University of Ulm

Broad-spectrum antivirals are urgently required to counter present and emerging viral threats. It has previously been shown that the parental molecular tweezers CLR01 and CLR05 disrupt viral envelopes by complexing choline headgroups and that ester-functionalized "advanced" tweezers display markedly enhanced antiviral potency. Here, we determine the molecular basis of this improved activity. Using liposome leakage assays, giant unilamellar vesicles, NMR, Langmuir film balance experiments, and atomistic simulations, we demonstrate that advanced tweezers not only encapsulate choline-containing lipids but also engage lipids lacking choline headgroups via transient and conserved hydrophobic insertion events. These interactions preferentially destabilize membranes enriched in sphingomyelin, unsaturated acyl chains, or inverted cone-shaped lipids and are especially effective against small, highly curved particles resembling viral particles, explaining their broad antiviral activity for enveloped viruses. Our findings reveal a dual mechanism of action, choline binding and hydrophobic insertion, that underpins the broad-spectrum antiviral activity of advanced molecular tweezers and establish them as a promising new class of membrane-targeting antivirals for prophylactic and therapeutic use.

BackgroundTumor-derived small extracellular vesicles were shown to contribute to immunosuppression in various cancer types, including head and neck squamous cell carcinoma. Dendritic cells, major regulators of specific anti-tumor immune response, are often impaired in their function in the context of cancer.MethodsMonocyte-derived dendritic cells were incubated with isolated small extracellular vesicles during or after maturation. Cell surface markers and antigen processing machinery were assessed by flow cytometry. Vesicle-treated dendritic cells were tested for interleukin 12p70 production by ELISA, and differences in uptake of labeled vesicles were shown by confocal microscopy.ResultsSmall extracellular vesicles derived from HPV(+) tumor cell lines increased maturation and activation of immature dendritic cells, priming them for more rapid phagocytosis. Immature dendritic cells co-incubated with vesicles had lower levels of antigen presenting machinery components and produced less IL12p70 than controls, while similarly co-incubated mature dendritic cells remained unaffected. Vesicles in plasma of patients with head and neck cancer inhibited functions of mature dendritic cells by downregulating expression of antigen presenting machinery components.ConclusionOur results uncover mechanisms through which tumor-derived small extracellular vesicles modulate dendritic cell functions locally and systemically. These mechanisms may also affect dendritic cell-based vaccine efficacy.

BackgroundLeadership in small and medium-sized enterprises (SMEs) is associated with a variety of challenges and stressors, which are reflected in their managers’ commonly experienced high stress levels. In this context, psychological strain can arise, but compared to large companies, SMEs face particular difficulties in implementing mental health promotion intervention. These difficulties partially originate in a profound lack of comprehensive research on the effectiveness and prospects of success of intervention strategies in SMEs. This study aims to close this gap by evaluating a stress management training for managers in SMEs (KMU-GO). Implementing established stress management strategies and making them more accessible within the SME context, the training aims to improve participants’ psychological and physiological well-being.MethodsWe conducted a randomized controlled trial with an intervention and a waitlist control group in Germany. The intervention comprised 1.5 days of stress management training and two refresher sessions, focusing on short- and long-term coping strategies and self-reflection. Based on a sample of N = 155 managers, we conducted a multilevel analysis of covariance on psychological measures, namely stress reactivity, depression, and anxiety. Additionally, changes in physiological stress indices (i.e., hair cortisol concentration and salivary alpha-amylase activity) were examined.ResultsRegarding the psychological measures, we found significant training effects six months after baseline. Twelve months after baseline, there were no significant differences between the intervention and control groups for either psychological or physiological variables.ConclusionIn conclusion, the present stress management training is effective in reducing psychological strain in SME managers. In order to achieve more sustainable effects, a continuation of the refresher sessions could be considered.Trial registrationBefore including the first participant, the KMU-GO trial is registered at the German Clinical Trial Register (DRKS): DRKS00023457 (registered on 5 November 2020).

Photocatalytic production of H2 or hydrocarbons requires multiple electrons, and therefore the absorption of multiple photons and accumulation of photoexcited charges. Alternatively, multiexciton generation (MEG) could loosen this requirement. Despite intense studies of the MEG process singlet fission (SF) for solar cells, its use in photocatalysis has only recently been demonstrated. Herein, we present a detailed investigation of electron transfer (ET) from the triplet pair state (TT) and triplet states in two SF-based tetracene dimers. We find that the TT state behaves similarly to the singlet and thus can be used to increase the lifetime of singlet reactivity. We also show that in these covalently linked SF dimers, where TT recombines to form one free triplet, achieving more than 100% ET is challenging. Together with these findings and the input from theoretical calculations, we discuss the possibilities and limitations of ET from these dimers. By highlighting strategies to mitigate detrimental TT recombination pathways, these insights provide design principles for next-generation SF chromophores tailored for solar energy conversion and photoredox catalysis.

Children with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) continue to face relapse and treatment resistance, emphasizing the urgent need for novel therapeutic strategies. In this study, we developed and characterized a recombinant oncolytic measles virus (MV-Blina) engineered to locally secrete a bispecific T cell engager (bsTE) targeting CD19 and CD3 (secBlina) to enhance antitumor immunity while minimizing systemic toxicity. MV-Blina demonstrated superior replication kinetics and cytotoxicity in vitro compared to the parental MV-Edm strain. MV-Blina infected ALL cells, secreted functional secBlina capable of engaging and activating T cells, leading to selective leukemia cell death. In in vitro and in vivo models, including patient-derived xenografts, MV-Blina demonstrated an additive yet heterogeneous anti-leukemic effect, with significant survival benefits and reduced CNS leukemic burden in MV-Blina-treated mice. Importantly, MV-Blina did not induce either short- or long-term toxicity in in vitro neuronal models encompassing PBMCs, nor in immunocompromised CD46 transgenic mice, even under additional immunosuppression. Collectively, these findings support further investigations of MV-Blina as a potential treatment for patients with relapsed or refractory BCP-ALL.

IntroductionThe overarching goal of ACT is to increase psychological flexibility, which can be enhanced through mechanisms such as acceptance, valued-driven actions, or mindfulness. Several meta-analyses confirm the effectiveness of Acceptance and Commitment Therapy (ACT) in the treatment of clinical and subclinical populations, including patients diagnosed with depressive disorder and insomnia, largely within outpatient settings. However, there is no scientific research evaluating the efficacy of ACT as an adjunct treatment for psychiatric inpatients with depression. This study aimed to evaluate the efficacy of a manualized ACT treatment in addition to treatment as usual (TAU), within an inpatient setting for patients diagnosed with depressive disorder and comorbid insomnia.MethodEight psychiatric inpatients received eight ACT sessions (two per week), in addition to TAU, which involved cognitive behavioral therapy (CBT) and psychiatric medication. A single case series design with an A-B replication across inpatients was implemented. Patients were assessed one week (T1) and one day (T2) before ACT treatment (while already receiving TAU), as well as one week (T3) and three months (T4) after treatment termination. Symptom improvement was assessed using self-report questionnaires: Beck Depression Inventory-II (BDI-II), Regensburger Insomnia Scale (RIS), Acceptance and Action Questionnaire-II (AAQ-II), Sleep Problem Acceptance Questionnaire (SPAQ), and quality of life (WHOQOL-BREF).ResultsNo significant change was observed from T1 to T2 (p >.05). However, significant improvement from T2 to T3 and T2 to T4 was found for depressive symptoms, insomnia, psychological flexibility, acceptance of insomnia symptomatology, and quality of life related to physical and psychological symptoms.DiscussionThe findings suggest that ACT is a promising adjunct intervention, applicable transdiagnostically for individuals suffering from depression and comorbid insomnia in inpatient settings. By enhancing psychological flexibility and symptom acceptance, ACT may offer unique benefits beyond traditional CBT, particularly for patients with residual symptoms, chronic distress, or recurrent depressive episodes. Despite these promising findings, results must be interpreted with caution due to the small sample size and lack of a control group. Future research should replicate and extend these findings in larger randomized controlled trials to further evaluate ACT’s potential in inpatient psychiatric care.

Multi-bit quantization allows Delta-Sigma modulators to achieve low oversampling ratios (OSRs), improved jitter tolerance, and relaxed dynamic requirements of the loop filter, but face nonlinearity challenges in the feedback digital-to-analog converter (DAC), requiring complex calibration techniques. Dual quantization using digital DSM (DDSM) has been proposed to overcome this limitation, but state-of-the art DDSM suffers from limited resolution, stability concerns, and digital-analog matching requirements. This work applies a sturdy multistage noise shaping (SMASH) DDSM feedback DAC within a wideband DSM to address these issues. This results in low element mismatch sensitivity, eliminating the need for any DAC calibration. To reduce the effect of dynamic errors in the outer DAC, an inter-symbol-interference (ISI) shuffler is proposed and gain boosting is applied within the DAC elements to address memory effects due to parasitic capacitance. The DSM allows an excess loop-delay (ELD) <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$= 1.5\times T_{s}$</tex-math> </inline-formula> in the outermost feedback path to give enough processing time for the SMASH DDSM. The prototype implementation of the 3rd-order continuous-time (CT) DSM shows a 106.2dB spurious-free dynamic range (SFDR) in an 80MHz bandwidth without any DAC calibration. Using reference folding and shuffling in the internal Flash quantizer, the DSM is clocked at 2.75 GHz. Implemented in 28 nm CMOS, CT DSM achieves a competitive figure-of-merit (FOM) = 163.7dB for such extreme linearity.