From the Total Synthesis of Semi-Viriditoxin, Semi-Viriditoxic Acid and Dimeric Naphthopyranones to their Biological Activities in Burkitt B Cell Lymphoma.

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,β-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,β-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction.

Regulation of Cathelicidin Antimicrobial Peptide (CAMP) Gene Expression by TNFα and cfDNA in Adipocytes.

Understanding the complex interactions between metabolism and the immune system ("metaflammation") is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP, therefore, might play a role as an adipokine in metaflammation and adipose inflammation.

MRTF-A gain-of-function in mice impairs homeostatic renewal of the intestinal epithelium.

The actin-regulated transcription factor MRTF-A represents a central relay in mechanotransduction and controls a subset of SRF-dependent target genes. However, gain-of-function studies in vivo are lacking. Here we characterize a conditional MRTF-A transgenic mouse model.

Bursting of the upper jaw prosthesis and fractures of the lower jaw as indirect injury pattern caused by a headshot: a case report.

Gunshots to the human body can cause direct and indirect injuries. Direct injuries are a consequence of the projectile guiding its way through the body, creating a permanent wound channel and thereby damaging the penetrated as well as the adjacent tissue. In addition, the temporary wound cavity is responsible for indirect injuries occurring distant to the actual wound tract.

Skin laceration caused by a short distance shot from a pepper spray launcher: a case report.

Pepper spray launchers are more precise and wind stable compared to conventional pepper sprays and are commonly used as a self-defensive tool. With the advanced potential, they may also harbour a greater risk for injuries, especially if they are not used within the suggested safety distance. If the shooting distance is below 1.

miRNA mediated downregulation of cyclase-associated protein 1 (CAP1) is required for myoblast fusion.

Myoblast fusion is essential for the formation, growth, and regeneration of skeletal muscle, but the molecular mechanisms that govern fusion and myofiber formation remain poorly understood. Past studies have shown an important role of the actin cytoskeleton and actin regulators in myoblast fusion. The Cyclase-Associated Proteins (CAP) 1 and 2 recently emerged as critical regulators of actin treadmilling in higher eukaryotes including mammals.

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

Background: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic.

Methods: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic.

Mobile apps as a sustainable shopping guide: The effect of eco-score rankings on sustainable food choice.

Consumers often struggle to assess food's environmental impact. A product ranking based on a standardized scoring approach (aggregating multiple indicators) that is easily accessible, for instance, via a mobile app, could serve as a simple decision aid for consumers. However, to avoid information overload, research is needed in which format such information should be presented.

Direct observation of spin correlations in an artificial triangular lattice Ising spin system with grazing-incidence small-angle neutron scattering.

The triangular lattice with Ising magnetic moments is an archetypical example of geometric frustration. In the case of dipolar-coupled out-of-plane moments, the geometric frustration results in a disordered classical spin-liquid state at higher temperatures while the system is predicted to transition to an anti-ferromagnetic stripe ground state at low temperatures. In this work we fabricate artificial triangular Ising spin systems without and with uniaxial in-plane compression to tune the nature and temperature of the correlations.

Experimental and Computational Investigations of the Reactions between α,β-Unsaturated Lactones and 1,3-Dienes by Cooperative Lewis Acid/Brønsted Acid Catalysis.

The reactions of α,β-unsaturated δ-lactones with activated dienes such as 1,3-dimethoxy-1-[(trimethylsilyl)oxy]-1,3-butadiene (Brassard's diene) are barely known in literature and show high potential for the synthesis of isocoumarin moieties. An in-depth investigation of this reaction proved a stepwise mechanism via the vinylogous Michael-products. Subsequent cyclisation and oxidation by LHMDS and DDQ, respectively, provided six mellein derivatives (30-84 %) and four angelicoin derivatives (40-78 %) over three steps.

Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation.

Background: Overexpression of AXL receptor tyrosine kinase (AXL) in various human cancers correlates with reduced patients overall survival and resistance to first line therapies. Therefore, several AXL tyrosine kinase inhibitors (TKIs) are currently under clinical evaluation.

Results: AXL TKI BMS777607 treatment increased AXL protein levels after 24 h as observed by Western blot and flow cytometry analysis.

Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5.

Multidrug resistance (MDR) in tumors and pathogens remains a major problem in the efficacious treatment of patients by reduction of therapy options and subsequent treatment failure. Various mechanisms are described to be involved in the development of MDR with overexpression of ATP-binding cassette (ABC) transporters reflecting the most extensively studied. These membrane transporters translocate a wide variety of substrates utilizing energy from ATP hydrolysis leading to decreased intracellular drug accumulation and impaired drug efficacy.

Selective inhibition of P-gp transporter by goniothalamin derivatives sensitizes resistant cancer cells to chemotherapy.

Overexpression of efflux transporters of the ATP-binding cassette (ABC) transporter family, primarily P-glycoprotein (P-gp), is a frequent cause of multidrug resistance in cancer and leads to failure of current chemotherapies. Thus, identification of selective P-gp inhibitors might provide a basis for the development of novel anticancer drug candidates. The natural product goniothalamin and 21 derivatives were characterized regarding their ability to inhibit ABC transporter function.

Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells.

The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells.

Inhibition of Nox4-dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal-mediated protumorigenic interactions.

Carcinoma-associated fibroblasts (CAFs) play a key onco-supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1-mediated activation of primary prostate human fibroblasts to a CAF-like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine-mediated PCa-relevant processes.

Synthesis and cytotoxic activities of goniothalamins and derivatives.

Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity.

Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture.

Androgen receptor (AR) targeting remains the gold standard treatment for advanced prostate cancer (PCa); however, treatment resistance remains a major clinical problem. To study the therapeutic effects of clinically used anti-androgens we characterized herein a tissue-mimetic three-dimensional (3D) in vitro model whereby PCa cells were cultured alone or with PCa-associated fibroblasts (CAFs). Notably, the ratio of PCa cells to CAFs significantly increased in time in favor of the tumor cells within the spheroids strongly mimicking PCa in vivo.

Oxidative phosphorylation and mitochondrial function differ between human prostate tissue and cultured cells.

Altered mitochondrial metabolism plays a pivotal role in the development and progression of various diseases, including cancer. Cell lines are frequently used as models to study mitochondrial (dys)function, but little is known about their mitochondrial respiration and metabolic properties in comparison to the primary tissue of origin. We have developed a method for assessment of oxidative phosphorylation in prostate tissue samples of only 2 mg wet weight using high-resolution respirometry.

Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding.

The myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF)-mediated gene expression. Activation of MRTF-A occurs in response to alterations in actin dynamics and critically requires the dissociation of repressive G-actin-MRTF-A complexes. However, the mechanism leading to the release of MRTF-A remains unclear.

Direct magnetic patterning due to the generation of ferromagnetism by selective ion irradiation of paramagnetic FeAl alloys.

Sub-100-nm magnetic dots embedded in a non-magnetic matrix are controllably generated by selective ion irradiation of paramagnetic Fe(60)Al(40) (atomic %) alloys, taking advantage of the disorder-induced magnetism in this material. The process is demonstrated by sequential focused ion beam irradiation and by in-parallel broad-beam ion irradiation through lithographed masks. Due to the low fluences used, this method results in practically no alteration of the surface roughness.

Dynamic contour tonometry in comparison to intracameral IOP measurements.

Purpose: The purpose of the study was to examine the effect of central corneal thickness (CCT), corneal curvature, astigmatism, axial length (AL), and age on measurements with the Pascal Dynamic Contour Tonometer (DCT).

Methods: In a prospective clinical trial 75 eyes of 75 patients undergoing phacoemulsification were examined. Before phacoemulsification, the anterior chamber was cannulated at the temporal corneal limbus.

Shifts in microbial community functions and nitrifying communities as a result of combined application of copper and mefenoxam.

In this microcosm study, we focused on the effect of a combined application of copper and mefenoxam on the functional diversity of soil microbial communities. Treatments with combined and separate applications of copper and mefenoxam were sampled at 24 and 60 days and control soil was sampled at 0, 24 and 60 days. Structural and metabolic profiling of microorganisms were performed by arbitrarily primed (AP) and RNA arbitrarily primed-PCR (RAP-PCR).