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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.
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.
We apply the charge simulation method (CSM) in order to compute the logarithmic capacity of compact sets consisting of (infinitely) many “small” components. This application allows to use just a single charge point for each component. The resulting method therefore is significantly more efficient than methods based on discretizations of the boundaries (for example, our own method presented in Liesen et al. (Comput. Methods Funct. Theory 17, 689–713, 2017)), while maintaining a very high level of accuracy. We study properties of the linear algebraic systems that arise in the CSM, and show how these systems can be solved efficiently using preconditioned iterative methods, where the matrix-vector products are computed using the fast multipole method. We illustrate the use of the method on generalized Cantor sets and the Cantor dust.
Background
Neuroinflammation and maladaptive neuroplasticity play pivotal roles in migraine (MIG), trigeminal autonomic cephalalgias (TAC), and complex regional pain syndrome (CRPS). Notably, CRPS shares connections with calcitonin gene-related peptide (CGRP) in its pathophysiology. This study aims to assess if the documented links between CRPS and MIG/TAC in literature align with clinical phenotypes and disease progressions. This assessment may bolster the hypothesis of shared pathophysiological mechanisms.
Methods
Patients with CRPS (n = 184) and an age-/gender-matched control group with trauma but without CRPS (n = 148) participated in this case–control study. Participant answered well-established questionnaires for the definition of CRPS symptoms, any headache complaints, headache entity, and clinical management.
Results
Patients with CRPS were significantly more likely to suffer from migraine (OR: 3.23, 95% CI 1.82–5.85), TAC (OR: 8.07, 95% CI 1.33–154.79), or non-classified headaches (OR: 3.68, 95% CI 1.88–7.49) compared to the control group. Patients with MIG/TAC developed CRPS earlier in life (37.2 ± 11.1 vs 46.8 ± 13.5 years), had more often a central CRPS phenotype (60.6% vs. 37.0% overall) and were three times more likely to report allodynia compared to CRPS patients with other types of headaches. Additionally, these patients experienced higher pain levels and more severe CRPS, which intensified with an increasing number of headache days. Patients receiving monoclonal antibody treatment targeting the CGRP pathway for headaches reported positive effects on CRPS symptoms.
Conclusion
This study identified clinically relevant associations of MIG/TAC and CRPS not explained by chance. Further longitudinal investigations exploring potentially mutual pathomechanisms may improve the clinical management of both CRPS and primary headache disorders.
Trial registration
German Clinical Trials Register (DRKS00022961).
Perception of climate change-related forest dieback in mountain forests among the local population
(2023)
Mountain forests provide multiple benefits but are threatened by climate change-induced forest dieback. Although many studies summarize perceptions of forest ecosystem services, relatively few deal with mountain forests. The local population’s perception of forest dieback in mountain forests in relation to climate change has rarely been investigated so far. Their perspective is relevant as local people are often deeply attached to “their” forests, they actively use forest ecosystems and—as voters and taxpayers—they need to support the state’s adaptation and funding measures. Therefore, this study investigates the climate change and forest dieback perception of local inhabitants in two mountain areas of Southern Germany (the German Alps and the Bavarian Forest) with a quantitative survey based on representative online samples (n = 709). Relying conceptually on van der Linden’s (J Environ Psychol 41:112–124, 2015. https://doi.org/10.1016/j.jenvp.2014.11.012) climate change risk perception model, the results show that experiential processing, cognitive and socio-cultural factors are related to locals’ forest dieback and climate change perception, while socio-demographics show no or few connections. Nearly two-thirds (64.7%) of the respondents perceive moderate to strong forest dieback, while more than half (55.0%) of the respondents already observe consequences of climate change. The perceptions of climate change and forest dieback are positively correlated with medium to high strength. This shows that forest dieback could be interpreted as an indicator of climate change, which is difficult to observe due to its long-term nature. We identify three groups of respondents regarding preferred forest adaptation strategies to climate change. In general, respondents support nature-based forest adaptation strategies over intense measures.
Toarciconiopteryx dipterosimilis gen. et sp. nov. is described from the Lower Toarcian of Grimmen (Western Pomerania, Germany) based on a hind wing. This enigmatic wing superficially resembles a dipteran forewing, but analysis in detail establishes that it belongs to the Neuroptera. We assign it to the Coniopterygidae with great confidence by its great concordance with the hind wings of that family, but a small possibility remains that it might belong to the Dipteromantispidae, although the very derived haltere-like hind wings of all its known members are entirely unlike it. We, therefore, consider it to be the oldest record of Coniopterygidae. We create the new subfamily Toarciconiopteryginae subfam. nov. for it, which is distinguished from other Coniopterygidae by its hind wings possessing two branches of RP and a proximal forking of M. These conditions are also known in some Sialidae (Megaloptera), supporting the hypothesis that Coniopterygidae is the sister group of all other Neuroptera, as Megaloptera is considered by most authors to be sister to Neuroptera. New interpretations of some aspects of the Coniopterygidae venation are proposed.
Seventeen bacterial strains able to suppress plant pathogens have been isolated from healthy Vietnamese crop plants and taxonomically assigned as members of the Bacillus cereus group. In order to prove their potential as biocontrol agents, we perform a comprehensive analysis that included the whole-genome sequencing of selected strains and the mining for genes and gene clusters involved in the synthesis of endo- and exotoxins and secondary metabolites, such as antimicrobial peptides (AMPs). Kurstakin, thumolycin, and other AMPs were detected and characterized by different mass spectrometric methods, such as MALDI-TOF-MS and LIFT-MALDI-TOF/TOF fragment analysis. Based on their whole-genome sequences, the plant-associated isolates were assigned to the following species and subspecies: B. cereus subsp. cereus (6), B. cereus subsp. bombysepticus (5), Bacillus tropicus (2), and Bacillus pacificus. These three isolates represent novel genomospecies. Genes encoding entomopathogenic crystal and vegetative proteins were detected in B. cereus subsp. bombysepticus TK1. The in vitro assays revealed that many plant-associated isolates enhanced plant growth and suppressed plant pathogens. Our findings indicate that the plant-associated representatives of the B. cereus group are a rich source of putative antimicrobial compounds with potential in sustainable agriculture. However, the presence of virulence genes might restrict their application as biologicals in agriculture.
Peatlands contribute to a wide range of ecosystem services. They play an important role as carbon sinks in their natural state, but when they are drained, they cause carbon emissions. Rewetting drained peatlands is required to reduce carbon emissions and create new carbon sinks. However, drained peatlands are commonly used as grassland or croplands; therefore, alternative agriculture schemes are required following rewetting. Paludiculture, i.e., agriculture on wet and rewetted peatlands, is an option in these areas after rewetting to produce biomass sustainably. Monitoring of peatland management is challenging, yet needed to ensure a successful rewetting and plantation of, e.g., Phragmites australis and Typha spp., two plants which are commonly used in paludiculture. Remote sensing is an excellent tool for monitoring the vegetation composition of vast rewetted peatland regions. However, because many peatland species have similar spectral characteristics, such monitoring is ideally based on high-spatial, high-temporal hyperspectral images. Data that complies with all these requirements does not exist on a regular basis. Therefore, we assessed the potential for mapping peatland vegetation communities in the Peene and Trebel river basins of the federal state of Mecklenburg-Western Pomerania, Germany, using multi-date hyperspectral (PRISMA) data. We used regression-based unmixing to map fractions of different peatland vegetation classes. Results were analyzed with regard to the contribution of multi-date observations and, in comparison, to multispectral datasets (Landsat-8/Sentinel-2). Our results showed that different classes are best mapped at different observation dates. The multi-date hyperspectral datasets produced less Mean Absolute Error (MAE = 16.4%) than the single-date hyperspectral images (ΔMAE + 1%), with high accuracies for all classes of interest. Compared to the results obtained with multispectral data from similar acquisition dates and annual spectral-temporal metrics (STM), the results from hyperspectral data were always clearly superior (ΔMAE + 4%). Besides the superior performance during comparisons, our results also indicate that information that can be derived from the hyperspectral data with the regression-based unmixing goes clearly beyond that of discrete classification. With more hyperspectral sensors coming up and an expected higher availability of multi-data hyperspectral imagery, these data can be expected to play a bigger role in the future monitoring of peatlands.
The male genitalia of pholcid spiders, which is one of the most species-rich spider families, are characterized by a procursus, which is a morphologically diverse projection of the copulatory organ. It has been shown that the procursus interacts with the female genitalia during copulation. Here, we investigate the function of the procursus in Gertschiola neuquena, a species belonging to the early branched and understudied subfamily Ninetinae, using behavioural and morphological data. Although many aspects of the copulatory behaviour of G. neuquena follow the general pattern described for the family, males use only one pedipalp during each copulation. Based on our micro-CT analysis of cryofixed mating pairs using virgin females, we can show that the long and filiform procursus is inserted deeply into the unpaired convoluted female spermatheca, and the intromittent sclerite, the embolus, is rather short and stout only reaching the most distal part of the female sperm storage organ. Histological data revealed that sperm are present in the most proximal part of the spermatheca, suggesting that the procursus is used to allocate sperm deeply into the female sperm storage organ. This represents the first case of a replacement of the sperm allocation function of the intromittent sclerite in spiders.
The multi-cell Penning–Malmberg trap concept has been proposed as a way to accumulate and confine unprecedented numbers of antiparticles, an attractive but challenging goal. We report on the commissioning and first results (using electron plasmas) of the World's second prototype of such a trap, which builds and improves on the findings of its predecessor. Reliable alignment of both ‘master’ and ‘storage’ cells with the axial magnetic field has enabled confinement of plasmas, without use of the ‘rotating wall’ (RW) compression technique, for over an hour in the master cell and tens of seconds in the storage cells. In the master cell, attachment to background neutrals is found to be the main source of charge loss, with an overall charge-confinement time of 8.6 h. Transfer to on-axis and off-axis storage cells has been demonstrated, with an off-axis transfer rate of 50% of the initial particles, and confinement times in the storage cells in the tens of seconds (again, without RW compression). This, in turn, has enabled the first simultaneous plasma confinement in two off-axis cells, a milestone for the multi-cell trap concept.
The controlled formation and adjustment of size and density of magnetic skyrmions in Ta/CoFeB/MgO trilayers with low Dzyaloshinskii–Moriya interaction is demonstrated. Close to the out-of-plane to in-plane magnetic spin reorientation transition, we find that small energy contributions enable skyrmion formation in a narrow window of 20 pm in CoFeB thickness. Zero-field stable skyrmions are established with proper magnetic field initialization within a 10 pm CoFeB thickness range. Using magneto-optical imaging with quantitative image processing, variations in skyrmion distribution and diameter are analyzed quantitatively, the latter for sizes well below the optical resolution limit. We demonstrate the controlled merging of individual skyrmions. The overall demonstrated degree of comprehension of skyrmion control aids to the development of envisioned skyrmion based magnetic memory devices.
Minced Cartilage Implantation in Acetabular Cartilage Defects: Case Series with 2-Year Results
(2023)
Objective
The objective was to evaluate clinical outcome and safety of arthroscopic, autologous minced cartilage implantation for acetabular cartilage lesions observed during hip arthroscopy to treat femoroacetabular impingement syndrome (FAIS).
Design
Eleven male patients, average age: 29.4 ± 5.4 years, average body mass index (BMI): 24.2 ± 2.2 kg/m2, scheduled for hip arthroscopy due to FAIS accompanied by an acetabular cartilage lesion were included in the case series. Cartilage tissue was harvested and minced from the loose cartilage flap at the chondrolabral lesion by arthroscopic shaver, augmented with autologous conditioned plasma, implanted into the defect, and fixated by autologous thrombin. Concomitant interventions were performed as indicated. The patients were evaluated preoperatively and at 24-month follow-up, using the International Hip Outcome Tool-12 (iHOT-12) and Visual Analog Scale (VAS) pain score and by magnetic resonance imaging (MRI) using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) grading scale at the 2-year follow-up.
Results
The defect size was on average 3.5 cm2 (1.5-4.5 cm2). From preoperatively to 2 years postoperatively, the iHOT-12 significantly improved from 50.2 ± 18 to 86.5 ± 19 (P < 0.0001), and pain score decreased from 5.6 ± 1.8 to 1.0 ± 1.5 (P < 0.0001) on the Visual Analog Scale pain score. Regarding functional outcome and pain, 10 of the 11 patients and all patients reached the minimal clinically important difference (MCID), respectively. The postoperative average MOCART score was 87.2 (± 9.2). No adverse events or reoperations were observed.
Conclusions
Arthroscopic, autologous minced cartilage implantation for treating full-thickness acetabular cartilage lesions in FAIS shows statistically and clinically significant improvement at short-term follow-up.
Background:
Minced cartilage implantation (MCI) has seen a renaissance in recent years. In this evolved technique, human articular cartilage is harvested with an arthroscopic shaver, augmented with platelet-rich plasma (PRP), and implanted with autologous thrombin. This modified technique combines the possibility of cell-based surgical cartilage repair with a minimally invasive autologous 1-step procedure. However, evidence on cell survival and preserved function after shaver-based mincing and PRP supplementation is limited.
Purpose:
To evaluate the effects of arthroscopic shaver mincing and augmentation with PRP on human cartilage tissue.
Study Design:
Controlled laboratory study.
Methods:
Standardized samples were taken from 12 donors during autologous MCI. A comparison of cell outgrowth, cell viability, proliferation capacity, and ability to produce extracellular matrix–specific proteoglycans after chondrogenic redifferentiation was made between cartilage taken by curettage from the border of the cartilage defect, cartilage tissue minced by an arthroscopic shaver, and cartilage tissue minced by an arthroscopic shaver that was additionally augmented with autologous PRP.
Results:
There was no difference between all 3 groups in terms of cell outgrowth or proliferation capacity. Metabolic activity relative to the cell number of chondrocytes isolated from shaver-minced cartilage was higher compared with chondrocytes isolated from cartilage that was derived by curettage or shaver-minced cartilage that was augmented with PRP. After chondrogenic stimulation, the normalized proteoglycan content was higher in spheroids of cells derived from shaver-minced cartilage augmented with PRP than in spheroids of cells derived from curettage. A high correlation of cell outgrowth, proliferation capacity, and viability between isolated cells from all 3 groups taken from an individual donor was observed.
Conclusion:
Chondrocytes isolated from human cartilage tissue that was harvested and minced with an arthroscopic shaver remained viable and proliferative. The augmentation of shaver-minced cartilage with PRP led to the enhanced proteoglycan production of chondrogenic spheroids in vitro, pointing toward the development of a cartilage-specific extracellular matrix. This in vitro study yields promising results regarding the use of an arthroscopic shaver and augmentation with PRP in the context of MCI.
Clinical Relevance:
Knowledge that shaver mincing and augmentation with PRP are feasible for processing articular cartilage during MCI is highly relevant for surgical cartilage repair.
Introduction: Vessel-associated retinal diseases are a major cause of blindness and severe visual impairment. The identification of appropriate biomarkers is of great importance to better anticipate disease progression and establish more targeted treatment options. MicroRNAs (miRNAs) are short, single-stranded, noncoding ribonucleic acids that are involved in the posttranscriptional regulation of gene expression through hybridization with messenger RNA. The expression of certain miRNAs can be different in patients with pathological processes and can be used for the detection and differentiation of various diseases. In this study, we investigate to what extent previously in vitro identified miRNAs are present as cell-free circulating miRNAs in the serum and vitreous of human patients with and without vessel-associated retinal diseases. Methods: Relative quantification by quantitative real-time polymerase chain reaction was used to analyze miRNA expression in patients with vessel-associated retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion compared with control patients. Results: In serum samples, miR-29a-3p and miR-192-5p showed increased expression in patients with neovascular AMD relative to control patients. Similarly, miR-335-5p, miR-192-5p, and miR-194-5p showed increased expression in serum from patients with proliferative DR. In vitreous samples, miR-100-5p was decreased in patients with proliferative DR. Differentially expressed miRNAs showed good diagnostic accuracy in receiver operating characteristic (ROC) and area under the ROC curve analysis. Conclusion: The miRNAs investigated in this study may have the potential to serve as biomarkers for vessel-associated retinal diseases. Combining multiple miRNAs may enhance the predictive power of the analysis.
In future fusion reactors disruptions must be avoided at all costs. Disruptions due to the density limit (DL) are typically described by the power-independent Greenwald scaling. Recently, a power dependence of the disruptive DL was predicted by several authors (Zanca et al 2019 Nucl. Fusion 59 126011; Giacomin et al 2022 Phys. Rev. Lett. 128 185003; Singh and Diamond 2022 Plasma Phys. Control. Fusion 64 084004; Stroth et al 2022 Nucl. Fusion 62 076008; Brown and Goldston 2021 Nucl. Mater. Energy 27 101002). It is investigated whether this increases the operational range of the tokamak. Increasing the heating power in the L-mode can induce an L-H transition, and therefore a power-dependent DL and the L-H transition cannot be considered independently. The different models are tested on a data base for separatrix parameters at the separatrix of ASDEX Upgrade and compared with the concept (SepOS) presented in Eich and Manz (2021 Nucl. Fusion 61 086017). The disruptive separatrix density scales with the power ne ∝ P0.38±0.08 in good agreement to all models. Also the back transition from high to low (H-L) confinement shows an approximately Greenwald scaling with an additional power dependence ne ∝ P0.4 according to the SepOS concept. For future devices operating at much higher heating power such a power scaling may allow operation at much higher separatrix densities than are common in H-mode operation. Preconditions to extrapolation for future devices are discussed.
The pulse length dependence of a reactive high power impulse magnetron sputtering (HiPIMS) discharge with a tungsten cathode in an argon+oxygen gas mixture gas was investigated. The HiPIMS discharge is operated with a variable pulse length of 20–500 µs. Discharge current measurements, optical emission spectroscopy of neutral Ar, O, and W lines, and energy-resolved ion mass spectrometry are employed. A pronounced dependence of the discharge current on pulse length is noted while the initial discharge voltage is maintained constant. Energy-resolved mass spectrometry shows that the oxygen-to-tungsten (O+/W+) and the tungsten oxide-to-tungsten (WO+/W+) ion ratio decreases with pulse length due to target cleaning. Simulation results employing the SDTrimSP program show the formation of a non-stoichiometric sub-surface compound layer of oxygen which depends on the impinging ion composition and thus on the pulse length.
The current study analyzes the trajectory of the goose vowel in Received Pronunciation (RP) over ten decades (1920s-2010s). Recordings of eighty-seven RP speakers were transcribed in ELAN, and vowel tokens were extracted by FAVE, measuring F1 and F2 values at the midpoint. Showing the life-cycle of a sound change from start to (almost) completion, the results confirm that goose-fronting has been an active sound change for many decades in RP, with F2 starting to increase in the middle of the twentieth century and accelerated changes in the 1970s and the 2010s. We observe similar predictor strengths of linguistic factors as in previous studies. The results are interpreted in light of the social changes in the social composition of the RP group in the second part of the twentieth century, involving increased dialect contact.
Properties of self-excited dust acoustic waves under the influence of active compression of the dust particle system were experimentally studied in the laboratory and under microgravity conditions (parabolic flight). Ground based laboratory experiments clearly show that wave properties can be manipulated by changing the discharge volume, its aspect ratio, and thus the dust particle density. Complementary experiments under microgravity conditions, performed to exclude the effects of gravity inflicted sedimentation and anisotropic behavior, were less conclusive due to residual fluctuations in the planes acceleration indicating the need for a better microgravity environment. A theoretical model, using plasma parameters obtained from particle-in-cell simulations as input, supports the experimental findings. It shows that the waves can be described as a new observation of the dust acoustic mode, which demonstrates their generic character.
This article is the first to show that gender shapes the degree to which legislators use formal mechanisms to oversee government activities. Extensive scholarly work has analysed the use of oversight instruments, especially regarding who monitors whom. Whether, how, and why the conformity of men and women with institutional roles differs, has not yet received scholarly attention. We hypothesise that women become more active than men in overseeing the executive when in opposition while reducing their monitoring activities even more strongly than men when in government because of different social roles ascribed to men and women as well as differences in risk aversity between sexes. We analyse panel data for three oversight tools from the German Bundestag between 1949 and 2013 to test this proposition. Our findings imply that characteristics of political actors influence even a strongly institutionalised process as oversight and further clarify the gender bias in political representation.
Objective: In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the Treg/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.
Design: AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (Treg) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed Treg activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.
Results: The prophylactic Treg-depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8+/γδTCR+ IELs. Treg depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa Escherichia/Shigella which associates with severe disease and infected necrosis was diminished in Treg depleted animals.
Conclusion: Tregs play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, Treg-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting Tregs in AP may help to ameliorate the disease course.
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.
Purpose
The significance of the underlying literature in clinical guidelines can be weakened by the risk of bias, which could negatively affect the recommendations. Especially in controversial matters, such as fluoride use for caries prevention in children, biased results may be not reliable and lead to incorrect conclusions. This study was performed to detect bias in underlying literature of the German guideline for caries prevention using fluoride in children, where no consensus was reached between paediatricians and paediatric dentists.
Methods
Three tools used for risk of bias assessments of different study designs were RoB 2 for RCTs, ROBINS-I for non-randomized studies, and ROBIS for systematic reviews. For each study cited in the guideline two independent risk of bias assessments were performed. Disagreements were resolved by consensus.
Results
Out of 58 papers, 48.3% (n = 28) showed high risk of bias, with the majority in sections regarding fluoride tablets, fluoridated toothpaste, and paediatricians’ recommendations. 9 out of 20 recommendations and statements were based on studies with high risk of bias, all of which were in these three controversial sections. 13 out of 29 RCTs showed high risk of bias (44.8%), as all 13 non-randomized trials did, while only 2 of 16 (12.5%) systematic reviews had high risk of bias.
Conclusion
Considering risk of bias of cited studies in clinical guidelines may result in substantial changes in its recommendations and aid in reaching consensus. Efforts should be made to assess risk of bias of underlying literature in future clinical guidelines.
Urbanization, industrialization, and intensification of agriculture have led to considerable heavy metal pollution across the globe, harming our ecosystems. Concentrations of arsenic (As), cadmium (Cd), copper (Cu), and lead (Pb) have been analysed in 249 eggshells collected between 2006 and 2021 from 83 female Common Cranes (Grus grus) nesting within north-eastern Germany. Information on the presence of trace elements in cranes from Europe and their potential adverse effects on the reproduction are largely missing. Only Cu and Pb were found to be present in eggshell samples. Levels of both metals did not exceed concentrations considered potentially toxic in birds and unhatched eggs did not contain higher metal concentrations compared to eggshell residues from hatched eggs. Statistical analysis revealed that trace element concentrations decreased significantly over the course of the study period. The ban of leaded gasoline in the early twenty-first century and strict limitations of heavy metal-based biocontrol products are likely responsible for this decrease over the years. However, as Cu levels gradually increase with increasing proportions of agricultural areas within the cranes’ home ranges, we suggest that considerable amounts of Cu originating from agricultural practises are still being released into the environment. We found no increase in metal concentrations in eggshells with increasing female age, suggesting that heavy metals do not accumulate in the circulatory systems of the adults over time. This study is the first to assess heavy metal contamination in Common Cranes and indicates the suitability of crane’s eggshells as bioindicator for monitoring environmental pollution.
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.
o-Hydroxyarylphosphanes are fascinating compounds by their multiple-reactivity features, attributed to the ambident hard and soft Lewis- and also Brønstedt acid-base properties, wide tuning opportunities via backbone substituents with ±mesomeric and inductive, at P and in o-position to P and O also steric effects, and in addition, the configurational stability at three-valent phosphorus. Air sensitivity may be overcome by reversible protection with BH3, but the easy oxidation to P(V)-compounds may also be used. Since the first reports on the title compounds ca. 50 years ago the multiple reactivity has led to versatile applications. This includes various P−E−O and P=C−O heterocycles, a multitude of O-substituted derivatives including acyl derivatives for traceless Staudinger couplings of biomolecules with labels or functional substituents, phosphane-phosphite ligands, which like the o-phosphanylphenols itself form a range of transition metal complexes and catalysts. Also main group metal complexes and (bi)arylphosphonium-organocatalysts are derived. Within this review the various strategies for the access of the starting materials are illuminated, including few hints to selected applications.
Aim
To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance (1H-NMR) spectroscopy with periodontitis and tooth loss.
Materials and Methods
A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing.
Results
While only spurious associations between lipoprotein levels from conventional blood tests were found—that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity.
Conclusions
Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed.
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.
Protein engineering is essential for altering the substrate scope, catalytic activity and selectivity of enzymes for applications in biocatalysis. However, traditional approaches, such as directed evolution and rational design, encounter the challenge in dealing with the experimental screening process of a large protein mutation space. Machine learning methods allow the approximation of protein fitness landscapes and the identification of catalytic patterns using limited experimental data, thus providing a new avenue to guide protein engineering campaigns. In this concept article, we review machine learning models that have been developed to assess enzyme-substrate-catalysis performance relationships aiming to improve enzymes through data-driven protein engineering. Furthermore, we prospect the future development of this field to provide additional strategies and tools for achieving desired activities and selectivities.
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.
Aim
To estimate association between the use of interdental cleaning aids (IDAs) and type on 7-year follow-up levels of interdental plaque, interdental gingival inflammation, interdental periodontitis severity, the number of interdental sound surfaces and the number of missing teeth in a population-based cohort study.
Materials and Methods
We used 7-year follow-up data of 2224 participants from the Study of Health in Pomerania (SHIP-TREND). We applied generalized linear and ordinal logistic models, adjusting for confounding and selection bias using inverse probability treatment weighting and multiple imputation.
Results
Flossers were 32% less likely to have higher interdental plaque (iPlaque) levels than non-users of IDAs (odds ratio [OR] = 0.68; 95% confidence interval [CI]: 0.50–0.94); flossing resulted in 5% lower means of iPlaque. Effects on interdental bleeding on probing (iBOP), mean interdental probing depths and mean interdental clinical attachment levels were direction-consistent but statistically non-significant. Interdental brushing was associated with lower follow-up levels for interdental plaque (OR = 0.73; 95% CI: 0.57–0.93) and iBOP (OR = 0.69; 95% CI: 0.53–0.89). IDAs were more effective in reducing iPlaque in participants with periodontitis, whereas iBOP reduction was more pronounced in participants with no or mild periodontitis. The analyses did not suggest that the use of IDAs affected caries. Finally, applying change score analyses, flossing reduced tooth loss incidence (incidence rate ratio [IRR] = 0.71) compared with non-users of IDAs.
Conclusions
Recommending flossing and interdental brushing in dental practices represents an approach to the prevention of gingivitis and consequently periodontitis.
Animals face strong environmental variability even on short time scales particularly in shallow coastal habitats, forcing them to permanently adjust their metabolism. Respiration rates of aquatic ectotherms are directly influenced by water temperature, whereas ingestion rates might additionally be influenced by behavior. We aim to understand how respiration and ingestion rates of an aquatic invertebrate respond to changing temperature during a diurnal thermal fluctuation cycle and how both processes are related. We studied the benthopelagic mysid Neomysis integer as an important food web component of coastal ecosystems. Mysids were collected at the southern Baltic Sea coast and exposed in the laboratory to either constant temperature of 15°C or daily temperature fluctuation of 15 ± 5°C. Short-term (1–2 h) respiration and ingestion rates were measured at four equidistant time points within 24 h and did not differ among time points at constant temperature, but differed among time points in the fluctuating treatment. Respiration was highest at the thermal maximum and lowest at the thermal minimum. Ingestion rates showed the opposite pattern under fluctuation, likely due to differences in underlying thermal performance curves. When temperature transited the average, the direction of temperature change influenced the animals' response in respiration and ingestion rates differently. Our results suggest that respiration is not only instantaneously affected by temperature, but also influenced by the previously experienced direction of thermal change. Our experiment, using an important non-model organism, delivered new insights on the relationship between the crucial organismal processes ingestion and respiration under thermal variability.
Introduction
The number of mentally altered patients a dentist meets in practice is increasing and interaction with them can be very challenging. As a baseline for an interventional study, we want to assess the attitude of dental students and identify areas of improvement in patient communication. This work compares the attitude of dental students towards people suffering from dementia to the attitudes of trained medical caregivers and the general population. Our aim is to use the results to assess the need for training in communicating with mentally altered patients.
Materials and Methods
Fourth-year dental students attended two lectures on dementia given by a psychiatrist as part of the geriatric dentistry lecture and were questioned afterwards using the Dementia Attitude Scale. In 2016 and 2017, 73 students at the University of Greifswald were interviewed. The response rate was 84%. Using a factor analysis, the Dementia Attitude Scale's validated questions were interpreted and compared with data from nursing staff from Switzerland and the USA.
Results
The factor analysis of the data showed the same two-factor loadings as the comparative groups, and that dental students' attitude is more comparable to the general population than to medically trained nursing staff.
Conclusion
Given the results, we conclude that the implementation of a communication module can serve in improving the attitude of dental students towards patients with dementia.
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.
In this article, we address the transition of the Kolbe electrolysis of valeric acid (VA) to n-octane as an exemplary electrosynthesis process from a batch reaction to a continuous, self-regulated process. Based on a systematic assessment of chemical boundary conditions and sustainability aspects, we propose a continuous electrosynthesis including a simple product separation and electrolyte recirculation, as well as an online-pH-controlled VA feeding. We demonstrate how essential performance parameters such as product selectivity (S) and coulombic efficiency (CE) are significantly improved by the transition from batch to a continuous process. Thus, the continuous and pH-controlled electrolysis of a 1 M valeric acid, starting pH 6.0, allowed a constantly high selectivity of around 47 % and an average Coulomb efficiency about 52 % throughout the entire experimental duration. Under otherwise identical conditions, the conventional batch operation suffered from lower and strongly decreasing performance values (Sn-octane, 60min=10.4 %, Sn-octane, 240min=1.3 %; CEn-octane, 60min=7.1 %, CEn-octane, 240min=0.5 %). At the same time, electrolyte recirculation significantly reduces wastes and limits the use of electrolyte components.
Aims
To investigate factors that influence the willingness of inactive nurses to return to nursing in a crisis situation and to identify aspects that need to be considered with regard to a possible deployment.
Design
A deductive and inductive qualitative content analysis of semi-structured focus group interviews.
Methods
Semi-structured focus group interviews with inactive or marginally employed nurses, nurses who have been inactive for some time and nursing home managers in October and November 2021. The participating inactive nurses had declared their willingness for a deployment during the COVID-19 pandemic or not. Data were analysed using qualitative content analysis.
Results
Communication was seen as essential by the participants for an informed decision for or against a temporary return to nursing and to potential or actual deployments. To make them feel safe, inactive nurses need to know what to expect and what is expected of them, for example, regarding required training and responsibilities. Considering their current employment status, some flexibility in terms of deployment conditions is needed.
A remaining attachment to care can trigger a sense of duty. Knowledge of (regular) working conditions in nursing can lead to both a desire to support former colleagues and a refusal to be exposed to these conditions again.
Conclusion
Past working experiences and the current employment situation play a major role in the willingness of inactive nurses to return to nursing in a crisis situation. Unbureaucratic arrangements must be provided for those who are willing to return.
Summary Statement
What already is known - In crisis situations, not every inactive nurse is willing or able to return to nursing and therefore, the ‘silent reserve’ may not be as large as suspected.
What this paper adds - Inactive nurses need to know what to expect and what is expected of them for their decision regarding a return to active patient care during a crisis situation.
Implications for practice/policy – Inactive nurses need to be informed and should be offered free training and refresher courses to ensure patient safety.
Impact
This research shows that the group of inactive nurses are not a silent workforce which can be activated anytime. Those who are able and willing to return to direct patient care in crisis situations need the best possible support – during and between crises.
Reporting Method
This study adhered to COREQ guidelines.
No Patient or Public Contribution
The involvement of patients or members of the public did not apply for the study, as the aim was to gain insight into the motivations and attitudes of the group of inactive nurses.
Enzymatic degradation and recycling can reduce the environmental impact of plastics. Despite decades of research, no enzymes for the efficient hydrolysis of polyurethanes have been reported. Whereas the hydrolysis of the ester bonds in polyester‐polyurethanes by cutinases is known, the urethane bonds in polyether‐polyurethanes have remained inaccessible to biocatalytic hydrolysis. Here we report the discovery of urethanases from a metagenome library constructed from soil that had been exposed to polyurethane waste for many years. We then demonstrate the use of a urethanase in a chemoenzymatic process for polyurethane foam recycling. The urethanase hydrolyses low molecular weight dicarbamates resulting from chemical glycolysis of polyether‐polyurethane foam, making this strategy broadly applicable to diverse polyether‐polyurethane wastes.
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.
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.
For the characterization of Kv7.2/3 channel activators, several analytical methods are available that vary in effort and cost. In addition to the technically elaborate patch-clamp method, which serves as a reference method, there exist several medium to high-throughput screening methods including a rubidium efflux flame-atomic absorption spectrometry (F-AAS) assay and a commercial thallium uptake fluorescence-based assay. In this study, the general suitability of a graphite furnace atomic absorption spectrometry (GF-AAS)-based rubidium efflux assay as a screening method for Kv7.2/3 channel activators was demonstrated. With flupirtine serving as a reference compound, 16 newly synthesizedcompounds and the known Kv7.2/3 activator retigabine were first classified as either active or inactive by using the GF-AAS-based rubidium (Rb) efflux assay. Then, the results were compared with a thallium (Tl) uptake fluorescence-based fluorometric imaging plate reader (FLIPR) potassium assay. Overall, 16 of 17 compounds were classified by the GF-AAS-based assay in agreement with their channel-activating properties determined by the more expensive Tl uptake, fluorescence-based assay. Thus, the performance of the GF-AAS-based Rb assay for primary drug screening of Kv7.2/3-activating compounds was clearly demonstrated, as documented by the calculated Z’-factor of the GF-AAS-based method. Moreover, method development included optimization of the coating of the microtiter plates and the washing procedure, which extended the range of this assay to poorly adherent cells such as the HEK293 cells used in this study.
In temperate regions, climate warming alters temperature and precipitation regimes. During winter, a decline in insulating snow cover changes the soil environment, where especially frost exposure can have severe implications for soil microorganisms and subsequently for soil nutrient dynamics. Here, we investigated winter climate change responses in European beech forests soil microbiome. Nine study sites with each three treatments (snow exclusion, insolation, and ambient) were investigated. Long-term adaptation to average climate was explored by comparing across sites. Triplicated treatment plots were used to evaluate short-term (one single winter) responses. Community profiles of bacteria, archaea and fungi were created using amplicon sequencing. Correlations between the microbiome, vegetation and soil physicochemical properties were found. We identify core members of the forest-microbiome and link them to key processes, for example, mycorrhizal symbiont and specialized beech wood degraders (fungi) and nitrogen cycling (bacteria, archaea). For bacteria, the shift of the microbiome composition due to short-term soil temperature manipulations in winter was similar to the community differences observed between long-term relatively cold to warm conditions. The results suggest a strong link between the changes in the microbiomes and changes in environmental processes, for example, nitrogen dynamics, driven by variations in winter climate.
Being a master of metaphors
(2023)
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 %.
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.
In mandibulate arthropods, the primary olfactory centers, termed olfactory lobes in crustaceans, are typically organized in distinct fields of dense synaptic neuropils called olfactory glomeruli. In addition to olfactory sensory neuron terminals and their postsynaptic efferents, the glomeruli are innervated by diverse neurochemically distinctive interneurons. The functional morphology of the olfactory glomeruli is understudied in crustaceans compared with insects and even less well understood and described in a particular crustacean subgroup, the Peracarida, which embrace, for example, Amphipoda and Isopoda. Using immunohistochemistry combined with confocal laser scanning microscopy, we analyzed the neurochemistry of the olfactory pathway in the amphipod Parhyale hawaiensis. We localized the biogenic amines serotonin and histamine as well as the neuropeptides RFamide, allatostatin, orcokinin, and SIFamide. As for other classical neurotransmitters, we stained for γ-aminobutyric acid and glutamate decarboxylase and used choline acetyltransferase as indicator for acetylcholine. Our study is another step in understanding principles of olfactory processing in crustaceans and can serve as a basis for understanding evolutionary transformations of crustacean olfactory systems.
Boronate esters formed by reaction of an oligonucleotide carrying a 5′-boronic acid moiety with the 3′-terminal cis-diol of another have been shown previously to assist assembly of fragmented DNAzymes. Here we demonstrate that boronate esters replacing the natural phosphodiester linkage at selected sites of two functional RNAs, the hairpin ribozyme and the Mango aptamer, allow assembly of functional structures. The hairpin ribozyme, a small naturally occurring RNA that supports the reversible cleavage of appropriate RNA substrates, is very sensitive to fragmentation. Splitting the ribozyme at four different sites led to a significant decrease or even loss of cleavage and ligation activity. Ribozymes assembled from fragments capable of boronate ester formation showed restoration of cleavage activity in some but not all cases, dependent on the split site. Ligation proved to be more challenging, no supportive effect of the boronate ester was observed. Split variants of the Mango aptamer also showed a dramatic loss of functionality, which however, was restored when 5′-boronic acid modified fragments were used for assembly. These studies show for the first time that boronate esters as internucleoside linkages can act as surrogates of natural phosphodiesters in functional RNA molecules.
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. Machine learning provides a promising approach for protein engineering, but activity prediction models for ATAs remain elusive due to the difficulty of obtaining high-quality training data. Thus, we first created variants of the ATA from Ruegeria sp. (3FCR) with improved catalytic activity (up to 2000-fold) as well as reversed stereoselectivity by a structure-dependent rational design and collected a high-quality dataset in this process. Subsequently, we designed a modified one-hot code to describe steric and electronic effects of substrates and residues within ATAs. Finally, we built a gradient boosting regression tree predictor for catalytic activity and stereoselectivity, and applied this for the data-driven design of optimized variants which then showed improved activity (up to 3-fold compared to the best variants previously identified). We also demonstrated that the model can predict the catalytic activity for ATA variants of another origin by retraining with a small set of additional data.
Chronic kidney disease is a major public health burden associated with a drastically reduced quality of living and life span that lacks suitable, individualized therapeutic strategies. Here we present a human induced pluripotent stem cell line (iPSC, UMGACBi001-A) reprogrammed from urine cells of an acute septic dialysis patient suffering from chronic kidney disease using non-integrating administration of RNAs. The generated iPSCs were positively characterized for typical morphology, pluripotency marker expression, directed differentiation potential, non-contamination, chromosomal consistency and donor identity. This iPSC-line can be a useful source for in vitro disease modelling and individualized therapeutic approaches.
Background and Aims
Hepatocellular ballooning is a common finding in chronic liver disease, mainly characterized by rarefied cytoplasm that often contains Mallory-Denk bodies (MDB). Ballooning has mostly been attributed to degeneration but its striking resemblance to glycogenotic/steatotic changes characterizing preneoplastic hepatocellular lesions in animal models and chronic human liver diseases prompts the question whether ballooned hepatocytes (BH) are damaged cells on the path to death or rather viable cells, possibly involved in neoplastic development.
Methods
Using specimens from 96 cirrhotic human livers, BH characteristics were assessed for their glycogen/lipid stores, enzyme activities, and proto-oncogenic signaling cascades by enzyme- and immunohistochemical approaches with serial paraffin and cryostat sections.
Results
BH were present in 43.8% of cirrhotic livers. Particularly pronounced excess glycogen storage of (glycogenosis) and/or lipids (steatosis) were characteristic, ground glass features and MDB were often observed. Decreased glucose-6-phosphatase, increased glucose-6-phosphate dehydrogenase activity and altered immunoreactivity of enzymes involved in glycolysis, lipid metabolism, and cholesterol biosynthesis were discovered. Furthermore, components of the insulin signaling cascade were upregulated along with insulin dependent glucose transporter glucose transporter 4 and the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin signaling pathway associated with de novo lipogenesis.
Conclusions
BH are hallmarked by particularly pronounced glycogenosis with facultative steatosis, many of their features being reminiscent of metabolic aberrations documented in preneoplastic hepatocellular lesions in experimental animals and chronic human liver diseases. Hence, BH are not damaged entities facing death but rather viable cells featuring metabolic reprogramming, indicative of a preneoplastic nature.
Global and even national genome surveillance approaches do not provide the resolution necessary for rapid and accurate direct response by local public health authorities. Hence, a regional network of microbiological laboratories in collaboration with the health departments of all districts of the German federal state of Mecklenburg-Western Pomerania (M-V) was formed to investigate the regional molecular epidemiology of circulating SARS-CoV-2 lineages between 11/2020 and 03/2022. More than 4750 samples from all M-V counties were sequenced using Illumina and Nanopore technologies. Overall, 3493 (73.5%) sequences fulfilled quality criteria for time-resolved and/or spatially-resolved maximum likelihood phylogenic analyses and k-mean/ median clustering (KMC). We identified 116 different Pangolin virus lineages that can be assigned to 16 Nextstrain clades. The ten most frequently detected virus lineages belonged to B.1.1.7, AY.122, AY.43, BA.1, B.1.617.2, BA.1.1, AY.9.2, AY.4, P.1 and AY.126. Time-resolved phylogenetic analyses showed the occurrence of virus clades as determined worldwide, but with a substantial delay of one to two months. Further spatio-temporal phylogenetic analyses revealed a regional outbreak of a Gamma variant limited to western M-V counties. Finally, KMC elucidated a successive introduction of the various virus lineages into M-V, possibly triggered by vacation periods with increased (inter-) national travel activities. The COVID-19 pandemic in M-V was shaped by a combination of several SARS-CoV-2 introductions, lockdown measures, restrictive quarantine of patients and the lineage specific replication rate. Complementing global and national surveillance, regional surveillance adds value by providing a higher level of surveillance resolution tailored to local health authorities.
Counting of microbial colonies is a common technique employed in research and diagnostics. To simplify this tedious and time-consuming process, automated systems have been proposed. This study aimed to elucidate the reliability of automated colony counting. We evaluated a commercially available instrument (UVP ColonyDoc-It Imaging Station) in regard to its accuracy and potential time savings. Suspensions of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecium, and Candida albicans (n = 20 each) were adjusted to achieve growth of approximately 1,000, 100, 10, and 1 colony per plate, respectively, after overnight incubation on different solid media. Compared with manual counting, each plate was automatically counted by the UVP ColonyDoc-It with and without visual adjustment on a computer display. For all bacterial species and concentrations automatically counted without visual correction, an overall mean difference from manual counts of 59.7%, a proportion of isolates with overestimation/underestimation of colony numbers of 29%/45%, respectively, and only a moderate relationship (R2 = 0.77) with the manual counting were shown. Applying visual correction, the overall mean difference from manual counts was 1.8%, the proportion of isolates with overestimation/underestimation of colony numbers amounted to 2%/42%, respectively, and a strong relationship (R2 = 0.99) with the manual counting was observed. The mean time needed for manual counting compared with automated counting without and with visual correction was 70 s, 30 s, and 104 s, respectively, for bacterial colonies through all concentrations tested. Generally, similar performance regarding accuracy and counting time was observed with C. albicans. In conclusion, fully automatic counting showed low accuracy, especially for plates with very high or very low colony numbers. After visual correction of the automatically generated results, the concordance with manual counts was high; however, there was no advantage in reading time.
IMPORTANCE Colony counting is a widely utilized technique in the field of microbiology. The accuracy and convenience of automated colony counters are essential for research and diagnostics. However, there is only sparse evidence on performance and usefulness of such instruments. This study examined the current state of reliability and practicality of the automated colony counting with an advanced modern system. For this, we thoroughly evaluated a commercially available instrument in terms of its accuracy and counting time required. Our findings indicate that fully automatic counting resulted in low accuracy, particularly for plates with very high or very low colony numbers. Visual correction of the automated results on a computer screen improved concordance with manual counts, but there was no benefit in counting time.
Neuroblastoma is the most common extracranial, malignant, solid tumor found in children. In more than one-third of cases, the tumor is in an advanced stage, with limited resectability. The treatment options include resection, with or without (neo-/) adjuvant therapy, and conservative therapy, the latter even with curative intent. Contrast-enhanced MRI is used for staging and therapy monitoring. Diffusion-weighted imaging (DWI) is often included. DWI allows for a calculation of the apparent diffusion coefficient (ADC) for quantitative assessment. Histological tumor characteristics can be derived from ADC maps. Monitoring the response to treatment is possible using ADC maps, with an increase in ADC values in cases of a response to therapy. Changes in the ADC value precede volume reduction. The usual criteria for determining the response to therapy can therefore be supplemented by ADC values. While these changes have been observed in neuroblastoma, early changes in the ADC value in response to therapy are less well described. In this study, we evaluated whether there is an early change in the ADC values in neuroblastoma under therapy; if this change depends on the form of therapy; and whether this change may serve as a prognostic marker. We retrospectively evaluated neuroblastoma cases treated in our institution between June 2007 and August 2014. The examinations were grouped as ‘prestaging’; ‘intermediate staging’; ‘final staging’; and ‘follow-up’. A classification of “progress”, “stable disease”, or “regress” was made. For the determination of ADC values, regions of interest were drawn along the borders of all tumor manifestations. To calculate ADC changes (∆ADC), the respective MRI of the prestaging was used as a reference point or, in the case of therapies that took place directly after previous therapies, the associated previous staging. In the follow-up examinations, the previous examination was used as a reference point. The ∆ADC were grouped into ∆ADCregress for regressive disease, ∆ADCstable for stable disease, and ∆ADC for progressive disease. In addition, examinations at 60 to 120 days from the baseline were grouped as er∆ADCregress, er∆ADCstable, and er∆ADCprogress. Any differences were tested for significance using the Mann–Whitney test (level of significance: p < 0.05). In total, 34 patients with 40 evaluable tumor manifestations and 121 diffusion-weighted MRI examinations were finally included. Twenty-seven patients had INSS stage IV neuroblastoma, and seven had INSS stage III neuroblastoma. A positive N-Myc expression was found in 11 tumor diseases, and 17 patients tested negative for N-Myc (with six cases having no information). 26 patients were assigned to the high-risk group according to INRG and eight patients to the intermediate-risk group. There was a significant difference in mean ADC values from the high-risk group compared to those from the intermediate-risk group, according to INRG. The differences between the mean ∆ADC values (absolute and percentage) according to the course of the disease were significant: between ∆ADCregress and ∆ADCstable, between ∆ADCprogress and ∆ADCstable, as well as between ∆ADCregress and ∆ADCprogress. The differences between the mean er∆ADC values (absolute and percentage) according to the course of the disease were significant: between er∆ADCregress and er∆ADCstable, as well as between er∆ADCregress and er∆ADCprogress. Forms of therapy, N-Myc status, and risk groups showed no further significant differences in mean ADC values and ∆ADC/er∆ADC. A clear connection between the ADC changes and the response to therapy could be demonstrated. This held true even within the first 120 days after the start of therapy: an increase in the ADC value corresponds to a probable response to therapy, while a decrease predicts progression. Minimal or no changes were seen in cases of stable disease.
The cortical silent period (CSP), assessed with transcranial magnetic stimulation (TMS), provides insights into motor cortex excitability. Alterations in the CSP have been observed in multiple sclerosis (MS), although a comparison of the sometimes contradictory results is difficult due to methodological differences. The aim of this study is to provide a more profound neurophysiological understanding of fatigue’s pathophysiology and its relationship to the CSP. Twenty-three patients with MS, along with a matched control group, underwent comprehensive CSP measurements at four intensities (125, 150, 175, and 200% resting motor threshold), while their fatigue levels were assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and its motor and cognitive subscore. MS patients exhibited a significantly increased CSP duration compared to controls (p = 0.02), but CSP duration was not associated with the total FSMC, or the motor or cognitive subscore. Our data suggest a systematic difference in MS patients compared to healthy controls in the CSP but no association with fatigue when measured with the FSMC. Based on these results, and considering the heterogeneous literature in the field, our study highlights the need for a more standardized approach to neurophysiological data collection and validation. This standardization is crucial for exploring the link between TMS and clinical impairments in diseases like MS.
Immunotherapies against high-risk neuroblastoma (NB), using the anti-GD2 antibody (Ab) dinutuximab beta (DB), significantly improved patient survival. Ab-dependent cellular cytotoxicity (ADCC) is one of the main mechanisms of action and it is primarily mediated by NK cells. To further improve antitumor efficacy, we investigated here a combinatorial immunotherapy with DB and the double immune checkpoint blockade of T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death ligand-1 (PD-L1). The effects of ADCC, mediated by DB against NB cells on NK-cell activity, and the expression of TIGIT and CD226 and their ligands CD112 and CD155, as well as of PD-1 and PD-L1 on NB and effector cells, were investigated using flow cytometry. ADCC was assessed with a calcein-AM-based cytotoxicity assay. The efficacy of a combinatorial immunotherapy with DB, given as a long-term treatment, and the double immune checkpoint blockade of TIGIT and PD-L1 was shown using a resistant murine model of NB, followed by an analysis of the tumor tissue. We detected both TIGIT ligands, CD112 and CD155, on all NB cell lines analyzed. Although ADCC by DB resulted in a strong activation of NK cells leading to an effective tumor cell lysis, a remarkable induction of PD-L1 expression on NB cells, and of TIGIT and PD-1 on effector cells, especially on NK cells, was observed. Additional anti-TIGIT or anti-PD-L1 treatments effectively inhibited tumor growth and improved survival of the mice treated with DB. The superior antitumor effects were observed in the “DB + double immune checkpoint blockade” group, showing an almost complete eradication of the tumors and the highest OS, even under resistant conditions. An analysis of tumor tissue revealed both TIGIT and TIGIT ligand expression on myeloid-derived suppressor cells (MDSCs), suggesting additional mechanisms of protumoral effects in NB. Our data show that the targeting of TIGIT and PD-L1 significantly improves the antitumor efficacy of anti-GD2 immunotherapy, with DB presenting a new effective combinatorial treatment strategy against high-risk tumors.
This study investigated, if a mixed electroactive bacterial (EAB) culture cultivated heterotrophically at a positive applied potential could be adapted from oxidative to reductive or bidirectional extracellular electron transfer (EET). To this end, a periodic potential reversal regime between − 0.5 and 0.2 V vs. Ag/AgCl was applied. This yielded biofilm detachment and mediated electroautotrophic EET in combination with carbonate, i.e., dissolved CO2, as the sole carbon source, whereby the emerged mixed culture (S1) contained previously unknown EAB. Using acetate (S2) as well as a mixture of acetate and carbonate (S3) as the main carbon sources yielded primarily alternating electrogenic organoheterotropic metabolism with the higher maximum oxidation current densities recorded for mixed carbon media, exceeding on average 1 mA cm−2. More frequent periodic polarization reversal resulted in the increase of maximum oxidative current densities by about 50% for S2-BES and 80% for S3-BES, in comparison to half-batch polarization. The EAB mixed cultures developed accordingly, with S1 represented by mostly aerobes (84.8%) and being very different in composition to S2 and S3, dominated by anaerobes (96.9 and 96.5%, respectively). S2 and S3 biofilms remained attached to the electrodes. There was only minor evidence of fully reversible bidirectional EET. In conclusion the three triplicates fed with organic and/or inorganic carbon sources demonstrated two forms of diauxie: Firstly, S1-BES showed a preference for the electrode as the electron donor via mediated EET. Secondly, S2-BES and S3-BES showed a preference for acetate as electron donor and c-source, as long as this was available, switching to CO2 reduction, when acetate was depleted.
The impact of the COVID-19 pandemic on social-emotional developmental risks (SE-DR) of preschool children is largely unknown. Therefore, the aim of this prospective longitudinal dynamic cohort study was to assess changes in preschoolers’ SE-DR from before the pandemic to after the first COVID-19 wave. SE-DR were assessed annually with the instrument “Dortmund Developmental Screening for Preschools” (DESK). Longitudinal DESK data from 3- to 4-year-old children who participated both in survey wave (SW) three (DESK-SW3, 2019) and SW four (DESK-SW4, 2020) from August 1 to November 30 were used, respectively. Additionally, data from previous pre-pandemic SW were analyzed to contextualize the observed changes (SW1: 2017; SW2: 2018). A total of N = 786 children were included in the analysis. In the pre-pandemic DESK-SW3, the proportion of children with SE-DR was 18.2%, whereas in DESK-SW4 after the first COVID-19 wave, the proportion decreased to 12.4% (p = 0.001). Thus, the prevalence rate ratio (PRR) was 0.68. Compared to data from previous SW (SW1-SW2: PRR = 0.88; SW2-SW3: PRR = 0.82), this result represents a notable improvement. However, only short-term effects were described, and the study region had one of the highest preschool return rates in Germany. Further studies are needed to examine long-term effects of the pandemic on preschoolers’ SE-DR.
Background
The ‘wallflower’ hypothesis proposes females mate indiscriminately to avoid reproductive delays. Post-copulatory mechanisms may then allow ‘trading up’, favouring paternity of future mates. We tested links between pre- and post-copulatory choice in Latrodectus geometricus female spiders paired sequentially with two males. These females copulate as adults or as subadults and store sperm in paired spermathecae. Choosy adults have a higher risk of delays to reproduction than subadults.
Results
We predicted low pre-copulatory, but high post-copulatory choice at first matings for adults and the opposite for subadults. At second matings, we expected all females would prefer males superior to their first. We found all females mated indiscriminately at their first pairing, but in contrast to subadults, adults usually allowed only a single insertion (leaving one of their paired spermatheca empty); a mechanism of post-copulatory choosiness. Adult-mated females were more likely to remate than subadult-mated females when they became adults, showing a preference for larger males, while subadult-mated females tended to prefer males of greater size-corrected mass.
Conclusions
Our results show that the ‘wallflower’ effect and ‘trading up’ tactics can be utilized at different life stages, allowing females to employ choice even if rejecting males is costly.
This dynamic cohort was established to evaluate the targeted individual promotion of children affected by developmental risks as part of the German federal state law for child day-care and preschools in Mecklenburg-Western Pomerania. The project has been conducted in preschools in regions with a low socio-economic profile since 2011. Since 2017, the revision of the standardized Dortmund Developmental Screening for Preschools (DESK 3–6 R) has been applied. Developmental risks of 3 to 6-year-old children in the domains of motor, linguistic, cognitive and social competencies are monitored. The cohort is followed up annually. In 2020, n = 7,678 children from n = 152 preschools participated. At the baseline (2017), n = 8,439 children participated. Due to the defined age range of this screening, 3,000 to 4,000 5-6-year-old children leave the cohort annually. Simultaneously, an approximately equal number of 3-year-old children enters the cohort per survey wave. N = 702 children participated in all 4 survey waves. On the basis of DESK 3–6 R scores available from survey waves 2017 to 2019 it is possible to compute expected values for the survey wave 2020 and to compare those with the measured values to evaluate the effects of the COVID-19 pandemic (i.e. parental home care due to restrictions related to COVID-19).
Background
Only about half the people with depression seek professional health care services. To constitute the different predictors and associating variables of health care utilisation, we model the process and aim to test our hypothesised Seeking Mental Health Care Model. The model includes empirical influences on the help-seeking process to predict actual behaviour and incorporates superordinate (stigma, treatment experiences) as well as intermediate attitudinal variables (continuum and causal beliefs, depression literacy and self-efficacy).
Method
All variables are examined in an online study (baseline, three- and six-month follow-up). The sample consisted of adults with depressive symptoms (PHQ-9 sum score ≥ 8), currently not receiving mental health care treatment. To examine the prediction of variables explaining help-seeking behaviour, a path model analysis was carried out (lavaan package, software R).
Results
Altogether, 1368 participants (Mage = 42.38, SDage = 15.22, 65.6% female) were included, 983 participating in at least one follow-up. Model fit was excellent (i.e., RMSEA = 0.059, CFI = 0.989), and the model confirmed most of the hypothesised predictions. Intermediary variables were significantly associated with stigma and experiences. Depression literacy (ß = .28), continuum beliefs (ß = .11) and openness to a balanced biopsychosocial causal model (ß = .21) significantly influenced self-identification (R2 = .35), which among the causal beliefs and self-efficacy influenced help-seeking intention (R2 = .10). Intention (ß = .40) prospectively predicted help-seeking behaviour (R2 = .16).
Conclusion
The Seeking Mental Health Care Model provides an empirically validated conceptualisation of the help-seeking process of people with untreated depressive symptoms as a comprehensive approach considering internal influences. Implications and open questions are discussed, e.g., regarding differentiated assessment of self-efficacy, usefulness of continuum beliefs and causal beliefs in anti-stigma work, and replication of the model for other mental illnesses.
Trial registration
German Clinical Trials Register: DRKS00023557. Registered 11 December 2020. World Health Organization, Universal Trial Number: U1111–1264-9954. Registered 16 February 2021.
Although serious accidents remain the leading cause of pediatric mortality, protocols to orient diagnostic procedures towards a certain type of initial imaging are widely needed. Since 2007, we have performed whole-body magnetic resonance imaging (WBMR) and whole-body computed tomography (WBCT) for diagnoses of severely injured children. We retrospectively reviewed 134 WBMR and 158 WBCT in patients younger than 16 years that were performed at two trauma centers between 2007 and 2018. A higher Injury Severity Score (ISS) was found in WBCT vs. WBMR (10.6 vs. 5.8; p = 0.001), but without any significant difference in mortality. The WBMR was significantly preferred at younger ages (9.6 vs. 12.8 years; p < 0.001). The time between patient’s arrival until diagnosis was 2.5 times longer for WBCT (92.1 vs. 37.1 min; p < 0.001). More patients in the CT group received analgesic sedation and/or intubation at 37.3% vs. 21.6% in the MRI group. Of these patients, 86.4% (CT) and 27.6% (MRI) were already preclinically sedated (p < 0.001). Correspondingly, 72.4% of the patients were first sedated in-hospital for MRIs. In conclusion, WBMR is an alternative and radiation-free imaging method for high-energy-traumatized children. Although the selected diagnostics seemed appropriate, limitations regarding longer duration or additional analgesic sedation are present, and further studies are needed.
Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.
Background
Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.
Methods
In this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.
Results
Of the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108–290). Three-year progression-free and overall survival rates were 31% (95% CI 17–47) and 66% (95% CI 47–79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.
Conclusion
Long-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.
Clinical trial registration
The study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).
Objective
To conduct a systematic review of the published scientific evidence to evaluate the efficacy of nonsurgical periodontal therapy (NSPT) in treating periodontitis in patients with concurrent systemic conditions (diabetes, CVD, erectile dysfunction, chronic kidney disease, rheumatoid arthritis, polycystic ovarian syndrome, obesity, pregnancy). We hypothesised that NSPT results in better periodontal outcomes when compared to untreated controls after follow-up.
Materials and methods
A systematic search (PUBMED/EMBASE) was conducted from 1995 to 2023 to identify randomised controlled trials (RCTs) with a minimum follow-up of 3 months. The primary outcome was the difference in mean probing depth (PD), and the secondary outcomes were mean clinical attachment loss (CAL), percentage of sites with PD ≤ 3 mm (%PD ≤ 3 mm) and percentage of sites with bleeding on probing (%BOP) between the treated and untreated control group in patients with comorbidities.
Results
The electronic search resulted in 2,403 hits. After removing duplicates, 1,565 titles and abstracts were screened according to the eligibility criteria, resulting in 126 articles for full-text screening. Following this, 44 studies were analysed. Restricting to studies with low bias or some concerns, NSPT group demonstrated a 0.55 mm lower mean PD (95%CI: −0.69; −0.41) after 3 months compared to the control group.
Conclusion
Compared to the untreated controls, NSPT notably reduced mean PD, mean CAL, and %BOP while increasing %PD ≤ 3 mm in patients with concurrent systemic conditions. These findings suggest that NSPT is also an effective procedure in managing periodontitis in patients with concurrent systemic conditions.
Trial registration
This systematic review was registered under the protocol registration number CRD42021241517/PROSPERO.
Binding of general transcription factors TFIID and TFIIA to basal promoters is rate-limiting for transcriptional initiation of eukaryotic protein-coding genes. Consequently, activator proteins interacting with subunits of TFIID and/or TFIIA can drastically increase the rate of initiation events. Yeast transcriptional activator Ino2 interacts with several Taf subunits of TFIID, among them the multifunctional Taf1 protein. In contrast to mammalian Taf1, yeast Taf1 lacks bromodomains which are instead encoded by separate proteins Bdf1 and Bdf2. In this work, we show that Bdf1 not only binds to acetylated histone H4 but can also be recruited by Ino2 and unrelated activators such as Gal4, Rap1, Leu3 and Flo8. An activator-binding domain was mapped in the N-terminus of Bdf1. Subunits Toa1 and Toa2 of yeast TFIIA directly contact sequences of basal promoters and TFIID subunit TBP but may also mediate the influence of activators. Indeed, Ino2 efficiently binds to two separate structural domains of Toa1, specifically with its N-terminal four-helix bundle structure required for dimerization with Toa2 and its C-terminal β-barrel domain contacting TBP and sequences of the TATA element. These findings complete the functional analysis of yeast general transcription factors Bdf1 and Toa1 and identify them as targets of activator proteins.
Neutron scattering is a very high-performance method for studying the structure and dynamics of condensed matter with similar approaches in wide ranges of space and time, matching dimensions in space from single atoms to macromolecules and in time from atomic vibrations over crystal phonons to low-lying transitions in the microwave range, and to motions of large molecular units. Concerning the number and depth of physical concepts, neutron scattering may be compared to modern nuclear magnetic resonance. Neutrons have contributed essential results to the understanding of atomic and molecular processes and are, in this respect, complementary to other materials science probes. Among others, three properties of thermal neutrons make them especially appropriate for such work: the neutron mass is similar to atomic masses, and both neutron energies and the wavelengths of the neutron material wave match typical values for condensed matter. A further important feature of neutron scattering, making it especially valuable in biochemistry and polymer sciences, is that hydrogen and deuterium atoms very significantly and specifically contribute to the signal in both diffraction and spectroscopy. Additionally, neutrons are scattered at the nuclei and directly reflect the nuclear structure and motions. Results from neutron scattering are of great general interest. This paper aims to provide an introduction for chemists on a level understandable also to students and researchers who are not going to become part of the neutron community and will not be involved in the experiments, but shall be able to understand the basic concepts of the method and its relevance to modern chemistry. The paper focuses on basic theory, typical experiments, and some examples demonstrating the applications. As for many modern experimental techniques, the interpretation of the results of neutron scattering is based on theoretical models and requires a significant mathematical overhead. Most results are only meaningful when compared with computer simulations. For understanding this, in this paper, the theory of scattering is developed, starting with intuitive models and presenting typical concepts such as the scattering triangle, energy and momentum transfer, and the relation of inelastic and elastic scattering to space- and time-dependent information. The interaction of neutrons with matter, scattering cross sections, beam attenuation, and coherent versus incoherent scattering are explained in detail. Two further typical concepts that are not generally familiar to scientists outside the community are the use of wave and particle equivalence, and of handling results as a scattering function that depends simultaneously on momentum and energy transfers. The possibility of obtaining neutron beams for scattering experiments at a few research centers around high-performance sources is explained, and experimentally relevant features of research reactors and spallation sources are mentioned. As neutron experiments always have to deal with small flux and extended beams and shielding, experimental conditions are very far away from laboratory methods where handling of samples and instruments is concerned. Experimental details are given for making experiments more understandable and familiarizing the reader with the method. Related to this are extended possibilities for handling samples in a large variety of different environments. In a further part of the manuscript, a variety of techniques and typical instruments are presented, together with some characteristic applications bringing alive the theory developed so far. This covers powder diffraction and structure of liquid water, triple-axis spectrometers and lattice phonons, backscattering spectrometry and rotational tunneling, time-of-flight spectrometry, and simultaneously probing the energy and shape of low lying vibrations and diffusion, filter spectrometer and vibrational spectroscopy without selection rules, small-angle neutron scattering and protein unfolding, as well as micelles, neutron spin echo spectroscopy, and polymer dynamics.
Lack of a shared vision has been identified as a major obstacle in transdisciplinary research involving both scientists and other stakeholders. Without a shared vision, the implementation of scientific findings is difficult. The diverse partners of collaborative research, however, imply a plurality in the valuation of nature and a need for deliberative mechanisms. If visioning processes are to do justice to local contexts, research must apply deliberative mechanisms to cover the plurality in the valuation of nature. This paper proposes a visioning approach for local communities, based on prior transdisciplinary research. This participatory workshop method invites stakeholders to approach nature conservation and livelihoods via a deliberation of desirable futures, barriers for achieving them and associated responsibilities for taking action. The paper explores this method via a case study of visioning workshops on sacred swamps in the Western Ghats (India), and their role for both freshwater swamp protection and livelihoods. The visioning exercise offered discussion opportunities facilitating conscientization, conciliation and collaboration in local bottom-up nature conservation. For conserving the tropical freshwater swamps, the results show the need for a more participatory forest governance, providing space for shared value creation. They also point to the need for further research on inter-faith nature conservation possibilities, along with innovations on value addition and value chain development for livelihood promotion and protection.
The cultivation of common reed (Phragmites australis) is one of the most promising practices of paludiculture on fen peatlands. This highly productive grass has a high adaptation capacity via high levels of genetic diversity and phenotypic plasticity. In this study, a reed experimental site established on a degraded fen in 1996/97 with a mixture of monoclonally (meristematically propagated plantlets) and polyclonally (pre-grown seedlings) planted plots was investigated by microsatellite genotyping. All nine genotypes of the monoclonal planted plots were recovered and could be genetically characterized; invasion by other genotypes was negligible. Similarly, the polyclonal plots sustained high clonal diversity with no prevalence of a single genotype. The growth characteristics of the five quantitatively investigated genotypes significantly differed from each other (α = 0.05): dry biomass per stem 5–18 g, panicles per m2 20–60, average stem diameter 3.5–6 mm, height 170–250 cm. Similarly, the persistence of genotypes at the planted plots and their invasiveness (ability to invade neighboured plots) varied. These results show that common reed stands are extremely persistent even if established with genotypes that are likely not to be locally adapted. Their genetic structure remained stable for at least 24 years regardless of the planting density (1, 4, and 10 plants per m2). Our results indicate that farmers may be able to maintain favourable genotypes for many years, thus the selection and breeding of common reed as a versatile crop for rewetted peatlands is a promising objective for paludiculture research.
Purpose
Patient-reported outcome (PRO) measures are increasingly important in evaluating medical care. The increased integration of technology within the healthcare systems allows for collection of PROs electronically. The objectives of this study were to Ashley et al. J Med Internet Res (2013) implement an electronic assessment of PROs in inpatient cancer care and test its feasibility for patients and Dawson et al. BMJ (2010) determine the equivalence of the paper and electronic assessment.
Methods
We analyzed two arms from a study that was originally designed to be an interventional, three-arm, and multicenter inpatient trial. A self-administered questionnaire based on validated PRO-measures was applied and completed at admission, 1 week after, and at discharge. For this analysis — focusing on feasibility of the electronic assessment — the following groups will be considered: Group A (intervention arm) received a tablet version, while group B (control arm) completed the questionnaire on paper. A feasibility questionnaire, that was adapted from Ashley et al. J Med Internet Res (2013), was administered to group A.
Results
We analyzed 103 patients that were recruited in oncology wards. ePRO was feasible to most patients, with 84% preferring the electronic over paper-based assessment. The feasibility questionnaire contained questions that were answered on a scale ranging from “1” (illustrating non achievement) to “5” (illustrating achieving goal). The majority (mean 4.24, SD .99) reported no difficulties handling the electronic tool and found it relatively easy finding time for filling out the questionnaire (mean 4.15, SD 1.05). There were no significant differences between the paper and the electronic assessment regarding the PROs.
Conclusion
Results indicate that electronic PRO assessment in inpatient cancer care is feasible.
Objective
Maternal pre-pregnancy underweight, overweight and obesity might increase the risk for worse short- and long-term outcome in the offspring. There is a need for further study into the relationship between maternal pre-pregnancy body mass index (BMI) and the combined outcome of physical development, state of health and social behavior in children. Question: Is maternal pre-pregnancy BMI associated with the child outcome in terms of physical development, state of health and social behavior (school and leisure time behavior) at the age of 9 to 15 years?
Methods
In the population-based birth cohort study Survey of Neonates in Pomerania (SNIP) children at the age 9–15 years and their families were re-examined by questionnaire-based follow-up. 5725 mother–child pairs were invited to SNiP-follow-up. This analysis is based on the recall fraction of 24.1% (n = 1379). Based on the maternal pre-pregnancy BMI (ppBMI), 4 groups were formed: underweight (ppBMI < 19 kg/m2, n = 117), normal weight (ppBMI 19–24.99 kg/m2, n = 913, reference), overweight (ppBMI 25–30 kg). /m2, n = 237) and obesity (ppBMI > 30 kg/m2, n = 109).
Results
In the multiple regression model, the BMI-z-score for children of mothers in the underweight group was −0.50 lower, and 0.50/1.07 higher in the overweight/obese group (p < 0.001) compared to reference at median age of 12 years. No differences were found in children of underweight mothers with regard to social behavior (interaction with friends and family), school and sports performance (coded from “very good” to “poor”), other leisure activities (watching television, using mobile phones, gaming), and health (occurrence of illnesses) compared to children of normal weight mothers. In contrast, maternal pre-pregnancy overweight and obesity were associated with lower school and sports performance, and higher screen time (smart phone, gaming, television) compared to children of normal weight mothers.
Conclusion
Maternal pre-pregnancy overweight and obesity but not underweight was negatively associated with school performance and leisure time behavior in the offspring at 9–15 years of age.
Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer’s disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50–81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.
This study primarily aims to determine the frequency of life-threatening conditions among pediatric patients served by the DRF, a German helicopter emergency service (HEMS) provider. It also seeks to explore the necessity of invasive procedures in this population, discussing the implications for HEMS crew training and service configuration based on current literature. We analyzed the mission registry from 31 DRF helicopter bases in Germany, focusing on 7954 children aged 10 or younger over a 5-year period (2014–2018). Out of 7954 identified children (6.2% of all primary missions), 2081 (26.2%) had critical conditions. Endotracheal intubation was needed in 6.5% of cases, while alternative airway management methods were rare (n = 14). Half of the children required intravenous access, and 3.6% needed intraosseous access. Thoracostomy thoracentesis and sonography were only performed in isolated cases.
Conclusions: Critically ill or injured children are infrequent in German HEMS operations. Our findings suggest that the likelihood of HEMS teams encountering such cases is remarkably low. Besides endotracheal intubation, life-saving invasive procedures are seldom necessary. Consequently, we conclude that on-the-job training and mission experience alone are insufficient for acquiring and maintaining the competencies needed to care for critically ill or injured children.
Background and objectives
Various cross-sectional studies have observed an association between high circulating concentrations of the adipokine chemerin and an unfavorable metabolic profile. However, the prognostic value of chemerin for the risk of associated diseases and mortality was examined only in a few studies mostly using small and highly selected patient populations. We aimed to analyze the association between plasma chemerin concentrations and all-cause as well as cause-specific mortality in the general population.
Study design and methods
From the Study of Health in Pomerania (SHIP), participants of two independent cohorts (SHIP-START-1 [n = 3037], SHIP-TREND-0 [n = 4193]) were followed up for 15 and 9 years (median), respectively. The association between plasma chemerin and all-cause mortality was analyzed using multivariable Cox proportional hazard regression models. Additionally, cause-specific hazards for cardiovascular disease (CVD) and cancer mortality were modeled considering competing events.
Results
A total number of 507 and 208 deaths occurred during follow-up in SHIP-START-1 and SHIP-TREND-0, respectively. Multivariable regression analyses revealed a significant association between high plasma chemerin concentrations and greater overall mortality that was independent of major confounders. Each 30 ng/mL increase in chemerin was associated with a 17% higher risk of all-cause mortality (95%-confidence interval: 1.10–1.26). Cause-specific analyses further showed that the chemerin concentration was significantly associated with cancer mortality but not with CVD mortality.
Conclusion
The present study detected a positive association between plasma chemerin concentrations and all-cause mortality in a large population-based study sample. Cause-specific analyses have shown that chemerin is likely to play a decisive role in cancer-related deaths. However, a direct association with cardiovascular mortality could not be established.
In general, concepts such as chemical equilibria and classical analytical chemistry, as well as instrumental methods such as potentiometry and flow injection analysis (FIA), are taught separately in the curricula of chemistry-related degree programs. However, FIA provides an opportunity to connect all of these important topics. This article shows how simple experiments can be used to link the fundamentals of FIA and potentiometry to the fundamentals of chemical equilibria and teach them in a sustainable way. The experiments were designed for undergraduate environmental science students with basic knowledge of chemical equilibria and classical analytical chemistry and minimal knowledge of electrochemistry. However, they can also be integrated into various courses on instrumental analysis in chemistry-related degree programs.
Background
One of the main treatment goals in cochlear implant (CI) patients is to improve speech perception. One of the target parameters is speech intelligibility in quiet. However, treatment results show a high variability, which has not been sufficiently explained so far. The aim of this noninterventional retrospective study was to elucidate this variability using a selected population of patients in whom etiology was not expected to have a negative impact on postoperative speech intelligibility.
Materials and methods
Audiometric findings of the CI follow-up of 28 adult patients after 6 months of CI experience were evaluated. These were related to the preoperative audiometric examination and evaluated with respect to a recently published predictive model for the postoperative monosyllabic score.
Results
Inclusion of postoperative categorical loudness scaling and hearing loss for Freiburg numbers in the model explained 55% of the variability in fitting outcomes with respect to monosyllabic word recognition.
Conclusion
The results of this study suggest that much of the cause of variability in fitting outcomes can be captured by systematic postoperative audiometric checks. Immediate conclusions for CI system fitting adjustments may be drawn from these results. However, the extent to which these are accepted by individual patients and thus lead to an improvement in outcome must be subject of further studies, preferably prospective.
Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members are conserved in mammalian hematopoiesis, they appear to be highly context dependent. Using CRISPR/Cas9-based genetic screening, we have identified Scribble complex-related liabilities in AML including LLGL1. Despite its reported suppressive function in HSC self-renewal, inactivation of LLGL1 in AML confirms its relevant role for proliferative capacity and development of AML. Its function was conserved in human and murine models of AML and across various genetic backgrounds. Inactivation of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 facilitates functional and phenotypic rescue. Collectively, these data establish LLGL1 as a specific dependency and putative target in AML and emphasizes its cell-type specific functions.
The classical Buscher rules d escribe T-duality for metrics and B-fields in a topologically trivial setting. On the other hand, topological T-duality addresses aspects of non-trivial topology while neglecting metrics and B-fields. In this article, we develop a new unifying framework for both aspects.
The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.
Aims
Sphingosine-1-phosphate (S1P) is a signaling lipid, which is involved in several cellular processes including cell growth, proliferation, migration and apoptosis. The associations of serum S1P levels with cardiac geometry and function are still not clear. We investigated the associations of S1P with cardiac structure and systolic function in a population-based sample.
Methods and results
We performed cross-sectional analyses of 858 subjects (467 men; 54.4%), aged 22 to 81 years, from a sub-sample of the population-based Study of Health in Pomerania (SHIP-TREND-0). We analyzed the associations of serum S1P with structural and systolic function left ventricular (LV) and left atrial (LA) parameters as determined by magnetic resonance imaging (MRI) using sex-stratified multivariable-adjusted linear regression models. In men, MRI data showed that a 1 µmol/L lower S1P concentration was associated with an 18.1 mL (95% confidence interval [CI] 3.66–32.6; p = 0.014) larger LV end-diastolic volume (LVEDV), a 0.46 mm (95% CI 0.04–0.89; p = 0.034) greater LV wall thickness (LVWT) and a 16.3 g (95% CI 6.55–26.1; p = 0.001) higher LV mass (LVM). S1P was also associated with a 13.3 mL/beat (95% CI 4.49–22.1; p = 0.003) greater LV stroke volume (LVSV), an 18.7 cJ (95% CI 6.43–30.9; p = 0.003) greater LV stroke work (LVSW) and a 12.6 mL (95% CI 1.03–24.3; p = 0.033) larger LA end-diastolic volume (LAEDV). We did not find any significant associations in women.
Conclusions
In this population-based sample, lower levels of S1P were associated with higher LV wall thickness and mass, larger LV and LA chamber sizes and greater stroke volume and work of the LV in men, but not in women. Our results indicate that lower levels of S1P were associated with parameters related with cardiac geometry and systolic function in men, but not in women.
Marine algae produce complex polysaccharides, which can be degraded by marine heterotrophic bacteria utilizing carbohydrate-active enzymes. The red algal polysaccharide porphyran contains the methoxy sugar 6-O-methyl-D-galactose (G6Me). In the degradation of porphyran, oxidative demethylation of this monosaccharide towards D-galactose and formaldehyde occurs, which is catalyzed by a cytochrome P450 monooxygenase and its redox partners. In direct proximity to the genes encoding for the key enzymes of this oxidative demethylation, genes encoding for zinc-dependent alcohol dehydrogenases (ADHs) were identified, which seem to be conserved in porphyran utilizing marine Flavobacteriia. Considering the fact that dehydrogenases could play an auxiliary role in carbohydrate degradation, we aimed to elucidate the physiological role of these marine ADHs. Although our results reveal that the ADHs are not involved in formaldehyde detoxification, a knockout of the ADH gene causes a dramatic growth defect of Zobellia galactanivorans with G6Me as a substrate. This indicates that the ADH is required for G6Me utilization. Complete biochemical characterizations of the ADHs from Formosa agariphila KMM 3901T (FoADH) and Z. galactanivorans DsijT (ZoADH) were performed, and the substrate screening revealed that these enzymes preferentially convert aromatic aldehydes. Additionally, we elucidated the crystal structures of FoADH and ZoADH in complex with NAD+ and showed that the strict substrate specificity of these new auxiliary enzymes is based on a narrow active site.
Transcriptional corepressors Sin3, Cyc8 and Tup1 are important for downregulation of gene expression by recruiting various histone deacetylases once they gain access to defined genomic locations by interaction with pathway-specific repressor proteins. In this work we systematically investigated whether 17 yeast repressor proteins (Cti6, Dal80, Fkh1, Gal80, Mig1, Mot3, Nrg1, Opi1, Rdr1, Rox1, Sko1, Ume6, Ure2, Xbp1, Yhp1, Yox1 and Whi5) representing several unrelated regulatory pathways are able to bind to Sin3, Cyc8 and Tup1. Our results show that paired amphipathic helices 1 and 2 (PAH1 and PAH2) of Sin3 are functionally redundant for some regulatory pathways. WD40 domains of Tup1 proved to be sufficient for interaction with repressor proteins. Using length variants of selected repressors, we mapped corepressor interaction domains (CIDs) in vitro and assayed gene repression in vivo. Systematic comparison of CID minimal sequences allowed us to define several related positional patterns of hydrophobic amino acids some of which could be confirmed as functionally supported by site-directed mutagenesis. Although structural predictions indicated that certain CIDs may be α-helical, most repression domains appear to be randomly structured and must be considered as intrinsically disordered regions (IDR) adopting a defined conformation only by interaction with a corepressor.
Purpose
The WHO 2016 re-classification of myeloproliferative neoplasms resulted in a separation of essential thrombocythemia (ET) from the pre-fibrotic and fibrotic (overt) phases of primary myelofibrosis (MF). This study reports on a chart review conducted to evaluate the real life approach regarding clinical characteristics, diagnostic assessment, risk stratification and treatment decisions for MPN patients classified as ET or MF after implementation of the WHO 2016 classification.
Methods
In this retrospective chart review, 31 office-based hematologists/oncologists and primary care centers in Germany participated between April 2021 and May 2022. Physicians reported available data obtained from patient charts via paper–pencil based survey (secondary use of data). Patient features were evaluated using descriptive analysis, also including diagnostic assessment, therapeutic strategies and risk stratification.
Results
Data of 960 MPN patients diagnosed with essential thrombocythemia (ET) (n = 495) or myelofibrosis (MF) (n = 465) after implementation of the revised 2016 WHO classification of myeloid neoplasms was collected from the patient charts. While they met at least one minor WHO-criteria for primary myelofibrosis, 39.8% of those diagnosed with ET did not have histological BM testing at diagnosis. 63.4% of patients who were classified as having MF, however, did not obtain an early prognostic risk assessment. More than 50% of MF patients showed characteristics consistent with the pre-fibrotic phase, which was emphasized by the frequent use of cytoreductive therapy. Hydroxyurea was the most frequently used cytoreductive medication in 84.7% of ET and 53.1% of MF patients. While both ET and MF cohorts showed cardiovascular risk factors in more than 2/3 of the cases, the use of platelet inhibitors or anticoagulants varied between 56.8% in ET and 38.1% in MF patients.
Conclusions
Improved histopathologic diagnostics, dynamic risk stratification including genetic risk factors for cases of suspected ET and MF are recommended for precise risk assessment and therapeutic stratification according to WHO criteria.
Monitoring and assessing groundwater quality according to European directives and national regulations is usually based on interpolation techniques, e.g. Kriging. However, contour maps of hydrochemical parameters often suggest a spurious local accuracy and can therefore lead to inappropriate action measures. Here, the early concept of extension variance combined with the Voronoi tessellation regionalization is proposed. The mosaic-like representation of pollutant concentrations in Voronoi polygons avoids misinterpretations caused by interpolation. The additional calculation of the extension variance, which is based on fundamental geostatistical assumptions, allows for estimating the probability that a given threshold is exceeded. This concept is further extended to hydraulically delimitable groundwater bodies, thus ensuring that hydraulic boundaries are considered. A method is here described for the assessment of groundwater quality with respect to nitrate concentration in the principal aquifer of the state Mecklenburg-Western Pomerania in Germany.
Mobile Apps for Sexual and Reproductive Health Education: a Systematic Review and Quality Assessment
(2023)
Purpose of Review
The aim of this study was to present the current state of research on mobile health apps for sexual and reproductive health (SRH) education. Apps were analysed based on contents (by using the World Health Organization’s SRH framework), features, intended audiences and quality of evidence (by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach). Taking German sexuality education apps as an example, the rapid development in the field of SRH apps over the last 3 years has been revealed by comparing the quality of apps available in 2019 with apps from 2022.
Recent Findings
SRH apps allow health information to be disseminated quickly, at low thresholds and in a practical and cost-effective manner. Moreover, they allow for anonymous usage independently of time and place. In the absence of network coverage, offline use is also possible. Previous research focused on individual SRH aspects (e.g. human immunodeficiency virus (HIV), contraception). However, some studies were designed to cover a broader range of SRH topics, but identified only a few relevant apps.
Summary
To improve SRH, it would be helpful if the apps would be of high-quality design and be made up of relevant content. Furthermore, they should be tailored to the target group and have been tested in real-life settings. A total of 50 SRH apps with sufficiently high-quality ratings were included. The apps cover a variety of SRH topics, but they often lack field-based evaluation. The effectiveness of SRH apps has not yet been sufficiently studied in a scientific manner. Only 9 apps were deemed to be adequate for a moderate GRADE level. Despite this grading, the study nevertheless shows that there are several apps that could potentially promote SRH.
The potential of several ion-sensitive electrodes responds to the incorporated cations and anions. This has led some authors to misinterpret the potential of metal salt membrane electrodes and of electrodes of the second kind. Neglecting the kinetics of potential establishment and interpreting the potentials solely based on thermodynamics produce completely irrelevant data and suggest that ion concentrations down to 10−45 mol L−1 are accessible by simple potentiometric measurements. The switching from cation to anion response mechanism cannot be derived from thermodynamic equations. It bears complete similarity to the switching of response in the case of foreign interfering ions.
Purpose
A setting-sensitive instrument for assessing Quality of Life (QoL) in Telemedicine (TM) was unavailable. To close this gap, a content-valid “add-on” measure was developed. In parallel, a brief index was derived featuring six items that summarise the main content of the multidimensional assessment. After pre- and pilot-testing, the psychometric performance of the final measures was investigated in an independent validation study.
Methods
The questionnaires were applied along with other standardised instruments of similar concepts as well as associated, yet disparate concepts for validation purposes. The sample consisted of patients with depression or heart failure, with or without TM (n = 200). Data analyses were aimed at calculating descriptive statistics and testing the psychometric performance on item, scale, and instrument level, including different types of validity and reliability.
Results
The proposed factor structure of the multidimensional Tele-QoL measure has been confirmed. Reliability coefficients for internal consistency, split-half, and test-retest reliability of the subscales and index reached sufficient values. The Tele-QoL subscales and the index demonstrated Rasch scalability. Validity of both instruments can be assumed. Evidence for discriminant construct validity was provided. Known-groups validity was indicated by respective score differences for various classes of disease severity.
Conclusion
Both measures show convincing psychometric properties. The final multidimensional Tele-QoL assessment consists of six outcome scales and two impact scales assessing (un-)intended effects of TM on QoL. In addition, the Tele-QoL index provides a short alternative for outcome assessment. The Tele-QoL measures can be used as complementary modules to existing QoL instruments capturing healthcare-related aspects of QoL from the patients’ perspective.
SLC35F1 is a member of the sugar-like carrier (SLC) superfamily that is expressed in the mammalian brain. Malfunction of SLC35F1 in humans is associated with neurodevelopmental disorders. To get insight into the possible roles of Slc35f1 in the brain, we generated Slc35f1-deficient mice. The Slc35f1-deficient mice are viable and survive into adulthood, which allowed examining adult Slc35f1-deficient mice on the anatomical as well as behavioral level. In humans, mutation in the SLC35F1 gene can induce a Rett syndrome-like phenotype accompanied by intellectual disability (Fede et al. Am J Med Genet A 185:2238–2240, 2021). The Slc35f1-deficient mice, however, display only a very mild phenotype and no obvious deficits in learning and memory as, e.g., monitored with the novel object recognition test or the Morris water maze test. Moreover, neuroanatomical parameters of neuronal plasticity (as dendritic spines and adult hippocampal neurogenesis) are also unaltered. Thus, Slc35f1-deficient mice display no major alterations that resemble a neurodevelopmental phenotype.
How can powerful states best extract domestic concessions from their junior allies? What are the conditions under which the powerful state is more likely to succeed in inducing such domestic policy change? This article explores the link between US security commitments and Washington’s ability to attain favourable policy outcomes within the allied domestic arena. It provides an illustrative case of how the USA, using security guarantees as leverage, can enter allied domestic space and shape its decision-making process. After it was revealed that Latvia had served as a key node through which North Korea attempted to evade the sanctions regime, the USA, by playing its security guarantor card, pressured Riga to carry out substantial policy reforms in relation to its financial system. This approach yielded considerable results. In order to preserve the existing security arrangements with the dominant alliance member, Latvia offered significant policy concessions. This finding demonstrates that US security alliances come with side benefits that are often underrated or neglected in the scholarly literature.
Background
A bidirectional functional link between vestibular and fear-related disorders has been previously suggested.
Objective
To test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps.
Methods
By use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers.
Results
Common clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2.
Conclusions
The structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety.
Background and objective
Political, economic, communicative and cultural borders still limit the accessibility of acute healthcare services for patients so that they frequently have to accept longer distances to travel to the next provider within their own country. In this paper, we analyze the impact of borders and opening of borders on acute medical care in hospitals and on patients in border regions.
Methods
We develop a conceptual framework model of cross-border healthcare and apply it to the Polish–German border area. The model combines the distance decay effect, a catchment area analysis, economies of scale and the learning curve.
Results
Borders have a major impact on acute medical care in hospitals and on patients. Setting of new borders will reduce the accessibility of health facilities for patients or require the establishment of new hospitals. Reopening borders might induce a vicious circle leading to the insolvency of a hospital which might result in poorer health for some patients.
Conclusion
Strong effort should be invested to overcome political and cultural borders to improve the health of the population in border regions. Similarly, increased cross-border acute healthcare must be seen in the context of rural health and the special situation of small rural hospitals in rural peripheral areas.
Animals often respond to climate change with changes in morphology, e.g., shrinking body size with increasing temperatures, as expected by Bergmann’s rule. Because small body size can have fitness costs for individuals, this trend could threaten populations. Recent studies, however, show that morphological responses to climate change and the resulting fitness consequences cannot be generalized even among related species. In this long-term study, we investigate the interaction between ambient temperature, body size and survival probability in a large number of individually marked wild adult female Natterer’s bats (Myotis nattereri). We compare populations from two geographical regions in Germany with a different climate. In a sliding window analysis, we found larger body sizes in adult females that were raised in warmer summers only in the northern population, but not in the southern population that experienced an overall warmer climate. With a capture-mark-recapture approach, we showed that larger individuals had higher survival rates, demonstrating that weather conditions in early life could have long-lasting fitness effects. The different responses in body size to warmer temperatures in the two regions highlight that fitness-relevant morphological responses to climate change have to be viewed on a regional scale and may affect local populations differently.
Cationic and anionic clusters of the group-14 elements carbon, silicon, germanium, tin, and lead are produced by high-vacuum laser ablation and studied with a multi-reflection time-of-flight mass spectrometer. In-trap photodissociation is performed for cluster species in the size range n=2–10. The clusters’ production rates as well as their dissociation pathways are used to probe the nonmetal–metal transition throughout the group. Carbon clusters show neutral-trimer break-off, while those of the other elements evaporate neutral monomers and, in some cases, form specific charged fragment sizes.
Purpose
Outcomes of multiple myeloma (MM) patients who are refractory to daratumumab are dismal and no standard of treatment exists for this patients’ population. Here, we investigate the role of pomalidomide combinations in daratumumab-refractory MM patients.
Methods
We performed a retrospective analysis of myeloma patients treated at four referral centers (three in Germany and one in Italy). Review chart identified 30 patients with relapsed and refractory myeloma, who progressed during treatment with daratumumab and were treated with pomalidomide-based combinations in the subsequent lines of therapy.
Results
Responses improved from 37% with daratumumab to 53% with pomalidomide. Of seven patients with extramedullary MM (EMM), four achieved a clinical stabilization with pomalidomide, including one patient with a long-lasting complete response. Median progression-free survival and overall survival were 6 and 12 months, respectively. Pomalidomide combinations were well tolerated, no patient discontinued treatment due to adverse events.
Conclusion
These data show that pomalidomide-based combinations can be an effective and safe salvage regimen for daratumumab-refractory patients, including those with EMM.
In teaching electrochemistry, it is of primary importance to make students always aware of the relations between electrochemistry and all the non-electrochemical topics, which are taught. The vast majority of students will not specialise in electrochemistry, but they all can very much benefit from the basics and concepts of electrochemistry. This paper is aimed to give suggestions how the teaching of electrochemistry can easily be interrelated to topics of inorganic, organic, analytical, environmental chemistry, biochemistry and biotechnology.
There is still considerable controversy surrounding the impact of mastication on obesity. The aim of this study was to identify the interplay between the masticatory muscles, teeth, and general muscular fitness and how they contribute to body adiposity in a general German population. This cross-sectional study included 616 participants (300 male, 316 female, age 31–93 years) from the population-based Study of Health in Pomerania. The cross-sectional areas of the masseter, medial and lateral pterygoid muscles were measured using magnetic resonance imaging (MRI), muscular fitness assessed by hand grip strength (HGS) and body fat distribution was measured by bioelectrical impedance analysis (BIA) and MRI. The overall prevalence of obesity was high in our cohort. The cross-sectional area of the masseter muscles was positively associated with the number of teeth, body mass index (BMI) and HGS, and negatively associated with the BIA-assessed body fat when adjusted for age, sex, teeth, and BMI. Especially the correlation was strong (p < 0.001). Analogous relationships were observed between the masseter, HGS and MRI-assessed subcutaneous fat. These associations were most pronounced with masseter, but also significant with both pterygoid muscles. Though the masticatory muscles were affected by the number of teeth, teeth had no impact on the relations between masseter muscle and adiposity. Physical fitness and masticatory performance are associated with body shape, controlled and directed by the relevant muscles.
Electrochemical Raman spectroscopy can provide valuable insights into electrochemical reaction mechanisms. However, it also shows various pitfalls and challenges. This paper gives an overview of the necessary theoretical background, crucial practical considerations for successful measurement, and guidance for in situ/in operando electrochemical Raman spectroscopy. Several parameters must be optimized for suitable reaction and measurement conditions. From the experimental side, considerations for the setup, suitable signal enhancement methods, choice of material, laser, and objective lens are discussed. Different interface phenomena are reviewed in the context of data interpretation and evaluation.
Objectives
To investigate the effect of layer height of FFF-printed models on aligner force transmission to a second maxillary premolar during buccal torquing, distalization, extrusion, and rotation using differing foil thicknesses.
Materials and methods
Utilizing OnyxCeph3™ Lab (Image Instruments GmbH, Chemnitz, Germany, Release Version 3.2.185), the following movements were programmed for the second premolar: buccal torque (0.1–0.5 mm), distalization (0.1–0.4 mm), extrusion (0.1–0.4 mm), rotation (0.1–0.5 mm), and staging 0.1 mm. Via FFF, 91 maxillary models were printed for each staging at different layer heights (100 µm, 150 µm, 200 µm, 250 µm, 300 µm). Hence, 182 aligners, made of polyethylene terephthalate glycol (PET-G) with two thicknesses (0.5 mm and 0.75 mm), were prepared. The test setup comprised an acrylic maxillary model with the second premolar separated and mounted on a sensor, measuring initial forces and moments exerted by the aligners. A generalized linear model for the gamma distribution was applied, evaluating the significance of the factors layer height, type of movement, aligner thickness, and staging on aligner force transmission.
Results
Foil thickness and staging were found to have a significant influence on forces delivered by aligners, whereas no significance was determined for layer height and type of movement. Nevertheless, at a layer height of 150 µm, the most appropriate force transmission was observed.
Conclusions
Printing aligner models at particularly low layer heights leads to uneconomically high print time without perceptible better force delivery properties, whereas higher layer heights provoke higher unpredictability of forces due to scattering. A z-resolution of 150 µm appears ideal for in-office aligner production combining advantages of economic print time and optimal force transmission.
Flies form high-density associations with human settlements and groups of nonhuman primates and are implicated in transmitting pathogens. We investigate the movement of nonhuman primate-associated flies across landscapes surrounding Kibale National Park, Uganda, using a mark–recapture experiment. Flies were marked in nine nonhuman primate groups at the forest edge (x̄ = 929 flies per group), and we then attempted to recapture them in more anthropized areas (50 m, 200 m and 500 m from where marked; 2–21 days after marking). Flies marked in nonhuman primate groups were recaptured in human areas (19/28,615 recaptured). Metabarcoding of the flies in nonhuman primate groups revealed the DNA of multiple eukaryotic primate parasites. Taken together, these results demonstrate the potential of flies to serve as vectors between nonhuman primates, livestock and humans at this biodiverse interface.
Background
Telephone-Cardiopulmonary Resuscitation (T-CPR) significantly increases rate of bystander resuscitation and improves patient outcomes after out-of-hospital cardiac arrest (OHCA). Nevertheless, securing correct execution of instructions remains a difficulty. ERC Guidelines 2021 recommend standardised instructions with continuous evaluation. Yet, there are no explicit recommendations on a standardised wording of T-CPR in the German language. We investigated, whether a modified wording regarding check for breathing in a German T-CPR protocol improved performance of T-CPR.
Methods
A simulation study with 48 OHCA scenarios was conducted. In a non-randomised trial study lay rescuers were instructed using the real-life-CPR protocol of the regional dispatch centre and as the intervention a modified T-CPR protocol, including specific check for breathing (head tilt-chin lift instructions). Resuscitation parameters were assessed with a manikin and video recordings.
Results
Check for breathing was performed by 64.3% (n = 14) of the lay rescuers with original wording and by 92.6% (n = 27) in the group with modified wording (p = 0.035). In the original wording group the head tilt-chin manoeuvre was executed by 0.0% of the lay rescuers compared to 70.3% in the group with modified wording (p < 0.001). The average duration of check for breathing was 1 ± 1 s in the original wording group and 4 ± 2 s in the group with modified wording (p < 0.001). Other instructions (e.g. check for consciousness and removal of clothing) were well performed and did not differ significantly between groups. Quality of chest compression did not differ significantly between groups, with the exception of mean chest compression depth, which was slightly deeper in the modified wording group.
Conclusion
Correct check for breathing seems to be a problem for lay rescuers, which can be decreased by describing the assessment in more detail. Hence, T-CPR protocols should provide standardised explicit instructions on how to perform airway assessment. Each protocol should be evaluated for practicability.
Platelet factor 4 (PF4, synonym: CXCL4) is an evolutionary old chemokine with proposed roles in hemostasis and antimicrobial defense. In addition, PF4 has attracted considerable attention as a crucial mediator of one of the most prothrombotic adverse drug effects affecting blood cells, heparin-induced thrombocytopenia (HIT). Interest in PF4 substantially increased in 2021 when it was identified as the target antigen in the life-threatening adverse effect, vaccine-induced immune thrombotic thrombocytopenia (VITT). We address the concept that a major biological function of PF4—a strongly cationic chemokine—is to bind to negatively-charged prokaryotic microorganisms, resulting in structural changes in PF4 that trigger a danger signal recognized by the adaptive immune system. Application of biophysical tools has provided substantial insights into the molecular mechanisms by which PF4 becomes immunogenic, providing insights into a new mechanism of autoimmunity. Binding of autoantibodies with high affinity induces conformational change(s) in the endogenous protein, which are then recognized as foreign antigen, as exemplified by the prothrombotic disorders, autoimmune HIT and VITT. The final part of our review summarizes current assays for HIT and VITT, explaining how structural aspects of anti-PF4 pathobiology relate to assay design and performance characteristics. Currently, functional (platelet activation) assays using washed platelets detect HIT antibodies when heparin is added, and VITT antibodies when PF4 is added. Solid-phase PF4-dependent immunoassays using microtiter plates are sensitive for both HIT and VITT antibodies, while rapid immunoassays, in which the PF4/heparin antigen is coated on beads, are sensitive and specific for HIT, but not for VITT antibodies.