DERS

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure-guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intra-protein "tunnel" as the main inhibitor binding site (AI), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix-turn-helix (HTH) motifs...

In the current guidelines to prevent hemotherapyinduced nausea and vomiting, multiple antiemetic drugs are administered simultaneously. In patients who receive highly emetogenic chemotherapy, aprepitant, an NK1-receptor antagonist, is combined with ondansetron and dexamethasone. Aprepitant can influence the pharmacokinetics of other drugs, as it is an inhibitor and inducer of CYP3A4. Some anticancer drugs and other co-medication frequently used in cancer patients are CYP3A4 or CYP29C substrates. We give an overview of the metabolism and current data on clinically relevant drug-drug interactions with aprepitant during chemotherapy...

Efficient osteogenic differentiation of mesenchymal stem cells (MSCs) is crucial to accelerate bone formation. In this context, the use of extracellular matrix (ECM) as natural 3D-framework mimicking in vivo tissue architecture is of interest. The aim of this study was to generate a devitalized human osteogenic MSC-derived ECM and to investigate its impact on MSC osteogenic differentiation to improve MSC properties in bone regeneration. The devitalized ECM significantly enhanced MSC adhesion and proliferation...

BACKGROUND: Involving patients in decision-making is considered to be particularly appropriate towards the end of life. Professional guidelines emphasize that the decision to initiate continuous sedation should be made in accordance with the wishes of the dying person and be preceded by their consent. AIM: To describe the decision-making process preceding continuous sedation until death with particular attention to the involvement of the person who is dying. DESIGN: Qualitative case studies using interviews...

PURPOSE: Amino acids are involved in many physiological processes in the body and serve as building blocks of proteins which are the main component of muscle mass. Often patients with cancer experience muscle wasting, which is associated with poor outcomes. The purpose of this paper is to discuss amino acid kinetics in cancer, review the evidence on the response to nutrition in patients with cancer, and to give recommendations on the appropriate level of amino acid or protein intake in cancer...

During the plant life cycle, diverse signalling inputs are continuously integrated and engage specific genetic programs depending on the cellular or developmental context. Consistent with an important role in this process, HECATE (HEC) bHLH transcription factors display diverse functions, from photomorphogenesis to the control of shoot meristem dynamics and gynoecium patterning. However, the molecular mechanisms underlying their functional versatility and the deployment of specific HEC sub-programs still remain elusive...

The combined quantum mechanical (QM) and molecular mechanical (MM) approach (QM/MM) is a popular method to study reactions in biochemical macromolecules. Even if the general procedure of using QM for a small, but interesting part of the system and MM for the rest is common to all approaches, the details of the implementations vary extensively, especially the treatment of the interface between the two systems. For example, QM/MM can use either additive or subtractive schemes, of which the former is often said to be preferable, although the two schemes are often mixed up with mechanical and electrostatic embedding...

Van der Woude syndrome (VWS) shows an autosomal dominant pattern of inheritance with two known candidate genes, IRF6 and GRHL3. In this study, by employing genome-wide linkage analyses on two VWS affected families, we report the cosegregation of an intronic rare variant in NOL4 in one family, and a haplotype consisting of three variants in the noncoding region of IRF6 (introns 1, 8 and 3'UTR) in the other family. Using mouse, as well as human embryos as a model, we demonstrate the expression of NOL4 in the lip and palate primordia during their development...

Picornaviruses induce dramatic rearrangements of endomembranes in the cells that they infect to produce dedicated platforms for viral replication. These structures, termed replication organelles (ROs), have been well characterized for the Enterovirus genus of the Picornaviridae However, it is unknown whether the diverse RO morphologies associated with enterovirus infection are conserved among other picornaviruses. Here, we use serial electron tomography at different stages of infection to assess the three-dimensional architecture of ROs induced by encephalomyocarditis virus (EMCV), a member of the Cardiovirus genus of the family of picornaviruses that is distantly related...

Treatment of knee joint instability in patients with hypermobile Ehlers-Danlos syndrome (EDS) can be challenging. A 53-year-old woman with hypermobile EDS underwent bilateral total knee replacement (TKR) due to valgus osteoarthritis. During follow-up, she developed hypermobility of both knee replacements. Revision of the insert resolved the issue in her left knee; however, the right TKR required two insert exchanges and unfortunately instability persisted. Therefore, a revision to a constrained prosthesis was performed...

Vertically stacked two-dimensional materials form an ideal platform for controlling and exploiting light-matter interactions at the nanoscale. As a unique feature, these materials host electronic excitations of both intra- and interlayer type with distinctly different properties. In this Letter, using first-principles many-body calculations, we provide a detailed picture of the most prominent excitons in bilayer MoS2 , a prototypical van der Waals material. By applying an electric field perpendicular to the bilayer, we explore the evolution of the excitonic states as the band alignment is varied from perfect line-up to staggered (Type II) alignment...

SCOPE: Mannan oligosaccharides (MOS) have proven effective at improving growth performance, while also reducing hyperlipidemia and inflammation. As atherosclerosis is accelerated both by hyperlipidemia and inflammation, we aimed to determine the effect of dietary MOS on atherosclerosis development in hyperlipidemic ApoE*3-Leiden.CETP (E3L.CETP) mice, a well-established model for human-like lipoprotein metabolism. METHODS AND RESULTS: Female E3L.CETP mice were fed a high cholesterol diet, with or without 1% MOS for 14 weeks...

The increasing availability of ultra-high field scanners has led to a growing number of submillimetre fMRI studies in humans, typically targeting the gray matter at different cortical depths. In most analyses, the definition of surfaces at different cortical depths is based on an anatomical image with different contrast and distortions than the functional images. Here, we introduce a novel sequence providing bias-field corrected T1 -weighted images and T1 -maps with distortions that match those of the fMRI data, with an image acquisition time significantly shorter than standard T1 -weighted anatomical imaging...

The interaction of pepsin with sunset yellow food additive (SY) was studied by fluorescence spectroscopy and molecular dynamics simulation. The experimental results indicated that SY can quench the fluorescence of pepsin with static quenching. The apparent binding constant Ka and binding site number n were evaluated at different temperatures. Thermodynamic analysis suggests that SY interact with pepsin spontaneously by van der Waal's forces and hydrogen bond formation. Three-dimensional fluorescence spectra showed that pepsin undergoes a slightly conformation change when it interacts with SY...

RATIONALE: While theoretical frameworks for optimization of the outpatient processes are abundant, practical step-by-step analyses to give leads for improvement, to forecast capacity, and to support decision making are sparse. AIMS AND OBJECTIVES: This article demonstrates how to evaluate and optimize the triad of demand, (future) capacity, and access time of the outpatient clinic using a structured six-step method. METHODS: All individual logistical patient data of an orthopaedic outpatient clinic of one complete year were analysed using a 6-step method to evaluate demand, supply, and access time...

BACKGROUND: Patients with severe haemophilia A who have been treated extensively with factor VIII (FVIII) products face a low but potentially serious risk of inhibitor development. It is unknown why these patients break immunological tolerance and data on product-related immunogenicity is scarce. AIMS: To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients with severe haemophilia A...

Photodetectors based on Weyl semimetal promise extreme performance in terms of highly sensitive, broadband and self-powered operation owing to its extraordinary material properties. Layered Type-II Weyl semimetal that break Lorentz invariance can be further integrated with other two-dimensional materials to form van der Waals heterostructures and realize multiple functionalities inheriting the advantages of other two-dimensional materials. Herein, we report the realization of a broadband self-powered photodetector based on Type-II Weyl semimetal Td -MoTe2 ...

Neuromorphic computing represents an innovative technology that can perform intelligent and energy-efficient computation, whereas construction of neuromorphic systems requires biorealistic synaptic elements with rich dynamics that can be tuned based on a robust mechanism. Here, an ionic-gating-modulated synaptic transistor based on layered crystals of transitional metal dichalcogenides and phosphorus trichalcogenides is demonstrated, which produce a diversity of short-term and long-term plasticity including excitatory postsynaptic current, paired pulse facilitation, spiking-rate-dependent plasticity, dynamic filtering, etc...

The nontrivial topological origin and pseudospinorial character of electron wavefunctions make edge states possess unusual electronic properties. Twenty years ago, the tight-binding model calculation predicted that zigzag termination of 2D sheets of carbon atoms have peculiar edge states, which show potential application in spintronics and modern information technologies. Although scanning probe microscopy is employed to capture this phenomenon, the experimental demonstration of its optical response remains challenging...

BACKGROUND: The incidence, treatment and outcome of patients with newly diagnosed gastrointestinal stromal tumour (GIST) were studied in an era known for advances in diagnosis and treatment. METHODS: Nationwide population-based data were retrieved from the Netherlands Cancer Registry. All patients with GIST diagnosed between 2001 and 2012 were included. Primary treatment, defined as any treatment within the first 6-9 months after diagnosis, was studied. Age-standardized incidence was calculated according to the European standard population...