Synthesis and Antibacterial Evaluation of Novel Small-Molecule Antibacterials of a Reduced Acridine Structure in S. aureus Strains Including MRSA.

BACKGROUND: The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies to combat the increasing antibacterial drug resistance.

Evaluation of Novel Benzo-annelated 1,4-dihydropyridines as MDR Modulators in Cancer Cells.

BACKGROUND: Multidrug resistance (MDR) is the main problem in anticancer therapy today. Causative transmembrane efflux pumps in cancer cells have been reconsidered as promising anticancer target structures to restore anticancer drug sensitivity by various strategies, including MDR modulators. MDR modulators interfere with the efflux pumps and improve the cellular efficiency of chemotherapeutics. So far, only a few candidates have gone through clinical trials with disappointing results because of low specificity and toxic properties. AIM: This study aimed to find Novel MDR modulators to effectively combat multidrug resistance in cancer cells. OBJECTIVE: We synthesized various novel benzo-annelated 1,4-dihydropyridines to evaluate them as MDR modulators towards ABCB1 in cancer cells. METHODS: Synthesized compounds were purified by column chromatography. The MDR modulation of ABCB1 was determined in cellular efflux assays using the flow cytometry technique and cellular fluorescent measurements by the use of each fluorescent substrate. RESULTS: Compounds were yielded in a two-step reaction with structurally varied components. Further, substituent- dependent effects on the determined MDR inhibiting properties towards ABCB1 were discussed. Cellular studies prove that there is no toxicity or restoration of cancer cell sensitivity towards the used anticancer drug. CONCLUSION: Novel MDR modulators could be identified with favorable methoxy and ester group functions. Their use in both ABCB1 non-expressing and overexpressing cells proves a selective toxicity-increasing effect of the applied anticancer agent in the ABCB1 overexpressing cells, whereas the toxicity effect of the anticancer drug was almost unchanged in the non-expressing cells. These results qualify our novel compounds as perspective anticancer drugs compared to MDR modulators with nonselective toxicity properties.

Optimized finite-time work protocols for the Higgs RNA model with external force.

The Higgs RNA model with an added term for a coupling to an external force is studied in regard to finite-time force-driving protocols with a minimal-work requirement. In this paper, RNA sequences which at low temperature exhibit hairpins are considered, which are often cited as typical template systems in stochastic thermodynamics. The optimized work protocols for this glassy many-particle system are determined numerically using the parallel tempering method. The protocols show distinct jumps at the beginning and end, which have been observed for single-particle systems and are proven to be optimal in the fast protocol limit generally. Optimality seems to be achieved by staying close to the equilibrium unfolding transition point, in agreement with experimental and theoretical observations. The change of work distributions, compared to those resulting from a naive linear driving protocol, are discussed generally and in terms of free energy estimation as well as the effect of optimized protocols on rare work process starting conditions.

Photothermomechanical Nanopump: A Flow-Through Plasmonic Sensor at the Fiber Tip.

Optical fibers equipped with plasmonic flow sensors at their tips are fabricated and investigated as photothermomechanical nanopumps for the active transport of target analytes to the sensor surface. The nanopumps are prepared using a bottom-up strategy: i.e., by sequentially stacking a monolayer of a thermoresponsive polymer and a plasmonic nanohole array on an optical fiber tip. The temperature-dependent collapse and swelling of the polymer is used to create a flow-through pumping mechanism. The heat required for pumping is generated by exploiting the photothermal effect in the plasmonic nanohole array upon irradiation with laser light (405 nm). Simultaneous detection of analytes by the plasmonic sensor is achieved by monitoring changes in its optical response at longer wavelengths (∼500-800 nm). Active mass transport by pumping through the holes of the plasmonic nanohole array is visualized by particle imaging velocimetry. Finally, the performance of the photothermomechanical nanopumps is investigated for two types of analytes, namely nanoscale objects (gold nanoparticles) and molecules (11-mercaptoundecanoic acid). In the presence of the pumping mechanism, a 4-fold increase in sensitivity was observed compared to the purely photothermal effect, demonstrating the potential of the presented photothermomechanical nanopumps for sensing applications.

Mineralization generates megapascal contractile stresses in collagen fibrils.

During bone formation, collagen fibrils mineralize with carbonated hydroxyapatite, leading to a hybrid material with excellent properties. Other minerals are also known to nucleate within collagen in vitro. For a series of strontium- and calcium-based minerals, we observed that their precipitation leads to a contraction of collagen fibrils, reaching stresses as large as several megapascals. The magnitude of the stress depends on the type and amount of mineral. Using in-operando synchrotron x-ray scattering, we analyzed the kinetics of mineral deposition. Whereas no contraction occurs when the mineral deposits outside fibrils only, intrafibrillar mineralization generates fibril contraction. This chemomechanical effect occurs with collagen fully immersed in water and generates a mineral-collagen composite with tensile fibers, reminiscent of the principle of reinforced concrete.

Introducing Beneficial Alleles from Plant Genetic Resources into the Wheat Germplasm.

Wheat (Triticum sp.) is one of the world's most important crops, and constantly increasing its productivity is crucial to the livelihoods of millions of people. However, more than a century of intensive breeding and selection processes have eroded genetic diversity in the elite genepool, making new genetic gains difficult. Therefore, the need to introduce novel genetic diversity into modern wheat has become increasingly important. This review provides an overview of the plant genetic resources (PGR) available for wheat. We describe the most important taxonomic and phylogenetic relationships of these PGR to guide their use in wheat breeding. In addition, we present the status of the use of some of these resources in wheat breeding programs. We propose several introgression schemes that allow the transfer of qualitative and quantitative alleles from PGR into elite germplasm. With this in mind, we propose the use of a stage-gate approach to align the pre-breeding with main breeding programs to meet the needs of breeders, farmers, and end-users. Overall, this review provides a clear starting point to guide the introgression of useful alleles over the next decade.

Similarity of extremely rare nonequilibrium processes to equilibrium processes.

For system coupled to heat baths, typical nonequilibrated processes, e.g., induced by varying an external parameter without waiting for equilibration in between, are very different from the corresponding equilibrium infinitely slow processes. Nevertheless, there are connections between equilibrium and nonequilibrated behaviors, e.g., the theorems of Jarzynski and Crooks, which relate the distribution P(W) of nonequilibrium work to the free energy differences ΔF. Here we study the naturally arising question, whether those relevant but rare trajectories, which exhibit these work values, show a higher degree of similarity to equilibrium. For convenience, we have chosen a simple model of RNA secondary structures (or single-stranded DNA), here modeling a medium-size hairpin structure, under influence of a varying external force. This allows us to measure the work W during the resulting fast unfolding and refolding processes within Monte Carlo simulations, i.e., in nonequilibrium. Also we sample numerically efficiently directly in exact equilibrium, for comparison. Using a sophisticated large-deviation algorithm, we are able to measure work distributions with high precision down to probabilities as small as 10^{-46}, enabling us to verify the Crooks and Jarzynski theorems. Furthermore, we analyze force-extension curves and the configurations of the secondary structures during unfolding and refolding for typical equilibrium processes and nonequilibrated processes. We find that the nonequilibrated processes where the work values are close to those which are most relevant for applying Crooks and Jarzynski theorems, respectively, but which occur with exponential small probabilities, are most and quite similar to the equilibrium processes.

Ceruloplasmin expression in renal cell carcinoma correlates with higher-grade and shortened survival.

Aim: We aimed to explore ceruloplasmin (CP) expression in clear cell renal cell carcinoma (ccRCC). Materials & methods: CP was analyzed in biofluid samples of 63 ccRCC patients, divided into three grading groups, and immunohistochemically, in 308 ccRCC. Results: Significant differences of mean plasma and urine CP levels in different grading groups were found. CP immunoreactivity was significantly linked to high-grade disease. Log rank tests showed a significant shorter overall survival rate in CP-positive cases (all p < 0.05). Conclusion: CP protein levels in biofluid samples confirmed differential CP expressions, depending on nuclear grade in ccRCC as previously seen in RNA expression analysis. CP expression was linked to high-grade disease and reduced survival rate in RCC.

Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy.

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.

Design Principles of Lipid-like Ionic Liquids for Gene Delivery.

We developed lipid-like ionic liquids, containing 2-mercaptoimidazolium and 2-mercaptothiazolinium headgroups tethered to two long saturated alkyl chains, as carriers for in vitro delivery of plasmid HEK DNA into 293T cells. We employed a combination of modular design, synthesis, X-ray analysis, and computational modeling to rationalize the self-assembly and desired physicochemical and biological properties. The results suggest that thioamide-derived ionic liquids may serve as a modular platform for lipid-mediated gene delivery. This work represents a step toward understanding the structure-function relationships of these amphiphiles with long-range ordering and offering insight into design principles for synthetic vectors based on self-assembly behavior.

Transient Howell-Jolly-body-like cytoplasmic inclusions in neutrophils after severe intoxication with alpha-lipoic acid.

After intravenous supplementation of an unintentionally high dose of the antioxidant alpha-lipoic acid (ALA), a 53-year-old female complained of myalgia, chills and nausea, and showed signs of haemorrhagic diathesis. The laboratory findings were excessive hyperferritinemia, leukoerythroblastosis, severe thrombocytopenia, elevated liver enzymes and impaired coagulation. The toxicological tests resulted in an ALA serum concentration of 10 280 µg/L. The peripheral blood film of the patient showed some neutrophil dysplasia with unusual small dark-blue stained round cytoplasmic inclusions resembling 'Howell-Jolly-body-like' (HJBL) cytoplasmic inclusions, aptly named due to the morphologic similarity to their erythrocytic counterparts. Such HJBL inclusions are occasionally associated with acquired immunodeficiency, or immunosuppressive or cytostatic treatment. An association with ALA intoxication has not been described before. There are only a few reports on unintentional, harmful and lethal intoxications with ALA. The underlying molecular background of its toxicity on liver function or haematopoiesis is not yet known in detail, but ALA seems to interact with enzyme functions, e.g. with mitochondrial enzyme-complexes, possibly due to its pro-oxidant potential at high doses.

Tunable Magnetic Antiskyrmion Size and Helical Period from Nanometers to Micrometers in a D2d Heusler Compound.

Skyrmions and antiskyrmions are magnetic nano-objects with distinct chiral, noncollinear spin textures that are found in various magnetic systems with crystal symmetries that give rise to specific Dzyaloshinskii-Moriya exchange vectors. These magnetic nano-objects are associated with closely related helical spin textures that can form in the same material. The skyrmion size and the period of the helix are generally considered as being determined, in large part, by the ratio of the magnitude of the Heisenberg to that of the Dzyaloshinskii-Moriya exchange interaction. In this work, it is shown by real-space magnetic imaging that the helix period λ and the size of the antiskyrmion daSk in the D2d compound Mn1.4 PtSn can be systematically tuned by more than an order of magnitude from ≈100 nm to more than 1.1 µm by varying the thickness of the lamella in which they are observed. The chiral spin texture is verified to be preserved even up to micrometer-thick layers. This extreme size tunability is shown to arise from long-range magnetodipolar interactions, which typically play a much less important role for B20 skyrmions. This tunability in size makes antiskyrmions very attractive for technological applications.

Characterisation of barley landraces from Syria and Jordan for resistance to rhynchosporium and identification of diagnostic markers for Rrs1Rh4.

KEY MESSAGE: Diagnostic markers for Rrs1Rh4 have been identified by testing for associations between SNPs within the Rrs1 interval in 150 barley genotypes and their resistance to Rhynchosporium commune isolates recognised by lines containing Rrs1. Rhynchosporium or barley scald, caused by the destructive fungal pathogen Rhynchosporium commune, is one of the most economically important diseases of barley in the world. Barley landraces from Syria and Jordan demonstrated high resistance to rhynchosporium in the field. Genotyping of a wide range of barley cultivars and landraces, including known sources of different Rrs1 genes/alleles, across the Rrs1 interval, followed by association analysis of this genotypic data with resistance phenotypes to R. commune isolates recognised by Rrs1, allowed the identification of diagnostic markers for Rrs1Rh4. These markers are specific to Rrs1Rh4 and do not detect other Rrs1 genes/alleles. The Rrs1Rh4 diagnostic markers represent a resource that can be exploited by breeders for the sustainable deployment of varietal resistance in new cultivars. Thirteen out of the 55 most resistant Syrian and Jordanian landraces were shown to contain markers specific to Rrs1Rh4. One of these lines came from Jordan, with the remaining 12 lines from different locations in Syria. One of the Syrian landraces containing Rrs1Rh4 was also shown to have Rrs2. The remaining landraces that performed well against rhynchosporium in the field are likely to contain other resistance genes and represent an important novel resource yet to be exploited by European breeders.

Inhibition of agonist-induced platelet aggregation by magnesium sulfate warrants its use as an alternative in vitro anticoagulant in pseudothrombocytopenia.

MgSO4 is effective in preventing spontaneous in vitro platelet agglutination in anticoagulant-induced pseudothrombocytopenia (PTCP). In order to learn more about its potential as an in vitro anticoagulant, platelets from MgSO4-anticoagulated blood were stimulated by several differentially-acting agonists (ADP, ARA, TRAP, epinephrine, collagen and ristocetin). Platelet aggregation in blood samples from 11 and 17 volunteers was measured by light-transmission aggregometry (LTA) according to Born and impedance aggregometry (MultiplateTM), respectively. Agonist-induced platelet aggregation was markedly lower in MgSO4-anticoagulated samples when compared with citrate-anticoagulated samples (decrease of 95.75% (ristocetin), 69.02% (collagen) and 75.73% (epinephrine)) or hirudin-anticoagulated samples (decrease of 85.99% (ADP), 80.98% (ARA), 77.24% (ristocetin), 54.37% (collagen) and 50.14% (TRAP)). The anti-aggregatory effect of MgSO4 is dose-dependent and readily detectable at a concentration of 7.5 mmol/l. Analysis of the agonist signaling pathways suggest that MgSO4 interferes with the final step of platelet aggregation, namely the intracellular mobilization of Ca2+.

Observation of Magnetic Antiskyrmions in the Low Magnetization Ferrimagnet Mn2Rh0.95Ir0.05Sn.

Recently, magnetic antiskyrmions were discovered in Mn1.4Pt0.9Pd0.1Sn, an inverse tetragonal Heusler compound that is nominally a ferrimagnet, but which can only be formed with substantial Mn vacancies. The vacancies reduce considerably the compensation of the moments between the two expected antiferromagnetically coupled Mn sub-lattices so that the overall magnetization is very high and the compound is almost a "ferromagnet". Here, we report the observation of antiskyrmions in a second inverse tetragonal Heusler compound, Mn2Rh0.95Ir0.05Sn, which can be formed stoichiometrically without any Mn vacancies and which thus exhibits a much smaller magnetization. Individual and lattices of antiskyrmions can be stabilized over a wide range of temperature from near room temperature to 100 K, the base temperature of the Lorentz transmission electron microscope used to image them. In low magnetic fields helical spin textures are found which evolve into antiskyrmion structures in the presence of small magnetic fields. A weaker Dzyaloshinskii-Moriya interaction (DMI), that stabilizes the antiskyrmions, is expected for the 4d element Rh as compared to the 5d element Pt, so that the observation of antiskyrmions in Mn2Rh0.95Ir0.05Sn establishes the intrinsic stability of antiskyrmions in these Heusler compounds. Moreover, the finding of antiskyrmions with substantially lower magnetization promises, via chemical tuning, even zero moment antiskyrmions with important technological import.

Intrinsic stability of magnetic anti-skyrmions in the tetragonal inverse Heusler compound Mn1.4Pt0.9Pd0.1Sn.

Magnetic anti-skyrmions are one of several chiral spin textures that are of great current interest both for their topological characteristics and potential spintronic applications. Anti-skyrmions were recently observed in the inverse tetragonal Heusler material Mn1.4Pt0.9Pd0.1Sn. Here we show, using Lorentz transmission electron microscopy, that anti-skyrmions are found over a wide range of temperature and magnetic fields in wedged lamellae formed from single crystals of Mn1.4Pt0.9Pd0.1Sn for thicknesses ranging up to ~250 nm. The temperature-field stability window of the anti-skyrmions varies little with thickness. Using micromagnetic simulations we show that this intrinsic stability of anti-skyrmions can be accounted for by the symmetry of the crystal lattice which is imposed on that of the Dzyaloshinskii-Moriya exchange interaction. These distinctive behaviors of anti-skyrmions makes them particularly attractive for spintronic applications.

Extremely high conductivity observed in the triple point topological metal MoP.

Weyl and Dirac fermions have created much attention in condensed matter physics and materials science. Recently, several additional distinct types of fermions have been predicted. Here, we report ultra-high electrical conductivity in MoP at low temperature, which has recently been established as a triple point fermion material. We show that the electrical resistivity is 6 nΩ cm at 2 K with a large mean free path of 11 microns. de Haas-van Alphen oscillations reveal spin splitting of the Fermi surfaces. In contrast to noble metals with similar conductivity and number of carriers, the magnetoresistance in MoP does not saturate up to 9 T at 2 K. Interestingly, the momentum relaxing time of the electrons is found to be more than 15 times larger than the quantum coherence time. This difference between the scattering scales shows that momentum conserving scattering dominates in MoP at low temperatures.