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Spreading depolarization (SD) causes a massive neuronal/glial depolarization, disturbs ionic homeostasis and deranges neuronal network function. The metabolic burden imposed by SD may also generate marked amounts of reactive oxygen species (ROS). Yet, proper optical tools are required to study this aspect with spatiotemporal detail. Therefore, we earlier generated transgenic redox indicator mice. They express in excitatory projection neurons the cytosolic redox-sensor roGFP, a reduction/oxidation sensitive green fluorescent protein which is ratiometric by excitation and responds reversibly to redox alterations. Using adult male roGFPc mice, we analyzed SD-related ROS production in CA1 stratum pyramidale of submerged slices. SD was induced by K+ microinjection, O2 withdrawal or mitochondrial uncoupling (FCCP). The extracellular DC potential deflection was accompanied by a spreading wavefront of roGFP oxidation, confirming marked neuronal ROS generation. Hypoxia-induced SD was preceded by a moderate oxidation, which became intensified as the DC potential deflection occurred. Upon K+-induced SD, roGFP oxidation slowly recovered within 10–15 min in some slices. Upon FCCP-or hypoxia-induced SD, recovery was limited. Withdrawing extracellular Ca2+ markedly dampened the SD-related roGFP oxidation and improved its reversibility, confirming a key-role of neuronal Ca2+ load in SD-related ROS generation. Neither mitochondrial uncoupling, nor inhibition of NADPH oxidase or xanthine oxidase abolished the SD-related roGFP oxidation. Therefore, ROS generation during SD involves mitochondria as well as non-mitochondrial sources. This first-time analysis of SD-related ROS dynamics became possible based on quantitative redox imaging in roGFP mice, an advanced approach, which will contribute to further decipher the molecular understanding of SD in brain pathophysiology.

Abstract Background Fragility fractures of the pelvis (FFPs) represent a significant health burden, particularly for the elderly. The role of sarcopenia, an age-related loss of muscle mass and function, in the development and impact of these fractures is not well understood. This study aims to investigate the prevalence and impact of osteoporosis and sarcopenia in patients presenting with FFPs. Methods This retrospective study evaluated 140 elderly patients with FFPs. The diagnosis of sarcopenia was assessed by psoas muscle area (PMA) and the height-adjusted psoas muscle index (PMI) measured on computed tomography (CT) scans. Clinical data, radiological findings and functional outcomes were recorded and compared with the presence or absence of sarcopenia and osteoporosis. Results Our study cohort comprised 119 female (85.0%) and 21 (15.0%) male patients. The mean age at the time of injury or onset of symptoms was 82.26 ± 8.50 years. Sarcopenia was diagnosed in 68.6% (n = 96) patients using PMA and 68.8% (n = 88) using PMI. 73.6% (n = 103) of our study population had osteoporosis and 20.0% (n = 28) presented with osteopenia. Patients with sarcopenia and osteoporosis had longer hospital stays (p

Abstract Background PRiVENT (PRevention of invasive VENTilation) is an evaluation of a bundle of interventions aimed at the prevention of long-term invasive mechanical ventilation. One of these elements is an e-learning course for healthcare professionals to improve weaning expertise. The aim of our analysis is to examine the implementation of the course in cooperating intensive care units. Methods The course has been developed through a peer review process by pulmonary and critical care physicians in collaboration with respiratory therapists, supported by health services researchers and a professional e-learning agency. The e-learning platform “weLearn” was made available online to participating healthcare professionals. Feedback on the e-learning programme was obtained and discussed in quality circles (QCs). We measured the acceptance and use of the programme through access statistics. Results The e-learning course “Joint Prevention of Long-Term Ventilation” consists of 7 separate modules with practice-oriented training units as well as a cross-module area and corresponding interactive case studies. Users can receive 23 CME (continuing medical education) credits. The platform was released on July 1, 2021. By June 28, 2023, 214 users from 33 clinics had registered. Most users (77–98%) completed the modules, thus performing well in the test, where 90–100% passed. In the QCs, the users commended the structure and practical relevance of the programme, as well as the opportunity to earn CME credits. Conclusion Especially for medical staff in intensive care units, where continuous training is often a challenge during shift work, e-learning is a useful supplement to existing medical training. Trial registration The PRiVENT study is registered at ClinicalTrials.gov (NCT05260853) on 02/03/2022.

The Mediterranean diet (MD) and its bioactive constituents have been advocated for their neuroprotective properties along with their capacity to affect gut microbiota speciation and metabolism. Mediated through the gut brain axis, this modulation of the microbiota may partly contribute to the neuroprotective properties of the MD. To explore this potential interaction, we evaluated the neuroprotective properties of a novel bioactive blend (Neurosyn240) resembling the Mediterranean diet in a rodent model of chronic low-grade inflammation. Behavioral tests of cognition, brain proteomic analysis, 16S rRNA sequencing, and 1H NMR metabolomic analyses were employed to develop an understanding of the gut-brain axis interactions involved. Recognition memory, as assessed by the novel object recognition task (NOR), decreased in response to LPS insult and was restored with Neurosyn240 supplementation. Although the open field task performance did not reach significance, it correlated with NOR performance indicating an element of anxiety related to this cognitive change. Behavioral changes associated with Neurosyn240 were accompanied by a shift in the microbiota composition which included the restoration of the Firmicutes: Bacteroidota ratio and an increase in Muribaculum, Rikenellaceae Alloprevotella, and most notably Akkermansia which significantly correlated with NOR performance. Akkermansia also correlated with the metabolites 5-aminovalerate, threonine, valine, uridine monophosphate, and adenosine monophosphate, which in turn significantly correlated with NOR performance. The proteomic profile within the brain was dramatically influenced by both interventions, with KEGG analysis highlighting oxidative phosphorylation and neurodegenerative disease-related pathways to be modulated. Intriguingly, a subset of these proteomic changes simultaneously correlated with Akkermansia abundance and predominantly related to oxidative phosphorylation, perhaps alluding to a protective gut-brain axis interaction. Collectively, our results suggest that the bioactive blend Neurosyn240 conferred cognitive and microbiota resilience in response to the deleterious effects of low-grade inflammation.

Single-shot X-ray phase-contrast imaging is used to take high-resolution images of laser-driven strong shock waves. Employing a two-grating Talbot interferometer, we successfully acquire standard absorption, differential phase-contrast, and dark-field images of the shocked target. Good agreement is demonstrated between experimental data and the results of two-dimensional radiation hydrodynamics simulations of the laser–plasma interaction. The main sources of image noise are identified through a thorough assessment of the interferometer’s performance. The acquired images demonstrate that grating-based phase-contrast imaging is a powerful diagnostic tool for high-energy-density science. In addition, we make a novel attempt at using the dark-field image as a signal modality of Talbot interferometry to identify the microstructure of a foam target.

Abstract Background Long-term invasive mechanical ventilation (IMV) is a major burden for those affected and causes high costs for the health care system. Early risk assessment is a prerequisite for the best possible support of high-risk patients during the weaning process. We aimed to identify risk factors for long-term IMV within 96 h (h) after the onset of IMV. Methods The analysis was based on data from one of Germany's largest statutory health insurance funds; patients who received IMV ≥ 96 h and were admitted in January 2015 at the earliest and discharged in December 2017 at the latest were analysed. OPS and ICD codes of IMV patients were considered, including the 365 days before intubation and 30 days after discharge. Long-term IMV was defined as evidence of invasive home mechanical ventilation (HMV), IMV ≥ 500 h, or readmission with (re)prolonged ventilation. Results In the analysis of 7758 hospitalisations, criteria for long-term IMV were met in 38.3% of cases, of which 13.9% had evidence of HMV, 73.1% received IMV ≥ 500 h and/or 40.3% were re-hospitalised with IMV. Several independent risk factors were identified (p

BaCe0.65Zr0.2Y0.15O3-δ (BCZ20Y15) has raised great interest due to its good protonic conductivity and chemical stability. However, the sintering of the material is considerably challenged by its refractory nature. In the current work, almost fully densified single-phase BCZ20Y15 with grain sizes exceeding 10 μm was successfully fabricated by sintering at 1500 °C by using calcined powders consisting of naturally separated perovskite phases and 0.5 wt% NiO. The role of NiO as sintering aid was elucidated by Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) and Atom Probe Tomography (APT) methods, concerning global and local material composition. Furthermore, the mechanism leading to the promoted densification and grain growth is elucidated based on current experimental results and a comprehensive review of the literature.

Abstract Background Patella fractures are relatively rare fractures and only little is known about the postoperative return to sports after patella fractures. Methods This retrospective study presents information on functional outcome after operative treatment of patella fractures as well as time until return to sports and patients’ complaints after open-reduction internal-fixation (ORIF) of patella fractures. Results Overall, 39 patients after ORIF of patella fractures were evaluated at our Level-I trauma center with a mean follow-up of 42 months. The mean time until return to sports was 7 ± 3.9 months. No significant difference was found for functional outcome with respect to body mass index (BMI) or age. Fracture consolidation was accomplished after a mean of 6.9 ± 2.9 months besides a relatively low complication rate of 5.1% (n = 2). Conclusion The results demonstrate a high return to sports rate of 90.3%. However, only 51.6% were able to perform sports on their pre-injury level or above. Trial Registration The study was retrospectively registered at DRKS (No: DRKS00031146).

Abstract Background Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS. Objectives The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy. Methods B cells were obtained from blood samples of patients with relapsing–remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration. Results Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction. Conclusions We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.

BackgroundAcute hemorrhage is one of the most common causes of death in multiple trauma patients. Due to physiological changes, pre-existing conditions, and medication, older trauma patients are more prone to poor prognosis. Tranexamic acid (TXA) has been shown to be beneficial in multiple trauma patients with acute hemorrhage in general. The relation of tranexamic acid administration on survival in elderly trauma patients with pre-existing anticoagulation is the objective of this study. Therefore, we used the database of the TraumaRegister DGU® (TR-DGU), which documents data on severely injured trauma patients.MethodsIn this retrospective analysis, we evaluated the TR-DGU data from 16,713 primary admitted patients with multiple trauma and age > =50 years from 2015 to 2019. Patients with pre-existing anticoagulation and TXA administration (996 patients, 6%), pre-existing anticoagulation without TXA administration (4,807 patients, 28.8%), without anticoagulation as premedication but TXA administration (1,957 patients, 11.7%), and without anticoagulation and TXA administration (8,953 patients, 53.6%) were identified. A regression analysis was performed to investigate the influence of pre-existing antithrombotic drugs and TXA on mortality. A propensity score was created in patients with pre-existing anticoagulation, and matching was performed for better comparability of patients with and without TXA administration.ResultsRetrospective trauma patients who underwent tranexamic acid administration were older and had a higher ISS than patients without tranexamic acid donation. Predicted mortality (according to the RISC II Score) and observed mortality were higher in the group with tranexamic acid administration. The regression analysis showed that TXA administration was associated with lower mortality rates within the first 24 h in older patients with anticoagulation as premedication. The propensity score analysis referred to higher fluid requirement, higher requirement of blood transfusion, and longer hospital stay in the group with tranexamic acid administration. There was no increase in complications. Despite higher transfusion volumes, the tranexamic acid group had a comparable all-cause mortality rate.ConclusionTXA administration in older trauma patients is associated with a reduced 24-h mortality rate after trauma, without increased risk of thromboembolic events. There is no relationship between tranexamic acid and overall mortality in patients with anticoagulation as premedication. Considering pre-existing anticoagulation, tranexamic acid may be recommended in elderly trauma patients with acute bleeding.

The development of new high temperature materials for coatings as well as structural components is an important topic to contribute to a higher efficiency and sustainability of e.g. gas turbine engines. One promising new class of high temperature materials are NiAl-based alloys. Within this study, the microstructure and microhardness of NiAl-Ta-Cr alloys with varying Cr and Ta content were investigated. Graded specimens were fabricated by laser-based directed energy deposition utilizing an in situ alloying approach by mixing elemental Ta and Cr as well as pre-alloyed NiAl powder. Thermodynamic calculations were performed to design the alloy compositions beforehand. Inductive preheating of the substrate was used to counter the challenge of cracking due to the high brittleness. The results show that the cracking decreases with increasing preheating temperature. However, even at 700 °C, the cracking cannot be fully eliminated. Scanning electron microscopy, X-ray diffraction and electron backscatter diffraction revealed the formation of the phases B2-NiAl, A2-Cr and C14-NiAlTa within NiAl-Ta and NiAl-Cr alloys. For NiAl-Ta-Cr compositions, deviations regarding the phase formation between calculation and experiment were observed. Maximum hardness values were achieved within the NiAl-Ta and NiAl-Ta-Cr systems for the eutectic compositions at 14 at.-% Ta with maximum values above 900 HV0.1.

BackgroundMedical photography plays a pivotal role in modern health care, serving multiple purposes ranging from patient care to medical documentation and education. Specifically, it aids in wound management, surgical planning, and medical training. While digital cameras have traditionally been used, smartphones equipped with specialized apps present an intriguing alternative. Smartphones offer several advantages, including increased usability and efficiency and the capability to uphold medicolegal standards more effectively and consistently. ObjectiveThis study aims to assess whether implementing a specialized smartphone app could lead to more frequent and efficient use of medical photography. MethodsWe carried out this study as a comprehensive single-center panel investigation at a level 1 trauma center, encompassing various settings including the emergency department, operating theaters, and surgical wards, over a 6-month period from June to November 2020. Using weekly questionnaires, health care providers were asked about their experiences and preferences with using both digital cameras and smartphones equipped with a specialized medical photography app. Parameters such as the frequency of use, time taken for image upload, and general usability were assessed. ResultsA total of 65 questionnaires were assessed for digital camera use and 68 for smartphone use. Usage increased significantly by 5.4 (SD 1.9) times per week (95% CI 1.7-9.2; P=.005) when the smartphone was used. The time it took to upload pictures to the clinical picture and archiving system was significantly shorter for the app (mean 1.8, SD 1.2 min) than for the camera (mean 14.9, SD 24.0 h; P

Chemical looping gasification (CLG) is a novel gasification technology, allowing for the efficient conversion of different solid feedstocks (e.g. biogenic residues) into a high-calorific syngas. As in any chemical looping technology, the oxygen carrier (OC), transporting heat and oxygen from the air to the fuel reactor, is crucial in attaining high process efficiencies. To investigate the fate of the OC during CLG in an industrial environment, ilmenite samples, collected during >400 hours of chemical operation in 1 MWth scale using three different biomass feedstocks, were analyzed using different lab techniques. In doing so, changes in OC particle morphology and composition induced by CLG operation were determined. Moreover, the most important physical and chemical characteristics of the utilized OC were measured. The ensuing dataset allowed for an in-depth evaluation of the CLG technology in semi-industrial scale in terms of OC lifetime and durability. It was found that in the absence of agglomeration, the cycled OC exhibits an oxygen transport capacity of 2.6 wt.-%, a particle density of 3400 kg/m3 and particle diameters between 60 and 250 µm in steady-state conditions. Moreover, it was found that OC loss via particle attrition determines the lifetime of the OC inside the 1 MWth CLG system. On the other hand, feedstock-related agglomeration, observed during CLG operation with wheat straw, was shown to impede OC circulation between AR and FR and thus prevent efficient CLG operation. In summary, the present study thus not only highlights that generally long-term CLG operation in industry-like conditions is feasible, but also provides important insights into measures to improve OC lifetime and durability inside an industrial chemical looping system, such as an optimization of cyclone efficiency or tailored pre-treatment of the utilized feedstock.

Proximity-inducing compounds (PICs) are an emergent drug technology through which a protein of interest (POI), often a drug target, is brought into the vicinity of a second protein which modifies the POI’s function, abundance or localisation, giving rise to a therapeutic effect. One of the best-known examples for such compounds are heterobifunctional molecules known as proteolysis targeting chimeras (PROTACs). PROTACs reduce the abundance of the target protein by establishing proximity to an E3 ligase which labels the protein for degradation via the ubiquitin-proteasomal pathway. Design of PROTACs in silico requires the computational prediction of the ternary complex consisting of POI, PROTAC molecule, and the E3 ligase.We present a novel machine learning-based method for predicting PROTAC-mediated ternary complex structures using Bayesian optimization. We show how a fitness score combining an estimation of protein-protein interactions with PROTAC conformation energy calculations enables the sample-efficient exploration of candidate structures. Furthermore, our method presents two novel scores for filtering and reranking which take PROTAC stability (Autodock-Vina based PROTAC stability score) and protein interaction restraints (the TCP-AIR score) into account. We evaluate our method using DockQ scores on a number of available ternary complex structures (including previously unevaluated cases) and demonstrate that even with a clustering that requires members to have a high similarity, i.e., with smaller clusters, we can assign high ranks to those clusters that contain poses close to the experimentally determined native structure of the ternary complexes. We also demonstrate the resultant improved yield of near-native poses33 The near-native pose is defined as a pose that has DockQ score ≥0.23. in these clusters.

Abstract Placental development relies on coordinated cell fate decisions governed by signalling inputs. However, little is known about how signalling cues are transformed into repressive mechanisms triggering lineage-specific transcriptional signatures. Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with the Nuclear Receptor Co-Repressor Complex 1 and 2 (NCoR1/2) and recruits it to key trophoblast genes. Genetic ablation of Erf or Tbl1x (a component of the NCoR1/2 complex) abrogates the Erf/NCoR1/2 interaction. This leads to mis-expression of Erf/NCoR1/2 target genes, resulting in a TSC differentiation defect. Mechanistically, Erf regulates expression of these genes by recruiting the NCoR1/2 complex and decommissioning their H3K27ac-dependent enhancers. Our findings uncover how the Fgf/Erf/NCoR1/2 repressive axis governs cell fate and placental development, providing a paradigm for Fgf-mediated transcriptional control.

Abstract Background Invasive mechanical ventilation (IMV) is a standard therapy for intensive care patients with respiratory failure. With increasing population age and multimorbidity, the number of patients who cannot be weaned from IMV increases, resulting in impaired quality of life and high costs. In addition, human resources are tied up in the care of these patients. Methods The PRiVENT intervention is a prospective, mixed-methods interventional, multicentre study with a parallel comparison group selected from insurance claims data of the health insurer Allgemeine Ortskrankenkasse Baden-Württemberg (AOK-BW) conducted in Baden-Württemberg, Germany, over 24 months. Four weaning centres supervise 40 intensive care units (ICUs), that are responsible for patient recruitment. The primary outcome, successful weaning from IMV, will be evaluated using a mixed logistic regression model. Secondary outcomes will be evaluated using mixed regression models. Discussion The overall objective of the PRiVENT project is the evaluation of strategies to prevent long-term IMV. Additional objectives aim to improve weaning expertise in and cooperation with the adjacent Intensive Care Units. Trial registration This study is registered at ClinicalTrials.gov (NCT05260853).

As the population ages, the incidence of age-related neurodegenerative diseases is rapidly increasing, and novel approaches to mitigate this soaring prevalence are sorely needed. Recent studies have highlighted the importance of gut microbial homeostasis and its impact on brain functions, commonly referred to as the gut–brain axis, in maintaining overall health and wellbeing. Nonetheless, the mechanisms by which this system acts remains poorly defined. In this review, we will explore how (poly)phenols, a class of natural compounds found in many plant-based foods and beverages, can modulate the gut–brain axis, and thereby promote neural health. While evidence indicates a beneficial role of (poly)phenol consumption as part of a balanced diet, human studies are scarce and mechanistic insight is still lacking. In this regard, we make the case that dietary (poly)phenols should be further explored to establish their therapeutic efficacy on brain health through modulation of the gut–brain axis, with much greater emphasis on carefully designed human interventions.

The present study provides fundamental information on the resource recyclability of the interconnect assembly, i.e., the steel interconnector and the nickel meshes, from an end-of-life JÜLICH Solid Oxide Cell Stack—F10 design. The interconnector is composed of iron, chromium, and less than 4 wt.% of other alloying elements, mainly cobalt and manganese. Calculated blended compositions with the nickel meshes revealed their potential as a raw material in the production of 4xx, 2xx, or 3xx stainless steels. The melting behavior of the interconnect assembly was investigated under different conditions, i.e., in inert and oxidizing atmospheres, with and without the addition of slag-forming fluxes. The results demonstrated preferential oxidation of chromium in a trivalent state within the stable cubic spinel phase. Finally, the experimental results were compared with the thermodynamic equilibrium calculations based on the available databases (FToxid, SGTE, and SGPS) in FactSage 8.1 software. The calculated tendency to oxidize is in the order of Cr > Mn > Fe > Co > Ni at P(O2) greater than 10−10 bar, validating the experimental results.

Adhesive bonding has become increasingly popular in the manufacturing industry due to its many advantages. However, the need to completely fill the joint gap with adhesive for optimum force transfer remains a significant challenge. To ensure full gap filling and therefore joint integrity, safety critical applications often require the adhesive to flow beyond the bonded edges. Due to inadequate design of this process, the adhesive volume that escapes is often more than 30–50% of the adhesive volume. This current practice represents a suboptimal way of proceeding, which the current paper may mitigate.As a result, excessive amounts of adhesive are typically applied due to the lack of suitable models for predicting the flow and final distribution of the adhesive, including the excess amount. This limitation has hindered progress in adhesive bonding technology, and urgent action is needed to address this issue.This paper offers a solution to the significant challenge of predicting adhesive flow and distribution in manufacturing applications. The authors have developed and validated a model that allows the simulation of these complex processes. The paper goes further to present initial application patterns aimed at minimising adhesive waste while ensuring the full filling of the overlap. To achieve this, the authors employ a procedure that involves an advanced reverse squeeze flow simulation to derive an optimal application pattern from a simple initial design. It turns out that a wide range of different final distributions can be produced by a variety of initial star-shaped forms. This paper represents a significant contribution to adhesive bonding technology for anyone interested in manufacturing efficiency.

Abstract The load-bearing behaviour of lubricated contacts depends primarily on the normal force, the relative velocity, and the geometry. Thus, with the aid of the Stribeck curve, it is usually well possible to characterize whether hydrodynamics, mixed friction, or boundary friction is more likely to be present. The fact that the load regime can also depend on the fluid quantity is obvious, but has hardly been systematically investigated so far. Especially for contacts with microscopic roughness, the defined application of a very small amount of fluid is a very challenging requirement. In this paper, a very fundamental study shows how a pin-on-disc tribometer can be used to achieve the transition from dry friction via mixed friction to predominant hydrodynamics by the amount of supplied fluid. The experiments are carried out on samples filed with different coarseness. In addition, the simultaneous influence of partial filling and normal force as well as relative velocity is also shown. Very good reproducibility has been practically reached over the entire range of the tests. Regarding the quantities for the coefficient of friction (COF), it was concluded that close to full filling, a reduction of the fluid quantity has a similar effect on the COF as the reduction of the velocity. This property goes along with the common theory of starved lubricated systems. Such behaviour was not observed to the same extent for the normal force. In the vicinity of smaller fluid quantities, the COF increases very rapidly with further reduction in fluid quantity, far more disproportionately than that with reduction in velocity. With a deeper understanding of this problem, various practical issues such as idling or the run-up process in bearings can also be studied in a more focused manner.

Abstract Aims To save time and have more consistent contours, fully automatic segmentation of targets and organs at risk (OAR) is a valuable asset in radiotherapy. Though current deep learning (DL) based models are on par with manual contouring, they are not perfect and typical errors, as false positives, occur frequently and unpredictably. While it is possible to solve this for OARs, it is far from straightforward for target structures. In order to tackle this problem, in this study, we analyzed the occurrence and the possible dose effects of automated delineation outliers. Methods First, a set of controlled experiments on synthetically generated outliers on the CT of a glioblastoma (GBM) patient was performed. We analyzed the dosimetric impact on outliers with different location, shape, absolute size and relative size to the main target, resulting in 61 simulated scenarios. Second, multiple segmentation models where trained on a U-Net network based on 80 training sets consisting of GBM cases with annotated gross tumor volume (GTV) and edema structures. On 20 test cases, 5 different trained models and a majority voting method were used to predict the GTV and edema. The amount of outliers on the predictions were determined, as well as their size and distance from the actual target. Results We found that plans containing outliers result in an increased dose to healthy brain tissue. The extent of the dose effect is dependent on the relative size, location and the distance to the main targets and involved OARs. Generally, the larger the absolute outlier volume and the distance to the target the higher the potential dose effect. For 120 predicted GTV and edema structures, we found 1887 outliers. After construction of the planning treatment volume (PTV), 137 outliers remained with a mean distance to the target of 38.5 ± 5.0 mm and a mean size of 1010.8 ± 95.6 mm3. We also found that majority voting of DL results is capable to reduce outliers. Conclusions This study shows that there is a severe risk of false positive outliers in current DL predictions of target structures. Additionally, these errors will have an evident detrimental impact on the dose and therefore could affect treatment outcome.

Modeling tools and technologies that will allow reaching decarbonization goals in the most cost-effective way are imperative for the transition to a climate-friendly energy system. This includes models which are able to optimize the design of energy systems with a large number of spatially distributed energy generation sources coupled with adequate short, medium, and long duration storage technologies. Solar photovoltaic and wind energy are likely to become the backbone in a future greenhouse gas neutral energy system and will require low-cost, geographically independent storage technologies in order to balance their intermittent availability. As an alternative to lithium-ion batteries and hydrogen systems, thermal energy storage coupled with a power block (e.g., Carnot batteries, pumped thermal storage, etc.) could be a promising option. Therefore, the current study aims to investigate the influence of renewable generation profiles coupled with alternate storage options (i.e., Li-ion and hydrogen cavern) on the installed capacity of electric-to-thermal-to-electric systems using a 100% renewable electricity system in Germany as a case study. The analyses reveal that Carnot batteries complement established and near-future storage technologies, as they could fill the gap between daily storage such as batteries and seasonal storage such as hydrogen salt caverns. Furthermore, Carnot Batteries could offer multiple options for heat integration further increasing their potential.

The number of available automated insulin delivery (AID) systems is increasing in Austria and people with diabetes (PwD) replace sensor-augmented pump (SAP) therapy more and more frequently. The present study is the two years follow-up of our prior monocentric, retrospective analysis conducted between 2019 and 2021, comparing SAP and open-source AID systems in people with type 1 diabetes. This second-year analysis included 25 PwD and investigated glycemic changes based on ambulatory glucose profiles (AGP). In comparison to the first year, a worsening of mean glucose (125.4 to 135.2 mg/dl, P = 0.038), time in range ((TIR), 84.2 to 77.0%, P = 0.012), time above range ((TAR), 11.6% to 18.5%, P = 0.017) and glycemia risk index ((GRI), 24.8 to 35.0%, P = 0.026) was observed. The reduction of mean glucose and glucose variability with AID in the first year was due to a significant decrease in time in hyperglycemia with resulting higher TIR and lower GRI. In this second-year follow up, TIR and GRI showed a significant deterioration, a familiar phenomenon in diabetology. However, open-source AID systems showed continuous safety, as there was no increase in time below range (TBR) even after two years. Despite the slight deterioration in the glycemic parameters, open-source AID systems were able to demonstrate sufficient glycemic control according to international consensus guidelines while offering the characteristic benefits of a reduced burden of diabetes management. A descriptive comparison of different AID algorithms indicated an improved glycemic control with more advanced features such as basal rate modification, auto bolus function and autotuning.

The tropical forests in the Amazon store large amounts of carbon and are still considered a carbon sink. There is evidence that deforestation can turn a forest landscape into a carbon source due to land use and forest degradation. Deforestation causes fragmented forest landscapes. It is known from field experiments that forest dynamics at the edge of forest fragments are altered by changes in the microclimate and increased tree mortality (“edge effects”). However, it is unclear how this will affect large fragmented forest landscapes, and thus the entire Amazon region. The aim of this study is to investigate different forest attributes in edge and core forest areas at high resolution, and thus to identify the large-scale impacts of small-scale edge effects. Therefore, a well-established framework combining forest modelling and lidar-generated forest structure information was combined with radar-based forest cover data. Furthermore, forests were also analyzed at the landscape level to investigate changes between highly fragmented and less-fragmented landscapes. This study found that the aboveground biomass in forest edge areas is 27% lower than in forest core areas. In contrast, the net primary productivity is 13% higher in forest edge areas than in forest core areas. In the second step, whole fragmented landscapes were analyzed. Nearly 30% of all forest landscapes are highly fragmented, particularly in the regions of the Arc of Deforestation, on the edge of the Andes and on the Amazon river banks. Less-fragmented landscapes are mainly located in the central Amazon rainforest. The aboveground biomass is 28% lower in highly fragmented forest landscapes than in less-fragmented landscapes. The net primary productivity is 13% higher in highly fragmented forest landscapes than in less-fragmented forest landscapes. In summary, fragmentation of the Amazon rainforest has an impact on forest attributes such as biomass and productivity, with mostly negative effects on forest dynamics. If deforestation continues and the proportion of highly fragmented forest landscapes increase, the effect may be even more intense. By combining lidar, radar and forest modelling, this study shows that it is possible to map forest structure, and thus the degree of forest degradation, over a large area and derive more detailed information about the carbon dynamics of the Amazon region.

Abstract A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline.

The immune system is closely linked to bone homeostasis and plays a pivotal role in several pathological and inflammatory conditions. Through various pathways it modulates various bone cells and subsequently sustains the physiological bone metabolism. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous immature myeloid-derived cells that can exert an immunosuppressive function through a direct cell-to-cell contact, secretion of anti-inflammatory cytokines or specific exosomes. These cells mediate the innate immune response to chronic stress on the skeletal system. In chronic inflammation, MDSCs act as an inner offset to rebalance overactivation of the immune system. Moreover, they have been found to be involved in processes responsible for bone remodeling in different musculoskeletal disorders, autoimmune diseases, infection, and cancer. These cells can not only cause bone erosion by differentiating into osteoclasts, but also alleviate the immune reaction, subsequently leading to long-lastingly impacted bone remodeling. In this review, we discuss the impact of MDSCs on the bone metabolism under several pathological conditions, the involved modulatory pathways as well as potential therapeutic targets in MDSCs to improve bone health.

Background:. Despite the general success of total knee arthroplasty (TKA), addressing periprosthetic joint infection (PJI) and the resulting long-term complications is a growing medical need given the aging population and the increasing demand for arthroplasty. A larger proportion of patients face revision surgery because of the long-term complication of aseptic loosening despite clearance of the infection. The pathomechanisms leading to prosthetic loosening are not understood as it has been widely assumed that the bone stock recovers after explantation revision surgery. While clinical observations suggest a reduced osteogenic potential in patients with PJI, knowledge regarding the relevant biology is sparse. In the present study, we investigated the inflammatory impact of PJI on the bone and bone marrow in the vicinity of the joint. Additionally, we evaluated changes in the local inflammatory environment in a 2-stage exchange at both explantation and reimplantation. Methods:. In this study, we analyzed 75 human bone and bone-marrow specimens (obtained from 65 patients undergoing revision arthroplasty with cement for the treatment of PJI) for markers of inflammation. Samples were analyzed using hematoxylin and eosin overview staining, fluorescent immunohistochemical staining, flow cytometry, and polymerase chain reaction (PCR). Results:. Leukocyte prevalence was significantly elevated at explantation (femur, +218.9%; tibia, +134.2%). While leukocyte prevalence decreased at reimplantation (femur, −49.5%; tibia, −34.2%), the number of cells remained significantly higher compared with the control group (femur, +61.2%; tibia, +54.2%). Expression of inflammatory markers interleukin (IL)-1α (femur, +2,748.7%; tibia, +1,605.9%), IL-6 (femur, +2,062.5%; tibia, +2,385.7%), IL-10 (femur, +913.7%; tibia, +897.5%), IL-12 (femur, +386.1%; tibia, +52.5%), IL-18 (femur, +805.3%; tibia, +547.7%), and tumor necrosis factor (TNF)-α (femur, +296.9%; tibia, +220.9%) was significantly elevated at prosthesis explantation in both femoral and tibial specimens. Expression remained significantly elevated at reimplantation for all inflammatory markers except IL-12 compared with the control group. Conversely, there were only limited inflammatory changes in the bone marrow environment. Conclusions:. The present study demonstrated a strong and lasting upregulation of the proinflammatory environment in the joint-surrounding osseous scaffold in patients with PJI. Our data suggest that modulating the inflammatory environment has substantial potential to improve the clinical outcome in affected patients.

Abstract Background While vaccination programs against the severe acute respiratory syndrome virus 2 (SARS-CoV-2) are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness. Methods In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell, and antibody dynamics. Results AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein-specific effector T cells which were dominated by type 1 helper T cell responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA. Conclusions Our results suggest that the strategy for spike protein delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.

Abstract Background Metatarsal fractures are common skeletal injuries of the lower extremity in adults. The majority involves the proximal fifth metatarsal bone. In the current literature, there still exists controversy regarding treatment recommendations for the different fracture entities. Methods All patients suffering from single fractures to the proximal fifth metatarsal bone between 2003 and 2015 were enrolled in this retrospective analysis. Only patients with a minimum follow-up of 12 months were included. The fractures were classified according to Lawrence and Botte (L&B). Data were collected via patient registry, radiographs and a standardized questionnaire (Foot and Ankle Outcome Score = FOAS). For outcome analysis, the nonparametric Mann–Whitney U test was performed and Spearman’s rank correlation coefficient calculated. Results In total, the functional outcomes of 103 patients suffering from fractures to the proximal fifth metatarsal bone were analyzed. L&B type I fractures (n = 13) had a FAOS score of 91 ± 23, L&B type II (n = 67) presented a score of 91 ± 15 and L&B type III (n = 23) a score of 93 ± 11. Surgically treated patients with an L&B type II fracture had no statistically significant better functional outcome in comparison to conservative management (p = 0.89). Operatively treated L&B type III fractures tended to have a better functional score (p = 0.16). The follow-up time was 58 (min: 15; max: 164) months. Conclusions Overall, the functional outcome following fractures to the proximal fifth metatarsal bone is satisfactory. Conservatively treated L&B type II fractures showed an equivalent functional outcome compared to surgical management. Patients with an L&B type III fracture mainly were treated surgically, but difference in FAOS score did not reach level of significance.

Introduction: Exercise is widely recognized as prophylaxis for osteoporosis. However, exactly which type of exercise is best to prevent loss of bone mass remains undefined. To find an appropriate form of treadmill exercise that would ameliorate postmenopausal loss of cortical and trabecular structures, we compared various training regimen in ovariectomized (OVX) C57BL/6J mice.Methods: Common to all regimen were training durations of 14 weeks including five 30 min-sessions per week. Two groups—one sham operated, one OVX—served as controls that did not perform any training. Three OVX groups ran at constant speed, either without any incline or at 20° in- and 20° decline, respectively. An additional OVX group ran an interval training, an alternation between intensive tempo sections and so-called slower regeneration phases. Femoral and humeral bone structures were assessed via micro-computed tomography (μCT), biomechanical stability of the femora via 3-point bending test, muscle volumes of the posterior extremities via magnetic resonance imaging (MRI), and bone metabolic parameters via ELISA on peripheral blood.Result: OVX resulted in loss of bone mass and stability and a transient rise in the N-terminal collagen type I pro-peptide (PINP). Training resulted in increased muscle volumes of the heart and the lower extremities as well as increased running velocities. However, none of the exercise programs was able to prevent ovariectomyinduced loss of bone mass.Discussion: These data therefore suggest that axial loading and tensile strain do not suffice as prophylaxis for postmenopausal osteoporosis yet may need to be complemented by low dose pharmaceutics or dietary supplements.

BackgroundRecovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms.ObjectiveThe objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVIDDesignA systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE (via Pubmed) and Web of Science.ResultsThe literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome’s etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population.ConclusionsPersistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies.

Abstract Background Optimal multiple trauma care should be continuously provided during the day and night. Several studies have demonstrated worse outcomes and higher mortality in patients admitted at night. This study involved the analysis of a population of multiple trauma patients admitted at night and a comparison of various indicators of the quality of care at different admission times. Methods Data from 58,939 multiple trauma patients from 2007 to 2017 were analyzed retrospectively. All data were obtained from TraumaRegister DGU®. Patients were grouped by the time of their admission to the trauma center (6.00 am–11.59 am (morning), 12.00 pm–5.59 pm (afternoon), 6.00 pm–11.59 pm (evening), 0.00 am–5.59 am (night)). Incidences, patient demographics, injury patterns, trauma center levels and trauma care times and outcomes were evaluated. Results Fewer patients were admitted during the night (6.00 pm–11.59 pm: 18.8% of the patients, 0.00–5.59 am: 4.6% of the patients) than during the day. Patients who arrived between 0.00 am–5.59 am were younger (49.4 ± 22.8 years) and had a higher injury severity score (ISS) (21.4 ± 11.5) and lower Glasgow Coma Scale (GCS) score (11.6 ± 4.4) than those admitted during the day (12.00 pm–05.59 pm; age: 55.3 ± 21.6 years, ISS: 20.6 ± 11.4, GCS: 12.6 ± 4.0). Time in the trauma department and time to an emergency operation were only marginally different. Time to imaging was slightly prolonged during the night (0.00 am–5.59 am: X-ray 16.2 ± 19.8 min; CT scan 24.3 ± 18.1 min versus 12.00 pm- 5.59 pm: X-ray 15.4 ± 19.7 min; CT scan 22.5 ± 17.8 min), but the delay did not affect the outcome. The outcome was also not affected by level of the trauma center. There was no relevant difference in the Revised Injury Severity Classification II (RISC II) score or mortality rate between patients admitted during the day and at night. There were no differences in RISC II scores or mortality rates according to time period. Admission at night was not a predictor of a higher mortality rate. Conclusion The patient population and injury severity vary between the day and night with regard to age, injury pattern and trauma mechanism. Despite the differences in these factors, arrival at night did not have a negative effect on the outcome.

Abstract Background Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and l-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. Results Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. Conclusion Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function. Video abstract

Abstract Objectives Osteoporotic fractures of the pelvis (OFP) are an increasing issue in orthopedics. Current classification systems (CS) are mostly CT-based and complex and offer only moderate to substantial inter-rater reliability (interRR) and intra-rater reliability (intraRR). MRI is thus gaining importance as a complement. This study aimed to develop a simple and reliable CT- and MRI-based CS for OFP. Methods A structured iterative procedure was conducted to reach a consensus among German-speaking spinal and pelvic trauma experts over 5 years. As a result, the proposed OF-Pelvis CS was developed. To assess its reliability, 28 experienced trauma and orthopedic surgeons categorized 25 anonymized cases using X-ray, CT, and MRI scans twice via online surveys. A period of 4 weeks separated the completion of the first from the second survey, and the cases were presented in an altered order. While 13 of the raters were also involved in developing the CS (developing raters (DR)), 15 user raters (UR) were not deeply involved in the development process. To assess the interRR of the OF-Pelvis categories, Fleiss’ kappa (κF) was calculated for each survey. The intraRR for both surveys was calculated for each rater using Kendall’s tau (τK). The presence of a modifier was calculated with κF for interRR and Cohen’s kappa (κC) for intraRR. Results The OF-Pelvis consists of five subgroups and three modifiers. Instability increases from subgroups 1 (OF1) to 5 (OF5) and by a given modifier. The three modifiers can be assigned alone or in combination. In both surveys, the interRR for subgroups was substantial: κF = 0.764 (Survey 1) and κF = 0.790 (Survey 2). The interRR of the DR and UR was nearly on par (κF Survey 1/Survey 2: DR 0.776/0.813; UR 0.748/0.766). The agreement for each of the five subgroups was also strong (κF min.–max. Survey 1/Survey 2: 0.708–0.827/0.747–0.852). The existence of at least one modifier was rated with substantial agreement (κF Survey 1/Survey 2: 0.646/0.629). The intraRR for subgroups showed almost perfect agreement (τK = 0.894, DR: τK = 0.901, UR: τK = 0.889). The modifier had an intraRR of κC = 0.684 (DR: κC = 0.723, UR: κC = 0.651), which is also considered substantial. Conclusion The OF-Pelvis is a reliable tool to categorize OFP with substantial interRR and almost perfect intraRR. The similar reliabilities between experienced DRs and URs demonstrate that the training status of the user is not important. However, it may be a reliable basis for an indication of the treatment score.

The experimental determination of cure-dependent viscoelastic properties is of utmost importance for processing and use of epoxy (EP) resin-based materials and structures. Although this complex topic is frequently addressed in literature and in practice, no standards and few general guidelines for this task are available. Hence, a comprehensive review on rheological experiments and dynamic-mechanical analysis (DMA) including their preparation, conduction and evaluation was conducted. According to the results of our literature research, operators are well advised to rely on holistic test protocols that take care of the strong interaction between the curing process, the realistic device capabilities and the viscoelastic phenomena to be measured. We show that erroneous data or misinterpretations may occur if inappropriate measurement setups are employed. Methods for the prevention of both material- and device-related disturbances are suggested. Finally, remaining experimental challenges and future trends in the context of cure-dependent viscoelastic properties of EP are pointed out.

Before the advent of TIRF microscopy the fate of the insulin granule prior to secretion was deduced from biochemical investigations, electron microscopy and electrophysiological measurements. Since Calcium-triggered granule fusion is indisputably necessary to release insulin into the extracellular space, much effort was directed to the measure this event at the single granule level. This has also been the major application of the TIRF microscopy of the pancreatic beta cell when it became available about 20 years ago. To better understand the metabolic modulation of secretion, we were interested to characterize the entirety of the insulin granules which are localized in the vicinity of the plasma membrane to identify the characteristics which predispose to fusion. In this review we concentrate on how the description of granule mobility in the submembrane space has evolved as a result of progress in methodology. The granules are in a state of constant turnover with widely different periods of residence in this space. While granule fusion is associated +with prolonged residence and decreased lateral mobility, these characteristics may not only result from binding to the plasma membrane but also from binding to the cortical actin web, which is present in the immediate submembrane space. While granule age as such affects granule mobility and fusion probability, the preceding functional states of the beta cell leave their mark on these parameters, too. In summary, the submembrane granules form a highly dynamic heterogeneous population and contribute to the metabolic memory of the beta cells.

Ambient atmospheric concentrations of isoprene and monoterpenes were measured at two forest sites, one deciduous and one coniferous, over the year 2022. Both sites in a regional area were sampled monthly between April and September. The samples were taken using sorbent tubes and analyzed with thermal desorption–gas chromatography–mass spectrometry. The highest concentrations were determined in August at both sites. While isoprene is the most abundant compound at the deciduous forest with an average concentration of 5.59 µg m−3 in August, α-pinene and β-pinene dominate throughout the year at the coniferous forest with the highest concentrations also in August (3.44 µg m−3 and 1.51 µg m−3). Because other monoterpenes (camphene, sabinene, 3-carene, p-cymene and limonene) are also emitted in significant amounts, the total concentration measured in the coniferous forest is higher (7.96 µg m−3 in August) in comparison to the deciduous forest (6.08 µg m−3). Regarding the detected monoterpenes in the deciduous forest, sabinene is the dominant monoterpene in addition to α-pinene and is sometimes present in higher (July) or equal (August) concentrations. The seasonal and diurnal concentrations of all monoterpenes correlate very well with each other at both sites. An exception is sabinene with a diurnal concentration profile similar to isoprene.

Rett syndrome (RTT) is a genetic neurodevelopmental disorder with mutations in the X-chromosomal MECP2 (methyl-CpG-binding protein 2) gene. Most patients are young girls. For 7–18 months after birth, they hardly present any symptoms; later they develop mental problems, a lack of communication, irregular sleep and breathing, motor dysfunction, hand stereotypies, and seizures. The complex pathology involves mitochondrial structure and function. Mecp2−/y hippocampal astrocytes show increased mitochondrial contents. Neurons and glia suffer from oxidative stress, a lack of ATP, and increased hypoxia vulnerability. This spectrum of changes demands comprehensive molecular studies of mitochondria to further define their pathogenic role in RTT. Therefore, we applied a comparative proteomic approach for the first time to study the entity of mitochondrial proteins in a mouse model of RTT. In the neocortex and hippocampus of symptomatic male mice, two-dimensional gel electrophoresis and subsequent mass-spectrometry identified various differentially expressed mitochondrial proteins, including components of respiratory chain complexes I and III and the ATP-synthase FoF1 complex. The NADH-ubiquinone oxidoreductase 75 kDa subunit, NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, NADH dehydrogenase [ubiquinone] flavoprotein 2, cytochrome b-c1 complex subunit 1, and ATP synthase subunit d are upregulated either in the hippocampus alone or both the hippocampus and neocortex of Mecp2−/y mice. Furthermore, the regulatory mitochondrial proteins mitofusin-1, HSP60, and 14-3-3 protein theta are decreased in the Mecp2−/y neocortex. The expressional changes identified provide further details of the altered mitochondrial function and morphology in RTT. They emphasize brain-region-specific alterations of the mitochondrial proteome and support the notion of a metabolic component of this devastating disorder.

Abstract Background The incidence of rheumatoid arthritis is correlated with age. In this study, we analyzed the association of the incidence and severity of glucose-6-phosphate isomerase (G6PI)-induced arthritis with age in two different mouse strains. Methods Young and very old mice from two different arthritis-susceptible wild-type mouse strains were analyzed after a single subcutaneous injection of G6PI s.c. The metabolism and the function of synoviocytes were analyzed in vitro, the production of bioactive lipid mediators by myeloid cells and synoviocytes was assessed in vitro and ex vivo by UPLC-MS-MS, and flow cytometry was used to verify age-related changes of immune cell composition and function. Results While the severity of arthritis was independent from age, the onset was delayed in old mice. Old mice showed common signs of immune aging like thymic atrophy associated with decreased CD4+ effector T cell numbers. Despite its decrease, the effector T helper (Th) cell compartment in old mice was reactive and functionally intact, and their Tregs exhibited unaltered suppressive capacities. In homeostasis, macrophages and synoviocytes from old mice produced higher amounts of pro-inflammatory cyclooxygenase (COX)-derived products. However, this functional difference did not remain upon challenge in vitro nor upon arthritis reactions ex vivo. Conclusion While old mice show a higher baseline of inflammatory functions, this does not result in increased reaction towards self-antigens in arthritis-susceptible mouse strains. Together, our data from two different mouse strains show that the susceptibility for G6PI-induced arthritis is not age-dependent.

Purpose: Filler injections for aesthetic purposes are very popular, but can have far-reaching and irreversible consequences. This report describes the course of a patient with devastating complications after glabellar hyaluronic acid injection, their pathomechanism, management and outcome. Observations: A healthy, 43-year-old woman underwent her first hyaluronic acid injection in the glabella and went blind on her left eye immediately thereafter. Massaging of the injection area and observation were performed, before she presented with swelling of the left forehead and upper lid, ptosis, complete ophthalmoplegia and blindness in our hospital. Immediate massaging of the globe and systemic therapy including acetylsalicylic acid, tinzaparin sodium and cortisone was initiated and hyaluronidase injections in the injection area were performed. In the further course, the patient developed necrotic and hemorrhagic skin and mucosal lesions, lagophthalmos, anterior and posterior segment ischemia and globe hypotonia with consecutive globe deformation. In the follow-up of 2.5 months, lid swelling, lagophthalmos and ptosis resolved and keratopathy improved but blindness, skin lesions and strabismus with reduced eye motility were still present and madarosis and early enophthalmos were detected. Conclusions and Importance: The outcome of ophthalmic artery occlusion after hyaluronic acid filler injection is poor. Sufficient knowledge about facial anatomy, the implementation of filler injections and the management of complications is essential for the practitioner. The patient should be clarified about potential and even rare risks of these procedures.

Abstract In grinding processes, heat is generated by the contact of the grains with the workpiece. In order to reduce damages on the workpiece and the grinding tool, cutting fluids are necessary for most grinding processes. They have the tasks of cooling and lubricating the contact zone and to remove the chips from the contact area. Different types of cutting fluids perform differently regarding these tasks, which can be investigated on a laboratory scale. However, the results of those experiments are limited to certain workpieces and processes and information about the contact mechanics are not available. The experimental investigation of contact mechanics under cutting fluid influence is hardly possible. For this reason, this paper uses a measurement strategy that uses scaled topographies and has already been successfully applied to contact mechanics problems. With such a setup, it is intended that at an early stage in the development of cutting fluids, their characteristics in terms of contact mechanics can be determined very efficiently. To demonstrate this approach, two different cutting fluids were tested with the help of the associated test rig—a water miscible emulsion and a non-water miscible grinding oil. The two fluids showed fundamentally different characteristics regarding their hydrodynamic load bearing effect, their influence on the friction behavior of the contact and their fluid flow in the gap. The properties analyzed here correspond to the practical application of cutting fluids. The results underline the potential of the presented setup for an integration into the development process of cutting fluids.

Rubromycin family of natural products belongs to aromatic polyketides with diverse bioactivities, but details of their biosynthesis are limited. Here, the authors report the complete in vitro reconstitution of enzymatic formation of the spiroketal moiety of rubromycin polyketides, driven by flavin-dependent enzymes, and characterize reaction intermediates.

Free-living anaerobic ciliates are of considerable interest from an ecological and an evolutionary standpoint. Extraordinary tentacle-bearing predatory lineages have evolved independently several times within the phylum Ciliophora, including two rarely encountered anaerobic litostomatean genera, Legendrea and Dactylochlamys. In this study, we significantly extend the morphological and phylogenetic characterization of these two poorly known groups of predatory ciliates. We provide the first phylogenetic analysis of the monotypic genus Dactylochlamys and the three valid species of Legendrea based on the 18S rRNA gene and ITS-28S rRNA gene sequences. Prior to this study, neither group had been studied using silver impregnation methods. We provide the first protargol-stained material and also a unique video material including documentation, for the first time, of the hunting and feeding behavior of a Legendrea species. We briefly discuss the identity of methanogenic archaeal and bacterial endosymbionts of both genera based on 16S rRNA gene sequences, and the importance of citizen science for ciliatology from a historical and contemporary perspective.

We develop a theoretical model to predict the sublimation vapor pressure of pure substances. Moreover, we present a simple monoatomic molecule approximation, which reduces the complexity of the vapor pressure expression for polyatomic gaseous molecules at a convincing level of accuracy, with deviations of the Arrhenius prefactor for NaCl and NaF being 5.02% and 7.08%, respectively. The physical model is based on ab initio calculations, statistical mechanics, and thermodynamics. We illustrate the approach for Ni, Cr, Cu (metallic bond), NaCl, NaF, ZrO2 (ionic bond) and SiO2 (covalent bond). The results are compared against thermodynamic databases, which show high accuracy of our theoretical predictions, and the deviations of the predicted sublimation enthalpy are typically below 10%, for Cu even only 0.1%. Furthermore, the partial pressures caused by gas phase reactions are also explored, showing good agreement with experimental results.

The mechanisms that shape the regulatory T cell repertoire in patients with cancer are not completely understood. Here, the authors observe that, in breast cancer patients, tumor-resident regulatory T cells do not show clonal relationship with their circulating counterpart, but share a common origin with intratumoral antigen-experienced conventional T cells.

Abstract Background Early prognostication in patients with acute consciousness impairment is a challenging but essential task. Current prognostic guidelines vary with the underlying etiology. In particular, electroencephalography (EEG) is the most important paraclinical examination tool in patients with hypoxic ischemic encephalopathy (HIE), whereas it is not routinely used for outcome prediction in patients with traumatic brain injury (TBI). Method Data from 364 critically ill patients with acute consciousness impairment (GCS ≤ 11 or FOUR ≤ 12) of various etiologies and without recent signs of seizures from a prospective randomized trial were retrospectively analyzed. Random forest classifiers were trained using 8 visual EEG features—first alone, then in combination with clinical features—to predict survival at 6 months or favorable functional outcome (defined as cerebral performance category 1–2). Results The area under the ROC curve was 0.812 for predicting survival and 0.790 for predicting favorable outcome using EEG features. Adding clinical features did not improve the overall performance of the classifier (for survival: AUC = 0.806, p = 0.926; for favorable outcome: AUC = 0.777, p = 0.844). Survival could be predicted in all etiology groups: the AUC was 0.958 for patients with HIE, 0.955 for patients with TBI and other neurosurgical diagnoses, 0.697 for patients with metabolic, inflammatory or infectious causes for consciousness impairment and 0.695 for patients with stroke. Training the classifier separately on subgroups of patients with a given etiology (and thus using less training data) leads to poorer classification performance. Conclusions While prognostication was best for patients with HIE and TBI, our study demonstrates that similar EEG criteria can be used in patients with various causes of consciousness impairment, and that the size of the training set is more important than homogeneity of ACI etiology.

BackgroundAgeing is highly associated with cognitive decline and modifiable risk factors such as diet are believed to protect against this process. Specific dietary components and in particular, (poly)phenol-rich fruits such as berries have been increasingly recognised for their protection against age-related neurodegeneration. However, the impact of cranberries on cognitive function and neural functioning in older adults remains unclear.DesignA 12-week parallel randomised placebo-controlled trial of freeze-dried cranberry powder was conducted in 60 older adults aged between 50 and 80 years. Cognitive assessment, including memory and executive function, neuroimaging and blood sample collection were conducted before and after the intervention to assess the impact of daily cranberry consumption on cognition, brain function and biomarkers of neuronal signalling.ResultsCranberry supplementation for 12 weeks was associated with improvements in visual episodic memory in aged participants when compared to placebo. Mechanisms of action may include increased regional perfusion in the right entorhinal cortex, the accumbens area and the caudate in the cranberry group. Significant decrease in low-density lipoprotein (LDL) cholesterol during the course of the intervention was also observed. No significant differences were, however, detected for BDNF levels between groups.ConclusionsThe results of this study indicate that daily cranberry supplementation (equivalent to 1 small cup of cranberries) over a 12-week period improves episodic memory performance and neural functioning, providing a basis for future investigations to determine efficacy in the context of neurological disease. This trial was registered at clinicaltrials.gov as NCT03679533 and at ISRCTN as ISRCTN76069316.

Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and naïve B cells to be relevant drivers of disease progression. Additionally, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.

Monooxygenases catalyse the hydroxylation of C-H bonds using oxygen as a co-substrate, which, in turn, is unavailable for anaerobic bacteria. Here, the authors report a three-step reaction cascade involving two hydroxylases and one dehydratase which hydroxylate the C26 methyl group of cholesterol with water as a co-substrate.