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Abstract Background Despite advances in total knee arthroplasty, many patients are still unsatisfied with the functional outcome. Multibody simulations enable a more efficient exploration of independent variables compared to experimental studies. However, to what extent numerical models can fully reproduce knee joint kinematics is still unclear. Hence, models must be validated with different test scenarios before being applied to biomechanical questions. Methods In our feasibility study, we analyzed a human knee specimen on a six degree of freedom joint simulator, applying a passive flexion and different laxity tests with sequential states of ligament resection while recording the joint kinematics. Simultaneously, we generated a subject-specific multibody model of the native tibiofemoral joint considering ligaments and contact between articulating cartilage surfaces. Results Our experimental data on the sequential states of ligament resection aligned well with the literature. The model-based knee joint kinematics during passive flexion showed good agreement with the experiment, with root-mean-square errors of less than 1.61 mm for translations and 2.1° for knee joint rotations. During laxity tests, the experiment measured up to 8 mm of anteroposterior laxity, while the numerical model allowed less than 3 mm. Conclusion Although the multibody model showed good agreement to the experimental kinematics during passive flexion, the validation showed that ligament parameters used in this feasibility study are too stiff to replicate experimental laxity tests correctly. Hence, more precise subject-specific ligament parameters have to be identified in the future through model optimization.

Purpose: The 'globalisation backlash' poses a challenge to society and civic education. This article develops future approaches to teaching globalisation by drawing on past concepts of economic education. Approach: An in-depth literature review on the contemporary challenges of globalisation is given and compared to the conventional approaches of teaching globalisation. Past concepts of economic education are introduced and examined for their applicability in this context. Findings: Since the 'globalisation backlash' is rooted in subjective experiences of the local environment, approaches such as lifeworld-orientation are useful to activated students' understandings. Socio-economic approaches can complement this with sociological, economic, and political theories that reveal the mechanisms behind personal experiences. Practical implications: Diagnostic teaching becomes necessary to link the students' realm of experience and globalised reality. [Note: The page numbers (93-95) shown following page 124 are incorrect. The correct page numbers are 125-127.]

Nitric oxide (NO) and cytokinins (CKs) are known for their crucial contributions to plant development, growth, senescence, and stress response. Despite the importance of both signals in stress responses, their interaction remains largely unexplored. The interplay between NO and CKs emerges as particularly significant not only regarding plant growth and development but also in addressing plant stress response, particularly in the context of extreme weather events leading to yield loss. In this review, we summarize NO and CKs metabolism and signaling. Additionally, we emphasize the crosstalk between NO and CKs, underscoring its potential impact on stress response, with a focus on hypoxia tolerance. Finally, we address the most urgent questions that demand answers and offer recommendations for future research endeavors.

The flooding of agricultural land leads to hypoxia and nitrate leaching. While understanding the plant’s response to these conditions is essential for crop improvement, the effect of extended nitrate limitation on subsequent hypoxia has not been studied in an organ-specific manner. We cultivated Arabidopsis thaliana without nitrate for 1 week before inducing hypoxia by bubbling the hydroponic solution with nitrogen gas for 16 h. In the roots, the transcripts of two transcription factor genes (HRA1, HRE2) and three genes involved in fermentation (SUS4, PDC1, ADH1) were ~10- to 100-fold upregulated by simultaneous hypoxia and nitrate starvation compared to the control condition (replete nitrate and oxygen). In contrast, this hypoxic upregulation was ~5 to 10 times stronger when nitrate was available. The phytoglobin genes PGB1 and PGB2, involved in nitric oxide (NO) scavenging, were massively downregulated by nitrate starvation (~1000-fold and 105-fold, respectively), but only under ambient oxygen levels; this was reflected in a 2.5-fold increase in NO concentration. In the leaves, HRA1, SUS4, and RAP2.3 were upregulated ~20-fold by hypoxia under nitrate starvation, whereas this upregulation was virtually absent in the presence of nitrate. Our results highlight that the plant’s responses to nitrate starvation and hypoxia can influence each other.

ABSTRACT The human pathogen Pseudomonas aeruginosa (Pa) poses a major risk for a range of severe infections, particularly lung infections in patients suffering from cystic fibrosis (CF). As previously reported, the virulent behavior of this pathogen is enhanced by elevated levels of Ca2+ that are commonly present in CF nasal and lung fluids. In addition, a Ca2+-binding EF-hand protein, EfhP (PA4107), was partially characterized and shown to be critical for the Ca2+-regulated virulence in P. aeruginosa. Here, we describe the rapid (10 min, 60 min), and adaptive (12 h) transcriptional responses of PAO1 to elevated Ca2+ detected by genome-wide RNA sequencing and show that efhP deletion significantly hindered both rapid and adaptive Ca2+ regulation. The most differentially regulated genes included multiple Fe sequestering mechanisms, a large number of extracytoplasmic function sigma factors (ECFσ), and several virulence factors, such as the production of pyocins. The Ca2+ regulation of Fe uptake was also observed in CF clinical isolates and appeared to involve the global regulator Fur. In addition, we showed that the efhP transcription is controlled by Ca2+ and Fe, and this regulation required a Ca2+-dependent two-component regulatory system CarSR. Furthermore, the efhP expression is significantly increased in CF clinical isolates and upon pathogen internalization into epithelial cells. Overall, the results established for the first time that Ca2+ controls Fe sequestering mechanisms in P. aeruginosa and that EfhP plays a key role in the regulatory interconnectedness between Ca2+ and Fe signaling pathways, the two distinct and important signaling pathways that guide the pathogen’s adaptation to the host.IMPORTANCEPseudomonas aeruginosa (Pa) poses a major risk for severe infections, particularly in patients suffering from cystic fibrosis (CF). For the first time, kinetic RNA sequencing analysis identified Pa rapid and adaptive transcriptional responses to Ca2+ levels consistent with those present in CF respiratory fluids. The most highly upregulated processes include iron sequestering, iron starvation sigma factors, and self-lysis factors pyocins. An EF-hand Ca2+ sensor, EfhP, is required for at least 1/3 of the Ca2+ response, including the majority of the iron uptake mechanisms and the production of pyocins. Transcription of efhP itself is regulated by Ca2+ and Fe, and increases during interactions with host epithelial cells, suggesting the protein’s important role in Pa infections. The findings establish the regulatory interconnectedness between Ca2+ and iron signaling pathways that shape Pa transcriptional responses. Therefore, understanding Pa’s transcriptional response to Ca2+ and associated regulatory mechanisms will serve in the development of future therapeutics targeting Pa’s dangerous infections.

The unstable N=42 nucleus 72Zn has been studied using multiple safe Coulomb excitation in inverse kinematics. The experiment was performed at the REX-ISOLDE facility at CERN making first use of the silicon detector array C-REX in combination with the γ-ray spectrometer Miniball. The high angular coverage of C-REX allowed to determine the reduced transition strengths for the decay of the yrast 01+, 21+ and 41+ as well as of the 02+ and 22+ states in 72Zn. The quadrupole moments of the 21+, 41+ and 22+ states were extracted. Using model independent quadrupole invariants, the ground state of 72Zn was found to have an average deformation in the γ degree of freedom close to maximum triaxiality. In comparison to experimental data in zinc isotopes with N

Abstract Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Abstract Background Afforestation of non-forestland is a new measure by the European Union to enhance climate mitigation and biodiversity. Hybrid aspen (Populus tremula L. × P. tremuloides Michx.) is among the suitable tree species for afforestation to produce woody biomass. However, the best performing genotypic material for intensive biomass production and its physiological adaptation capacity is still unclear. We compared 22 hybrid aspen genotypes growth and leaf physiological characteristics (stomatal conductance, net photosynthesis, intrinsic water-use efficiency) according to their geographical north- or southward transfer (European P. tremula parent from 51° to 60° N and North American P. tremuloides parent from 45° to 54° N) to hemiboreal Estonia (58° N) in a completely randomized design progeny trial. We tested whether the growth ranking of genotypes of different geographical origin has changed from young (3-year-old) to mid-rotation age (13-year-old). The gas exchange parameters were measured in excised shoots in 2021 summer, which was characterised with warmer (+ 4 °C) and drier (17% precipitation from normal) June and July than the long-term average. Results We found that the northward transfer of hybrid aspen genotypes resulted in a significant gain in growth (two-fold greater diameter at breast height) in comparison with the southward transfer. The early selection of genotypes was generally in good accordance with the middle-aged genotype ranking, while some of the northward transferred genotypes showed improved growth at the middle-age period in comparison with their ranking during the early phase. The genotypes of southward transfer demonstrated higher stomatal conductance, which resulted in higher net photosynthesis, and lower intrinsic water-use efficiency (iWUE) compared with northward transfer genotypes. However, higher photosynthesis did not translate into higher growth rate. The higher physiological activity of southern transferred genotypes was likely related to a better water supply of smaller and consequently more shaded trees under drought. Leaf nitrogen concentration did not have any significant relation with tree growth. Conclusions We conclude that the final selection of hybrid aspen genotypes for commercial use should be done in 10–15 years after planting. Physiological traits acquired during periods of droughty conditions may not fully capture the growth potential. Nonetheless, we advocate for a broader integration of physiological measurements alongside traditional traits (such as height and diameter) in genotype field testing to facilitate the selection of climate-adapted planting material for resilient forests.

An important factor in the decline of global animal diversity is road traffic, where many animals are killed. This study aimed to collect data on vertebrate roadkill in the city of Vienna, Austria, between 2017 and 2022 using three different approaches: citizen science, systematic monitoring by bicycle along a 15 km route, and systematic monitoring on foot along a 3 km route. During 359 monitoring events, only four roadkill incidences (three Erinaceus sp., one Rattus sp.) were found by bicycle or on foot. At the same time citizen scientists reported 1 roadkill squirrel on the bicycle route and 84 roadkill incidences for the entire city area. Hedgehogs and urban birds were commonly reported species by citizen scientists. Although no amphibian or reptile roadkill was found during systematic monitoring, they were reported by citizen scientists. The low number of roadkill incidences found suggests a potentially low population density that makes the impact of roadkill even more severe – a hypothesis that should be further investigated amidst the global decline in biodiversity.

Abstract Background Non-sputum-based tests are needed to predict or diagnose tuberculosis (TB) disease in people living with HIV (PWH). The enzyme indoleamine 2, 3-dioxygenase-1 (IDO1) is expressed in tuberculoid granuloma and catabolizes tryptophan (Trp) to kynurenine (Kyn). IDO1 activity compromises innate and adaptive immune responses, promoting mycobacterial survival. The plasma Kyn-to-Trp (K/T) ratio is a potential TB diagnostic and/or predictive biomarker in PWH on long-term antiretroviral therapy (ART). Methods We compared plasma K/T ratios in samples from PWH, who were followed up prospectively and developed TB disease after ART initiation. Controls were matched for age and duration of ART. Kyn and Trp were measured at 3 timepoints; at TB diagnosis, 6 months before TB diagnosis and 6 months after TB diagnosis, using ultra performance liquid chromatography combined with mass spectrometry. Results The K/T ratios were higher for patients with TB disease at time of diagnosis (median, 0.086; IQR, 0.069–0.123) compared to controls (0.055; IQR 0.045–0.064; p = 0.006), but not before or after TB diagnosis. K/T ratios significantly declined after successful TB treatment, but increased upon treatment failure. The K/T ratios showed a parabolic correlation with CD4 cell counts in participants with TB (p = 0.005), but there was no correlation in controls. Conclusions The plasma K/T ratio helped identify TB disease and may serve as an adjunctive biomarker for for monitoring TB treatment in PWH. Validation studies to ascertain these findings and evaluate the optimum cut-off for diagnosis of TB disease in PWH should be undertaken in well-designed prospective cohorts. Trial registration ClinicalTrials.gov Identifier: NCT00411983.

BackgroundVitamin A deficiency (VAD) is common in populations with limited dietary diversity and access to vitamin A-rich foods.ObjectivesThis analysis aimed to determine the impact of supplementing children's diets with 1 egg/d on the concentration of plasma retinol and RBP and the prevalence of VAD.MethodsChildren age 6-9 mo living in the Mangochi district of Malawi were individually randomly assigned to receive 1 egg/d for 6 mo (n = 331) or continue their usual diet (n = 329) in the Mazira trial (clinicaltrials.gov; NCT03385252). This secondary analysis measured plasma retinol by HPLC and RBP, CRP, and α-1-acid glycoprotein (AGP) by ELISA techniques at enrollment and 6 mo follow-up. Retinol and RBP were adjusted for inflammation, and mean concentrations were compared between groups using linear regression models. In addition, prevalence ratios of VAD (retinol 5 mg/L or AGP >1 g/L: 62%) and inflammation-adjusted VAD (7%) at enrollment did not differ between groups. At follow-up, the egg intervention group did not differ from the control in inflammation-adjusted retinol [geometric mean (95% CI); egg: 1.10 μmol/L (1.07, 1.13); control: 1.08 (1.05, 1.12)], RBP [egg: 0.99 μmol/L (0.96, 1.02); control: 0.97 (0.94, 1.00)], or prevalence of VAD [egg: 6%; control: 3%; prevalence ratio: 1.87 (0.83, 4.24)].ConclusionsProvision of 1 egg/d did not impact VAD, plasma retinol, or RBP among young children in rural Malawi, where the prevalence of VAD was low. Curr Dev Nutr 2023;x:xx.This trial was registered at [clinicaltrials.gov] as [NCT03385252].

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP's propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

Mineral deficiencies are common in children living in low-resource areas. Eggs are a rich source of essential nutrients and have been shown to improve growth in young children, although little is known about their impact on mineral status. Children aged 6-9 months (n = 660) were randomized to receive either one egg/day for 6-months or no intervention. Anthropometric data, dietary recalls, and venous blood were collected at baseline and 6-months follow-up. Quantification of plasma minerals (n = 387) was done using inductively coupled plasma-mass spectroscopy. Difference-in-difference mean plasma mineral concentrations was determined from baseline and follow-up values and assessed between groups by intention-to-treat using ANCOVA regression models. Prevalence of zinc deficiency was 57.4% at baseline and 60.5% at follow-up. Mean difference (MD) of plasma magnesium, selenium, copper, and zinc levels were not different between groups. Plasma iron concentrations were significantly lower in the intervention compared to the control group (MD = - 9.29; 95% CI: - 15.95, - 2.64). Zinc deficiency was widely prevalent in this population. Mineral deficiencies were not addressed with the egg intervention. Further interventions are needed to improve the mineral status of young children.

IntroductionEarly recognition and indicated prevention is a promising approach to decrease the incidence of Major depressive episodes (MDE), targeting the patients during their clinical high-risk state of MDE (CHR-D). The identification of a set of stressors at the CHR-D increases the success of indicated prevention with personalized early interventions. The study evaluated stressors in the early phase of depression, developed on the basis of a patient survey on stressors.MethodsSixty-eight inpatients (ICD10: F3x.xx) with a reported high risk state for major depressive episode (CHR-D) were included in the current study. Stressors during CHR-D were retrospectively explored using a semi-structured clinical interview supplemented by open-ended questions. A qualitative explorative content analysis was provided to identify a pattern of stressors during the prodromal phase of the patients, based on the patient’s perspective. A frequency analysis was performed for the evaluation of the prevalence of reported source of stress.ResultsAll patients reported stressors in the prodromal phase of depression. Results demonstrates that patients with depressive disorder typically report multiple stressors, with the most common number being four. First, 18 stressors-groups were identified during coding. Interpersonal conflicts and disappointments in close relationships were most frequently reported stressors during the prodromal phase at 44.1%. The second most frequent stressor mentioned was the high qualitative or quantitative demands at work (38.2%). The third frequent source of stress was changes in close relationships and in family relationships (33.8%). Based on the categories of stressors described in the patient survey during the prodromal phase we suggested a model of stressors in CHR-D during the prodromal phase of the MDE.DiscussionThe identification of a set of stressors at the early stage of MDE may increase opportunities for early intervention. In everyday clinical practice, preventive psychiatry needs clinical and adapted instruments for recording stressors in today’s society. This knowledge is necessary in order to develop precisely indicated prevention for depressive disorders.

Background: Torsional malalignment of the femur and/or tibia is associated with patellar maltracking, and torsional osteotomies have shown to improve clinical symptoms. In patients with severe torsional malalignment, a double-level torsional osteotomy may be necessary. Indications: Symptomatic torsional malalignment leading to patellofemoral maltracking associated with anterior knee pain and/or patellofemoral instability. Technique Description: A double-level torsional osteotomy correcting both increased internal femoral torsion and increased external tibial torsion, is described. Meticulous preoperative deformity analysis and planning of the osteotomy is mandatory. An arthroscopy of the knee is performed first to evaluate the patellofemoral joint and patellar tracking. Tibial torsional correction is performed by a lateral approach. A biplanar osteotomy is performed, and the amount of torsional correction is controlled by 2 Schanz screws. Osteosynthesis can be done via a bended 5-hole DC-Plate or an angle-stable plate. The femoral osteotomy is performed by a medial approach. A uniplanar osteotomy is performed perpendicular to the mechanical axis of the femur. The amount of torsional correction is controlled by 2 Schanz screws. Osteosynthesis is achieved by an angle-stable plate. Results: Double-level torsional osteotomy has been shown to be an effective treatment for patients with patellar dislocation or subluxation associated with severe torsional malalignment. In a series of 18 patients, double-level osteotomy led to improved patellofemoral stability, decreased pain, and increases subjective outcome scores. Discussion/Conclusion: In patients with patellofemoral problems caused by a combined increased tibial external torsion and increased femoral internal torsion, a double-level torsional osteotomy is able to correct torsional angles to normal. Available clinical data on this procedure are promising. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Economic water productivity, gross value added per volume of water use, is a widely used metric by international and national organizations to monitor the impacts of economic activity on water use. In fact, this metric is often used synonymously with water efficiency. Considering this, our study analyzes the adequacy of economic water productivity as a Key Performance Indicator (KPI) for monitoring if water use has become more efficient. Using 15-year panel data for the 27 European countries and carrying out a sensitivity analysis with seven Asian countries to extrapolate our results, we address our hypothesis that changes in economic water productivity are not driven by increases in physical water efficiency but mostly originate from different sources of economic growth. Our results show that the improvements in economic water productivity are not necessarily associated with improvements in water efficiency but with advances in capital intensity and, hence, in labor productivity. Accordingly, we encourage policy-makers to replace this indicator – which is based solely on an economic vision rather than ecological concerns – with indicators that report the actual pressure on the water resources (e.g., absolute water consumption or physical water-efficiency indicators) or those that at least include their driving factors in the analysis (e.g. capital intensity, labor productivity). This would allow decision makers designing policies that are more effective and genuinely ensure sustainable water management. Otherwise, economically biased political assessments likely will provide erroneous results, leading to policy recommendations causing undesired environmental impacts in the medium and long term.

Objectives: To investigate the change in severity of mitral regurgitation (MR) after transcatheter aortic valve replacement (TAVR) and its effect on 5-year mortality. Background: There is inconsistency in literature on pre-existing MR influencing long-term survival in patients who undergo TAVR. Methods: Patients who underwent TAVR at the University Hospital Schleswig-Holstein (USKH) Campus Kiel between March 2009 and February 2018 have been enrolled. Echocardiography determined the degree of MR before and within 7 days after TAVR. Patients were divided into two groups according to their MR at baseline: MR-grade ≤ 2 (non-relevant MR, nr-MR) and baseline MR-grade > 2 (relevant MR, r-MR). Primary endpoint was a composite of MR baseline influence on mortality and MR reduction and its’ impact on mortality. Results: A total of 820 patients (642 nr-MR and 178 in r-MR) were included in this study. Of these, 167 patients showed an improvement in MR-grade. Thereof 106 (63.5 %) referred to r-MR with a significant decrease in mean MR-grade (p

ObjectiveThe circadian clock aligns physiology with the 24-hour rotation of Earth. Light and food are the main environmental cues (zeitgebers) regulating circadian rhythms in mammals. Yet, little is known about the interaction between specific dietary components and light in coordinating circadian homeostasis. Herein, we focused on the role of essential amino acids.MethodsMice were fed diets depleted of specific essential amino acids and their behavioral rhythms were monitored and tryptophan was selected for downstream analyses. The role of tryptophan metabolism in modulating circadian homeostasis was studied using isotope tracing as well as transcriptomic- and metabolomic- analyses.ResultsDietary tryptophan depletion alters behavioral rhythms in mice. Furthermore, tryptophan metabolism was shown to be regulated in a time- and light- dependent manner. A multi-omics approach and combinatory diet/light interventions demonstrated that tryptophan metabolism modulates temporal regulation of metabolism and transcription programs by buffering photic cues. Specifically, tryptophan metabolites regulate central circadian functions of the suprachiasmatic nucleus and the core clock machinery in the liver.ConclusionsTryptophan metabolism is a modulator of circadian homeostasis by integrating environmental cues. Our findings propose tryptophan metabolism as a potential point for pharmacologic intervention to modulate phenotypes associated with disrupted circadian rhythms.