Recent publications
The yeast Komagataella phaffii (syn. Pichia pastoris) is a highly effective and well‐established host for the production of recombinant proteins. The redox balance of its secretory pathway, which is multi‐organelle dependent, is of high importance for producing secretory proteins. Redox imbalance and oxidative stress can significantly influence protein folding and secretion. Glutathione serves as the main redox buffer of the cell and cellular redox conditions can be assessed through the status of the glutathione redox couple (GSH‐GSSG). Previous research often focused on the redox potential of the endoplasmic reticulum (ER), where oxidative protein folding and disulphide bond formation occur. In this study, in vivo measurements of the glutathione redox potential were extended to different subcellular compartments by targeting genetically encoded redox sensitive fluorescent proteins (roGFPs) to the cytosol, ER, mitochondria and peroxisomes. Using these biosensors, the impact of oxygen availability on the redox potentials of the different organelles was investigated in non‐producing and producing K. phaffii strains in glucose‐limited chemostat cultures. It was found that the transition from normoxic to hypoxic conditions affected the redox potential of all investigated organelles, while the exposure to hyperoxic conditions did not impact them. Also, as reported previously, hypoxic conditions led to increased recombinant protein secretion. Finally, transcriptome and proteome analyses provided novel insights into the short‐term response of the cells from normoxic to hypoxic conditions.
Objective
This study was undertaken to evaluate retention and treatment characteristics of cenobamate (CNB) in patients with developmental and epileptic encephalopathies (DEEs) in clinical practice.
Methods
This multicenter, retrospective cohort study recruited all patients with DEEs who started CNB treatment between October 2020 and April 2023 at participating epilepsy centers.
Results
A total of 41 patients (mean age = 28.3 ± 13.1 years, median = 26 years, range = 4–73 years; 24 male [58.5%]) were treated with CNB. Of these, 33 had Lennox–Gastaut syndrome, seven had tuberous sclerosis complex, and one had Dravet syndrome. The median number of antiseizure medications (ASMs) at enrollment was three, and patients had a median of eight failed ASMs in the past. The retention rate for CNB was 94.9% at 3 months, 82.9% at 6 months, and 72.4% at 12 months of follow‐up. Cumulative exposure to CNB was 477 months (39.2 years). Efficacy (50% responder rate) at 3 months was 39% including 7.3% seizure‐free patients. Long‐term, the 50% responder rate at 12 months was 34.5% (seizure‐free [10.3%]). There was no difference in response at 3 months regarding sex, age (adult vs. children), previous and concomitant number of ASMs, or first target dose of CNB. Treatment‐emergent adverse events were predominantly sedation and dizziness and were observed in 58.5% of patients. Children and adolescents showed comparable efficacy, retention, and tolerability compared to adults.
Significance
The findings from this open‐label, retrospective study suggest that CNB may be effective in some patients with DEEs. Its overall use in DEEs seems to be safe and well tolerated. We observed similar response, retention, and adverse event profiles in children and adults.
Introduction
Interpersonal problems are a transdiagnostic risk factor for the development and maintenance of various psychiatric disorders, including anxiety and depression. Interventions that address these interpersonal challenges could therefore play a crucial role in enhancing mental health. This study aims to evaluate the efficacy and feasibility of a transdiagnostic group intervention, the Kiesler Circle Training (KCT), in improving interpersonal skills.
Methods and analysis
In a prospective randomised controlled trial (RCT), 156 outpatients with a primary diagnosis of either depression or anxiety disorder according to DSM-5, and significant interpersonal problems, will be investigated. All patients will receive individual, state-of-the-art cognitive behavioural therapy (CBT) during the study. They will be randomly assigned to one of two conditions: the experimental group will receive the KCT in group sessions, in addition to individual CBT, while the control group will receive only individual CBT. The KCT intervention consists of 1 introductory individual session and 12 weekly group sessions, each lasting 100 min, with groups of up to 10 patients. KCT includes five sequential modules: the interpersonal circle, nonverbal communication, verbal communication, conflict resolution and empathy training. It is hypothesised that the experimental group will show (a) greater reduction in interpersonal problems from pre-assessment to post-assessment and (b) greater symptomatic improvement regarding the primary diagnosis. Child maltreatment is expected to moderate the trajectory of interpersonal problems. This study aims to provide evidence for the feasibility of KCT as a modular transdiagnostic add-on approach for patients with interpersonal difficulties.
Ethics and dissemination
This study obtained approval from the ethics committees at the Charité Berlin, the Medical School of Berlin and the University of Greifswald. All results will be disseminated through peer-reviewed articles in scientific journals and contributions to national and international conferences.
Trial registration number
DRKS00032467, NCT06170801 (see Supplementary Material).
We consider a compact manifold with a foliation , and a smooth affine connection on the tangent bundle of the foliation . We introduce and study a foliated completeness problem. Namely, under which conditions on the leaves are complete? We consider different natural geometric settings: the first one is the case of a totally geodesic lightlike foliation of a compact Lorentzian manifold, and the second one is the case where the leaves have particular affine structures. In the first case, we characterize the completeness, and obtain in particular that if a compact Lorentzian manifold admits a null Killing field V such that the distribution orthogonal to V is integrable, then it defines a (totally geodesic) foliation with complete leaves. In the second case, we give a completeness result for a specific affine structure called “the unimodular affine lightlike geometry”, and characterize the completeness for a natural relaxation of the geometry. On the other hand, we study the global completeness of a compact Lorentzian manifold in the presence of a null Killing field. We give two non-complete examples, starting from dimension 3: one is a locally homogeneous manifold, and the other is a 3D example where the Killing field dynamics is equicontinuous.
Background
Early stroke complications (ESCs) impair recovery and provide an important therapeutic target. Our multicenter prospective cohort study examined the prevalence and amount of poor outcomes attributable to ESCs.
Methods and Results
In patients with stroke, 16 ESCs were monitored by clinical assessment (“basic definition”) and by inclusion of laboratory values and clinical scales (“extended definition”). The association of complications with poor outcome (death or functional impairment: modified Rankin Scale score >3 or Barthel Index <60) at 3 months was analyzed using multiple logistic regression adjusted for stroke severity, age, and sex. Complications were stratified by their early treatment options, and average sequential population‐attributable fractions were estimated for treatable early complications. Of 1202 patients, outcome data were available for 1105 (91.9%; 43.0% women; mean age 68.3 years; baseline median National Institutes of Health Stroke Scale score on admission 3 points). Poor outcome was recorded for 100 patients (9.0%). By basic definition, recurrent stroke, fever, pneumonia, depression, urinary tract infection, and delirium were significantly associated with poor outcomes. The occurrence of 1 or more of these ESCs was associated with up to 19.6% of poor outcomes. By extended definition, urinary tract infection, depression, and delirium were significantly associated with poor outcomes. The occurrence of 1 or more of these ESCs was associated with up to 15.9% of poor outcomes.
Conclusions
In our cohort of patients with mild to moderate stroke, we identified a set of treatable ESCs with clinically relevant impact on outcome that may be targeted in future interventional trials.
Registration
URL: https://www.bfarm.de ; Unique identifier: DRKS00004712.
In dual tasks, with a visual-manual choice reaction time task in Task 1 and a go/no-go task in Task 2, not responding to Task 2 can have adverse effects on Task 1 performance, as demonstrated by no-go backward crosstalk effects (no-go BCE). Here, the response inhibition required to not respond to Task 2 spills over and slows response execution in Task 1. Over three experiments, we investigated whether the prospect of reward, which is a potent cognitive control modulator, influences no-go BCE. In Experiment 1, reward for fast and accurate responses in both tasks was modulated as a within-subject factor, and in Experiments 2 and 3, as a between-subject factor. The results revealed three major insights. In all three experiments, reward led to faster Task 1 and Task 2 performance. Secondly, despite this speeding, the no-go BCE was not modulated by reward. Finally, the reward led to more errors in Task 2 no-go trials. These results reveal a reward-induced bias for action, suggesting better preparedness to respond and, consequently, larger commission errors in Task 2 no-go trials. The absence of a reward-based modulation of the no-go BCE indicates that the reward-induced bias for action does not necessarily translate into larger response inhibition. These findings point towards the complex interactions between reward and inhibitory control and shed light on the potentials and limitations of reward-based modulation of dual-task interference.
Fine roots play a crucial role in many ecological and biogeochemical processes in temperate forests. Generally, fine root biomass is expected to increase during the growing season, when water and nutrient demands are high, but information on seasonal variability is still scarce. Here, seasonal differences in root length of European beech (Fagus sylvatica L.) were analysed at eight sites within its north-eastern distribution range. Fine roots of mature trees were monitored using minirhizotrons. Scans were taken for three different depths at the beginning of winter, the end of winter and over the summer for two consecutive years, and analysed automatically by an AI-algorithm (RootDetector). An additional experiment was carried out to show that the RootDetector was unaffected by changes in soil moisture. Root-length density was 40% higher at the beginning of winter and 51% higher at the end of winter than in summer. Our results indicate a net root loss during adverse conditions in early summer, but no trend towards deeper root growth over these drier periods. Interestingly, the root loss was compensated afterwards during more favourable conditions in autumn. We could show that fine root length in temperate forests is seasonally more variable and, so far, less predictable than previously assumed. A profound understanding of this seasonal variability is important for modelling terrestrial biogeochemical processes and global carbon fluxes.
Polyurethane (PUR), the fifth most prevalent synthetic polymer, substantially contributes to the global plastic waste problem. Biotechnology‐based recycling methods have recently emerged as innovative solutions to plastic waste disposal and sparked interest among scientific communities and industrial stakeholders in discovering and designing highly active plastic‐degrading enzymes. Here, the ligand‐free crystal structure of UMG‐SP2, a metagenome‐derived urethanase with depolymerization activities, at 2.59 Å resolution, as well as its (co‐)structures bound to a suicide hydrolase inhibitor and a short‐chain carbamate substrate at 2.16 and 2.40 Å resolutions, respectively, is reported. Structural analysis and molecular dynamics simulations reveal that the flexible loop L3 consisting of residues 219–226 is crucial for regulating the hydrolytic activity of UMG‐SP2. The semi‐rational redesign of UMG‐SP2 reveals superior variants, A141G and Q399A, exhibiting over 30.7‐ and 7.4‐fold increased activities on polyester‐PUR and a methylene diamine derivative of PUR, respectively, compared to the wild‐type enzyme. These findings advance the understanding of the structure–function relationship of PUR‐hydrolyzing enzymes, which hold great promise for developing effective industrial PUR recycling processes and mitigating the environmental footprint of plastic waste.
Targeting the RNA genome of SARS‐CoV‐2 is a viable option for antiviral drug development. We explored three ligand binding sites of the core pseudoknot RNA of the SARS‐CoV‐2 frameshift element. We iteratively optimized ligands, based on improved affinities, targeting these binding sites and report on structural and dynamic properties of the three identified binding sites. Available experimental 3D structures of the pseudoknot element were compared to SAXS and NMR data to validate its dominant folding state in solution. In order to experimentally map in silico predicted binding sites, NMR assignments of the majority of nucleobases were achieved by segmental labeling of the pseudoknot RNA and isotope‐filtered NMR experiments at 1.2 GHz, demonstrating the value of NMR spectroscopy to supplement modelling and docking data. Optimized ligands with enhanced affinity were shown to specifically inhibit frameshifting without affecting 0‐frame translation in cell‐free translation assays, establishing the frameshift element as target for drug‐like ligands of low molecular weight.
Introduction
The rate of D‐alloimmunization amongst RhD‐negative recipients of RhD‐positive red blood cell (RBC) transfusions is not certain. Recipients with a short duration between the index RhD‐positive transfusion and the last antibody detection test that did not show anti‐D might become D‐alloimmunized in the future. A regression model was developed to predict how often such patients might develop D‐alloimmunization in the future to help account for the immunohematological uncertainty that accompanies having short serological follow up periods.
Methods
Using the published literature on recipients who were intentionally transfused with RhD‐positive RBCs and serially followed with antibody screens, as well as unpublished datasets, a regression model was constructed to demonstrate the timing of D‐alloimmunization for recipients who became D‐alloimmunized within 6 months following the index transfusion. The model was then applied to a series of RhD‐negative hospitalized recipients of at least one unit of RhD‐positive RBCs who did not become D‐alloimmunized but who had fewer than 6 months of serological follow up to weight their contribution to the D‐alloimmunization rate.
Results
Overall, the rate of D‐alloimmunization was 21/105 (20.0%). There were 39 patients whose last documented antibody screen was performed between 14 days and 6 months after the index RhD‐positive transfusion, and these patients were entered into the weighted model. After applying the model, the D‐alloimmunization rate rose to 26.3%.
Conclusion
Using a weighted model can help reduce the immunohematological uncertainty that accompanies the inclusion of patients with relatively short serological follow up in studies of RBC alloimmunization.
Background
Continuum beliefs of mental health and illness are robustly negatively correlated with mental illness stigma. However, there is a lack of multidimensional and validated measures, not entirely relying on vignettes.
Methods
To develop such a scale, a pool of 37 items adapted from other studies on continuum beliefs, was initially examined in expert discussions and a convenience sample (N = 227, Mage=32 years, 80.6% female). Items were selected based on theoretical tenability and assigned to pre-defined facets of “State”, “Person”, and nosological “Concept” in relation to mental illness. In a second sample (N = 1375; Mage=42 years; 65.2% female), the Continuum Beliefs of Mental Illness Scale (CB-MIS) was psychometrically tested (i.e. factorial, convergent, discriminant validity).
Results
The scale comprises three subscales with three items, and one optional vignette-based item each, rated on a 5-point Likert scale. It showed very good factorial and discriminant validity, associations with stigma were moderately negative. The scale exhibited good test-retest reliability over a period of six months.
Conclusions
A validated, practical, multifaceted measure is offered to evaluate beliefs regarding the continuum of mental health and illness. Future studies should conduct subgroup-specific investigations regarding sociodemographic and illness variables, and could apply this measure to anti-stigma interventions.
Trial registration
German Clinical Trials Register: DRKS00023557. Registered 11/12/2020. World Health Organization, Universal Trial Number: U1111–1264–9954. Registered 16/02/2021.
The prediction of survival rate probability for hip implants, based on clinical data acquired before and after surgery, incorporating patient-specific parameters, represents a pivotal advancement in enabling more precise risk assessment for potential complications, such as aseptic loosening and implant wear-related inflammation, on an individualized basis. This critical step marks a substantial progression toward the realization of digitized and personalized medicine. The objective of this study was to establish prediction aiding correlations between implant wear and migration data, derived from X-ray imaging of 149 patients diagnosed with hip arthritis, and the performance of hip implants. The patients underwent cementless hip replacement surgery, receiving implants consisting of ultra-high-molecular-weight polyethylene (UHMWPE) paired with titanium-aluminum-vanadium (Ti6Al4V) wedges. Over the course of a median follow-up period of 4 years, X-ray assessments were conducted to monitor the migration of the femoral head and acetabular components using Ein Bild Röntgen Analyse (EBRA). Clinical findings revealed a linear relationship between average migration and wear. Notably, it was observed that increased cup migration corresponded proportionally to greater wear values. Furthermore, in-depth analysis revealed significant distinctions based on gender and age. Specifically, the established relationship can confidently serve as a reliable predictive model for the behavior of hip implants in female subjects and individuals aged 50–60 years.
Background: Hyperthermic intrathoracic chemotherapy (HITOC) is an additive treatment option after surgical cytoreduction of pleural malignancies. Despite growing clinical experience and studies evaluating its feasibility, postoperative morbidity and mortality, as well as the effect on survival, there is still only little known about the local effects of HITOC on the lung parenchyma and tumour cells. The objective of this in vitro study was to evaluate the dose-dependent concentration and penetration depth of cisplatin in human lung tissue. Methods: In total, 40 patients were enrolled for elective lung resection, and wedge samples were taken to the laboratory. The visceral pleura was removed, and the decorticated lung tissue was incubated in cisplatin solutions of different concentrations (0.05, 0.075, and 0.1 mg/mL) at 42 °C over 60 min. Afterwards, platinum amounts in the lung tissue samples were measured using atomic absorption spectroscopy. Results: A strong decline of the cisplatin concentration was found until a depth of 3.5 mm, followed by a mild decline until a depth of 7.5 mm. In a depth of 0.5 mm, there was only a significant difference between 0.05 and 0.1 mg/mL (p = 0.03, Cohen’s d = 0.43). In a depth of 1.5 mm, there was an overall significant difference in cisplatin concentration dependent on dose (p = 0.027). In deeper tissue layers, no significant difference in cisplatin concentrations in the tissue was found. Conclusions: A dose-dependent increase of the cisplatin concentration was found for superficial tissue layers. This emphasises the relevance of sufficiently high intrathoracic concentrations of the chemotherapeutic agent. This study confirms that cisplatin penetrates lung tissue in therapeutically effective concentrations.
Objective
To investigate the effect of choosing the taste of a fluoride varnish on the behavior and acceptance of the children during the dental visit.
Material and Methods
This single‐blinded, randomized controlled trial (NCT05285228) involved 70 healthy children aged 5–10 years who presented for a dental recall visit including the indication of an application of fluoride varnish to the specialized pediatric university dental service. The control group received the fluoride varnish (Profluorid varnish, VOCO Germany) with an allocated taste, whereas the test group had to choose the taste of the fluoride varnish just before the dental check‐up.
Results
The vast majority of the children (n = 53, 75.7%) felt happy/very happy (Facial image scale) regarding the taste of the fluoride varnish, with no significant difference between both groups (p = 0.188). Dental behavior (Frankl behavior rating scale) was assessed generally as positive/definitely positive (n = 58, 82.2%). Interestingly, children with a history of previous negative dental behavior in the test group showed a tendency of more positive behavior than in the control group (66.6% vs. 33.4%, p = 0.244).
Conclusion
Sense of control performed via choosing the flavor of the fluoride varnish increases the chance for positive behavior during the dental visit, especially in children with a history of negative dental behavior. Concurrently, it improves the child's taste acceptance, which is important for dental caries prevention.
Trial Registration
The study protocol was registered on Cli ClinicalTrials.gov (NCT05285228).
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Information
Address
Greifswald, Germany
Head of institution
Prof. Hannelore Weber