Setup of 4‐Prenylated Quinolines through Suzuki‐Miyaura Coupling for the Synthesis of Aurachins A and B

A polyprenyl side chain could be introduced into the heterocyclic quinoline moiety through Suzuki-Miyaura coupling of the corresponding quinoline-N-oxide with a polyprenyl boronic acid. This tool could be utilized for the synthesis of the natural product Aurachin B from the myxobacterium Stigmatella aurantiaca. This prenylated quinoline could then be transformed into the related Aurachin A through an epoxidation-ring opening cascade

Atroposelective Synthesis of Isoriccardin C through a C−H Activated Heck Type Macrocyclization

Macrocyclization is typically the key step in syntheses of cyclophane‐type natural products. Considering compounds with axially chiral biaryl moieties, the control of atroposelectivity is essential for biological activity and is synthetically challenging. Herein we report on atroposelective macrocyclization involving an oxidative Heck type process and enabling the first atropo‐enantiopure synthesis of isoriccardin C. A chiral sulfinyl auxiliary in the ortho‐position of a biaryl axis (still flexible) was used to induce a C−H activated atropodiastereoselective oxidative Heck coupling (>98 % de). The traceless character of the sulfinyl auxiliary enables the introduction of a hydroxy group to give the target molecule with >98 % ee as well

The Role and Potentials of Field User Interaction Data in the Automotive UX Development Lifecycle: An Industry Perspective

We are interested in the role of field user interaction data in the development of IVIS, the potentials practitioners see in analyzing this data, the concerns they share, and how this compares to companies with digital products. We conducted interviews with 14 UX professionals, 8 from automotive and 6 from digital companies, and analyzed the results by emergent thematic coding. Our key findings indicate that implicit feedback through field user interaction data is currently not evident in the automotive UX development process. Most decisions regarding the design of IVIS are made based on personal preferences and the intuitions of stakeholders. However, the interviewees also indicated that user interaction data has the potential to lower the influence of guesswork and assumptions in the UX design process and can help to make the UX development lifecycle more evidence-based and user-centered

Optimizing a biopsy needle using a simulation model

The method of biopsying biological tissue is an established procedure of minimally invasive medicine to extract samples for the determination of the presence or extent of a disease. Therefore punch biopsy is the most frequently applied method in case of prostate or breast cancer. The biopsy system is monitored during the penetration process into tissue via sonography. These observations of the procedure showed a considerable deflection of the needle tip. It is caused by unbalanced forces acting on the tip and by the low bending stiffness of the system itself. Government financed experimental studies using realistic phantom tissue have been conducted to quantify the needle deflection and to develop a mathematical approach to simulate this effect. This simulation has used a combination of a deformable model of the biopsy system in combination with a parameterized tissue model in multibody simulation software Recurdyn. It is now possible to anticipate the needle deflection, to get to know about the acting forces and to optimize the geometry of the needle tip

Evaluation of a developed MRI-guided focused ultrasound system in 7 T small animal MRI and proof-of-concept in a prostate cancer xenograft model to improve radiation therapy

Focused ultrasound (FUS) can be used to physiologically change or destroy tissue in a non-invasive way. A few commercial systems have clinical approval for the thermal ablation of solid tumors for the treatment of neurological diseases and palliative pain management of bone metastases. However, the thermal effects of FUS are known to lead to various biological effects, such as inhibition of repair of DNA damage, reduction in tumor hypoxia, and induction of apoptosis. Here, we studied radiosensitization as a combination therapy of FUS and RT in a xenograft mouse model using newly developed MRI-compatible FUS equipment. Xenograft tumor-bearing mice were produced by subcutaneous injection of the human prostate cancer cell line PC-3. Animals were treated with FUS in 7 T MRI at 4.8 W/cm2 to reach ~45 °C and held for 30 min. The temperature was controlled via fiber optics and proton resonance frequency shift (PRF) MR thermometry in parallel. In the combination group, animals were treated with FUS followed by X-ray at a single dose of 10 Gy. The effects of FUS and RT were assessed via hematoxylin-eosin (H&E) staining. Tumor proliferation was detected by the immunohistochemistry of Ki67 and apoptosis was measured by a TUNEL assay. At 40 days follow-up, the impact of RT on cancer cells was significantly improved by FUS as demonstrated by a reduction in cell nucleoli from 189 to 237 compared to RT alone. Inhibition of tumor growth by 4.6 times was observed in vivo in the FUS + RT group (85.3%) in contrast to the tumor volume of 393% in the untreated control. Our results demonstrated the feasibility of combined MRI-guided FUS and RT for the treatment of prostate cancer in a xenograft mouse model and may provide a chance for less invasive cancer therapy through radiosensitization

Three-Dimensional Maps of All Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes

Studies of higher-order chromatin arrangements are an essential part of ongoing attempts to explore changes in epigenome structure and their functional implications during development and cell differentiation. However, the extent and cell-type-specificity of three-dimensional (3D) chromosome arrangements has remained controversial. In order to overcome technical limitations of previous studies, we have developed tools that allow the quantitative 3D positional mapping of all chromosomes simultaneously. We present unequivocal evidence for a probabilistic 3D order of prometaphase chromosomes, as well as of chromosome territories (CTs) in nuclei of quiescent (G0) and cycling (early S-phase) human diploid fibroblasts (46, XY). Radial distance measurements showed a probabilistic, highly nonrandom correlation with chromosome size: small chromosomes—independently of their gene density—were distributed significantly closer to the center of the nucleus or prometaphase rosette, while large chromosomes were located closer to the nuclear or rosette rim. This arrangement was independently confirmed in both human fibroblast and amniotic fluid cell nuclei. Notably, these cell types exhibit flat-ellipsoidal cell nuclei, in contrast to the spherical nuclei of lymphocytes and several other human cell types, for which we and others previously demonstrated gene-density-correlated radial 3D CT arrangements. Modeling of 3D CT arrangements suggests that cell-type-specific differences in radial CT arrangements are not solely due to geometrical constraints that result from nuclear shape differences. We also found gene-density-correlated arrangements of higher-order chromatin shared by all human cell types studied so far. Chromatin domains, which are gene-poor, form a layer beneath the nuclear envelope, while gene-dense chromatin is enriched in the nuclear interior. We discuss the possible functional implications of this finding

Bisbibenzyls, a New Type of Antifungal Agent, Inhibit Morphogenesis Switch and Biofilm Formation through Upregulation of DPP3 in Candida albicans

The yeast-to-hypha transition plays a crucial role in the pathogenesis of C. albicans. Farnesol, a quorum sensing molecule (QSM) secreted by the fungal itself, could prevent the formation of hyphae and subsequently lead to the defect of biofilm formation. The DPP3, encoding phosphatase, is a key gene in regulating farnesol synthesis. In this study, we screened 24 bisbibenzyls and 2 bibenzyls that were isolated from bryophytes or chemically synthesized by using CLSI method for antifungal effect. Seven bisbibenzyls were found to have antifungal effects with IC80 less than 32 µg/ml, and among them, plagiochin F, isoriccardin C and BS-34 were found to inhibit the hyphae and biofilm formation of C. albicans in a dose-dependent manner. To uncover the underlying relationship between morphogenesis switch and QSM formation, we measured the farnesol production by HPLC-MS and quantified Dpp3 expression by detecting the fluorescent intensity of green fluorescent protein tagged strain using Confocal Laser Scanning microscopy and Multifunction Microplate Reader. The DPP3 transcripts were determined by real-time PCR. The data indicated that the bisbibenzyls exerted antifungal effects through stimulating the synthesis of farnesol via upregulation of Dpp3, suggesting a potential antifungal application of bisbibenzyls. In addition, our assay provides a novel, visual and convenient method to measure active compounds against morphogenesis switch

Timeless Links Replication Termination to Mitotic Kinase Activation

The mechanisms that coordinate the termination of DNA replication with progression through mitosis are not completely understood. The human Timeless protein (Tim) associates with S phase replication checkpoint proteins Claspin and Tipin, and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites. We show here that human Tim can be isolated in a complex with mitotic entry kinases CDK1, Auroras A and B, and Polo-like kinase (Plk1). Plk1 bound Tim directly and colocalized with Tim at a subset of mitotic structures in M phase. Tim depletion caused multiple mitotic defects, including the loss of sister-chromatid cohesion, loss of mitotic spindle architecture, and a failure to exit mitosis. Tim depletion caused a delay in mitotic kinase activity in vivo and in vitro, as well as a reduction in global histone H3 S10 phosphorylation during G2/M phase. Tim was also required for the recruitment of Plk1 to centromeric DNA and formation of catenated DNA structures at human centromere alpha satellite repeats. Taken together, these findings suggest that Tim coordinates mitotic kinase activation with termination of DNA replication