The German Retina.net ROP registry and its Europe-wide successor, the EU-ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries.
Methods
Exemplary datasets from the two databases over a 1-year period each (German Retina.net ROP Registry, 2011, 22 infants; EU-ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments.
Results
The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU-ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10–12 clock hours in 29% of cases, 2021: 4–6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti-VEGF therapy in 2021 (86.1%). Within the anti-VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021.
Conclusion
Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti-VEGF, and within the anti-VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021.
Abstract
Objective
This study was undertaken to calculate epilepsy‐related direct, indirect, and total costs in adult patients with active epilepsy (ongoing unprovoked seizures) in Germany and to analyze cost components and dynamics compared to previous studies from 2003, 2008, and 2013. This analysis was part of the Epi2020 study.
Methods
Direct and indirect costs related to epilepsy were calculated with a multicenter survey using an established and validated questionnaire with a bottom‐up design and human capital approach over a 3‐month period in late 2020. Epilepsy‐specific costs in the German health care sector from 2003, 2008, and 2013 were corrected for inflation to allow for a valid comparison.
Results
Data on the disease‐specific costs for 253 patients in 2020 were analyzed. The mean total costs were calculated at €5551 (±€5805, median = €2611, range = €274–€21 667) per 3 months, comprising mean direct costs of €1861 (±€1905, median = €1276, range = €327–€13 158) and mean indirect costs of €3690 (±€5298, median = €0, range = €0–€11 925). The main direct cost components were hospitalization (42.4%), antiseizure medication (42.2%), and outpatient care (6.2%). Productivity losses due to early retirement (53.6%), part‐time work or unemployment (30.8%), and seizure‐related off‐days (15.6%) were the main reasons for indirect costs. However, compared to 2013, there was no significant increase of direct costs (−10.0%), and indirect costs significantly increased (p < .028, +35.1%), resulting in a significant increase in total epilepsy‐related costs (p < .047, +20.2%). Compared to the 2013 study population, a significant increase of cost of illness could be observed (p = .047).
Significance
The present study shows that disease‐related costs in adult patients with active epilepsy increased from 2013 to 2020. As direct costs have remained constant, this increase is attributable to an increase in indirect costs. These findings highlight the impact of productivity loss caused by early retirement, unemployment, working time reduction, and seizure‐related days off.
Abstract
The neritid snail Theodoxus fluviatilis has formed regional subgroups in northern Europe, where it appears in both freshwater (FW) and brackish water (BW) in coastal areas of the Baltic Sea. These ecotypes show clear differences in osmotolerance and in the modes of accumulating organic osmolytes under hyperosmotic stress. We reasoned that the expression patterns of soluble proteins in the two ecotypes may differ as well. BW snails have to deal with a higher salinity (up to 20‰) than FW snails (0.5‰) and also cope with frequent fluctuations in environmental salinity that occur after heavy rains or evaporation caused by extended periods of intense sunshine. Therefore, the protein expression patterns of specimens collected at five different FW and BW sites were analyzed using 2D SDS‐PAGE, mass spectrometry, and sequence comparisons based on a transcriptome database for Theodoxus fluviatilis. We identified 89 differentially expressed proteins. The differences in the expression between FW and BW snails may be due to phenotypic plasticity, but may also be determined by local genetic adaptations. Among the differentially expressed proteins, 19 proteins seem to be of special interest as they may be involved in mediating the higher tolerance of BW animals towards environmental change compared with FW animals.
Bradyrhizobium diazoefficiens, a bacterial symbiont of soybean and other leguminous plants, enters a nodulation‐promoting genetic programme in the presence of host‐produced flavonoids and related signalling compounds. Here, we describe the crystal structure of an isoflavonoid‐responsive regulator (FrrA) from Bradyrhizobium, as well as cocrystal structures with inducing and noninducing ligands (genistein and naringenin, respectively). The structures reveal a TetR‐like fold whose DNA‐binding domain is capable of adopting a range of orientations. A single molecule of either genistein or naringenin is asymmetrically bound in a central cavity of the FrrA homodimer, mainly via C–H contacts to the π‐system of the ligands. Strikingly, however, the interaction does not provoke any conformational changes in the repressor. Both the flexible positioning of the DNA‐binding domain and the absence of structural change upon ligand binding are corroborated by small‐angle X‐ray scattering (SAXS) experiments in solution. Together with a model of the promoter‐bound state of FrrA our results suggest that inducers act as a wedge, preventing the DNA‐binding domains from moving close enough together to interact with successive positions of the major groove of the palindromic operator.
Abstract
Modeling of metabolite kinetics after oral administration of ketamine is of special interest because of the higher concentrations of active metabolites because of the hepatic first‐pass effect. This holds especially in view of the potential analgesic and antidepressant effects of 2R,6R‐ and 2S,6S‐hydroxynorketamine at low doses of ketamine. Therefore, a 9‐compartment model was developed to analyze the pharmacokinetics of ketamine enantiomers and their metabolites after racemic ketamine administered intravenously (5 mg) and as 4 doses (10, 20, 40, and 80 mg) of a prolonged‐release formulation (PR‐ketamine). Using a population approach, the serum concentration‐time data of the enantiomers of ketamine, norketamine, dehydronorketamine, and 2,6‐hydroxynorketamine obtained in 15 healthy volunteers could be adequately fitted. The estimated model parameters were used to simulate serum concentration‐time profiles; after multiple dosing of PR‐ketamine (2 daily doses of 20 mg), the steady‐state concentrations of R‐ and S‐ketamine were 1.4 and 1.3 ng/mL, respectively. The steady‐state concentration of 2R,6R‐hydroxynorketamine exceeded those of R‐norketamine (4‐fold), R‐dehydonorketamine (8‐fold), and R‐ketamine (46‐fold), whereas that of 2S,6S‐hydroxynorketamine exceeded that of S‐ketamine by 14‐fold. The model may be useful for identifying dosing regimens aiming at optimal plasma concentrations of 2,6‐hydroxynorketamines.
The relationship between Alzheimer's-related brain atrophy patterns and sleep macro-architecture
(2022)
Introduction
Sleep is increasingly recognized as a major risk factor for neurodegenerative disorders such as Alzheimer's disease (AD).
Methods
Using an magnetic resonance imaging (MRI)–based AD score based on clinical data from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) case-control cohort, we investigated the associations between polysomnography-based sleep macro-architecture and AD-related brain atrophy patterns in 712 pre-symptomatic, healthy subjects from the population-based Study of Health in Pomerania.
Results
We identified a robust inverse association between slow-wave sleep and the AD marker (estimate: −0.019; 95% confidence interval: −0.03 to −0.0076; false discovery rate [FDR] = 0.0041), as well as with gray matter (GM) thicknesses in typical individual cortical AD-signature regions. No effects were identified regarding rapid eye movement or non–rapid eye movement (NREM) stage 2 sleep, and NREM stage 1 was positively associated with GM thickness, mainly in the prefrontal cortical regions.
Discussion
There is a cross-sectional relationship between AD-related neurodegenerative patterns and the proportion of sleep spent in slow-wave sleep.
Thermally treated kaolinite is used to develop a range of alumino‐silicate‐based precursor materials but its behavior during plasma spraying has not been well‐researched. In this study, two types of kaolinite samples were investigated in the form of low defect (KGa‐1b) and high defect (KGa‐2) varieties. The extreme temperatures of the plasma stream (up to 20 000 K) induced flash melting to produce a highly porous alumino‐silicate glass without any crystallization of new Al−Si oxide minerals. The glass is comprised largely of intact or deformed spheres (average diameters 1.14–1.44 μm), which indicates rapid quenching and solidification before impact. The subspherical structures contain up to 40 % closed pore space caused by the rapid escape of water during melting. The low‐density, porous alumino‐silicate glass coatings with predicted specific surface areas (>0.95 m2/g) and hardnesses >1.8 GPa represent a potentially reactive but physically stable substrate ideal for further chemical functionalization.
Poly(vinyl alcohol) (PVA) is a water‐soluble synthetic vinyl polymer with remarkable physical properties including thermostability and viscosity. Its biodegradability, however, is low even though a large amount of PVA is released into the environment. Established physical‐chemical degradation methods for PVA have several disadvantages such as high price, low efficiency, and secondary pollution. Biodegradation of PVA by microorganisms is slow and frequently involves pyrroloquinoline quinone (PQQ)‐dependent enzymes, making it expensive due to the costly cofactor and hence unattractive for industrial applications. In this study, we present a modified PVA film with improved properties as well as a PQQ‐independent novel enzymatic cascade for the degradation of modified and unmodified PVA. The cascade consists of four steps catalyzed by three enzymes with in situ cofactor recycling technology making this cascade suitable for industrial applications.
Obstructive sleep apnea is known to be an overall public health problem that, among other things, increases morbidity and mortality. Risk factors as well as symptoms of this multidimensional sleep-related breathing disorder negatively affect quality of life. With our study we aimed to expose the association between obstructive sleep apnea and quality of life in the population of Pomerania, Germany. We utilized data from the population-based Study of Health in Pomerania (SHIP). Information on health status and risk factors about 4420 participants (2275 women) were gathered within the cohort SHIP-TREND, of which 1209 (559 women) underwent an overnight polysomnography and completed sleep questionnaires. The quality of life of the participants was measured using the Short-Form 12 questionnaire. For our study, an ordinal regression analysis with age, sex, body mass index and the Short-Form 12 health survey as predictors for apnea–hypopnea index was computed. The potential factors affecting quality of life are different between physical and mental dimensions of quality of life. Significant effects were found regarding age, sex, body mass index and the Short-Form 12 Mental Component Score, but not the Physical Component Score.
Abstract
Higher biodiversity can stabilize the productivity and functioning of grassland communities when subjected to extreme climatic events. The positive biodiversity–stability relationship emerges via increased resistance and/or recovery to these events. However, invader presence might disrupt this diversity–stability relationship by altering biotic interactions. Investigating such disruptions is important given that invasion by non‐native species and extreme climatic events are expected to increase in the future due to anthropogenic pressure. Here we present one of the first multisite invader × biodiversity × drought manipulation experiment to examine combined effects of biodiversity and invasion on drought resistance and recovery at three semi‐natural grassland sites across Europe. The stability of biomass production to an extreme drought manipulation (100% rainfall reduction; BE: 88 days, BG: 85 days, DE: 76 days) was quantified in field mesocosms with a richness gradient of 1, 3, and 6 species and three invasion treatments (no invader, Lupinus polyphyllus, Senecio inaequidens). Our results suggest that biodiversity stabilized community productivity by increasing the ability of native species to recover from extreme drought events. However, invader presence turned the positive and stabilizing effects of diversity on native species recovery into a neutral relationship. This effect was independent of the two invader's own capacity to recover from an extreme drought event. In summary, we found that invader presence may disrupt how native community interactions lead to stability of ecosystems in response to extreme climatic events. Consequently, the interaction of three global change drivers, climate extremes, diversity decline, and invasive species, may exacerbate their effects on ecosystem functioning.
Rice husk, one of the main side products in the rice production, and its sustainable management represent a challenge in many countries. Herein, we describe the use of this abundant agricultural bio‐waste as feedstock for the preparation of silver‐containing carbon/silica nano composites with antimicrobial properties. The synthesis was performed using a fast and cheap methodology consisting of wet impregnation followed by pyrolysis, yielding C/SiO2 composite materials doped with varying amounts of silver from 28 to 0.001 wt %. The materials were fully characterized and their antimicrobial activity against ESKAPE pathogens, namely E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and E. coli, and the pathogenic yeast C. albicans was investigated. Sensitivities of these strains against the prepared materials were demonstrated, even with exceptional low amounts of 0.015 m% silver. Hence, we report a straightforward method for the synthesis of antimicrobial agents from abundant sources which addresses urgent questions like bio‐waste valorization and affordable alternatives to increasingly fewer effective antibiotics.
Understanding the effects of temperature and moisture on radial growth is vital for assessing the impacts of climate change on carbon and water cycles. However, studies observing growth at sub-daily temporal scales remain scarce.
We analysed sub-daily growth dynamics and its climatic drivers recorded by point dendrometers for 35 trees of three temperate broadleaved species during the years 2015–2020. We isolated irreversible growth driven by cambial activity from the dendrometer records. Next, we compared the intra-annual growth patterns among species and delimited their climatic optima.
The growth of all species peaked at air temperatures between 12 and 16°C and vapour pressure deficit (VPD) below 0.1 kPa. Acer pseudoplatanus and Fagus sylvatica, both diffuse-porous, sustained growth under suboptimal VPD. Ring-porous Quercus robur experienced a steep decline of growth rates with reduced air humidity. This resulted in multiple irregular growth peaks of Q. robur during the year. By contrast, the growth patterns of the diffuse-porous species were always right-skewed unimodal with a peak in June between day of the year 150–170.
Intra-annual growth patterns are shaped more by VPD than temperature. The different sensitivity of radial growth to VPD is responsible for unimodal growth patterns in both diffuse-porous species and multimodal growth pattern in Q. robur.
Lake‐level reconstructions are a key tool in hydro‐climate reconstructions, based on the assumption that lake‐level changes primarily reflect climatic changes. Although it is known that land cover changes can affect evapotranspiration and groundwater formation, this factor commonly receives little attention in the interpretation of past lake‐level changes. To address this issue in more detail, we explore the effects of land cover change on Holocene lake‐level fluctuations in Lake Tiefer See in the lowlands of northeastern Germany. We reconstruct lake‐level changes based on the analysis of 28 sediment records from different water depths and from the shore. We compare the results with land cover changes inferred from pollen data. We also apply hydrological modelling to quantify effects of land cover change on evapotranspiration and the lake level. Our reconstruction shows an overall lake‐level amplitude of about 10 m during the Holocene, with the highest fluctuations during the Early and Late Holocene. Only smaller fluctuations during the Middle Holocene can unambiguously be attributed to climatic fluctuations because the land cover was stable during that period. Fluctuations during the Early and Late Holocene are at least partly related to changes in natural and anthropogenic land cover. For several intervals the reconstructed lake‐level changes agree well with variations in modelled groundwater recharge inferred from land cover changes. In general, the observed amplitudes of lake‐level fluctuations are larger than expected from climatic changes alone and thus underline that land cover changes in lake catchments must be considered in climatic interpretations of past lake‐level fluctuations.
Neural mechanisms of behavioral improvement induced by repeated transcranial direct current stimulation (tDCS) combined with cognitive training are yet unclear. Previously, we reported behavioral effects of a 3-day visuospatial memory training with concurrent anodal tDCS over the right temporoparietal cortex in older adults. To investigate intervention-induced neural alterations we here used functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) datasets available from 35 participants of this previous study, acquired before and after the intervention. To delineate changes in whole-brain functional network architecture, we employed eigenvector centrality mapping. Gray matter alterations were analyzed using DTI-derived mean diffusivity (MD). Network centrality in the bilateral posterior temporooccipital cortex was reduced after anodal compared to sham stimulation. This focal effect is indicative of decreased functional connectivity of the brain region underneath the anodal electrode and its left-hemispheric homolog with other “relevant” (i.e., highly connected) brain regions, thereby providing evidence for reorganizational processes within the brain's network architecture. Examining local MD changes in these clusters, an interaction between stimulation condition and training success indicated a decrease of MD in the right (stimulated) temporooccipital cluster in individuals who showed superior behavioral training benefits. Using a data-driven whole-brain network approach, we provide evidence for targeted neuromodulatory effects of a combined tDCS-and-training intervention. We show for the first time that gray matter alterations of microstructure (assessed by DTI-derived MD) may be involved in tDCS-enhanced cognitive training. Increased knowledge on how combined interventions modulate neural networks in older adults, will help the development of specific therapeutic interventions against age-associated cognitive decline.
Combining solid acid catalysts with enzyme reactions in aqueous environments is challenging because either very acidic conditions inactivate the enzymes, or the solid acid catalyst is neutralized. In this study, Amberlyst-15 encapsulated in polydimethylsiloxane (Amb-15@PDMS) is used to deprotect the lignin depolymerization product G−C2 dioxolane phenol in a buffered system at pH 6.0. This reaction is directly coupled with the biocatalytic reduction of the released homovanillin to homovanillyl alcohol by recombinant horse liver alcohol dehydrogenase, which is subsequently acylated by the promiscuous acyltransferase/hydrolase PestE_I208A_L209F_N288A in a one-pot system. The deprotection catalyzed with Amb-15@PDMS attains up to 97 % conversion. Overall, this cascade enables conversions of up to 57 %.
An Enzyme Cascade Reaction for the Recovery of Hydroxytyrosol Dervatives from Olive Mill Wastewater
(2022)
Abstract
The valorization of olive mill wastewaters (OMWW), a by‐product of the olive milling, is getting rising attention. Lipophilization of the main phenolic compound 3‐hydroxytyrosol (HT) could facilitate its extraction. An immobilized variant of the promiscuous hydrolase/acyltransferase from Pyrobaculum calidifontis VA1 (PestE) was used to perform acetylation in water using ethyl acetate as acyl donor. PestE was used in a segmented flow setting to allow continuous operation. Additionally, HT precursors were made accessible by pretreatment with almond β‐glucosidase and the hydrolytic activity of PestE_I208A_L209F_N288A.
Abstract
Olive mill wastewater (OMWW) is produced annually during olive oil extraction and contains most of the health‐promoting 3‐hydroxytyrosol of the olive fruit. To facilitate its recovery, enzymatic transesterification of hydroxytyrosol (HT) was directly performed in an aqueous system in the presence of ethyl acetate, yielding a 3‐hydroxytyrosol acetate rich extract. For this, the promiscuous acyltransferase from Pyrobaculum calidifontis VA1 (PestE) was engineered by rational design. The best mutant for the acetylation of hydroxytyrosol (PestE_I208A_L209F_N288A) was immobilized on EziG2 beads, resulting in hydroxytyrosol conversions between 82 and 89 % in one hour, for at least ten reaction cycles in a buffered hydroxytyrosol solution. Due to inhibition by other phenols in OMWW the conversions of hydroxytyrosol from this source were between 51 and 62 %. In a preparative scale reaction, 13.8 mg (57 %) of 3‐hydroxytyrosol acetate was extracted from 60 mL OMWW.
Abstract
Peatlands are lands with a peat layer at the surface, containing a large proportion of organic carbon. Such lands cover ≈1 000 000 km2 in Europe, which is almost 10% of the total surface area. In many countries, peatlands have been artificially drained over centuries, leading to not only enormous emissions of CO2 but also soil subsidence, mobilization of nutrients, higher flood risks, and loss of biodiversity. These problems can largely be solved by stopping drainage and rewetting the land. Wet peatlands do not release CO2, can potentially sequester carbon, help to improve water quality, provide habitat for rare and threatened biodiversity, and can still be used for production of biomass (“paludiculture”). Wisely adjusted land use on peatlands can substantially contribute to low‐emission goals and further benefits for farmers, the economy, society, and the environment.
Abstract
Methylation of free hydroxyl groups is an important modification for flavonoids. It not only greatly increases absorption and oral bioavailability of flavonoids, but also brings new biological activities. Flavonoid methylation is usually achieved by a specific group of plant O‐methyltransferases (OMTs) which typically exhibit high substrate specificity. Here we investigated the effect of several residues in the binding pocket of the Clarkia breweri isoeugenol OMT on the substrate scope and regioselectivity against flavonoids. The mutation T133M, identified as reported in our previous publication, increased the activity of the enzyme against several flavonoids, namely eriodictyol, naringenin, luteolin, quercetin and even the isoflavonoid genistein, while a reduced set of amino acids at positions 322 and 326 affected both, the activity and the regioselectivity of the methyltranferase. On the basis of this work, methylated flavonoids that are rare in nature were produced in high purity.
Abstract
Halide methyltransferases (HMTs) enable the enzymatic synthesis of S‐adenosyl‐l‐methionine (SAM) from S‐adenosyl‐l‐homocysteine (SAH) and methyl iodide. Characterisation of a range of naturally occurring HMTs and subsequent protein engineering led to HMT variants capable of synthesising ethyl, propyl, and allyl analogues of SAM. Notably, HMTs do not depend on chemical synthesis of methionine analogues, as required by methionine adenosyltransferases (MATs). However, at the moment MATs have a much broader substrate scope than the HMTs. Herein we provide an overview of the discovery and engineering of promiscuous HMTs and how these strategies will pave the way towards a toolbox of HMT variants for versatile chemo‐ and regioselective biocatalytic alkylations.
Abstract
The efficient multifunctionalization by one‐pot or cascade catalytic systems has developed as an important research field, but is often challenging due to incompatibilities or cross‐reactivities of the catalysts leading to side product formation. Herein we report the stereoselective preparation of cis‐ and trans‐4‐aminocyclohexanol from the potentially bio‐based precursor 1,4‐cyclohexanedione. We identified regio‐ and stereoselective enzymes catalyzing reduction and transamination of the diketone, which can be performed in a one‐pot sequential or cascade mode. For this, we identified regioselective keto reductases for the selective mono reduction of the diketone to give 4‐hydroxycyclohexanone. The system is modular and by choosing stereocomplementary amine transaminases, both cis‐ and trans‐4‐aminocyclohexanol were synthesized with good to excellent diastereomeric ratios. Furthermore, we identified an amine transaminase that produces cis‐1,4‐cyclohexanediamine with diastereomeric ratios >98 : 2. These examples highlight that the high selectivity of enzymes enable short and stereoselective cascade multifunctionalizations to generate high‐value building blocks from renewable starting materials.
Introduction
Comparative neuroanatomy of the central nervous system in web-building and cursorial hunting spiders
(2023)
Spiders (Araneae) include cursorial species that stalk their prey and more stationary species that use webs for prey capture. While many cursorial hunting spiders rely on visual cues, web-building spiders use vibratory cues (mechanosensation) for prey capture. We predicted that the differences in primary sensory input between the species are mirrored by differences in the morphology/architecture of the central nervous system (CNS). Here, we investigated the CNS anatomy of four spider species, two cursorial hunters Pardosa amentata (Lycosidae) and Marpissa muscosa (Salticidae), and two web-building hunters Argiope bruennichi (Araneidae) and Parasteatoda tepidariorum (Theridiidae). Their CNS was analyzed using Bodian silver impregnations, immunohistochemistry, and microCT analysis. We found that there are major differences between species in the secondary eye pathway of the brain that pertain to first-order, second-order, and higher order brain centers (mushroom bodies [MB]). While P. amentata and M. muscosa have prominent visual neuropils and MB, these are much reduced in the two web-building species. Argiope bruennichi lacks second-order visual neuropils but has specialized photoreceptors that project into two distinct visual neuropils, and P. tepidariorum lacks MB, suggesting that motion vision might be absent in this species. Interestingly, the differences in the ventral nerve cord are much less pronounced, but the web-building spiders have proportionally larger leg neuropils than the cursorial spiders. Our findings suggest that the importance of visual information is much reduced in web-building spiders, compared to cursorial spiders, while processing of mechanosensory information requires the same major circuits in both web-building and cursorial hunting spiders.
Abstract
Background
The CRISPR/Cas9 system has opened new perspectives to study the molecular basis of cerebral cavernous malformations (CCMs) in personalized disease models. However, precise genome editing in endothelial and other hard‐to‐transfect cells remains challenging.
Methods
In a proof‐of‐principle study, we first isolated blood outgrowth endothelial cells (BOECs) from a CCM1 mutation carrier with multiple CCMs. In a CRISPR/Cas9 gene correction approach, a high‐fidelity Cas9 variant was then transfected into patient‐derived BOECs using a ribonucleoprotein complex and a single‐strand DNA oligonucleotide. In addition, patient‐specific CCM1 knockout clones were expanded after CRISPR/Cas9 gene inactivation.
Results
Deep sequencing demonstrated correction of the mutant allele in nearly 33% of all cells whereas no CRISPR/Cas9‐induced mutations in predicted off‐target loci were identified. Corrected BOECs could be cultured in cell mixtures but demonstrated impaired clonal survival. In contrast, CCM1‐deficient BOECs displayed increased resistance to stress‐induced apoptotic cell death and could be clonally expanded to high passages. When cultured together, CCM1‐deficient BOECs largely replaced corrected as well as heterozygous BOECs.
Conclusion
We here demonstrate that a non‐viral CRISPR/Cas9 approach can not only be used for gene knockout but also for precise gene correction in hard‐to‐transfect endothelial cells (ECs). Comparing patient‐derived isogenic CCM1+/+, CCM1+/−, and CCM1−/− ECs, we show that the inactivation of the second allele results in clonal evolution of ECs lacking CCM1 which likely reflects the initiation phase of CCM genesis.
Boronate esters, formed by the reaction of an oligonucleotide bearing a 5′-boronic acid moiety with the 3′-terminal cis-diol of another oligonucleotide, support the assembly of functional nucleic acid architectures. Reversible formation of boronate esters occurs in templated fashion and has been shown to restore the activity of split DNA and RNA enzymes as well as a split fluorescent light-up aptamer. Apart from their suitability for the design and application of split nucleic acid enzymes and aptamers in the field of biosensing, boronate esters may have played an important role in early life as surrogates of the natural phosphodiester bond. Their formation is reversible and thus fulfills an important requirement for biological self-assembly. Here we discuss the general concept of stimuli-dependent boronate formation and its application in biomolecules with implications for future research.
Increasing the information depth of single kidney biopsies can improve diagnostic precision, personalized medicine and accelerate basic kidney research. Until now, information on mRNA abundance and morphologic analysis has been obtained from different samples, missing out on the spatial context and single-cell correlation of findings. Herein, we present scoMorphoFISH, a modular toolbox to obtain spatial single-cell single-mRNA expression data from routinely generated kidney biopsies. Deep learning was used to virtually dissect tissue sections in tissue compartments and cell types to which single-cell expression data were assigned. Furthermore, we show correlative and spatial single-cell expression quantification with super-resolved podocyte foot process morphometry. In contrast to bulk analysis methods, this approach will help to identify local transcription changes even in less frequent kidney cell types on a spatial single-cell level with single-mRNA resolution. Using this method, we demonstrate that ACE2 can be locally upregulated in podocytes upon injury. In a patient suffering from COVID-19-associated collapsing FSGS, ACE2 expression levels were correlated with intracellular SARS-CoV-2 abundance. As this method performs well with standard formalin-fixed paraffin-embedded samples and we provide pretrained deep learning networks embedded in a comprehensive image analysis workflow, this method can be applied immediately in a variety of settings.
Abstract
Myxomycetes are terrestrial protists with many presumably cosmopolitan species dispersing via airborne spores. A truly cosmopolitan species would suffer from outbreeding depression hampering local adaptation, while locally adapted species with limited distribution would be at a higher risk of extinction in changing environments. Here, we investigate intraspecific genetic diversity and phylogeography of Physarum albescens over the entire Northern Hemisphere. We sequenced 324 field collections of fruit bodies for 1–3 genetic markers (SSU, EF1A, COI) and analysed 98 specimens with genotyping by sequencing. The structure of the three‐gene phylogeny, SNP‐based phylogeny, phylogenetic networks, and the observed recombination pattern of three independently inherited gene markers can be best explained by the presence of at least 18 reproductively isolated groups, which can be seen as cryptic species. In all intensively sampled regions and in many localities, members of several phylogroups coexisted. Some phylogroups were found to be abundant in only one region and completely absent in other well‐studied regions, and thus may represent regional endemics. Our results demonstrate that the widely distributed myxomycete species Ph. albescens represents a complex of at least 18 cryptic species, and some of these seem to have a limited geographical distribution. In addition, the presence of groups of presumably clonal specimens suggests that sexual and asexual reproduction coexist in natural populations of myxomycetes.
Background
Both vulnerability and integrity represent action-guiding concepts in nursing practice. However, they are primarily discussed regarding patients—not nurses—and considered independently from rather than in relation to each other.
Aim
The aim of this paper is to characterize the moral dimension of nurses' vulnerability and integrity, specify the concepts' relationship in nurses' clinical practice and, ultimately, allow a more fine-grained understanding.
Design
This discursive paper demonstrates how vulnerability and integrity relate to each other in nursing practice and carves out which types of vulnerability pose a threat to nurses' moral integrity. The concept of vulnerability developed by Mackenzie et al. (2014) is applied to the situation of nurses and expanded to include the concept of moral integrity according to Hardingham (2004). Four scenarios are used to demonstrate where and how nurses' vulnerabilities become particularly apparent in clinical practice. This leads to a cross-case discussion, in which the vulnerabilities identified are examined against the background of moral integrity and the relationship between the two concepts is determined in more detail.
Results and Conclusion
Vulnerability and integrity do not only form a conceptual pair but also represent complementary moral concepts. Their joint consideration has both a theoretical and practical added value. It is shown that only specific forms of vulnerability pose a threat to moral integrity and the vulnerability–integrity relationship is mediated via moral distress.
Implications for the Profession and/or Patient Care
The manuscript provides guidance on how the concrete threat(s) to integrity can be buffered and moral resilience can be promoted. Different types of threats also weigh differently and require specific approaches to assess and handle them at the micro-, meso- and macro-level of the healthcare system.
Decreased inflammatory profile in oral leukoplakia tissue exposed to cold physical plasma ex vivo
(2023)
Background
Oral leukoplakia (OL) is an unfavorable oral disease often resistant to therapy. To this end, cold physical plasma technology was explored as a novel therapeutic agent in an experimental setup.
Methods
Biopsies with a diameter of 3 mm were obtained from non-diseased and OL tissues. Subsequently, cold atmospheric pressure plasma (CAP) exposure was performed ex vivo in the laboratory. After 20 h of incubation, biopsies were cryo-conserved, and tissue sections were quantified for lymphocyte infiltrates, discriminating between naïve and memory cytotoxic and T-helper cells. In addition, the secretion pattern related to inflammation was investigated in the tissue culture supernatants by quantifying 10 chemokines and cytokines.
Results
In CAP-treated OL tissue, significantly decreased overall lymphocyte numbers were observed. In addition, reduced levels were observed when discriminating for the T-cell subpopulations but did not reach statistical significance. Moreover, CAP treatment significantly reduced levels of C-X-C motif chemokine 10 (CXCL10) and granulocyte-macrophage colony-stimulating factor in the OL biopsies' supernatants. In idiopathically inflamed tissues, ex vivo CAP exposure reduced T-cells and CXCL10 as well but also led to markedly increased interleukin-1β secretion.
Conclusion
Our findings suggest CAP to have immuno-modulatory properties, which could be of therapeutic significance in the therapy of OL. Future studies should investigate the efficacy of CAP therapy in vivo in a larger cohort.
Background
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a prothrombotic, heparin-induced thrombocytopenia (HIT)-mimicking, adverse reaction caused by platelet-activating anti-platelet factor 4 (PF4) antibodies that occurs rarely after adenovirus vector-based COVID-19 vaccination. Strength of PF4-dependent enzyme immunoassay (EIA) reactivity—judged by optical density (OD) measurements—strongly predicts platelet-activating properties of HIT antibodies in a functional test. Whether a similar relationship holds for VITT antibodies is unknown.
Objectives
To evaluate probability for positive platelet activation testing for VITT antibodies based upon EIA OD reactivity; and to investigate simple approaches to minimize false-negative platelet activation testing for VITT.
Methods
All samples referred for VITT testing were systematically evaluated by semiquantitative in-house PF4/heparin-EIA (OD readings) and PF4-induced platelet activation (PIPA) testing within a cohort study. EIA-positive sera testing PIPA-negative were retested following 1/4 to 1/10 dilution. Logistic regression was performed to predict the probability of a positive PIPA per magnitude of EIA reactivity.
Results
Greater EIA ODs in sera from patients with suspected VITT correlated strongly with greater likelihood of PIPA reactivity. Of 61 sera (with OD values >1.0) testing negative in the PIPA, a high proportion (27/61, 44.3%) became PIPA positive when tested at 1/4 to 1/10 dilution.
Conclusions
VITT serology resembles HIT in that greater EIA OD reactivity predicts higher probability of positive testing for platelet-activating antibodies. Unlike the situation with HIT antibodies, however, diluting putative VITT serum increases probability of a positive platelet activation assay, suggesting that optimal complex formation depends on the stoichiometric ratio of PF4 and anti-PF4 VITT antibodies.
Abstract
Root phenology influences the timing of plant resource acquisition and carbon fluxes into the soil. This is particularly important in fen peatlands, in which peat is primarily formed by roots and rhizomes of vascular plants. However, most fens in Central Europe are drained for agriculture, leading to large carbon losses, and further threatened by increasing frequency and intensity of droughts. Rewetting fens aims to restore the original carbon sink, but how root phenology is affected by drainage and rewetting is largely unknown.
We monitored root phenology with minirhizotrons in drained and rewetted fens (alder forest, percolation fen and coastal fen) as well as its soil temperature and water table depth during the 2018 drought. For each fen type, we studied a drained site and a site that was rewetted ~25 years ago, while all the sites studied had been drained for almost a century.
Overall, the growing season was longer with rewetting, allowing roots to grow over a longer period in the year and have a higher root production than under drainage. With increasing depth, the growing season shifted to later in time but remained a similar length, and the relative importance of soil temperature for root length changes increased with soil depth.
Synthesis and applications. Rewetting extended the growing season of roots, highlighting the importance of phenology in explaining root productivity in peatlands. A longer growing season allows a longer period of carbon sequestration in form of root biomass and promotes the peatlands' carbon sink function, especially through longer growth in deep soil layers. Thus, management practices that focus on rewetting peatland ecosystems are necessary to maintain their function as carbon sinks, particularly under drought conditions, and are a top priority to reduce carbon emissions and address climate change.
Human habitat disturbance affects both species diversity and intraspecific genetic diversity, leading to correlations between these two components of biodiversity (termed species–genetic diversity correlation, SGDC). However, whether SGDC predictions extend to host‐associated communities, such as the intestinal parasite and gut microbial diversity, remains largely unexplored. Additionally, the role of dominant generalist species is often neglected despite their importance in shaping the environment experienced by other members of the ecological community, and their role as source, reservoir and vector of zoonotic diseases. New analytical approaches (e.g. structural equation modelling, SEM) can be used to assess SGDC relationships and distinguish among direct and indirect effects of habitat characteristics and disturbance on the various components of biodiversity.
With six concrete and biologically sound models in mind, we collected habitat characteristics of 22 study sites from four distinct landscapes located in central Panama. Each landscape differed in the degree of human disturbance and fragmentation measured by several quantitative variables, such as canopy cover, canopy height and understorey density. In terms of biodiversity, we estimated on the one hand, (a) small mammal species diversity, and, on the other hand, (b) genome‐wide diversity, (c) intestinal parasite diversity and (d) gut microbial heterogeneity of the most dominant generalist species (Tome's spiny rat, Proechimys semispinosus). We used SEMs to assess the links between habitat characteristics and biological diversity measures.
The best supported SEM suggested that habitat characteristics directly and positively affect the richness of small mammals, the genetic diversity of P. semispinosus and its gut microbial heterogeneity. Habitat characteristics did not, however, directly impact intestinal parasite diversity. We also detected indirect, positive effects of habitat characteristics on both host‐associated assemblages via small mammal richness. For microbes, this is likely linked to cross species transmission, particularly in shared and/or anthropogenically altered habitats, whereas host diversity mitigates parasite infections. The SEM revealed an additional indirect but negative effect on intestinal parasite diversity via host genetic diversity.
Our study showcases that habitat alterations not only affect species diversity and host genetic diversity in parallel, but also species diversity of host‐associated assemblages. The impacts from human disturbance are therefore expected to ripple through entire ecosystems with far reaching effects felt even by generalist species.
Abstract
Introduction
Using the situated expectancy–value theory, it becomes possible to explain motivational functioning across alternating learning conditions not only at a particular moment but also over time. The situated expectancy–value theory provides evidence for the critical role of context. The present research examines how adolescents' success expectancies, task values, and effort develop when the conditions of the academic environment change. It also evaluates whether adolescents adopt more adaptive expectancy–value profiles in response to the need‐based nature of self‐directed learning as an extension of regular instruction. Within the self‐directed learning approach under investigation, adolescents take responsibility for their own learning processes.
Methods
The present research offers insights into the expectancy–value profiles of 754 German adolescents (Mage = 13.56; SD = 1.2; 49.4% female). A four‐wave study was used to examine perceptions of self‐efficacy, intrinsic value, utility value, and effort. Latent profile analyses and latent transition analyses were employed.
Results
Notably, the results provide evidence that expanding instruction via self‐directed learning intervals that occur for 1 week per semester contributes to more favorable expectancy–value profiles within a student's favorite subject. A mixed profile (highly confident, hardly interested) disappeared. Instead, success expectations aligned more closely with adolescents' task values and effort. All profiles settled at a higher level.
Conclusions
The findings indicate that instruction that is expanded via self‐directed learning intervals has positive consequences for motivational profiles over time. An initial self‐directed learning episode led to a shift to more interested profile groups. The continuation of a positive trend even after a self‐directed learning interval indicates that adolescents are able to continually adapt their learning to their needs during teacher‐directed instruction. This study provides clues about how to design curricula in a way that counteracts the downward trend in students' motivation to learn.
Summary
This study aimed to establish a robust and reliable metaproteomics protocol for an in‐depth characterization of marine particle‐associated (PA) bacteria. To this end, we compared six well‐established protein extraction protocols together with different MS‐sample preparation techniques using particles sampled during a North Sea spring algae bloom in 2009. In the final optimized workflow, proteins are extracted using a combination of SDS‐containing lysis buffer and cell disruption by bead‐beating, separated by SDS‐PAGE, in‐gel digested and analysed by LC–MS/MS, before MASCOT search against a metagenome‐based database and data processing/visualization with the in‐house‐developed bioinformatics tools Prophane and Paver. As an application example, free‐living (FL) and particulate communities sampled in April 2009 were analysed, resulting in an as yet unprecedented number of 9354 and 5034 identified protein groups for FL and PA bacteria, respectively. Our data suggest that FL and PA communities appeared similar in their taxonomic distribution, with notable exceptions: eukaryotic proteins and proteins assigned to Flavobacteriia, Cyanobacteria, and some proteobacterial genera were found more abundant on particles, whilst overall proteins belonging to Proteobacteria were more dominant in the FL fraction. Furthermore, our data points to functional differences including proteins involved in polysaccharide degradation, sugar‐ and phosphorus uptake, adhesion, motility, and stress response.
Abstract
Social organisation in species with fluctuating population sizes can change with density. Therefore, information on (future) density obtained during early life stages may be associated with social behaviour. Olfactory cues may carry important social information. We investigated whether early life experience of different experimental densities was subsequently associated with differences in attraction to adult conspecific odours. We used common voles (Microtus arvalis), a rodent species undergoing extreme density fluctuations. We found that individuals originating from high experimental density populations kept in large outdoor enclosures invested more time in inspecting conspecific olfactory cues than individuals from low‐density populations. Generally, voles from both treatments spent more time with the olfactory cues than expected by chance and did not differ in their latency to approach the odour samples. Our findings indicate either that early experience affects odour sensitivity or that animals evaluate the social information contained in conspecific odours differently, depending on their early life experience of conspecific density.
Solar Activity Driven 27‐Day Signatures in Ionospheric Electron and Molecular Oxygen Densities
(2022)
Abstract
The complex interactions in the upper atmosphere, which control the height‐dependent ionospheric response to the 27‐day solar rotation period, are investigated with the superposed epoch analysis technique. 27‐day signatures describing solar activity are calculated from a solar proxy (F10.7) and wavelength‐dependent extreme ultraviolet (EUV) fluxes (Thermosphere Ionosphere Mesosphere Energetics and Dynamics/Solar EUV Experiment), and the corresponding 27‐day signatures describing ionospheric conditions are calculated from electron density profiles (Pruhonice ionosonde station) and O2 density profiles (Global‐scale Observations of the Limb and Disk). The lag analysis of these extracted signatures is applied to characterize the delayed ionospheric response at heights from 100 to 300 km and the impact of major absorption processes in the lower (dominated by O2) and upper ionosphere (dominated by O) is discussed. The observed variations of the delay in these regions are in good agreement with model simulations in preceding studies. Additionally, the estimated significance and the correlation of the delays based on both ionospheric parameters are good. Thus, variations such as the strong shift in 27‐day signatures for the O2 density at low heights are also reliably identified (up to half a cycle). The analysis confirms the importance of ionospheric and thermospheric coupling to understand the variability of the delayed ionospheric response and introduces a method that could be applied to additional ionosonde stations in future studies. This would allow to describe the variability of the delayed ionospheric response spatially, vertically and temporally and therefore may contribute further to the understanding of processes and improve ionospheric modeling.
Abstract
Based on the analysis of electron density Ne profiles (Grahamstown ionosonde), a case study of the height‐dependent ionospheric response to two 27‐day solar rotation periods in 2019 is performed. A well‐defined sinusoidal response is observed for the period from 27 April 2019 to 24 May 2019 and reproduced with a Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model simulation. The occurring differences between model and observations as well as the driving physical and chemical processes are discussed based on the height‐dependent variations of Ne and major species. Further simulations with an artificial noise free sinusoidal solar flux input show that the Ne delay is defined by contributions due to accumulation of O+ at the Ne peak (positive delay) and continuous loss of O2+ ${\mathrm{O}}_{2}^{+}$ in the lower ionosphere (negative delay). The neutral parts' 27‐day signatures show stronger phase shifts. The time‐dependent and height‐dependent impact of the processes responsible for the delayed ionospheric response can therefore be described by a joint analysis of the neutral and ionized parts. The return to the initial ionospheric state (and thus the loss of the accumulated O+) is driven by an increase of downward transport in the second half of the 27‐day solar rotation period. For this reason, the neutral vertical winds (upwards and downwards) and their different height‐dependent 27‐day signatures are discussed. Finally, the importance of a wavelength‐dependent analysis, statistical methods (superposed epoch analysis), and coupling with the middle atmosphere is discussed to outline steps for future analysis.
Aim
Climate change challenges temperate forest trees by increasingly irregular precipitation and rising temperatures. Due to long generation cycles, trees cannot quickly adapt genetically. Hence, the persistence of tree populations in the face of ongoing climate change depends largely on phenotypic variation, that is the capability of a genotype to express variable phenotypes under different environmental conditions, known as plasticity. We aimed to quantify phenotypic variation of central Europe's naturally dominant forest tree across various intraspecific scales (individuals, mother trees (families), populations) to evaluate its potential to respond to changing climatic conditions.
Location
Europe.
Time Period
2016–2019.
Major Taxa Studied
European beech (Fagus sylvatica L.).
Methods
We conducted a fully reciprocal transplantation experiment with more than 9000 beech seeds from seven populations across a Europe-wide gradient. We compared morphological (Specific Leaf Area), phenological (leaf unfolding) and fitness-related (growth, survival) traits across various biological scales: within single mother trees, within populations and across different populations under the contrasting climates of the translocation sites.
Results
The experiment revealed significant phenotypic variation within the offspring of each mother tree, regardless of geographic origin. Initially, seedling height growth varied among mother trees and populations, likely due to maternal effects. However, the growth performance successively aligned after the first year. In summary, we observed a consistent growth response in different beech populations to diverse environments after initial maternal effects.
Main Conclusions
The study strikingly demonstrates the importance of considering intraspecific variation. Given the surprisingly broad spectrum of phenotypes each mother tree holds within its juvenile offspring, we conclude that Fagus sylvatica might have the potential for medium-term population persistence in face of climate change, provided that this pattern persists into later life stages. Hence, we also suggest further investigating the inclusion of passive adaptation and natural dynamics in the adaptive management of forests.
Abstract
Surface waters are warming due to climate change, potentially pushing aquatic organisms closer to their thermal tolerance limits. However, cyanobacterial blooms are expected to occur more often with rising temperature, increasing the likelihood of poor‐quality food available for herbivorous zooplankton. Zooplankton can adapt locally by genetic differentiation or via adaptive phenotypic plasticity to increasing temperatures, but there is limited knowledge on how these processes may be affected by food quality limitation imposed by cyanobacteria.
To test the effects of cyanobacteria‐mediated food quality on local temperature adaptation, we measured juvenile somatic growth and reproduction of five Daphnia magna clones from different latitudinal origin grown on three food qualities at 20, 24, and 28°C. Additionally we estimated short‐term heat tolerance, measured as knockout time (time to immobility) at lethally high temperature, of two clones acclimated to the three temperatures and two food quality levels to test for the effects of food quality on adaptive plastic responses.
As expected, clones from lower latitudes showed on average better somatic growth and reproduction than clones from higher latitudes at higher temperatures. However, the difference in somatic growth diminished with increasing cyanobacteria abundance in the diet, suggesting constraints on local genetic adaptation under predicted decreases in food quality. As expected, short‐term heat tolerance of the clones generally increased with increasing acclimation temperature. However, heat tolerance of animals acclimated to the highest temperature was larger when grown at medium than at good food quality, whereas the opposite response was observed for animals acclimated to the lowest temperature. This suggests a better adaptive phenotypic response of animals to elevated temperatures under higher cyanobacteria abundance, and thus shows an opposite pattern to the results for somatic growth.
Overall, we demonstrate that food quality limitation can mediate responses of D. magna life history traits and heat tolerance to increasing temperatures, and that the effects differ depending on the time scale studied, that is, mid‐term (somatic growth) versus short‐term (tolerance to acute heat stress). These aspects will need further attention to accurately predict of how organisms will cope with future global warming by local adaptation and adaptive phenotypic plasticity.
Baeyer-Villiger monooxygenases (BVMOs) are important flavin-dependent enzymes which perform oxygen insertion reactions leading to valuable products. As reported in many studies, BVMOs are usually unstable during application, preventing a wider usage in biocatalysis. Here, we discovered a novel NADPH-dependent BVMO which originates from Halopolyspora algeriensis using sequence similarity networks (SSNs). The enzyme is stable at temperatures between 10 °C to 30 °C up to five days after the purification, and yields the normal ester product. In this study, the substrate scope was investigated for a broad range of aliphatic ketones and the enzyme was biochemically characterized to identify optimum reaction conditions. The best substrate (86 % conversion) was 2-dodecanone using purified enzyme. This novel BVMO could potentially be applied as part of an enzymatic cascade or in bioprocesses which utilize aliphatic alkanes as feedstock.
Aim
To determine the long-term effects of the use of powered tooth brush (PTB) in comparison to manual tooth brush (MTB) on periodontitis severity, coronal caries experience, and the number of missing teeth using in a population-based cohort study.
Materials and Methods
Using 7-year follow-up data of 2214 participants of the Study of Health in Pomerania (SHIP-TREND), comprehensively adjusted linear models using generalized least squares and ordinal regression models estimated the effects of PTB usage on dental outcomes in complete case and imputed data.
Results
At follow-up, PTB users had lower medians for mean probing depth (PD; 2.21 mm) and mean clinical attachment levels (1.73 mm) than MTB users (2.30 and 1.96 mm, respectively). Adjusted models revealed the beneficial effects of PTB usage on follow-up levels of plaque, bleeding on probing, mean PD, percentage of sites with PDs ≥4 mm, mean clinical attachment levels (all, interdental, and non-interdental sites, respectively), and the number of missing teeth. For the number of missing teeth, the effects were more pronounced in participants aged ≥50 years. No significant effects of PTB usage on the number of decayed or filled surfaces (all and interdental sites) were found.
Conclusions
A recommendation of PTB usage in dental practice could contribute to the long-term promotion of oral health.
Abstract
Climate change will lead to more frequent and severe drought periods which massively reduce crop production worldwide. Besides drought, nitrogen (N)‐deficiency is another critical threat to crop yield production. Drought and N‐deficiency both decrease photosynthesis and induce similar adaptive strategies such as longer roots, reduction of biomass, induction of reactive oxygen species (ROS), and antioxidative enzymes. Due to the overlapping response to N‐deficiency and drought, understanding the physiological and molecular mechanisms involved in cross‐stresses tolerance is crucial for breeding strategies and achieving multiple stress resistance and eventually more sustainable agriculture. The objective of this study was to investigate the effect of a mild N‐deficiency on drought stress tolerance of tomato plants (Solanum lycopersicum L., cv. Moneymaker). Various morphological and physiological parameters such as dry biomass, root length, water potential, SPAD values, stomatal conductance, and compatible solutes accumulation (proline and sugar) were analyzed. Moreover, the expression of ROS scavenging marker genes, cytosolic ASCORBATE PEROXIDASES (cAPX1, cAPX2, and cAPX3), were investigated. Our results showed that a former mild N‐deficiency (2 mM NO3−) enhances plant adaptive response to drought stress (4 days) when compared to the plants treated with adequate N (5 mM NO3−). The improved adaptive response was reflected in higher aboveground biomass, longer root, increased specific leaf weight, enhanced stomatal conductance (without reducing water content), and higher leaf sugar content. Moreover, the APX1 gene showed a higher expression level compared to control under N‐deficiency and in combination with drought in the leaf, after a one‐week recovery period. Our finding highlights a potentially positive link between a former mild N‐deficiency and subsequent drought stress response in tomato. Combining the morphological and physiological response with underlying gene regulatory networks under consecutive stress, provide a powerful tool for improving multiple stress resistance in tomato which can be further transferred to other economically important crops.
Aim
The aim of this study was to evaluate whether extraction thresholds in persons with severe periodontitis have changed between 2000 and 2010 and whether potential shifts have contributed to the reported decrease in tooth extractions in German adults over the last decades.
Materials and Methods
Data from two German population-based cohort studies in Northeast Germany (Studies of Health in Pomerania; SHIP-START [baseline 1997–2001; 11-year follow-up] and SHIP-TREND [baseline 2008–2012; 7-year follow-up]) were used. In SHIP-START (SHIP-TREND), 522 (478) participants with severe periodontitis according to the CDC/AAP case definition were included. Patterns of maximum probing depth (PD) and maximum clinical attachment level (CAL) for retained and extracted teeth were compared between SHIP-START and SHIP-TREND participants.
Results
No major differences in patterns of baseline maximum CAL of retained or extracted teeth were detected between SHIP-START and SHIP-TREND. Extraction thresholds were identified at the baseline at maximum CAL ≥6 and ≥9 mm. Tooth-level incidence rates for extraction for baseline maximum CAL of 6 mm were comparable between SHIP-START and SHIP-TREND (17.1 vs. 15.9 events per 1000 person-years).
Conclusions
After a decade, teeth in persons with severe periodontitis were still undergoing extraction with minor or moderate attachment loss. A change in extraction pattern did not contribute to the higher tooth retention rate.
Abstract
Background
Identifying predictors for general cognitive training (GCT) success in healthy older adults has many potential uses, including aiding intervention and improving individual dementia risk prediction, which are of high importance in health care. However, the factors that predict training improvements and the temporal course of predictors (eg, do the same prognostic factors predict training success after a short training period, such as 6 weeks, as well as after a longer training period, such as 6 months?) are largely unknown.
Methods
Data (N = 4,184 healthy older individuals) from two arms (GCT vs. control) of a three‐arm randomized controlled trial were reanalyzed to investigate predictors of GCT success in five cognitive tasks (grammatical reasoning, spatial working memory, digit vigilance, paired association learning, and verbal learning) at three time points (after 6 weeks, 3 months, and 6 months of training). Possible investigated predictors were sociodemographic variables, depressive symptoms, number of training sessions, cognitive baseline values, and all interaction terms (group*predictor).
Results
Being female was predictive for improvement in grammatical reasoning at 6 weeks in the GCT group, and lower cognitive baseline scores were predictive for improvement in spatial working memory and verbal learning at 6 months.
Conclusion
Our data indicate that predictors seem to change over time; remarkably, lower baseline performance at study entry is only a significant predictor at 6 months training. Possible reasons for these results are discussed in relation to the compensation hypothesis. J Am Geriatr Soc 68:‐, 2020.
Hibernation is a widespread adaptation in animals to seasonally changing environmental conditions. In the face of global anthropogenic change, information about plastic adjustments to environmental conditions and associated mortality costs are urgently needed to assess population persistence of hibernating species. Here, we used a five-year data set of 1047 RFID-tagged individuals from two bat species, Myotis nattereri and Myotis daubentonii that were automatically recorded each time they entered or left a hibernaculum. Because the two species differ in foraging strategy and activity pattern during winter, we expected species–specific responses in the timing of hibernation relative to environmental conditions, as well as different mortality costs of early departure from the hibernaculum in spring. Applying mixed-effects modelling, we disentangled population-level and individual-level plasticity in the timing of departure. To estimate mortality costs of early departure, we used both a capture mark recapture analysis and a novel approach that takes into account individual exposure times to mortality outside the hibernaculum. We found that the timing of departure varied between species as well as among and within individuals, and was plastically adjusted to large-scale weather conditions as measured by the NAO (North Atlantic Oscillation) index. Individuals of M. nattereri, which can exploit milder temperatures for foraging during winter, tuned departure more closely to the NAO index than individuals of M. daubentonii, which do not hunt during winter. Both analytical approaches used to estimate mortality costs showed that early departing individuals were less likely to survive until the subsequent hibernation period than individuals that departed later. Overall, our study demonstrates that individuals of long-lived hibernating bat species have the potential to plastically adjust to changing climatic conditions, although the potential for adjustment differs between species.
Primary producer communities are often growth-limited by essential nutrients such as nitrogen (N) and phosphorus (P). The magnitude of limitation and whether N, P or both elements are limiting autotroph growth depends on the supply and ratios of these essential nutrients. Previous studies identified single, serial or co-limitation as predominant limitation outcomes in autotroph communities by factorial nutrient additions. Little is known about potential consequences of such scenarios for herbivores and whether their growth is primarily affected by changes in autotroph quantity or nutritional quality. We grew a community of phytoplankton species differing in various food quality aspects in experimental microcosms at varying N and P concentrations resulting in three different N:P ratios. At carrying capacity, N, P, both nutrients or none were added to reveal which nutrients were limiting. The nutrient-supplied communities were fed to the generalist herbivorous rotifer Brachionus calyciflorus to investigate how changing phytoplankton biomass and community composition affect herbivore abundance. We found phytoplankton being growth-limited either by N alone (single limitation) or serially, i.e. primarily by N and secondarily by P, altering available food quantity for rotifers. Rotifer growth showed a different response pattern compared to phytoplankton, suggesting that apart from food quantity food quality aspects played a substantial role in the transfer from primary to secondary production. The combined addition of N and P to phytoplankton had generally a positive effect on herbivore growth, whereas adding non-limiting nutrients had a rather detrimental effect probably due to stoichiometrically imbalanced food in terms of nutrient excess. Our experiment shows that adding various nutrients to primary producer communities will not always lead to increased autotroph and herbivore growth, and that differences between autotroph and herbivore responses under co-limiting conditions can be partly well explained by concepts of ecological stoichiometry theory.
Abstract
Aim
To examine the associations between bone turnover markers and periodontitis in two cross‐sectional population‐based studies.
Materials and Methods
We used data from two independent adult samples (N = 4993), collected within the Study of Health in Pomerania project, to analyse cross‐sectional associations of N‐procollagen type 1 amino‐terminal propeptide (P1NP), C‐terminal cross‐linking telopeptide, osteocalcin, bone‐specific alkaline phosphatase (BAP), fibroblast growth factor 23, wingless‐type mouse mammary tumour virus integration site family member 5a (WNT5A), and sclerostin values with periodontitis. Confounder‐adjusted gamma and fractional response regression models were applied.
Results
Positive associations were found for P1NP with mean pocket probing depth (PPD; eβ=1.008; 95% confidence interval [CI]: 1.001–1.015), mean clinical attachment loss (mean CAL; eβ=1.027; 95% CI: 1.011–1.044), and proportion of sites with bleeding on probing (%BOP; eβ=1.055; 95% CI: 1.005–1.109). Similar associations were seen for BAP with %BOP (eβ=1.121; 95% CI: 1.042–1.205), proportion of sites with PPD ≥4 mm (%PPD4) (eβ=1.080; 95% CI: 1.005–1.161), and sclerostin with %BOP (eβ=1.308; 95% CI: 1.005–1.704). WNT5A was inversely associated with mean PPD (eβ=0.956; 95% CI: 0.920–0.993) and %PPD4 (eβ=0.794; 95% CI: 0.642–0.982).
Conclusions
This study revealed scattered associations of P1NP, BAP, WNT5A, and sclerostin with periodontitis, but the results are contradictory in the overall context. Associations reported in previous studies could not be confirmed.
Do Belonging and Social Exclusion at School Affect Structural Brain Development During Adolescence?
(2021)
Students’ sense of belonging presents an essential resource for academic and health outcomes, whereas social exclusion at school negatively impacts students’ well‐being and academic performance. Aiming to understand how feelings of school‐related belonging and exclusion shape the structural brain development, this study applied longitudinal questionnaire‐based data and MRI data from 71 adolescent students (37 females, Mage at t1 = 15.0; t2 = 16.1 years). All were white participants from Germany. Voxel‐based morphometry revealed only an association of social exclusion (and not of belonging) and gray matter volume in the left anterior insula: From t1 to t2, there was less gray matter decrease, the more social exclusion students perceived. School‐related social exclusion and disturbed neurodevelopment are thus significantly associated.
Poor sleep quality or sleep deprivation may be related to decreased bone mineral density. We aimed to assess whether associations of sleep characteristics and bone turnover or strength are present in adults from the general population and whether these are independent of common risk factors such as sex, age, and obesity. A total of 1037 participants from the Study of Health in Pomerania-TREND underwent laboratory-based polysomnography and quantitative ultrasound measurements at the heel. Of these participants, 804 completed standardised questionnaires to assess daytime sleepiness, insomnia, and sleep quality. Serum concentrations of two bone turnover markers, intact amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal telopeptide of type 1 collagen (CTX) were measured. Cross-sectional associations of polysomnography variables (total sleep time, sleep efficiency, time spent wake after sleep onset, oxygen desaturation index, apnea–hypopnea index, and obstructive sleep apnea [OSA]), as well as sleep questionnaire scores with the bone turnover markers and the ultrasound-based stiffness index were assessed in linear regression models. In adjusted models, higher insomnia scores and lower sleep quality scores were related to a higher bone turnover in women but not in men. However, associations between polysomnography variables or questionnaire scores and the stiffness index were absent. Our study provides limited evidence for relationships between sleep characteristics and bone turnover and strength independent of common risk factors for OSA and osteoporosis. Nevertheless, women reporting poor sleep or insomnia in combination with risk factors for osteoporosis might benefit from an evaluation of bone health.
Geometric regularity of spider webs has been intensively studied in orb‐weaving spiders, although it is not exclusive of orb weavers. Here, we document the geometrically regular, repetitive elements in the webs of the non‐orb‐weaving groups Leptonetidae and Telemidae for the first time. Similar to orb weavers, we found areas with regularly spaced parallel lines in the webs of Calileptoneta helferi, Sulcia sp., and cf. Pinelema sp. Furthermore, we provide a detailed account of the regular webs of Ochyrocera (Ochyroceratidae). The sections of the web with regularly disposed parallel lines are built as U‐shaped modules reminiscent of orb webs. It has been suggested that the regularly spaced parallel lines in the webs of Ochyroceratidae and Psilodercidae may be produced in a single sweep of their posterior lateral spinnerets, which have regularly spaced aciniform gland spigots, perhaps involving expansion of the spinnerets. To test this hypothesis, we compared the spacing between parallel lines with the spacing between spigots, searched for expansible membranes in the spinnerets, and examined the junctions of regularly spaced lines. The distance between parallel lines was 10–20 times the distance between spigots, and we found no expansible membranes, and the intersection of parallel lines are cemented, which opposes the single sweep hypothesis. Furthermore, we found cues of viscid silk in the parallel lines of the psilodercid Althepus and broadened piriform gland spigots that may be responsible of its production. Finally, we evaluated the presence or absence of geometrically regular web elements across the spider tree of life. We found reports of regular webs in 31 spider families, including 20 families that are not orb weavers and hypothesize that the two basic aspects of regularity (parallel lines spaced at regular intervals, and radial lines spaced at regular angles) probably appeared many times in the evolution of spiders.
Are old regions less attractive? Interregional labour migration in a context of population ageing
(2021)
Abstract
Regional demographic change is often conceptualized as a circular process, where out‐migration continuously worsens conditions of population ageing and shrinkage. Thus, if migration acts as a consequence as well as cause of ageing, migration patterns should be influenced by the age structure of origin and destination regions. This paper analyses individual‐level migration decisions of full‐time employees across 326 German regions between 1997 and 2013 using binary choice models. The results show that individuals are more likely to migrate out of and less likely to migrate towards ageing regions. Moreover, the identified patterns are consistent with age‐selective migration reinforcing ageing processes and polarization of demographic structure.
Copulatory mechanics of ghost spiders reveals a new self-bracing mechanism in entelegyne spiders
(2023)
Spiders evolved a distinctive sperm transfer system, with the male copulatory organs located on the tarsus of the pedipalps. In entelegyne spiders, these organs are usually very complex and consist of various sclerites that not only allow the transfer of the sperm themselves but also provide a mechanical interlock between the male and female genitalia. This interlocking can also involve elements that are not part of the copulatory organ such as the retrolateral tibial apophysis (RTA)—a characteristic of the most diverse group of spiders (RTA clade). The RTA is frequently used for primary locking i.e., the first mechanical engagement between male and female genitalia. Despite its functional importance, some diverse spider lineages have lost the RTA, but evolved an apophysis on the femur instead. It can be hypothesized that this femoral apophysis is a functional surrogate of the RTA during primary locking or possibly serves another function, such as self-bracing, which involves mechanical interaction between male genital structures themselves to stabilize the inserted pedipalp. We tested these hypotheses using ghost spiders of the genus Josa (Anyphaenidae). Our micro-computed tomography data of cryofixed mating pairs show that the primary locking occurs through elements of the copulatory organ itself and that the femoral apophysis does not contact the female genitalia, but hooks to a projection of the copulatory bulb, representing a newly documented self-bracing mechanism for entelegyne spiders. Additionally, we show that the femoral self-bracing apophysis is rather uniform within the genus Josa. This is in contrast to the male genital structures that interact with the female, indicating that the male genital structures of Josa are subject to different selective regimes.
Abstract
Background
The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions.
Methods
This multicenter randomized controlled trial compared two variants of prediction error‐based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx‐I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx‐S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6‐months follow‐up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression.
Results
Both treatments resulted in substantial improvements at post (PeEx‐I: dwithin = 1.50, PeEx‐S: dwithin = 1.78) and follow‐up (PeEx‐I: dwithin = 2.34; PeEx‐S: dwithin = 2.03). Both groups showed formally equivalent symptom reduction at post and follow‐up. However, time until response during treatment was 32% shorter in PeEx‐I (median = 68 days) than PeEx‐S (108 days; TRPeEx‐I = 0.68). Interestingly, drop‐out rates were lower during intensified exposure. PeEx‐I was also superior in reducing disability days and improving quality of life at follow‐up without increasing relapse.
Conclusions
Both treatment variants focusing on the transdiagnostic exposure‐based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop‐out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.
Aim
This study aimed to identify the factors influencing the changes in the number of teeth present and the number of healthy or filled surfaces between two time points.
Materials and Methods
Repeated cross-sectional data from population-based studies, namely the German Oral Health Studies (DMS-III vs. DMS-V), the Studies of Health in Pomerania (SHIP-START-0 vs. SHIP-TREND-0), and the Jönköping study (2003 vs. 2013), were analysed. Oaxaca decomposition models were constructed for the outcomes (number of teeth, number of healthy surfaces, and number of filled surfaces).
Results
The number of teeth increased between examinations (DMS: +2.26 [adults], +4.92 [seniors], SHIP: +1.67, Jönköping: +0.96). Improvements in education and dental awareness brought a positive change in all outcomes. An increase in powered toothbrushing and inter-dental cleaning had a great impact in DMS (adults: +0.25 tooth, +0.78 healthy surface, +0.38 filled surface; seniors: +1.19 teeth, 5.79 healthy surfaces, +0.48 filled surface). Inter-dental cleaning decreased by 4% between SHIP-START-0 and SHIP-TREND-0, which negatively affected the outcomes.
Conclusions
From this study, it can be concluded that education may be the most important factor having a direct and indirect effect on the outcomes. However, for better oral health, powered toothbrushing and inter-dental cleaning should not be neglected.
Abstract
Differentiation of cardiac progenitor cells (CPC) into cardiomyocytes is a fundamental step in cardiogenesis, which is marked by changes in gene expression responsible for remodeling of the cytoskeleton and in altering the mechanical properties of cells. Here we have induced the differentiation of CPC derived from human pluripotent stem cells into immature cardiomyocytes (iCM) which we compare with more differentiated cardiomyocytes (mCM). Using atomic force microscopy and real‐time deformability cytometry, we describe the mechanodynamic changes that occur during the differentiation process and link our findings to protein expression data of cytoskeletal proteins. Increased levels of cardiac‐specific markers as well as evolution of cytoskeletal morphology and contractility parameters correlated with the expected extent of cell differentiation that was accompanied by hypertrophic growth of cells. These changes were associated with switching in the balance of the different actin isoforms where β‐actin is predominantly found in CPC, smooth muscle α‐actin is dominant in iCM cells and sarcomeric α‐actin is found in significantly higher levels in mCM. We link these cytoskeletal changes to differences in mechano‐dynamic behavior of cells that translate to changes in Young's modulus that depend on the cell adherence. Our results demonstrate that the intracellular balance of actin isoform expression can be used as a sensitive ruler to determine the stage of differentiation during early phases of cardiomyocyte differentiation that correlates with an increased expression of sarcomeric proteins and is accompanied by changes in cellular elasticity.
Abstract
Erucic (22:1, cisΔ13) and gondoic acids (20:1, cisΔ11) are building blocks obtained from renewable sources for the oleochemical industry. Different biocatalytic strategies for the enrichment of these compounds with high recovery yields were developed in our group. Geotrichum candidum lipases (GCL) strongly discriminate against fatty acids longer than 18 carbon atoms. Thus, GCL‐I and ‐II were investigated using hydrolysis or ethanolysis reactions with Crambe and Camelina oils. Hydrolysis was also studied using fatty acid ethyl esters (FAEE) derived from the corresponding oil. Both isoforms were highly selective; however, interesting differences were observed. Although it has been reported that GCL‐I displays a higher preference toward 18 cisΔ9, which is present in the studied oils at high levels, GCL‐II showed higher enrichment values during hydrolysis independent of the substrate used. Hence, enrichments of 87% (Crambe oil) and 82% (Crambe FAEE) for erucic acid and 50% (Camelina oil) and 45% (Camelina FAEE) for gondoic acid, with recovery values between 89% and 99%, were achieved. On the contrary, the best enzyme for ethanolysis was GCL‐I (82% and 41% for erucic and gondoic acid, respectively). In this case, although GCL‐II also displayed good enrichment and recovery levels (77% and 28%, respectively), they were lower compared to the former reactions. In both ethanolysis reactions, the FAEE fraction contained between 92% and 97% of 18 unsaturated fatty acids.
Abstract
Background
Heparins are usually produced from animal tissues. It is now possible to synthesize heparins. This provides the abilities to overcome shortages of heparin, to optimize biological effects, and to reduce adverse drug effects. Heparins interact with platelet factor 4 (PF4), which can induce an immune response causing thrombocytopenia. This side effect is called heparin‐induced thrombocytopenia (HIT). We characterized the interaction of PF4 and HIT antibodies with oligosaccharides of 6‐, 8‐, 10‐, and 12‐mer size and a hypersulfated 12‐mer (S12‐mer).
Methods
We utilized multiple methodologies including isothermal calorimetry, circular dichroism spectroscopy, single molecule force spectroscopy (SMFS), enzyme immunosorbent assay (EIA), and platelet aggregation test to characterize the interaction of synthetic heparin analogs with PF4 and anti‐PF4/heparin antibodies.
Results
The synthetic heparin‐like compounds display stronger binding characteristics to PF4 than animal‐derived heparins of corresponding lengths. Upon complexation with PF4, 6‐mer and S12‐mer heparins showed much lower enthalpy, induced less conformational changes in PF4, and interacted with weaker forces than 8‐, 10‐, and 12‐mer heparins. Anti‐PF4/heparin antibodies bind more weakly to complexes formed between PF4 and heparins ≤ 8‐mer than with complexes formed between PF4 and heparins ≥ 10‐mer. Addition of one sulfate group to the 12‐mer resulted in a S12‐mer, which showed substantial changes in its binding characteristics to PF4.
Conclusions
We provide a template for characterizing interactions of newly developed heparin‐based anticoagulant drugs with proteins, especially PF4 and the resulting potential antigenicity.
Background
Chronic pain of different aetiologies and localization has been associated with less grey matter volume (GMV) in several cortical and subcortical brain areas. Recent meta-analyses reported low reproducibility of GMV alterations between studies and pain syndromes.
Methods
To investigate GMV in common chronic pain conditions defined by body location (chronic back pain, n = 174; migraine, n = 92; craniomandibular disorder, n = 39) compared to controls (n = 296), we conducted voxel-based morphometry and determined GMV from high-resolution cranial MRIs obtained in an epidemiologic survey. Mediation analyses were performed between the presence of chronic pain and GMV testing the mediators stress and mild depression. The predictability of chronic pain was investigated with binomial logistic regression.
Results
Whole-brain analyses yielded reduced GMV within the left anterior insula and the anterior cingulate cortex, for a ROI approach additionally the left posterior insula and left hippocampus showing less GMV across all patients with chronic pain. The relationship of pain with GMV in the left hippocampus was mediated by self-reported stressors in the last 12 months. Binomial logistic regression revealed a predictive effect for GMV in the left hippocampus and left anterior insula/temporal pole for the presence of chronic pain.
Conclusions
Chronic pain across three different pain conditions was characterized by less GMV in brain regions consistently described for different chronic pain conditions before. Less GMV in the left hippocampus mediated by experienced stress during the last year might be related to altered pain learning mechanisms in chronic pain patients.
Significance
Grey matter reorganization could serve as a diagnostic biomarker for chronic pain. In a large cohort, we here replicated findings of less grey matter volume across three pain conditions in the left anterior and posterior insula, anterior cingulate and left hippocampus. Less hippocampal grey matter was mediated by experienced stress.
Abstract
Aim
Species ranges are highly dynamic, shifting in space and time as a result of complex ecological and evolutionary processes. Disentangling the relative contribution of both processes is challenging but of primary importance for forecasting species distributions under climate change. Here, we use the spectacular range expansion (ca. 1000 km poleward shift within 10 years) of the butterfly Pieris mannii to unravel the factors underlying range dynamics, specifically the role of (i) niche evolution (changes in host‐plant preference and acceptance) and (ii) ecological processes (climate change).
Location
Provence‐Alpes‐Côte d’Azur, France; North Rhine‐Westphalia, Rhineland‐Palatinate and Hesse, Germany.
Taxon
Insect and angiosperms.
Methods
We employed a combination of (i) common garden experiments, based on replicated populations from the species’ historical and newly established range and host‐plant species representative for each distribution range, co‐occurrence analyses and (ii) grid‐based correlative species distribution modelling (SDM) using Maxent.
Results
We observed changes in oviposition preference, with females from the newly established populations showing reduced host‐plant specialization and also an overall increased fecundity. These changes in behaviour and life history may have enabled using a broader range of habitats and thus facilitated the recent range expansion. In contrast, our results indicate that the range expansion is unlikely to be directly caused by anthropogenic climate change, as the range was not constrained by climate in the first place.
Main conclusions
We conclude that evolution of a broader dietary niche rather than climate change is associated with the rapid range expansion, and discuss potential indirect consequences of climate change as trigger for the genetic differences found. Our study thus illustrates the importance of species interactions in shaping species distributions and range shifts, and draws attention to indirect effects of climate change. Embracing this complexity is likely the key to a better understanding of range dynamics.
Currently, poleward range expansions are observed in many taxa, often in response to anthropogenic climate change. At the expanding front, populations likely face cooler and more variable temperature conditions, imposing thermal selection. This may result in changes in trait means or plasticity, the relative contribution of which is not well understood. We, here, investigate evolutionary change in range‐expanding populations of the butterfly Pieris mannii, by comparing populations from the core and the newly established northern range under laboratory conditions. We observed both changes in trait means and in thermal reaction norms. Range‐expanding populations showed a more rapid development, potentially indicative of counter‐gradient variation and an increased cold tolerance compared with core populations. Genotype‐environment interactions prevailed in all associated traits, such that the above differences were restricted to cooler environmental conditions. In range‐expanding populations, plasticity was decreased in developmental traits enabling relatively rapid growth even under cooler conditions but increased in cold tolerance arguably promoting higher activity under thermally challenging conditions. Notably, these changes must have occurred within a time period of ca. 10 years only. Our results suggest, in line with contemporary theory, that the evolution of plasticity may play a hitherto underestimated role for adaptation to climatic variation. However, rather than generally increased or decreased levels of plasticity, our results indicate fine‐tuned, trait‐specific evolutionary responses to increase fitness in novel environments.
Abstract
This work presents a stepwise reversible two‐electron transfer induced hydrogen shift leading to the conversion of a bis‐pyrrolinium cation to an E‐diaminoalkene and vice versa. Remarkably, the forward and the reverse reaction, which are both reversible, follow two completely different reaction pathways. Establishing such unprecedented property in this type of processes was possible by developing a novel synthetic route towards the starting dication. All intermediates involved in both the forward and the backward reactions were comprehensively characterized by a combination of spectroscopic, crystallographic, electrochemical, spectroelectrochemical, and theoretical methods. The presented synthetic route opens up new possibilities for the generation of multi‐pyrrolinium cation scaffold‐based organic redox systems, which constitute decidedly sought‐after molecules in contemporary chemistry.
S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids) – Update 2020
(2020)
Extra-organismal DNA (eoDNA) from material left behind by organisms (noninvasive DNA, e.g., feces, hair) or from environmental samples (eDNA, e.g., water, soil) is a valuable source of genetic information. However, the relatively low quality and quantity of eoDNA, which can be further degraded by environmental factors, results in reduced amplification and sequencing success. This is often compensated for through cost- and time-intensive replications of genotyping/sequencing procedures. Therefore, system- and site-specific quantifications of environmental degradation are needed to maximize sampling efficiency (e.g., fewer replicates, shorter sampling durations), and to improve species detection and abundance estimates. Using 10 environmentally diverse bat roosts as a case study, we developed a robust modeling pipeline to quantify the environmental factors degrading eoDNA, predict eoDNA quality, and estimate sampling-site-specific ideal exposure duration. Maximum humidity was the strongest eoDNA-degrading factor, followed by exposure duration and then maximum temperature. We also found a positive effect when hottest days occurred later. The strength of this effect fell between the strength of the effects of exposure duration and maximum temperature. With those predictors and information on sampling period (before or after offspring were born), we reliably predicted mean eoDNA quality per sampling visit at new sites with a mean squared error of 0.0349. Site-specific simulations revealed that reducing exposure duration to 2–8 days could substantially improve eoDNA quality for future sampling. Our pipeline identified high humidity and temperature as strong drivers of eoDNA degradation even in the absence of rain and direct sunlight. Furthermore, we outline the pipeline's utility for other systems and study goals, such as estimating sample age, improving eDNA-based species detection, and increasing the accuracy of abundance estimates.
Abstract
Certain hydrolases preferentially catalyze acyl transfer over hydrolysis in an aqueous environment. However, the molecular and structural reasons for this phenomenon are still unclear. Herein, we provide evidence that acyltransferase activity in esterases highly correlates with the hydrophobicity of the substrate‐binding pocket. A hydrophobicity scoring system developed in this work allows accurate prediction of promiscuous acyltransferase activity solely from the amino acid sequence of the cap domain. This concept was experimentally verified by systematic investigation of several homologous esterases, leading to the discovery of five novel promiscuous acyltransferases. We also developed a simple yet versatile colorimetric assay for rapid characterization of novel acyltransferases. This study demonstrates that promiscuous acyltransferase activity is not as rare as previously thought and provides access to a vast number of novel acyltransferases with diverse substrate specificity and potential applications.
Abstract
Background
Several leech species of the genera Hirudo, Hirudinaria, and Whitmania are widely used in traditional Chinese medicine (TCM) for the oral treatment of disorders associated with blood stasis. Among them, the non‐hematophagous leech Whitmania pigra expresses a variety of components that have the potential to act on the vertebrate blood coagulation system.
Objective
Whether the thrombin inhibitor hirudin, probably the most prominent leech‐derived anticoagulant, is actually present in Whitmania pigra, is still a matter of debate. To answer that open question was the aim of the study.
Methods
We identified several putative hirudin‐encoding sequences in transcriptome data of Whitmania pigra. Upon gene synthesis and molecular cloning the respective recombinant proteins were expressed in Escherichia coli, purified, processed, and eventually functionally characterized for thrombin‐inhibitory potencies in coagulation assays.
Results
We were successful in the identification and functional characterization of several putative hirudins in Whitmania pigra. Some, but not all, of these factors are indeed thrombin inhibitors. Whitmania pigra hence expresses both hirudins (factors that inhibit thrombin) and hirudin‐like factors (that do not or only very weakly inhibit thrombin). Furthermore, we revealed the exon/intron structures of the corresponding genes. Coding sequences of some putative hirudins of Whitmania pigra were present also in transcriptome datasets of Hirudo nipponia, a hematophagous leech that is likewise used in TCM.
Conclusions
Based on both structural and functional data we provide very strong evidence for the expression of hirudins in Whitmania pigra. This is the first description of hirudins in a non‐hematophagous leech.
The hirudin‐like factor 1 (HLF1) of Hirudo medicinalis belongs to a new class of leech‐derived factors. In previous investigations, HLF1 did not exhibit anticoagulatory activities. Here, we describe the analysis of natural and synthetic variants of HLF1 and HLF‐Hyb, a yet uncharacterized member of the HLF family. Modifications within the N terminus of HLF1 have a strong impact on its activity. Some variants of HLF1 exhibit thrombin‐inhibiting activity comparable to hirudins, whereas others have reduced or no activity. The analyses of HLF‐Hyb variants revealed a strong impact of the central globular domain on activity. Our results indicate a comparable mode of action of hirudins and thrombin‐inhibiting HLF variants. Finally, we propose and discuss criteria for classifying hirudins and HLFs.
Abstract
While chemical communication has been investigated intensively in vertebrates and insects, relatively little is known about the sensory world of spiders despite the fact that chemical cues play a key role in natural and sexual selection in this group. In insects, olfaction is performed with wall–pore and gustation with tip‐pore sensilla. Since spiders possess tip‐pore sensilla only, it is unclear how they accomplish olfaction. We scrutinized the ultrastructure of the trichoid tip‐pore sensilla of the orb weaving spider Argiope bruennichi—a common Palearctic species the males of which are known to be attracted by female sex pheromone. We also investigated the congener Argiope blanda. We examined whether the tip‐pore sensilla differ in ultrastructure depending on sex and their position on the tarsi of walking legs of which only the distal parts are in contact with the substrate. We hypothesized as yet undetected differences in ultrastructure that suggest gustatory versus olfactory functions. All tarsal tip‐pore sensilla of both species exhibit characters typical of contact‐chemoreceptors, such as (a) the presence of a pore at the tip of the sensillum shaft, (b) 2–22 uniciliated chemoreceptive cells with elongated and unbranched dendrites reaching up to the tip‐pore, (c) two integrated mechanoreceptive cells with short dendrites and large tubular bodies attached to the sensillum shaft's base, and (d) a socket structure with suspension fibres that render the sensillum shaft flexible. The newly found third mechanoreceptive cell attached to the proximal end of the peridendritic shaft cylinder by a small tubular body was likely overlooked in previous studies. The organization of tarsal tip‐pore sensilla did not differ depending on the position on the tarsus nor between the sexes. As no wall‐pore sensilla were detected, we discuss the probability that a single type of sensillum performs both gustation and olfaction in spiders.
Azide‐Modified Nucleosides as Versatile Tools for Bioorthogonal Labeling and Functionalization
(2022)
Abstract
Azide‐modified nucleosides are important building blocks for RNA and DNA functionalization by click chemistry based on azide‐alkyne cycloaddition. This has put demand on synthetic chemistry to develop approaches for the preparation of azide‐modified nucleoside derivatives. We review here the available methods for the synthesis of various nucleosides decorated with azido groups at the sugar residue or nucleobase, their incorporation into oligonucleotides and cellular RNAs, and their application in azide‐alkyne cycloadditions for labelling and functionalization.
Abstract
Climate change may force organisms to adapt genetically or plastically to new environmental conditions. Invasive species show remarkable potential for rapid adaptation. The ovoviviparous New Zealand mud snail (NZMS), Potamopyrgus antipodarum, has successfully established across Europe with two clonally reproducing mitochondrial lineages since its arrival in the first half of the 19th century. Its remarkable variation in shell morphology was shown to be fitness relevant. We investigated the effects of temperature on shell morphology across 11 populations from Germany and the Iberian Peninsula in a common garden across three temperatures. We analyzed size and shape using geometric morphometrics. For both, we compared reaction norms and estimated heritabilities. For size, the interaction of temperature and haplotype explained about 50% of the total variance. We also observed more genotype by environment interactions indicating a higher degree of population differentiation than in shape. Across the three temperatures, size followed the expectations of the temperature‐size rule, with individuals growing larger in cold environments. Changes in shape may have compensated for changes in size affecting space for brooding embryos. Heritability estimates were relatively high. As indicated by the very low coefficients of variation for clonal repeatability (CVA), they can probably not be compared in absolute terms. However, they showed some sensitivity to temperature, in haplotype t more so than in z, which was only found in Portugal. The low CVA values indicate that genetic variation among European populations is still restricted with a low potential to react to selection. A considerable fraction of the genetic variation was due to differences between the clonal lineages. The NZMS has apparently not been long enough in Europe to accumulate significant genetic variation relevant for morphological adaptation. As temperature is obviously not the sole factor influencing shell morphology, their interaction will probably not be a factor limiting population persistence under a warming climate in Europe.
Parental gender preferences in Central and Eastern Europe and differential early life disadvantages
(2023)
Parental gender preferences may affect partnership decisions and as a result lead to early life disadvantages. We study these preferences in five post-communist countries of Central and Eastern Europe, a region with strong traditional gender norms and persisting inequalities between women and men in labour market outcomes. Using subsamples of census from Belarus, Hungary, Poland, Romania and Russia around 2000 and 2010, we follow Dahl and Moretti (2008), The demand for sons, to examine the effect of the gender of the first-born child(ren) on fertility decisions and relationship stability of their parents. We only find strong evidence of ‘boy preferences’ in fertility decisions in the cases of Romania and Russia. However, unlike Dahl and Moretti (2008), The demand for sons, for the US, we cannot confirm a relationship between the children's gender and parental partnership decisions. This is the case for all examined Central and Eastern European countries, as well as for a number of countries from Western Europe. The cases of Romania and Russia raise questions about other potential consequences of the documented gender preferences. We argue that our approach can be applied more broadly to identify other countries characterised by parental gender preferences, and to motivate further examination of different forms of gender driven early life disadvantages.
Abstract
Spiders of the genus Micaria are ground‐living mimics of ants. Species delineation in these spiders is challenging, mainly because of exceptional high levels of intraspecific variation masking species boundaries. As implied by preliminary DNA barcode data from Central Europe, the Holarctic and very widely distributed glossy ant‐spider M. pulicaria shows cryptic diversity. Here, we disentangle the hidden diversity by means of an integrative taxonomy approach, using mitochondrial DNA, morphometrics, traditional genitalic characters and ecology. Our data suggest the clear delineation of two distinct species, which supports the conception of 19th century taxonomists. These early naturalists distinguished M. pulicaria and a second closely related species based on morphology and natural history, which were synonymized in subsequent taxonomic studies. Therefore, we re‐circumscribe M. pulicaria and revalidate the long forgotten M. micans. These two Micaria species co‐occur sympatrically in vast areas of the western Palearctic, while the Nearctic region is populated by M. pulicaria alone. Male genitalic traits are more dissimilar in the area of sympatry than in allopatry, suggesting a decisive role of reproductive character displacement in species diversification. Our study emphasizes the value of the early taxonomic literature in integrative taxonomic studies, as it may contain crucial information on natural history that are not regularly recorded by modern taxonomists.
How well populations can cope with global warming will often depend on the evolutionary potential and plasticity of their temperature-sensitive, fitness-relevant traits. In Bechstein's bats (Myotis bechsteinii), body size has increased over the last decades in response to warmer summers. If this trend continues it may threaten populations as larger females exhibit higher mortality. To assess the evolutionary potential of body size, we applied a Bayesian ‘animal model’ to estimate additive genetic variance, heritability and evolvability of body size, based on a 25-year pedigree of 332 wild females. Both heritability and additive genetic variance were reduced in hot summers compared to average and cold summers, while evolvability of body size was generally low. This suggests that the observed increase in body size was mostly driven by phenotypic plasticity. Thus, if warm summers continue to become more frequent, body size likely increases further and the resulting fitness loss could threaten populations.
Abstract
Aim
Climate limits the potential distribution ranges of species. Establishment and growth of individuals at range margins is assumed to be more limited by extreme events such as drought or frost events than in the centre of their range. We explore whether the growth of beech is more sensitive to drought towards the dry distribution margin and more sensitive to frost towards the cold distribution margin. Furthermore, we aim to gain insight into the adaptive potential of beech towards both the dry and cold distribution margins.
Location
European gradient from the dry (Spain) to the cold (Poland, Sweden) distribution margin of beech.
Taxon
European beech (Fagus sylvatica L.).
Methods
We applied a range‐wide dendroecological study to analyse spatial and temporal trends in climate–growth relationships. We further investigated negative growth anomalies and growth synchrony towards the range margins.
Results
We found beech to be drought sensitive across its whole range, except at the dry distribution margin. Furthermore, sensitivity to winter temperature was not found in the centre or at the cold distribution margin, but at the southern distribution margin. Growth synchrony was lower at the dry than at the cold distribution margin.
Main conclusions
Beech seems to be adapted to drought at the dry distribution margin with a high adaptive potential indicated by the lowest growth synchrony along the gradient. At the cold distribution margin, cold events in winter and spring were less important for growth than drought. Still, the importance of spring frost for beech growth appears to increase in recent decades. Considering a projected north‐eastward shift of the distribution range, beech is likely facing drought stress in combination with spring frost risk at the cold margin which could lead to a hampered range expansion.
Changes in food characteristics reveal indirect effects of lake browning on zooplankton performance
(2020)
Abstract
Browning caused by colored dissolved organic matter is predicted to have large effects on aquatic ecosystems. However, there is limited experimental evidence about direct and indirect effects of browning on zooplankton in complex field settings. We used a combination of an ecosystem‐scale enclosure experiment and laboratory incubations to test how prolonged browning affects physiological and life‐history traits of the water flea Daphnia longispina, a key species in lake food webs, and whether any such effects are reversible. Daphnids and water were collected from enclosures in a deep clear‐water lake, where the natural plankton community had been exposed for 10 weeks to browning or to control conditions in clear water. Daphnid abundance was much lower in the brown than in the clear enclosure. Surprisingly, however, daphnids continuously kept in brown enclosure water in the laboratory showed increased metabolic performance and survival, and also produced more offspring than daphnids kept in clear enclosure water. This outcome was related to more and higher‐quality seston in brown compared to clear water. Moreover, daphnids transferred from clear to brown water or vice versa adjusted their nucleic acid and protein contents, as indicators of physiological state, to similar levels as individuals previously exposed to the respective recipient environment, indicating immediate and reversible browning effects on metabolic performance. These results demonstrate the importance of conducting experiments in settings that capture both indirect effects (i.e., emerging from species interactions in communities) and direct effects on individuals for assessing impacts of browning and other environmental changes on lakes.
Abstract
Enzyme activity data for biocatalytic applications are currently often not annotated with standardized conditions and terms. This makes it extremely hard to retrieve, compare, and reuse enzymatic data. With advances in the fields of artificial intelligence (AI) and machine learning (ML), the automated usability of data in the form of machine‐readable annotations will play a crucial role for their success. It is becoming increasingly easy to retrieve complex data sets and extract relevant information; however, standardized data readability is a current limitation. In this contribution, we outline an iterative approach to develop standardized terms and create semantic relations (ontologies) to achieve this highly desirable goal of improving the discoverability, accessibility, interoperability, and reuse of digital resources in the field of biocatalysis.
Abstract
Streptococcus pneumoniae infections are a leading cause of death worldwide. Bacterial membrane vesicles (MVs) are promising vaccine candidates because of the antigenic components of their parent microorganisms. Pneumococcal MVs exhibit low toxicity towards several cell lines, but their clinical translation requires a high yield and strong immunogenic effects without compromising immune cell viability. MVs are isolated during either the stationary phase (24 h) or death phase (48 h), and their yields, immunogenicity and cytotoxicity in human primary macrophages and dendritic cells have been investigated. Death‐phase vesicles showed higher yields than stationary‐phase vesicles. Both vesicle types displayed acceptable compatibility with primary immune cells and several cell lines. Both vesicle types showed comparable uptake and enhanced release of the inflammatory cytokines, tumor necrosis factor and interleukin‐6, from human primary immune cells. Proteomic analysis revealed similarities in vesicular immunogenic proteins such as pneumolysin, pneumococcal surface protein A, and IgA1 protease in both vesicle types, but stationary‐phase MVs showed significantly lower autolysin levels than death‐phase MVs. Although death‐phase vesicles produced higher yields, they lacked superiority to stationary‐phase vesicles as vaccine candidates owing to their similar antigenic protein cargo and comparable uptake into primary human immune cells.
To suit a wide variety of space mission profiles, different designs of ion thrusters were developed, such as the High‐Efficiency‐Multistage‐Plasma thrusters (HEMP‐T). In the past, the optimization of ion thrusters was a difficult and time‐consuming process and evolved experimentally. Because the construction of new designs is expensive, cheaper methods for optimization were sought‐after. Computer‐based simulations are a cheap and useful method towards predictive modelling. The physics in HEMP‐T requires a kinetic model. The Particle‐in‐Cell (PIC) method delivers self‐consistent solutions for the plasmas of ion thrusters, but it is limited by the high amount of computing time required to study a specific system. Therefore, it is not suited to explore a wide operational and design space. An approach to decrease computing time is self‐similarity scaling schemes, which can be derived from the kinetic equations. One specific self‐similarity scheme is investigated quantitatively in this work for selected HEMP‐Ts, using PIC simulations. The possible application of the scaling is explained and the limits of this approach are derived.
Abstract
A device for the transaminase‐catalysed synthesis combined with continuous recovery of chiral amines was designed. The system enabled the separation of the reaction components in three liquid phases: a reaction phase, an organic solvent phase (where the poorly water soluble ketone substrate was supplied), and an aqueous extraction phase for continuous product recovery. The transaminase‐mediated asymmetric synthesis of (S)‐1‐methyl‐3‐phenylpropylamine was employed as model reaction. Factors influencing the performance of the system, such as reactor geometry, working volumes and operating parameters, were investigated. Specifically, reaction yield and product recovery were enhanced by i) reducing the thickness of the reaction phase, while continuously stirring and ii) reducing the volume of the extraction phase. Under the optimal condition tested, 85 % of the product formed was extracted and a product concentration value of 9 g/L was reached. However, co‐extraction of the unreacted amine donor (17 %) was observed. Advantages and drawbacks of this process compared to existing technologies, as well as possible optimization strategies are discussed.
Abstract
Metabolomics studies now approach large sample sizes and the health characterization of the study population often include complete blood count (CBC) results. Upon careful interpretation the CBC aids diagnosis and provides insight into the health status of the patient within a clinical setting. Uncovering metabolic signatures associated with parameters of the CBC in apparently healthy individuals may facilitate interpretation of metabolomics studies in general and related to diseases. For this purpose 879 subjects from the population‐based Study of Health in Pomerania (SHIP)‐TREND were included. Using metabolomics data resulting from mass‐spectrometry based measurements in plasma samples associations of specific CBC parameters with metabolites were determined by linear regression models. In total, 118 metabolites significantly associated with at least one of the CBC parameters. Strongest associations were observed with metabolites of heme degradation and energy production/consumption. Inverse association seen with mean corpuscular volume and mean corpuscular haemoglobin comprised metabolites potentially related to kidney function. The presently identified metabolic signatures are likely derived from the general function and formation/elimination of blood cells. The wealth of associated metabolites strongly argues to consider CBC in the interpretation of metabolomics studies, in particular if mutual effects on those parameters by the disease of interest are known.
Abstract
The two important mechanisms influencing the response of phytoplankton communities to alterations of abiotic factors in their environment are difficult to distinguish: species sorting resulting from a change in interspecific competitive pressure, and phenotypic plasticity (here explicitly physiological plasticity i.e. species‐specific physiological adjustment). A shift in species composition as well as physiological adjustments in species can lead to changes in fatty acid composition that determine the food quality for zooplankton consumers.
We used phytoplankton communities consisting of five species and exposed them to two different light intensities, two light conditions (constant and variable), and two levels of phosphorus supply. Changes in fatty acid and species composition were analyzed. We compared community pairs differing in one factor by calculating the Bray‐Curtis similarity index for the composition of both variables. Comparing the Bray‐Curtis similarity index of the species composition with the index of the fatty acid composition was used to estimate the effects of species sorting and physiological plasticity.
Changes in nutrient supply influenced fatty acid responses based on species sorting and physiological plasticity the most. On one hand, the relevance of physiological plasticity was highest at cultivation in different nutrient supplies but the same light environment. Conversely with low nutrients species sorting appeared to dominate the response to changes in light, while at high nutrients physiological plasticity appeared to influence the response. Overall, under low phosphorus supply the communities showed a lower total fatty acid content per carbon and had increased proportions of saturated and monounsaturated fatty acids. Instead, communities in low light produced more of eicosapentaenoic acid.
Our results suggest that the relevance of species sorting and physiological plasticity in shaping the community response highly depends on the environmental factors that influence the system. Nutrient supply had the largest effect, while light had more limited conditional effects. However, all of these factors are important in shaping the food quality of the phytoplankton community for higher trophic levels.
Background
Adolescents and young adults (AYAs) with chronic conditions face a transfer, defined as an actual shift from paediatric to adult-oriented health care. Transition competence as the self-perceived knowledge, skills and abilities regarding the transition process was considered extremely useful.
Aim
This study was designed to investigate the impact of transition competence before and after the transfer on disease-specific quality of life (QoL) and health care satisfaction of AYAs with diabetes.
Results
In total, a sample of N = 90 AYAs with diabetes self-reported their transition competence, diabetes-specific QoL and satisfaction with care. Multiple linear regressions were used to analyse the impact of transition competence on satisfaction with care and QoL. Transition competence positively influenced the outcomes of satisfaction with care and QoL.
Conclusion
Young adults with diabetes showed higher transition competence scores than adolescents with diabetes.
Background
Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia.
Methods
Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis.
Results
Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus.
Conclusions
mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy.
Abstract
A N‐heterocyclic olefin (NHO), a terminal alkene selectively activates aromatic C−F bonds without the need of any additional catalyst. As a result, a straightforward methodology was developed for the formation of different fluoroaryl‐substituted alkenes in which the central carbon–carbon double bond is in a twisted geometry.
Electrochemically active ϵ‐MnO2 and ɣ‐MnO2 as tunnel‐type host‐guest structures have been extensively studied by crystallography and electrochemical techniques for application in battery cathode materials. However, the Gibbs energies of the underlying ion and electron transfer processes across the electrode interfaces have not yet been determined. Here we report for the first time these data for ϵ‐MnO2. This was possible by measuring the mid‐peak potentials in cyclic voltammetry and the open‐circuit potentials under electrochemically reversible conditions.
The transition to Ni‐based battery cathodes enhances the energy density and reduces the cost of batteries. However, this comes at the expense of losing energy efficiency which could be a consequence of charge–discharge hysteresis. Here, a thermodynamic model is developed to understand the extent and origin of charge–discharge hysteresis in battery cathodes based on their cyclic voltammograms (CVs). This was possible by defining a Gibbs energy function that weights random ion insertion/expulsion, i. e., a solid solution pathway, against selective ion insertion/expulsion, i. e., a phase separation route. The model was verified experimentally by the CVs of CoOOH and Ni(OH)2 as solid‐solution and phase‐separating cathodes, respectively. Finally, a microscopic view reveals that phase separation and hysteresis are a consequence of large ionic radii difference of the reduced and oxidized central metal atoms.
Herein, we disclose cyclic(alkyl)(amino)carbenes (CAACs) to be one-electron reductants under the formation of a transient radical cation as indicated by EPR spectroscopy. The disclosed CAAC reducing reactivity was used to synthesize acyclic(amino)(aryl)carbene-based Thiele and Chichibabin hydrocarbons, a new class of Kekulé diradicaloids. The results demonstrate CAACs to be potent organic reductants. Notably, the acyclic(amino)(aryl)carbene-based Chichibabin's hydrocarbon shows an appreciable population of the triplet state at room temperature, as evidenced by both variable-temperature NMR and EPR spectroscopy.