Exploiting Atomic Control to Show When Atoms Become Molecules

Precision-placed atom qubits in silicon offer a unique means to confine electrons and control their spins with extreme accuracy, which can be leveraged to construct powerful quantum computers. To date atom qubits in silicon have been successfully realized using electrons hosted either on a single phosphorus atom or on a multi-donor quantum dot. Here, a novel molecular regime is explored in which electrons are bound to two donor dots separated by ≈8 nm in a natural silicon substrate. The molecular state, provided by these spatially separated donors, is used to study with exquisite precision the impact of confinement potential on the electronic and spin properties of qubits. Unique spin filling measurements, performed on up to five electrons, confirm how electrons are shared between both sites of the molecule, forming hybridized molecular states. The precise atomic locations of the donor atoms in the silicon lattice are determined by combining the experimental electron spin resonance spectra and the state-of-the-art atomistic modeling of multi-electron wave-functions in presence of realistic electric fields. The donor molecule studied in this work exhibits excellent qubit properties and addresses the impact that the confinement potential has, at the atomic scale, on the desired properties of electron spin qubits.     

Identification of specific relaxin-binding cells in the human female

Relaxin is secreted during pregnancy, but it has no verified effects in humans. The objective of the present study was to identify the cells containing specific relaxin-binding sites in the uterine cervix, vagina, uterus, mammary glands, mammary nipples, and term placenta in the human. The uterine cervix, vagina, and uterus were obtained from hysterectomy specimens. Mammary glands and nipples were obtained after modified radical mastectomy. Placenta was obtained after normal delivery. Tissue samples were cut into slices (0.5-3 cm3), frozen in liquid nitrogen, and cryosectioned (8 microm). Cells that bind relaxin were identified by sequential application of biotinylated porcine relaxin probe, antibiotin immunoglobulin G conjugated to 1 nm colloidal gold, and silver enhancement for signal amplification. Relaxin bound with specificity to epithelial cells, smooth muscle cells, and blood vessels in the cervix, vagina, uterus, and mammary nipples; to epithelial cells and blood vessels in the mammary glands; and to skin of the mammary nipples. In addition, relaxin bound to individual cell types within the term placenta (amnion epithelium, syncytiotrophoblasts, blood vessels), and to sebaceous glands within the nipples. We conclude that the specific relaxin-binding cells probably contain relaxin receptors. Identification of putative relaxin receptors may provide insight into physiological and/or therapeutic roles of relaxin in the human.     

Discovery of a Class of Potent and Selective Non-competitive Sentrin-Specific Protease 1 Inhibitors

Sentrin-specific proteases (SENPs) are responsible for the maturation of small ubiquitin-like modifiers (SUMOs) and the deconjugation of SUMOs from their substrate proteins. Studies on prostate cancer revealed an overexpression of SENP1, which promotes prostate cancer progression as well as metastasis. Therefore, SENP1 has been identified as a novel drug target against prostate cancer. Herein, we report the discovery and biological evaluation of potent and selective SENP1 inhibitors. A structure-activity relationship (SAR) of the newly identified pyridone scaffold revealed allosteric inhibitors with very attractive in vitro ADMET properties regarding plasma binding and plasma stability for this challenging target. This study also emphasizes the importance of biochemical mode of inhibition studies for de novo designed inhibitors.     

Multicellular Modelling of Difficult-to-Treat Gastrointestinal Cancers: Current Possibilities and Challenges

Cancers affecting the gastrointestinal system are highly prevalent and their incidence is still increasing. Among them, gastric and pancreatic cancers have a dismal prognosis (survival of 5–20%) and are defined as difficult-to-treat cancers. This reflects the urge for novel therapeutic targets and aims for personalised therapies. As a prerequisite for identifying targets and test therapeutic interventions, the development of well-established, translational and reliable preclinical research models is instrumental. This review discusses the development, advantages and limitations of both patient-derived organoids (PDO) and patient-derived xenografts (PDX) for gastric and pancreatic ductal adenocarcinoma (PDAC). First and next generation multicellular PDO/PDX models are believed to faithfully generate a patient-specific avatar in a preclinical setting, opening novel therapeutic directions for these difficult-to-treat cancers. Excitingly, future opportunities such as PDO co-cultures with immune or stromal cells, organoid-on-a-chip models and humanised PDXs are the basis of a completely new area, offering close-to-human models. These tools can be exploited to understand cancer heterogeneity, which is indispensable to pave the way towards more tumour-specific therapies and, with that, better survival for patients.     

The Novel Class IIa Selective Histone Deacetylase Inhibitor YAK540 Is Synergistic with Bortezomib in Leukemia Cell Lines

The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased p21 expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs.     

Dependence of opto-electric properties of (semi-)conducting films in polymer based solar cells on viscous shear during the coating process

Organic photovoltaic is a promising technology for low-cost energy conversion. One of its major challenges is the transfer of the manufacturing process to a continuous roll-to-roll process. Previous research showed that the coating method has a significant impact on film properties, which may be explained by a shear-rate induced crystallization of the polymer–fullerene-blend.In this paper we report on a controlled variation of the shear-rate during slot-die coating of photoactive and conductive layers for polymer solar cells. Light absorption of photoactive layers increased towards higher coating speed and thus higher shear-rate by up to 28% from 0.6 m/min to 12 m/min. The currently lower performance of roll-to-roll processed solar cells, compared to laboratory scale devices may be increased by intentionally applying a high shear rate during the coating process. In contrast, a shear induced crystallization is insignificant for conductive (PEDEOT:PSS and Ag-nanoparticle) films, where conductivity decreased when the operating point approached the stability limit. Thus, a low capillary number is desirable for PEDOT:PSS layers, whereas the performance of the photoactive layer increased within the investigated velocity range. These tendencies, shown here for a standard material system (P3HT:PCBM), are substantial for the design of a roll-to-roll process for efficient polymer solar cells.     

A massively parallel,multi-disciplinary Barnes–Hut tree code for extreme-scale N-body simulations

The efficient parallelization of fast multipole-based algorithms for the N-body problem is one of the most challenging topics in high performance scientific computing. The emergence of non-local, irregular communication patterns generated by these algorithms can easily create an insurmountable bottleneck on supercomputers with hundreds of thousands of cores. To overcome this obstacle we have developed an innovative parallelization strategy for Barnes–Hut tree codes on present and upcoming HPC multicore architectures. This scheme, based on a combined MPI–Pthreads approach, permits an efficient overlap of computation and data exchange. We highlight the capabilities of this method on the full IBM Blue Gene/P system JUGENE at Jülich Supercomputing Centre and demonstrate scaling across 294,912 cores with up to 2,048,000,000 particles. Applying our implementation pepc to laser–plasma interaction and vortex particle methods close to the continuum limit, we demonstrate its potential for ground-breaking advances in large-scale particle simulations.     

Hydrodynamics of quenching with impinging free-surface jet

The hydrodynamics of jet impingement quenching of a stainless steel specimen has been studied experimentally. The specimen is heated to an initial temperature of about 900 °C and then quenched by a subcooled free-surface water jet. High-speed imaging shows that the free-surface of the water film in the wetted region is smooth. The water film outside the wetted region is deflected away from the surface and then breaks into droplets due to surface tension and shear forces. The splashed droplet velocity is found to be low up to a wetting front radius of 6 mm (r/d_J ≈ 2), beyond which it increases rapidly before reaching a constant value at a wetting front radius of about 8 to 10 mm (2.67 ? r/d_J ? 3.34). The water film velocity at the wetting front is calculated using the single-phase boundary layer model suggested by Watson [2]. At moderate subcooling, the splashed droplet velocity up to a wetting front radius of 10 mm (r/d_J ≈ 3.34) is found to be much lower than the estimated single-phase film velocity. The study shows that although the wetted region may appear devoid of any bubbles, strong two-phase flow occurs within this region.