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Abstract Background The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) multimodal lifestyle intervention yielded cognitive and other health benefits in older adults at risk of cognitive decline. The two-year multinational randomized controlled LETHE trial evaluates the feasibility of a digitally supported, adapted FINGER intervention among at-risk older adults. Technology is used to complement in-person activities, streamline the intervention delivery, personalize recommendations, and collect digital biomarkers. Methods Trial includes older adults (60–77 years) with digital readiness/experience with smart devices and increased dementia risk but without substantial cognitive impairment. Participants are enrolled at four sites (Austria, Finland, Italy, Sweden). At baseline, participants were randomized 1:1 ratio to 1) intervention i.e., structured multimodal lifestyle program (including diet, exercise, cognitive training, vascular/metabolic risk management, social stimulation, sleep/stress management) where in-person activities led by professionals are supported with an Android mobile phone application developed by the consortium (the LETHE App); or 2) control i.e., self-guided program (regular health advice; simplified App with no personalized/interactive content). All participants wear smartwatches to gather passive data (e.g., physical activity, sleep). Primary outcomes are retention, adherence, and change in validated dementia risk scores. Secondary outcomes include changes in lifestyle, cognition, stress, sleep, health-related quality of life, and health literacy. Additional outcomes (exploratory) include e.g. participant experiences and dementia-related biomarkers (Alzheimer’s disease blood markers, neuroimaging). A sub-study explores the feasibility of novel interactive technology (audio glasses, social robot). Results Recruitment began in September 2022, and the last participant was randomized in June 2023. In total, 156 individuals were randomized (mean age 69 years, 65% women; balanced recruitment across the four sites). Vascular and lifestyle risk factors were common (e.g., 65% with hypertension, 69% with hypercholesterolemia, 39% physically inactive), indicating successful recruitment of a population with risk reduction potential. Trial will be completed by summer 2025. Retention until the first post-baseline visit at 6 months is high (n = 2 discontinued, retention 98.7%). Conclusion LETHE provides crucial information about the feasibility of technology and a digitally supported FINGER lifestyle program to promote brain health. Digital tools specifically designed for older adults could offer potential for large-scale, cost-effective prevention programs. Trial registration ClinicalTrials.gov (NCT05565170).

Perennial grasslands play an important role as an extensive CO2 sink. Fodder and biofuels can be produced in an ecologically acceptable manner on such sites. Projected future climate-change scenarios suggest that Central Europe’s grasslands will be increasingly affected by drought. In order to determine whether there is potential for some alternative drought-adapted grass species to contribute to herbage production for either forage or biomass, we tested the agronomic performance of ten grass species (Agropyron elongatum, Agropyron intermedium, Agropyron desertorum, Agropyron trachycaulum, Elymus hoffmannii, Elymus junceus, Bromus inermis, Bromus marginatus, Festuca arundinacea and Panicum virgatum) in comparison to four reference grasses (Dactylis glomerata, Arrhenatherum elatius, Agrostis gigantea and Agropyron repens). Experiments were conducted in small-plot cutting trials at two sites across two growing seasons with either one or multiple cuts per season. In the one-cut system, P. virgatum provided the highest average annual dry matter (DM) yield (14 258 kg ha–1), followed by A. elongatum (13 086 kg ha–1). The multi-annual persistence of these two species under the experimental conditions was given only when P. virgatum was not harvested before freezing off and A. elongatum was harvested only once per year. Moreover, both species are susceptible to lodging. In the multiple-cut system, F. arundinacea showed a high yield (12 533 kg DM ha–1 average annual yield) and a low presence of associated weeds (only 0.1% surface area). Cultivating this grass species requires considering its only moderate competitiveness during the establishment phase. Based on the rapid establishment of A. trachycaulum, this species is expected to be best suited as a cover crop in seed mixtures. The yields of A. desertorum, A. trachycaulum, A. repens, E. junceus and B. marginatus were below the experimental average (9255 kg DM ha–1 at multiple cuttings). DOI: 10.5073/JfK.2014.06.01, https://doi.org/10.5073/JfK.2014.06.01

The Institute of Sport Science at the University of West-Hungary, and the FH-Joanneum - together with students majoring in sport science - started a collaborative international research aimed at assessing the sport-specific skills of football players. The study closely monitored football players - from leagues at different levels - in terms of choice reaction time, short and long pass skills and agility skills with and without a ball. The most modern device available, the SmartSpeed - a photoelectric stopwatch system - was used for the measurements. The data obtained by the applied internationally standardized tests can be compared in terms of players from leagues at different levels. The study occurred using correlation analysis (p<0.05), and we used linear regression to compare laterality. The hypothesis that teams playing in higher league are significantly more successful in terms of the evaluated technical parameters has not been verified in all cases. There are interesting results regarding the differences between moving to the opposite side with and without ball. The results of the Hungarian team (N=97 players) can be compared to those of the Austrian and international players. [ABSTRACT FROM AUTHOR]

This paper presents an optimization algorithm for journal bearing profiles with respect to stiffness and load-carrying capacity and an application example of the same. An analytical approach for finding the optimum is derived. How the optimization procedure works when using numerical calculation tools is briefly explained. The application example is introduced and the expected performance of the optimized bearing profile is compared to the expected performance of state-of-the-art bearing profiles. Finally, the measured bearing performance data is compared to the expected values. The findings indicate the effectiveness of the introduced optimization algorithm. [ABSTRACT FROM AUTHOR]

The recovery of viscous oil can be significantly improved by injecting polymer solutions. The processes leading to increased oil production occur on a large scale--improving vertical and areal sweep efficiency--but they begin on a microscale. Micromodels with realistic pore geometries have been created. These micromodels were saturated with viscous oil, and the displacement of the oil by water and polymer solutions was investigated experimentally. Polymer injection reduced fingering compared with water injection and increased sweep efficiency accordingly. The micromodel pore-network geometry was digitized with scanning electron microscopy (SEM). The digitized model was used to perform computational-fluid-dynamics (CFD) simulation of the displacement processes. The displacement efficiencies and displacement patterns of the CFD simulations with water, polymer solutions, and polymer solutions after water breakthrough at the outlet end to displace oil were very similar to the results of the micromodel experiments. Then, the CFD simulations were used to investigate the displacement at the pore scale. Water injection leads to the creation of fingers along slightly more-permeable flow paths. The number and length of the fingers decrease if polymer solution is injected. Even for polymer injection after water breakthrough, the fingering is reduced, polymer solutions are diverted into less-favorable flow paths, and sweep efficiency is increased. CFD simulations can also be used to look into non-Newtonian fluid behavior at the pore scale. The polymers injected in the micromodel experiments exhibited shear-thinning behavior. On a pore scale, CFD simulations showed that the shear stress and viscosity of the polymer solutions accordingly are significantly lower in the pore throats than in the pores. Thus, the displacement efficiency of the polymer solutions is affected by the shear-thinning behavior. The CFD simulations are in remarkable agreement with the micromodel experiments and can be used to quantify the displacement processes at pore scale. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the roughness of the surface of one nanofill (Filtek Supreme XT, 3M Espe, St. Paul, USA) and one silorane (Filtek Silorane, 3MEspe, St. Paul, USA) composite after polishing. Five specimens of each composite were polymerized under a polyester strip for 40 seconds. After curing four probes were polished with different Sof-Lex discs and one probe with Pogo for ten seconds. For the surface appointment a contact stylus profilometer was used. The profilometer made ten tracings for each sample at different locations. There was a significant difference in roughness between both composites. The Ra (average surface roughness) results for the silorane composite were almost always significantly higher than for the nanofill composite (T-test). For both composites Sof-Lex fine and superfine discs produced smoother final surfaces than Pogo. The nanofill composite used showed the smoothest surfaces after the polishing and finishing procedures. [ABSTRACT FROM AUTHOR]

Of the various enhanced-oil-recovery (EOR) polymer formulations, newly developed associative polymers show special promise. We investigate pore and pore-network scales because polymer solutions ultimately flow through the pore space of rock to displace oil. We conduct and monitor optically water/oil and polymer-solution/oil displacements in a 2D etched-silicon micromodel. The micromodel has the geometrical and topological characteristics of sandstone. Conventional hydrolyzed-polyacrylamide solutions and newly developed associative-polymer solutions with concentrations ranging from 500 to 2,500 ppm were tested. The crude oil had a viscosity of 450 cp at test conditions. Our results provide new insight regarding the ability of polymer to stabilize multiphase flow. At zero and low polymer concentrations, relatively long and wide fingers of injectant developed, leading to early water breakthrough and low recoveries. At increased polymer concentration, a much greater number of relatively fine fingers formed. The width-to-length ratio of these fingers was quite small, and the absolute length of fingers decreased. At a larger scale of observation, the displacement front appears to be stabilized; hence, recovery efficiency improved remarkably. Above a concentration of 1,500 ppm, plugging of the micromodel by polymer and lower oil recovery was observed for both polymer types. For tertiary polymer injection that begins at breakthrough of water, the severe fingers resulting from water injection are modified significantly. Fingers become wider and grow in the direction normal to flow as polymer solution replaces water. Apparently, improved sweep efficiency of viscous oils is possible (at this scale of investigation) even after waterflooding. The associative- and conventional-polymer solutions improved oil recovery by approximately the same amount. The associative polymers, however, showed more-stable displacement fronts in comparison to conventional-polymer solutions. [ABSTRACT FROM AUTHOR]

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This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo., Competing Interests: Declaration of interests K.G., B.B, S.P., J.N., J.W., R.L., K.B, B.N., W.B., S.G., S.K., C.K., H.S., N.B., K.N-R., C.S., P.S., M.L. are/were employees of Nuvisan ICB GmbH and Bayer Pharma AG. P.L., J.K., L.P., A.M., S.P., S.H., A.K., A.St., A.Sc., P.B., N.A.F., T.H., L.K., A.O.W., S.B., M.O., A. L., F.v.N., D.M., K.E. are/were employees of Bayer Pharma AG. This study was funded by Bayer Pharma AG. The following patent applications in relation to this study have been submitted: WO-2020048826-A1, WO-2020048830-A1, WO-2020048829-A1, WO-2020048828-A1, WO-2020048831-A1, WO-2020048827-A1. S.P. served as consultant for Bayer in relation to this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2- a ]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28 . It turned out that BAY 1165747 (BAY-747, 28 ) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 ( 28 ) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

The excited-state dynamics of a series of Wurster's salts (p-phenylenediamine radical cations) with different subtituents on the nitrogen atoms was investigated under a variety of experimental conditions using a combination of ultrafast spectroscopic techniques. At room temperature, the lifetime of the lowest excited state of all radical cations is on the order of 200 fs, independently of the solvent, that is, water, nitriles, alcohols, and room-temperature ionic liquid. On the other hand, all cations, except that with the bulky nitrogen substituents, become fluorescent below 120 K. The observed dynamics can be accounted for by the presence of a conical intersection between the D(1) and D(0) states. For the cations with a small nitrogen substituent, this conical intersection could be accessed through a twist of one amino group, as already suggested for Wurster's Blue. However, this coordinate cannot be invoked for the cation with bulky nitrogen subtituents, and more probably, pyramidalization of the nitrogen center and/or deformation of the phenyl ring play an important role. Consequently, the excited-state dynamics of these structurally very similar Wurster's salts involves different decay mechanisms.

A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route.