DNA microbeads for spatio-temporally controlled morphogen release within organoids.

Organoids are transformative in vitro model systems that mimic features of the corresponding tissue in vivo. However, across tissue types and species, organoids still often fail to reach full maturity and function because biochemical cues cannot be provided from within the organoid to guide their development. Here we introduce nanoengineered DNA microbeads with tissue mimetic tunable stiffness for implementing spatio-temporally controlled morphogen gradients inside of organoids at any point in their development. Using medaka retinal organoids and early embryos, we show that DNA microbeads can be integrated into embryos and organoids by microinjection and erased in a non-invasive manner with light. Coupling a recombinant surrogate Wnt to the DNA microbeads, we demonstrate the spatio-temporally controlled morphogen release from the microinjection site, which leads to morphogen gradients resulting in the formation of retinal pigmented epithelium while maintaining neuroretinal cell types. Thus, we bioengineered retinal organoids to more closely mirror the cell type diversity of in vivo retinae. Owing to the facile, one-pot fabrication process, the DNA microbead technology can be adapted to other organoid systems for improved tissue mimicry.

Alignment and actuation of liquid crystals via 3D confinement and two-photon laser printing.

Liquid crystalline (LC) materials are especially suited for the preparation of active three-dimensional (3D) and 4D microstructures using two-photon laser printing. To achieve the desired actuation, the alignment of the LCs has to be controlled during the printing process. In most cases studied before, the alignment relied on surface modifications and complex alignment patterns and concomitant actuation were not possible. Here, we introduce a strategy for spatially aligning LC domains in three-dimensional space by using 3D-printed polydimethylsiloxane-based microscaffolds as confinement barriers, which induce the desired director field. The director field resulting from the boundary conditions is calculated with Landau de Gennes theory and validated by comparing experimentally measured and theoretically predicted birefringence patterns. We demonstrate our procedures for structures of varying complexity and then employed them to fabricate 4D microstructures that show the desired actuation. Overall, we obtain excellent agreement between theory and experiment. This opens the door for rational design of functional materials for 4D (micro)printing in the future.

Tailor-made polymer tracers reveal the role of clay minerals on colloidal transport in carbonate media.

HYPOTHESIS: Host rock weathering and incipient pedogenesis result in the exposition of minerals, e.g., clay minerals in sedimentary limestones. Once exposed, these minerals provide the surfaces for fluid-solid interactions that control the fate of dissolved or suspended compounds such as organic matter and colloids. However, the functional and compositional diversity of organic matter and colloids limits the assessment of reactivity and availability of clay mineral interfaces. Such assessment demands a mobile compound with strong affinity to clay surfaces that is alien to the subsurface. EXPERIMENT: We approached this challenge by using poly(ethylene glycol) (PEG) as interfacial tracer in limestone weathering experiments. FINDINGS: PEG adsorption and transport was dependent on the availability of clay mineral surfaces and carbonate dissolution dynamics. In addition, PEG adsorption featured adsorption-desorption hysteresis which retained PEG mass on clay mineral surfaces. This resulted in different PEG transport for experiments conducted consecutively in the same porous medium. As such, PEG transport was reconstructed with a continuum-scale model parametrized by a Langmuir-type isotherm including hysteresis. Thus, we quantified the influence of exposed clay mineral surfaces on the transport of organic colloids in carbonate media. This renders PEG a suitable model colloid tracer for the assessment of clay surface exposition in porous media.

[Patient and quality characteristics in the treatment with disulfiram (Antabus) in the German "Network for Alcohol Aversive Pharmacotherapy"]. / Patienten- und Qualitätsmerkmale bei der Behandlung mit Disulfiram ("Antabus") im deutschsprachigen "Netzwerk alkoholaversive Pharmakotherapie".

BACKGROUND: More than a decade ago disulfiram lost its approval for use in Germany. Nonetheless, a considerable number of psychiatric hospital outpatient departments as well as practicing physicians continue to prescribe it. These professionals have formed the "Network for Alcohol Aversive Pharmacotherapy" (NAP) to maintain a high quality of this treatment approach. OBJECTIVE: To describe the current use of disulfiram with respect to patient numbers and characteristics, side effects, and use of concomitant multimodal treatment forms. MATERIAL AND METHODS: Since 2019 the NAP has conducted an annual retrospective survey among its members regarding the aforementioned parameters. RESULTS: From 2019 to 2023 a total of 1579 treatment cases were described by 33 centers, 152 patients reported a total of 241 drinking events, 26 of them resulting in hospitalization but none causing complications or permanent harm. The most frequent side effects, in descending order, were unpleasant body odor (2.5%), fatigue, male sexual dysfunction, mildly elevated liver enzymes, allergic skin reactions and polyneuropathy (0.8%). More than one quarter of the patients suffered from comorbid depression, and approximately 5% from ADHD, borderline or other personality disorders, trauma-related disorders and anxiety disorders, respectively. Of the patients 33% were treated with antidepressants and 12% with sedating antipsychotics. Various forms of concomitant group therapy were offered to 66% of the patients. CONCLUSION: Treatment with disulfiram is legally possible, generally well-tolerated and safe. It is offered in most treatment centers as part of a comprehensive treatment plan that includes multimodal treatment of comorbid psychiatric disorders.

Surface functionalized cryogels - characterization methods, recent progress in preparation and application.

Cryogels are polymeric materials with a sponge-like microstructure and have attracted significant attention in recent decades. Research has focused on their composition, fabrication techniques, characterization methods as well as potential or existing fields of applications. The use of functional precursors or functionalizing ligands enables the preparation of cryogels with desired properties such as biocompatibility or responsivity. They can also exhibit adsorptive properties or can be used for catalytical purposes. Although a very brief overview about several functional (macro-)monomers and functionalizing ligands has been provided by previous reviewers for certain cryogel applications, so far there has been no particular focus on the evaluation of the functionalization success and the characterization methods used. This review will provide a comprehensive overview of different characterization methods most recently used for the evaluation of cryogel functionalization. Furthermore, new functional (macro-)monomers and subsequent cryogel functionalization strategies are discussed, based on synthetic polymers, biopolymers and a combination of both. This review highlights the importance of the functionalization aspect in cryogel research in order to produce materials with tailored properties for certain applications.

A geometrical theory of gliding motility based on cell shape and surface flow.

Gliding motility proceeds with little changes in cell shape and often results from actively driven surface flows of adhesins binding to the extracellular environment. It allows for fast movement over surfaces or through tissue, especially for the eukaryotic parasites from the phylum apicomplexa, which includes the causative agents of the widespread diseases malaria and toxoplasmosis. We have developed a fully three-dimensional active particle theory which connects the self-organized, actively driven surface flow over a fixed cell shape to the resulting global motility patterns. Our analytical solutions and numerical simulations show that straight motion without rotation is unstable for simple shapes and that straight cell shapes tend to lead to pure rotations. This suggests that the curved shapes of Plasmodium sporozoites and Toxoplasma tachyzoites are evolutionary adaptations to avoid rotations without translation. Gliding motility is also used by certain myxo- or flavobacteria, which predominantly move on flat external surfaces and with higher control of cell surface flow through internal tracks. We extend our theory for these cases. We again find a competition between rotation and translation and predict the effect of internal track geometry on overall forward speed. While specific mechanisms might vary across species, in general, our geometrical theory predicts and explains the rotational, circular, and helical trajectories which are commonly observed for microgliders. Our theory could also be used to design synthetic microgliders.

High altitudes and partial pressure of arterial oxygen in patients with chronic obstructive pulmonary disease - A systematic review and meta-analysis.

IMPORTANCE: Prior study in healthy subjects has shown a reduction of partial pressure of arterial oxygen (PaO2) by -1.60 kPa/kilometre of altitude gain. However, the association of altitude-related change in PaO2 and altitude-related adverse health effects (ARAHE) in patients with chronic obstructive pulmonary disease (COPD) remain unknown. OBJECTIVE: To provide an effect size estimate for the decline in PaO2 with each kilometre of altitude gain and to identify ARAHE in relation to altitude in patients with COPD. www.crd.york.ac.uk/prospero: CRD42020217938. DATA SOURCES: A systematic search of PubMed and Embase was performed from inception to May 30, 2023. STUDY SELECTION: Peer-reviewed and prospective studies in patients with COPD staying at altitudes >1500 m providing arterial blood gases within the first 3 days at the target altitude. DATA EXTRACTION AND SYNTHESIS: Aggregate data (AD) on study characteristics were extracted, and individual patient data (IPD) were requested. Estimates were pooled using random-effects meta-analysis. MAIN OUTCOME AND MEASURES: Relative risk estimates and 95 % confidence intervals for the association between PaO2 and altitude in patients with COPD. RESULTS: Thirteen studies were included in the AD analysis, of which 6 studies (222 patients, 45.2 % female) provided IPD, thus were included in the quantitative analysis. The estimated effect size of PaO2 was -0.84 kPa [95 %CI, -0.92 to -0.76] per 1000 m of altitude gain (I2=65.0 %, P < 0.001). In multivariable regression analysis, COPD severity, baseline PaO2, age and time spent at altitude were predictors for PaO2 at altitude. Overall, 37.8 % of COPD patients experienced an ARAHE, whereas older age, female sex, COPD severity, baseline PaO2, and target altitude were predictors for the occurrence of ARAHE (area under ROC curve: 0.9275, P < 0.001). CONCLUSIONS AND RELEVANCE: This meta-analysis, providing altitude-related decrease in PaO2 and risk of ARAHE in patients with COPD ascending to altitudes >1500 m, revealed a lower altitude-related decrease in PaO2 in COPD patients compared with healthy. However, these findings might improve patient care and facilitate decisions about initiating preventive measures against hypoxaemia and ARAHE in patients with COPD planning an altitude sojourn or intercontinental flight, i.e. supplemental oxygen or acetazolamide.

Amino-Acid-Derived Anionic Polyacrylamides with Tailored Hydrophobicity-Physicochemical Properties and Cellular Interactions.

Polyanions can internalize into cells via endocytosis without any cell disruption and are therefore interesting materials for biomedical applications. In this study, amino-acid-derived polyanions with different alkyl side-chains are synthesized via postpolymerization modification of poly(pentafluorophenyl acrylate), which is synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization, to obtain polyanions with tailored hydrophobicity and alkyl branching. The success of the reaction is verified by size-exclusion chromatography, NMR spectroscopy, and infrared spectroscopy. The hydrophobicity, surface charge, and pH dependence are investigated in detail by titrations, high-performance liquid chromatography, and partition coefficient measurements. Remarkably, the determined pK a-values for all synthesized polyanions are very similar to those of poly(acrylic acid) (pK a = 4.5), despite detectable differences in hydrophobicity. Interactions between amino-acid-derived polyanions with L929 fibroblasts reveal very slow cell association as well as accumulation of polymers in the cell membrane. Notably, the more hydrophobic amino-acid-derived polyanions show higher cell association. Our results emphasize the importance of macromolecular engineering toward ideal charge and hydrophobicity for polymer association with cell membranes and internalization. This study further highlights the potential of amino-acid-derived polymers and the diversity they provide for tailoring properties toward drug delivery applications.

[Family-focused treatment approaches for drug-addicted parents]. / Familienzentrierte Behandlungsansätze für drogenabhängige Eltern.

BACKGROUND: In Germany 1.5-2.75 million children live in families affected by substance use disorders. Substance abuse can impact on family interactions in many ways. If a dependent parental drug use continues over a longer period of time, this can have pronounced psychological and social consequences for the (co)affected children. Nevertheless, family-focused treatment approaches are not yet widely used in the context of addiction treatment. AIM: This review article aims to provide an overview of the prevalence of parenthood among dependent drug users in Germany, the impact of dependent drug use on families and family-focused treatment approaches. METHODS AND RESULTS: Recording parenthood is particularly difficult in the case of dependent drug users as they often do not openly discuss it with their therapists because of the fear of consequences from youth welfare services. In order to change this, a structured recording of parenthood by the treatment providers is required. This is the prerequisite for being able to offer family-focused treatment to those affected. In Germany, three evidence-based therapy programs are available for this purpose: SHIFT, SHIFT Plus and MAMADAM. Additionally, a number of programs developed in the Anglo-American region can also be used. In contrast, the evidence for web-based programs is much weaker. DISCUSSION: In order to establish family-focused treatment approaches for drug-using parents across the board, long-term, secure funding is required. The necessary framework conditions must be created at a political level.

Advancements and Challenges in the Synthesis of Oxymethylene Ethers (OMEs) as Sustainable Transportation Fuels.

The urgent need for sustainable alternatives to fossil fuels in the transportation sector is driving research into novel energy carriers that can meet the high energy density requirements of heavy-duty vehicles without exacerbating the climate change. This concept article examines the synthesis, mechanisms, and challenges associated with oxymethylene ethers (OMEs), a promising class of synthetic fuels potentially derived from carbon dioxide and hydrogen. We highlight the importance of OMEs in the transition towards non-fossil energy sources due to their compatibility with the existing Diesel infrastructure and their cleaner combustion profile. The synthesis mechanisms, including the Schulz-Flory distribution and its implications for OME chain length specificity, and the role of various catalysts and starting materials are discussed in depth. Despite advancements in the field, significant challenges remain, such as overcoming the Schulz-Flory distribution, efficiently managing water as an undesirable byproduct, and improving the overall energy efficiency of the OME synthesis. Addressing these challenges is crucial for OMEs to become a viable alternative fuel, contributing to the reduction of greenhouse gas emissions and the transition to a sustainable energy future in the transportation sector.

Investigation of the cooperative-effects of Lewis- and Brønstedt acids in homogeneously catalyzed OME fuel synthesis by inline-NMR monitoring.

Via inline-nuclear magnetic resonance measurements, the homogeneously catalyzed poly(oxymethylene dimethyl ether) fuel synthesis using trioxane and dimethoxy methane is investigated. Besides the Brønsted acid (BA) catalyst triflic acid (TfOH) different metal halides are studied as Lewis-acidic (LA) catalysts. Among the used LAs, MgCl2, the weakest based on electronegativity, reveals the highest catalytical activity. Additionally, the influence of the concentration of BA and LA is investigated. An increase in BA concentration leads to an exponential increase of the reaction rate, while increasing the concentration of the LA leads to a volcano plot with its optimum at a LA : BA ratio of 1 : 3. The influence of the LA on the electron density of the intermediate formaldehyde is concluded as the main factor for this behavior.

Baseline trait mindfulness moderates the efficacy of mindfulness interventions and active controls: A meta-analysis of 177 randomised controlled trials.

Previous evidence suggests that benefits of mindfulness-based interventions (MBIs) may depend on individuals' baseline trait mindfulness (BTM) levels. This meta-analysis investigated moderating effects of BTM on changes in mental health outcomes and trait mindfulness in randomised controlled trials (RCTs) of MBIs. A total of 177 primary studies (total N = 13,486), comparing the treatment effects of MBIs against active, treatment-as-usual (TAU) and waitlist control groups, were synthesised via three-level meta-analysis. Lower BTM was associated with larger changes in mental health outcomes (B = -0.14, 95% CI [-0.21, -0.06], p < .001) and trait mindfulness (B = -0.09 [-0.16, -0.02], p = .009) in MBIs and active controls combined. These associations were significantly larger than from those in TAU and waitlist controls. Moderating effects were less tangible for changes in trait mindfulness in MBIs and active controls individually and less tangible in various sensitivity analyses which, however, were confounded by client type across the RCTs. Individuals low in BTM may, by a small effect size, benefit more from MBIs and active control interventions. BTM may thus affect the evaluation of treatment efficacy. MBIs and active interventions could be offered specifically to persons low in BTM.

Biophysical investigation of liposome systems decorated with bioconjugated copolymers in the presence of amantadine.

Liposome-based technologies derived from lipids and polymers (e.g., PEGylated liposomes) have been recognized because of their applications in nanomedicine. However, since such systems represent myriad challenges and may promote immune responses, investigation of new biomaterials is mandatory. Here, we report on a biophysical investigation of liposomes decorated with bioconjugated copolymers in the presence (or absence) of amantadine (an antiviral medication). First, copolymers of poly(N,N-dimethylacrylamide-co-fluoresceinacrylate-co-acrylic acid-N-succinimide ester)-block-poly(N-isopropylacrylamide) (PDMA-b-PNIPAM) containing a fluorescence label were biofunctionalized with short peptides that resemble the sequence of the loops 220 and 130 of the binding receptor of the hemagglutinin (HA) protein of the influenza A virus. Then, the bioconjugated copolymers were self-assembled along with liposomes composed of 1,2 dimyristoyl-sn-glycero-3-phosphocholine, sphingomyelin, and cholesterol (MSC). These biohybrid systems, with and without amantadine, were systematically characterized using differential scanning calorimetry (DSC), dynamic light scattering (DLS), and cryogenic transmission electron microscopy (cryoTEM). Finally, the systems were tested in an in vitro study to evaluate cytotoxicity and direct immunofluorescence in Madin Darbin Canine Kidney (MDCK) cells. The biohybrid systems displayed long-term stability, thermo-responsiveness, hydrophilic-hydrophobic features, and fluorescence properties and were presumable endowed with cell targeting properties intrinsically integrated into the amino acid sequences of the utilized peptides, which indeed turn them into promising nanodevices for biomedical applications.

The role of the nucleus for cell mechanics: an elastic phase field approach.

The nucleus of eukaryotic cells typically makes up around 30% of the cell volume and has significantly different mechanics, which can make it effectively up to ten times stiffer than the surrounding cytoplasm. Therefore it is an important element for cell mechanics, but a quantitative understanding of its mechanical role during whole cell dynamics is largely missing. Here we demonstrate that elastic phase fields can be used to describe dynamical cell processes in adhesive or confining environments in which the nucleus acts as a stiff inclusion in an elastic cytoplasm. We first introduce and verify our computational method and then study several prevalent cell-mechanical measurement methods. For cells on adhesive patterns, we find that nuclear stress is shielded by the adhesive pattern. For cell compression between two parallel plates, we obtain force-compression curves that allow us to extract an effective modulus for the cell-nucleus composite. For micropipette aspiration, the effect of the nucleus on the effective modulus is found to be much weaker, highlighting the complicated interplay between extracellular geometry and cell mechanics that is captured by our approach. We also show that our phase field approach can be used to investigate the effects of Kelvin-Voigt-type viscoelasticity and cortical tension.

Day-to-day associations between mindfulness and perceived stress: insights from random intercept cross-lagged panel modeling.

Objective: Mindfulness is frequently seen as a protective factor of stress, but self-report measures of mindfulness may overlap with other related constructs, such as mental health, and could thus not only be a predictor, but also an outcome of stress. This study thus aimed to examine the longitudinal bidirectional associations between the use and perceived helpfulness of the four mindfulness facets Observe, Describe, Nonjudge, and Nonreact with daily perceived stress. Methods: Participants from a large (N = 1,276) mixed student and community group sample filled out a brief daily diary over the time span of 7 days. Bidirectional cross-lagged effects were investigated using the random-intercept cross-lagged panel model, an extension of the traditional cross-lagged panel model that allows to differentiate between stable between-unit differences and time-varying within-unit dynamics. In addition, we controlled for several baseline and sociodemographic confounders. Results: At the within-subject level, the use of Actaware was associated with higher perceived stress on the next day (ß = 0.03, p = 0.029). The use (ß = -0.04, p = 0.025) and perceived helpfulness (ß = -0.05, p = 0.014) of Nonreact were associated with lower perceived stress on the next day. In turn, perceived stress was associated with lower perceived helpfulness of Describe (ß = -0.04, p = 0.037) and Nonreact (ß = -0.03, p = 0.038) on the next day. In addition, there were several residual correlations between mindfulness facets and perceived stress within days. At the between-subject level, there was a positive association between the random intercept of Describe and daily stress (r = 0.15, p = 0.003). In addition, while baseline perceived stress was negatively associated with the random intercepts of the mindfulness facets, two baseline components of mindfulness were not associated with the random intercept of perceived stress. Conclusion: On the currently investigated time scale, our results challenge prior results and assumptions regarding mindfulness as a buffering and protective factor against daily stress. With the exception of Nonreact, mindfulness was either positively associated with perceived stress, or in turn perceived stress appeared to interfere with the ability to stay mindful in daily life.

Protocol for creating representations of molecular structures using a polymer-specific decoder.

To supply chemical structures of polymers for machine learning applications, decoding is necessary. Here, we present a protocol for generating polymer fingerprints (PFPs), which are representations of molecular structures, using a polymer-specific decoder. We outline steps for downloading, installing, and basic application of the software. Moreover, we present procedures for processing and analyzing polymer structure data and the preparation for integration into machine learning methods. On this basis, we explain how artificial neural networks can be utilized to predict polymer properties. For complete details on the use and execution of this protocol, please refer to Köster et al.1.

Radical Polymer-based Positive Electrodes for Dual-Ion Batteries: Enhancing Performance with γ-Butyrolactone-based Electrolytes.

Dual-ion batteries (DIBs) represent a promising alternative for lithium ion batteries (LIBs) for various niche applications. DIBs with polymer-based active materials, here poly(2,2,6,6-tetramethylpiperidinyl-N-oxyl methacrylate) (PTMA), are of particular interest for high power applications, though they require appropriate electrolyte formulations. As the anion mobility plays a crucial role in transport kinetics, Li salts are varied using the well-dissociating solvent γ-butyrolactone (GBL). Lithium difluoro(oxalate)borate (LiDFOB) and lithium bis(oxalate)borate (LiBOB) improve cycle life in PTMA||Li metal cells compared to other Li salts and a LiPF6- and carbonate-based reference electrolyte, even at specific currents of 1.0 A g-1 (≈10C), whereas LiDFOB reveals a superior rate performance, i. e., ≈90 % capacity even at 5.0 A g-1 (≈50C). This is attributed to faster charge-transfer/mass transport, enhanced pseudo-capacitive contributions during the de-/insertion of the anions into the PTMA electrode and to lower overpotentials at the Li metal electrode.

An Iridium Complex as Bidentate Halogen Bond-Based Anion Receptor Featuring an IncreasedOptical Response.

We present a luminescent Ir(III) complex featuring a bidentate halogen bond donor site capable of strong anion binding. The tailor-made Ir(III)(L)2 moiety offers a significantly higher emission quantum yield (8.4 %) compared to previous Ir(III)-based chemo-sensors (2.5 %). The successful binding of chloride, bromide and acetate is demonstrated using emission titrations. These experiments reveal association constants of up to 1.6×105 M-1. Furthermore, a new approach to evaluate the association constant by utilizing the shift of the emission was used for the first time. The experimentally observed characteristics are supported by quantum chemical simulations.

[Pharmacological pain management in cancer patients]. / Medikamentöse Schmerztherapie bei Patienten mit Tumorerkrankungen.

Pharmacological pain therapy in cancer patients is based on guideline recommendations, which, however, do not fully coincide in all aspects due to varying weighting of evidence. The present article discusses current issues including the decreasing significance of the World Health Organization (WHO) analgesic ladder, with its distinction between step 2 and 3 being increasingly questioned. Risks of nonopioid analgesics such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in older populations, are discussed. Paracetamol may potentially reduce the effectiveness of immunotherapies. Aspects of administering analgesics via a feeding tube are considered. Recommendations for the treatment of episodic pain, transitioning between different opioids, and some relevant interactions are also discussed.