Integrated Assessment of the Structure and Dynamics of Solid Proteins.

Understanding macromolecular function, interactions, and stability hinges on detailed assessment of conformational ensembles. For solid proteins, accurate elucidation of the spatial aspects of dynamics at physiological temperatures is limited by the qualitative character or low abundance of solid-state nuclear magnetic resonance internuclear distance information. Here, we demonstrate access to abundant proton-proton internuclear distances for integrated structural biology and chemistry with unprecedented accuracy.

Socially Assistive Devices in Healthcare-a Systematic Review of Empirical Evidence from an Ethical Perspective.

Socially assistive devices such as care robots or companions have been advocated as a promising tool in elderly care in Western healthcare systems. Ethical debates indicate various challenges. An important part of the ethical evaluation is to understand how users interact with these devices and how interaction influences users' perceptions and their ability to express themselves.

Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy.

Partial liver removal is an important therapy option for liver cancer. In most patients within a few weeks, the liver is able to fully regenerate. In some patients, however, regeneration fails with often severe consequences.

Association between School Contexts and the Development of Subjective Well-Being during Adolescence: A Context-Sensitive Longitudinal Study of Life Satisfaction and School Satisfaction.

The transition to secondary school may negatively impact adolescents' psychosocial and subjective well-being development. However, how subjective well-being develops during secondary school and how school contextual factors, including aspects of ability grouping and achievement composition, are associated with the development of subjective well-being still require clarification. This study examined two measures of subjective well-being, life satisfaction and school satisfaction, to investigate the development of subjective well-being during secondary school.

The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation.

Identification and analysis of small molecule bioactivity in target-agnostic cellular assays and monitoring changes in phenotype followed by identification of the biological target are a powerful approach for the identification of novel bioactive chemical matter in particular when the monitored phenotype is disease-related and physiologically relevant. Profiling methods that enable the unbiased analysis of compound-perturbed states can suggest mechanisms of action or even targets for bioactive small molecules and may yield novel insights into biology. Here we report the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines and the identification of Picoberin, a low picomolar inhibitor of Hedgehog (Hh)-induced osteoblast differentiation.

Effect of the high-level trigger for detecting long-lived particles at LHCb.

Long-lived particles (LLPs) show up in many extensions of the Standard Model, but they are challenging to search for with current detectors, due to their very displaced vertices. This study evaluated the ability of the trigger algorithms used in the Large Hadron Collider beauty (LHCb) experiment to detect long-lived particles and attempted to adapt them to enhance the sensitivity of this experiment to undiscovered long-lived particles. A model with a Higgs portal to a dark sector is tested, and the sensitivity reach is discussed.

Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors.

The PRMT5-MEP50 methyltransferase is a major target for anticancer drug discovery, and modulators of its interactions with different regulatory proteins are in high demand because they modulate PRMT5 substrate selectivity. We describe a strategy for the development of a PRMT5/adaptor protein PPI inhibitor, which includes the design and synthesis of macrocyclic peptides based on the motif for the interaction of PRMT5 with its adaptor protein RioK1. After the initial exploration of different macrocycle sizes and cyclization linkages, analysis of a peptide library identified hot spots for the variation of the amino acid structure.

Multimodal Agility-Based Exercise Training for Persons With Multiple Sclerosis: A New Framework.

Introduction: Multimodal agility-based exercise training (MAT) has been described as a framework for fall prevention in the elderly but might also be a valuable concept for exercise training in persons with Multiple Sclerosis (pwMS).

The Problem: Current recommendations advise pwMS to perform a multitude of different exercise training activities, as each of these has its separate evidence. However, pwMS struggle even more than the general population to be physically active.

Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells.

Tumor cells often have very high energy demands. Inhibition of glucose uptake is therefore a possible approach to limit the proliferation and survival of transformed cells. However, immune cells also require energy to initiate and to maintain anti-tumor immune reactions.

Phenotypic Discovery of Triazolo[1,5-]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype.

Phenotypic drug discovery (PDD) continues to fuel the research and development pipelines with first-in-class therapeutic modalities, but success rates critically depend on the quality of the underlying model system. Here, we employed a stem cell-based approach for the target-agnostic, yet pathway-centric discovery of small-molecule cytokine signaling activators to act as morphogens during development and regeneration. Unbiased screening identified triazolo[1,5-]quinazolines as a new-in-class in vitro and in vivo active amplifier of the bone morphogenetic protein (BMP) pathway.

A state-of-the-art examination of disaster management in Sierra Leone: the implementation drawbacks, research gaps, advances, and prospects.

Unfolding events have shown that Sierra Leone is enduring various disasters at a worrying rate. While progress is being made in disaster management, activities that degrade the fragile ecosystem, exacerbated by climate change, poverty, and bad governance, remain growing concerns. Amid these concerns, there is inadequate information to take appropriate actions.

Microscopic Origin of the Effective Spin-Spin Interaction in a Semiconductor Quantum Dot Ensemble.

We present a microscopic model for a singly charged quantum dot (QD) ensemble to reveal the origin of the long-range effective interaction between the electron spins in the QDs. Wilson's numerical renormalization group (NRG) is used to calculate the magnitude and the spatial dependency of the effective spin-spin interaction mediated by the growth-induced wetting layer. Surprisingly, we found an antiferromagnetic Heisenberg coupling for very short inter-QD distances that is caused by the significant particle-hole asymmetry of the wetting layer band at very low filling.

Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury.

The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). The canonical pathway topology is characterized by sequential phosphorylation of kinases in the cytoplasm that defines the subcellular localization of YAP and TAZ. However, the molecular mechanisms controlling the nuclear/cytoplasmic shuttling dynamics of both factors under physiological and tissue-damaging conditions are poorly understood.

Evidence for a transition in the cortical membranes of Paramecium.

Ever since the pioneering studies in the 1960s and 70s, the importance of order transitions for cell membrane functions has remained a matter of debate. Recently, it has been proposed that the nonlinear stimulus-response curve of excitable cells, which manifests in all-or-none pulses (action potentials (AP)), is due to a transition in the cell membrane. Indeed, evidence for transitions has accumulated in plant cells and neurons, but studies with other excitable cells are expedient in order to show if this finding is of a general nature.

Inhibition of cytochrome P450 enhances the nephro- and hepatotoxicity of ochratoxin A.

The mycotoxin ochratoxin A (OTA) is a contaminant in food that causes nephrotoxicity and to a minor degree hepatotoxicity. Recently, we observed that OTA induces liver damage preferentially to the cytochrome P450 (CYP)-expressing pericentral lobular zone, similar to hepatotoxic substances known to be metabolically toxified by CYP, such as acetaminophen or carbon tetrachloride. To investigate whether CYP influences OTA toxicity, we used a single dose of OTA (7.

Quintet Dinitrenes with Negative Zero-Field Splitting: Effect of Spin-Orbit Coupling on the Sign of Magnetic Anisotropy.

We report on W-band EPR and quantum chemical investigation of novel organic tetraradicals with negative axial zero-field splitting (ZFS) parameter These belong to the class of quintet 1,3,5-tribromophenylene-2,4-dinitrenes bearing different substituents in position 6 of the benzene ring (, N; , F; , CN; ; Cl; , Br). Analysis of the W-band EPR spectrum of dinitrene reveals its large negative ZFS parameter = -0.27 cm.

Short-range ENDOR distance measurements between Gd(III) and trifluoromethyl labels in proteins.

The measurement of distances in proteins can be challenging in the 5-20 Å range, which is outside those accessible through conventional NMR and EPR methods. Recently it was demonstrated that distances in this range could be measured between a nitroxide as a paramagnetic spin label and a nearby fluorine atom (F) as a nuclear spin label using high-field (W-band/3.4 T) ENDOR spectroscopy.

Ring contraction in synthesis of functionalized carbocycles.

Carbocycles are a key and widely present structural motif in organic compounds. The construction of structurally intriguing carbocycles, such as highly-strained fused rings, spirocycles or highly-functionalized carbocycles with congested stereocenters, remains challenging in organic chemistry. Cyclopropanes, cyclobutanes and cyclopentanes within such carbocycles can be synthesized through ring contraction.

Unitary Response of Solvatochromic Dye to Pulse Excitation in Lipid and Cell Membranes.

The existence of acoustic pulse propagation in lipid monolayers at the air-water interface is well known. These pulses are controlled by the thermodynamic state of the lipid membrane. Nevertheless, the role of acoustic pulses for intra- and inter-cellular communication is still a matter of debate.

Characterization of conformational heterogeneity via higher-dimensionality, proton-detected solid-state NMR.

Site-specific heterogeneity of solid protein samples can be exploited as valuable information to answer biological questions ranging from thermodynamic properties determining fibril formation to protein folding and conformational stability upon stress. In particular, for proteins of increasing molecular weight, however, site-resolved assessment without residue-specific labeling is challenging using established methodology, which tends to rely on carbon-detected 2D correlations. Here we develop purely chemical-shift-based approaches for assessment of relative conformational heterogeneity that allows identification of each residue via four chemical-shift dimensions.

Colchicine overdose impairs the capacity of Kupffer cells to clear foreign particles and endotoxins.

Colchicine is an anti-inflammatory drug with a narrow therapeutic index. Its binding to tubulin prevents microtubule polymerization; however, little is known about how depolymerization of microtubules interferes with the phagocytosis function of Kupffer cells (KC). Here, we applied functional intravital imaging techniques to investigate the influence of microtubule disruption by colchicine on KC morphology, as well as its capacity to clear foreign particles and bacterial lipopolysaccharide (LPS) in anesthetized mice.

Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone.

Pseudo-natural products (pseudo-NPs) are de novo combinations of natural product (NP) fragments that define novel bioactive chemotypes. For their discovery, new design principles are being sought. Previously, pseudo-NPs were synthesized by the combination of fragments originating from biosynthetically unrelated NPs to guarantee structural novelty and novel bioactivity.

Patterns of volatile organic compounds in excrements of preterm neonates.

Background: As neonates are susceptible for many diseases, establishing noninvasive diagnostic methods is desirable. We hypothesized that volatile organic compounds (VOCs) could be successfully measured in diaper samples.

Methods: We performed a feasibility study to investigate whether ambient air-independent headspace measurements of the VOC profiles of diapers from premature infants can be conducted using ion mobility spectrometer coupled with multi-capillary columns (B & S Analytik GmbH).