Pickering emulsions (PEs) are stabilized by particles at the water/oil interface and exhibit superior long-term stability compared to emulsions with molecular surfactants. Among colloidal stabilizers, nano/microgels facilitate emulsification and can introduce stimuli responsiveness. While increasing their hydrophobicity is connected to phase inversion from oil-in-water (O/W) to water-in-oil (W/O) emulsions, a predictive model to relate this phase inversion to the molecular structure of the nano/microgel network remains missing. Addressing this challenge, we developed a library of amphiphilic nanogels (ANGs) that enable adjusting their hydrophobicity while maintaining similar colloidal structures. This enabled us to systematically investigate the influence of network hydrophobicity on emulsion stabilization. We found that W/O emulsions are preferred with increasing ANG hydrophobicity, oil polarity, and oil/water ratio. For nonpolar oils, increasing emulsification temperature enabled the formation of W/O PEs that are metastable at room temperature. We connected this behavior to interfacial ANG adsorption kinetics and quantified ANG deformation and swelling in both phases via atomic force microscopy. Importantly, we developed a quantitative method to predict phase inversion by the difference in Flory–Huggins parameters between ANGs with water and oil (χwater – χoil). Overall, this study provides crucial structure–property relations to assist the design of nano/microgels for advanced PEs.

The generation of ligands that both are tailored to a given protein pocket and exhibit a range of desired chemical properties is a major challenge in structure-based drug design. Here, we propose an in silico approach for the de novo generation of 3D ligand structures using the equivariant diffusion model PILOT, combining pocket conditioning with a large-scale pre-training and property guidance. Its multi-objective trajectory-based importance sampling strategy is designed to direct the model towards molecules that not only exhibit desired characteristics such as increased binding affinity for a given protein pocket but also maintains high synthetic accessibility. This ensures the practicality of sampled molecules, thus maximizing their potential for the drug discovery pipeline. PILOT significantly outperforms existing methods across various metrics on the common benchmark dataset CrossDocked2020. Moreover, we employ PILOT to generate novel ligands for unseen protein pockets from the Kinodata-3D dataset, which encompasses a substantial portion of the human kinome. The generated structures exhibit predicted IC50 values indicative of potent biological activity, which highlights the potential of PILOT as a powerful tool for structure-based drug design.

PURPOSE/BACKGROUND

Lithium augmentation of antidepressants represents a common strategy to overcome treatment resistance in patients with major depressive disorder. The use of lithium has been associated with cardiovascular adverse effects such as QTc prolongation and tachyarrhythmia. Although the previous studies investigated monotherapy with lithium, the aim of this study was to investigate electrocardiographic changes in LA.

METHODS/PROCEDURES

A 12-lead surface electrocardiogram (ECG) was obtained from 38 patients with major depressive disorder before and during LA. Changes in heart rate, PQ, QRS and QTc interval, QT dispersion, ST segment, and T- and U-wave alterations were analyzed using a linear mixed model.

FINDINGS/RESULTS

The ECG readings of 33 patients were evaluated. Lithium augmentation was not significantly associated with changes in heart rate, QTc, PQ, or QRS interval. We found a significant decrease in QT dispersion. These results were independent of sex, age, stable comedication, and comorbidities. During LA, we observed 9 cases of T-wave alterations and 2 cases of new U waves.

CONCLUSIONS

Our data provide no evidence for serious ECG abnormalities at therapeutic serum lithium levels in patients treated with LA. In particular, we did not find evidence for QTc time lengthening or tachyarrhythmia, such as torsades des pointes. The recommended intervals for ECG checks should be considered to detect long-term effects of LA.

BACKGROUND

Lithium augmentation (LA) of antidepressants is an effective strategy for treatment-resistant depression (TRD). Nevertheless, it is rarely used in geriatric patients. The purpose of this study was to investigate treatment response of LA in geriatric compared to non-geriatric patients.

METHOD

In a prospective multicenter cohort study, severity of depression was measured weekly in 167 patients with unipolar depression (nage≥65years = 22; nage<65years = 145) at baseline and over at least four weeks of LA.

RESULTS

Geriatric patients showed a significantly better response to LA compared to non-geriatric patients (Hazard Ratio = 1.91; p = 0.04).

LIMITATIONS

An important limitation of our study is the lack of a control group of LA and the missing evaluation of side effects in both groups.

CONCLUSIONS

This is the first study investigating the efficacy of LA for TRD in geriatric compared to non-geriatric patients. Our data suggest that LA is an effective treatment option in geriatric patients that clinicians might consider more frequently and earlier on in the course of treatment.

This mini-review is dedicated to Carlo Corvaja (University of Padova) in recognition of his important contributions to the study of biomimetic donor–acceptor model dyads and triads and to the understanding of spin exchange in excited fullerene–nitroxide derivatives. We report on attractive examples of multi-frequency and multi-resonance EPR spectroscopy, highlighting recent work in Padova and Berlin/Mülheim. The examples selected include TR-EPR, ENDOR, and EDNMR experiments on photoexcited spin-labeled macromolecules, such as fullerene–nitroxide complexes or photosynthetic bacterial reaction centers, which were optionally NO spin-labeled. From the spin interaction parameters measured, detailed information about structure and dynamics of macromolecules embedded in liquid-solution or solid-state microenvironments could be extracted.

Der Esquire verkündet es Anfang Januar 1959 auf seiner Titelseite: »The Golden Age of Jazz«. Und meint damit das Hier und Jetzt: »Now is the time!« Was für eine Prophezeiung! Denn Alben wie Kind of Blue und Mingus Ah Um, The Shape of Jazz to Come und Time Out, Moanin' und Giant Steps, die in den Monaten danach erscheinen, bilden bis heute den Kern des Jazzkanons. Im Rückblick ein ›annus mirabilis‹. Nur liegt noch keine dieser Platten vor, als der Esquire herauskommt. Wie kann das sein? Frédéric Döhl rekonstruiert die Soundscape des Jazz jener Ära. Und vermittelt hierüber, wie wichtig es ist, dem eigenen Gehör zu folgen, um die Geschichte einer Musik zu erzählen – auch im Zeitalter von TDM, KI und ChatGPT.

Antimicrobial resistance mediated by extended-spectrum beta-lactamase (ESBL)- and plasmid-mediated cephalosporinase (AmpC)-producing Enterobacterales, as well as carbapenemase-producing Enterobacterales have globally increased among companion animals, posing a potential health risk to humans in contact with them. This prospective longitudinal study investigates the transfer of ESBL/AmpC- and carbapenemase-producing Enterobacterales between companion animals and their cohabitant humans in Portugal (PT) and the United Kingdom (UK) during animal infection. Fecal samples and nasal swabs collected from dogs and cats with urinary tract infection (UTI) or skin and soft tissue infection (SSTI), and their cohabitant humans were screened for resistant strains. Relatedness between animal and human strains was established by whole-genome sequencing (WGS). ESBL/AmpC-producing Enterobacterales were detected in companion animals (PT = 55.8%; UK = 36.4%) and humans (PT = 35.9%; UK = 12.5%). Carbapenemase-producing Enterobacterales carriage was observed in one dog from Portugal (2.6%) and another dog from the UK (4.5%). Transmission of index clinical ESBL-producing Escherichia coli and Klebsiella pneumoniae strains to cohabitant humans was observed in three Portuguese households (6.9%, n = 43), with repeated isolation of the index strains on fecal samples from the animals and their cohabiting humans. In addition, longitudinal sharing of E. coli strains carried by companion animals and their owners was observed in other two Portuguese households and two households from the UK. Furthermore, a multidrug-resistant ACT-24-producing Enterobacter hormaechei subsp. hoffmannii strains were also shared within another Portuguese household. These results highlight the importance of the household as an epidemiological unit in the efforts to mitigate the spread of antimicrobial resistance, further emphasizing the need for antimicrobial surveillance in this context, capable of producing data that can inform and evaluate public health actions.

Background: Marital status influences the presentation and outcome of various cancers. We explored the relationship between marital status and survival of uveal melanoma (UM) and factors influencing this relationship.

Methods: We conducted a retrospective cohort study on patients diagnosed with UM and registered in the Surveillance Epidemiology and End Results program between 1973 and 2017. Cox regression model was conducted to calculate the hazard ratio of overall and cancer-specific survival rate and delineate the effect of each confounder.

Results: The study involved 10,557 patients with a male-to-female ratio of 1:1.1. Most of the diagnosed patients were aged between 40 and 79 years (81%). Married patients (62%) represented the majority, followed by singles (12%), widowed (11%), and then divorced patients (7%). Single patients were the youngest group (mean age of 59.3 years) while widowed patients were the oldest (mean age of 75.8 years). In the Cox regression model for overall survival, married and single patients exhibited the best overall survival (no significant difference in between them), both surpassing divorced and widowed patients. Married patients were at a significantly lower risk to die from UM than divorced patients. Female patients and younger age groups showed the best overall and cancer-specific survival.

Conclusion: Maintained marriages improved the survival of UM patients. Widowed and divorced patients should be included in specially designed support programs during their cancer management.

Background/objectives: Sleeping behavior and individual prospensity in sleep timing during a 24 h period, known as chronotypes, are underestimated factors, which may favor the development of obesity and metabolic diseases. Furthermore, melatonin is known to play an important role in circadian rhythm, but was also suggested to directly influence metabolism and bodyweight regulation. Since disturbed and shifted sleep rhythms have been observed in adolescents with obesity, this study aimed to investigate potential interactions between melatonin secretion, chronobiology, and metabolism. In addition, the influence of artificial light especially emitted by electronic devices on these parameters was of further interest.

Subjects/methods: We performed a cross-sectional study including 149 adolescents (mean age 14.7 +/- 2.1 years) with obesity. Metabolic blood parameters (e.g., cholesterol, triglycerides, uric acid, and insulin) were obtained from patients and correlated with nocturnal melatonin secretion. Melatonin secretion was determined by measuring 6-sulfatoxymelatonin (MT6s), the major metabolite of melatonin in the first-morning urine, and normalized to urinary creatinine levels to account for the urinary concentration. Chronobiologic parameters were further assessed using the Munich ChronoType Questionnaire.

Results: Subjects with insulin resistance (n = 101) showed significantly lower nocturnal melatonin levels compared to those with unimpaired insulin secretion (p = 0.006). Furthermore, triglyceride (p = 0.012) and elevated uric acid levels (p = 0.029) showed significant associations with melatonin secretion. Patients with late chronotype showed a higher incidence of insulin resistance (p = 0.018). Moreover, late chronotype and social jetlag were associated with the time and duration of media consumption.

Conclusion: We identified an association of impaired energy metabolism and lower nocturnal melatonin secretion in addition to late chronotype and increased social jetlag (misalignment of biological and social clocks) in adolescents with obesity. This might point towards a crucial role of chronotype and melatonin secretion as risk factors for the development of pediatric and adolescent obesity.

Purpose: Careful assessment of the aortic root is paramount to select an appropriate prosthesis for transcatheter aortic valve implantation (TAVI). Relevant information about the aortic root anatomy, such as the aortic annulus diameter, can be extracted from pre-interventional CT. In this work, we investigate a neural network-based approach for segmenting the aortic root as a basis for obtaining these parameters.

Methods: To support valve prosthesis selection, geometric measures of the aortic root are extracted from the patient's CT scan using a cascade of convolutional neural networks (CNNs). First, the image is reduced to the aortic root, valve, and left ventricular outflow tract (LVOT); within that subimage, the aortic valve and ascending aorta are segmented; and finally, the region around the aortic annulus. From the segmented annulus region, we infer the annulus orientation using principal component analysis (PCA). The area-derived diameter of the annulus is approximated based on the segmentation of the aortic root and LVOT and the plane orientation resulting from the PCA.

Results: The cascade of CNNs was trained using 90 expert-annotated contrast-enhanced CT scans routinely acquired for TAVI planning. Segmentation of the aorta and valve within the region of interest achieved an F1 score of 0.94 on the test set of 36 patients. The area-derived diameter within the annulus region was determined with a mean error below 2 mm between the automatic measurement and the diameter derived from annotations. The calculated diameters and resulting errors are comparable to published results of alternative approaches.

Conclusions: The cascaded neural network approach enabled the assessment of the aortic root with a relatively small training set. The processing time amounts to 30 s per patient, facilitating time-efficient, reproducible measurements. An extended training data set, including different levels of calcification or special cases (e.g., pre-implanted valves), could further improve this method's applicability and robustness.

Background: Inflammation of the rectal remnant may affect the postoperative outcome of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). We aimed to determine the extent of inflammation in the anastomotic area during IPAA and to investigate the impact of proctitis on postoperative complications and long-term outcomes.

Methods: Three hundred thirty-four UC patients with primary IPAA were included in this retrospective case-control study. The histopathologic degree of inflammation in the anastomotic area was graded into three stages of no proctitis ("NOP"), mild to medium proctitis ("MIP"), and severe proctitis ("SEP"). Preoperative risk factors, 30-day morbidity, and follow-up data were assessed. Kaplan-Meier analysis was performed in the event of pouch failure.

Results: The prevalence of proctitis was high (MIP 40.4%, and SEP 42.8%). During follow-up, the incidence of complications was highest among SEP: resulting in re-intervention (n = 40; 28.2%, p = 0.017), pouchitis (n = 36; 25.2%, p < 0.01), and pouch failure (n = 32; 22.4%, p = 0.032). The time interval to pouch failure was 5.0 (4.0-6.9) years among NOP, and 1.2 (0.5-2.3) years in SEP (p = 0.036). ASA 3, pouchitis, and pouch fistula were independent risk factors for pouch failure.

Conclusion: Proctitis at the time of IPAA is common. A high degree of inflammation is associated with poor long-term outcomes, an effect that declines over time. In addition, a higher degree of proctitis leads to earlier pouch failure.

In bacteria, production of aberrant RNAs and transcription of foreign genes, including those on phages, are readily terminated by a hexameric ATPase, Rho. However, to make necessary transcripts, particularly during stress, bacteria depend on mechanisms to temper Rho activity. Similarly, phages have evolved diverse Rho-inhibitory mechanisms to enable the expression of their own genomes. In recent years, the structural bases of many such anti-termination mechanisms have been elucidated.

Terminal oxygen radicals involving p- and d-block atoms are quite common, but s-block compounds with an oxygen radical character remain rare. Here, we report that alkaline-earth metal beryllium atoms react with OF2 to form the oxygen beryllium fluorides OBeF and OBeF2. These species are characterized by matrix-isolation infrared spectroscopy with isotopic substitution and quantum-chemical calculations. The linear molecule OBeF has a 2Π ground state with an oxyl radical character. The 3A2 (C2v) ground state of OBeF2 represents the unusual case of a triplet oxygen atom stabilized by a relatively weak interaction by the Lewis acidic BeF2. The interaction involves both a donor component from oxygen to empty Be orbitals and a back-bonding contribution from fluorine substituents toward oxygen.

Rating scales are susceptible to response styles that undermine the scale quality. Optimizing a rating scale can tailor it to individuals’ cognitive abilities, thereby preventing the occurrence of response styles related to a suboptimal response format. However, the discrimination ability of individuals in a sample may vary, suggesting that different rating scales may be appropriate for different individuals. This study aims to examine (1) whether response styles can be avoided when individuals are allowed to choose a rating scale and (2) whether the psychometric properties of self-chosen rating scales improve compared to given rating scales. To address these objectives, data from the flourishing scale were used as an illustrative example. MTurk workers from Amazon’s Mechanical Turk platform (N = 7042) completed an eight-item flourishing scale twice: (1) using a randomly assigned four-, six-, or 11-point rating scale, and (2) using a self-chosen rating scale. Applying the restrictive mixed generalized partial credit model (rmGPCM) allowed examination of category use across the conditions. Correlations with external variables were calculated to assess the effects of the rating scales on criterion validity. The results revealed consistent use of self-chosen rating scales, with approximately equal proportions of the three response styles. Ordinary response behavior was observed in 55–58% of individuals, which was an increase of 12–15% compared to assigned rating scales. The self-chosen rating scales also exhibited superior psychometric properties. The implications of these findings are discussed.

In recent years, proximity labeling has established itself as an unbiased and powerful approach to map the interactome of specific proteins. While physiological expression of labeling enzymes is beneficial for the mapping of interactors, generation of the desired cell lines remains time-consuming and challenging. Using our established pipeline for rapid generation of C- and N-terminal CRISPR-Cas9 knock-ins (KIs) based on antibiotic selection, we were able to compare the performance of commonly used labeling enzymes when endogenously expressed. Endogenous tagging of the µ subunit of the AP-1 complex with TurboID allowed identification of known interactors and cargo proteins that simple overexpression of a labeling enzyme fusion protein could not reveal. We used the KI-strategy to compare the interactome of the different adaptor protein (AP) complexes and clathrin and were able to assemble lists of potential interactors and cargo proteins that are specific for each sorting pathway. Our approach greatly simplifies the execution of proximity labeling experiments for proteins in their native cellular environment and allows going from CRISPR transfection to mass spectrometry analysis and interactome data in just over a month.

The early Iron Age (800 to 450 BCE) in France, Germany and Switzerland, known as the ‘West-Hallstattkreis’, stands out as featuring the earliest evidence for supra-regional organization north of the Alps. Often referred to as ‘early Celtic’, suggesting tentative connections to later cultural phenomena, its societal and population structure remain enigmatic. Here we present genomic and isotope data from 31 individuals from this context in southern Germany, dating between 616 and 200 BCE. We identify multiple biologically related groups spanning three elite burials as far as 100 km apart, supported by trans-regional individual mobility inferred from isotope data. These include a close biological relationship between two of the richest burial mounds of the Hallstatt culture. Bayesian modelling points to an avuncular relationship between the two individuals, which may suggest a practice of matrilineal dynastic succession in early Celtic elites. We show that their ancestry is shared on a broad geographic scale from Iberia throughout Central-Eastern Europe, undergoing a decline after the late Iron Age (450 BCE to ~50 CE).

The study of many-body quantum dynamics in strongly correlated systems is extremely challenging. To date, few numerical methods exist that are capable of simulating the non-equilibrium dynamics of two-dimensional quantum systems, which is partly due to complexity theoretic obstructions. In this work, we present a technique able to overcome this obstacle, by combining continuous unitary flow techniques with the newly developed method of scrambling transforms. We overcome the assumption that approximately diagonalizing the Hamiltonian cannot lead to reliable predictions for relatively long times. Rather, we show that the method achieves good accuracy in both localized and delocalized phases and makes reliable predictions for a number of quantities including infinite-temperature autocorrelation functions. We complement our findings with rigorous incremental bounds on the truncation error. Our approach shows that, in practice, the exploration of intermediate-scale time evolution may be more feasible than is commonly assumed, challenging near-term quantum simulators.

The novel potassium sulfido cobaltate, K2[Co3S4] is introduced, with 25% vacancies of the cobalt positions within a layered anionic sublattice. The impedance and dielectric investigations indicate a remarkable ionic conductivity of 21.4 mS cm−1 at room temperature, which is in the range of highest ever reported values for potassium-ions, as well as a high electrical permittivity of 2650 at 1 kHz, respectively. Magnetometry results indicate an antiferromagnetic structure with giant intrinsic exchange bias fields of 0.432 and 0.161 T at 3 and 20 K respectively, potentially induced by a combination of the interfacial effect of combined magnetic anionic and nonmagnetic cationic sublattices, as well as partial spin canting. The stability of the exchange bias behavior is confirmed by a training effect of less than 18% upon 10 hysteresis cycles. The semiconductivity of the material is determined, both experimentally and theoretically, with a bandgap energy of 1.68 eV. The findings render this material as a promising candidate for both, active electrode material in potassium-ion batteries, and for spintronic applications.