Miracle-dz/UniFAR-FTUs huggingface dataset:
Static Model–Based Assessment of OATP1B1-Mediated Drug Interactions with Preincubation-Dependent Inhibitors Based on Inactivation and Recovery Kinetics

Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubation-dependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC50 values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENT Static model–based quantitative prediction of organic anion transporting polypeptide 1B1–mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.
Factors affecting the management of cattle grazing distribution in northern Australia: preliminary observations on the effect of paddock size and water points

Achieving more uniform grazing at landscape and paddock scales is seen as an important management objective by pastoralists in northern Australia, but it is difficult to attain in practice. This paper presents a brief review of some key factors to be considered in attempts to modify grazing distribution in extensive rangelands by drawing on the preliminary results of a project that is investigating several options for achieving more uniform grazing. Subdividing the landscape into smaller paddocks and, to a lesser extent, installing additional water points in large paddocks are effective in distributing grazing more widely across the landscape. However, these approaches are less effective in achieving uniform grazing within paddocks, and areas of concentrated use still occur even in small paddocks. To achieve spatial grazing objectives, it is necessary to use management tools that operate at the appropriate scale. Attaining more even use within paddocks should therefore be viewed as a separate management objective, requiring different techniques, to obtaining more effective use of the landscape as a whole. Integrating the use of several spatial management tools that act at different scales is likely to be most effective in improving grazing distribution. Our findings also highlight the importance of understanding paddocks in terms of the spatial arrangement of forage resources and their acceptability and quality in relation to water points and other landscape features. Differences between individual cattle in the way they use the landscape are important in producing more uniform use in larger paddocks and may also offer other opportunities for improving the use of landscape resources overall. Finally, the implications of more uniform use for livestock production and other land use values should be considered, with the protection of biodiversity values potentially requiring special management arrangements where more even use is achieved.
The AutGO Initiative: A Conceptual Framework for Developing Genetics‐Outcomes Research Hypotheses

The increasing emphasis on translational approaches to complex neuropsychiatric and neurodevelopmental conditions research requires scientists from a broad range of disciplines to build dynamic collaborations when formulating hypotheses and framing study designs. The need to integrate the knowledge and perspectives not only from multiple scientific silos but also from the populations impacted by these conditions presents a significant challenge to researchers, particularly for a heterogeneous condition like autism. As one path toward addressing these challenges, we have previously introduced Autism Genetics Outcomes (AutGO), an initiative to support broad stakeholder partnerships and promote a new integrated concept called GO (i.e., research approaches that draw on both genetics and clinical outcomes perspectives). Herein, we developed a workflow for collecting stakeholders' feedback toward the development of a GO hypothesis. AutGO is an evolving initiative, and here we describe how its three essential components (conceptual framework, applicability, and implementation) have been developed. As a proof‐of‐concept, the AutGO team sought to demonstrate how a GO hypothesis could be developed using a semi‐structured literature review workflow. We also developed a prototype from published reports and formulated a GO hypothesis for autism. Rather than seeking community stakeholder input after a research project is conceptualized and designed, the developed conceptual framework demonstrates the feasibility of formulating scientific hypotheses by engaging stakeholders in retrospective semi‐structured literature reviews. The presented workflow, prototype, and discussed recommendations will bring awareness in the autism research community about the benefits of applying the GO approach in order to promote translational aspects in genetics research.
Accelerating water dissociation in bipolar membranes and for electrocatalysis

Easing water apart Traditional setups for splitting water into hydrogen and oxygen operate either in acid or in base. A bipolar membrane can potentially enhance efficiency by bridging acidic hydrogen evolution to basic oxygen evolution. Oener et al. undertook a systematic study of how catalysts paired with such a membrane might accelerate the preliminary step of water dissociation into protons and hydroxide ions. Using insights from this study for optimal catalyst integration, they were able to substantially lower the overpotential of a bipolar membrane electrolyzer. Science, this issue p. 1099 A systematic study of water-dissociation catalysts enhanced performance of bipolar membranes for electrolysis. Catalyzing water dissociation (WD) into protons and hydroxide ions is important both for fabricating bipolar membranes (BPMs) that can couple different pH environments into a single electrochemical device and for accelerating electrocatalytic reactions that consume protons in neutral to alkaline media. We designed a BPM electrolyzer to quantitatively measure WD kinetics and show that, for metal nanoparticles, WD activity correlates with alkaline hydrogen evolution reaction activity. By combining metal-oxide WD catalysts that are efficient near the acidic proton-exchange layer with those efficient near the alkaline hydroxide-exchange layer, we demonstrate a BPM driving WD with overpotentials of <10 mV at 20 mA·cm−2 and pure water BPM electrolyzers that operate with an alkaline anode and acidic cathode at 500 mA·cm−2 with a total electrolysis voltage of ~2.2 V.
The in vivo and in vitro Roles of Epithelial Pattern Recognition Receptors in Pneumococcal Infections

Streptococcus pneumoniae, also called pneumococcus, is a major cause of infectious disease in human. Pneumococcus resides in the nasopharynx as an upper respiratory commensal, and most of pneumococcal colonizations are asymptomatic in immunocompetent individuals. When nasopharyngeal mucosal homeostasis is disrupted, pneumococcus migrates into middle ear and lower respiratory tract and causes detrimental colonization. In this regard, the epithelial cells of middle ear and lung act as first line of defense against pneumococcus to prevent invasive pneumococcal diseases. Respiratory epithelial cells express various cell-surface and intra-cellular receptors sensing microbial pathogens and respond to sensed pathogens by triggering intra-cellular signaling pathways and inducing pathogen-specific innate immune responses. Various epithelial cell-surface and intra-cellular receptors, such as Toll-like receptors (TLRs), Nod-like receptors (NLRs), intracellular DNA sensing receptors, and scavenger receptors (SRs), participate in sensing of pneumococcus, and the activation of these receptors by pneumococcal components induces anti-pneumococcal innate immune responses including epithelial apoptosis and inflammatory cytokine/chemokine expressions. Epithelial sensing of pneumococcus is a critical step for setting an early defense against pneumococcal infection, and also is required to recruit and activate innate immune cells and trigger adaptive immunity.
Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use. We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection. Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model. Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome. We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection. The cyclophilin inhibitors cyclosporin A and alisporivir activate host innate immunity by induction of interferon-λ via activation of IRF1 in human lung epithelial cells and in vivo, resulting in a significant inhibition of MERS-CoV https://bit.ly/37gzIBH
Relationship Between Endplate Defects, Modic Change, Facet Joint Degeneration, and Disc Degeneration of Cervical Spine

Objective The “disc degeneration precedes facet joint osteoarthritis” hypothesis and multidimensional analysis were actively discussed in lumbar spine. However, in cervical spine degeneration, the multifactorial analyzes of disc degeneration (DD), Modic changes (Mcs), facet degeneration, and endplate degeneration (ED) is still limited. In this cross-sectional study, we aimed to analyze the prevalence and interrelationship of cervical DD parameters. Methods We retrospectively recruited 62 patients aged between 60 and 70 years. The disc height, segmental angle, ossified posterior longitudinal ligament (OPLL), ED, facet joint degeneration (FD), uncovertebral joint degeneration (UD), DD, spinal stenosis (SS), Mc, and cord signal change (CS) were evaluated using a previously well-known grading system. Results The prevalence of cervical degenerative parameters were DD (grade 1, 1.2%; grade 2, 13.3%; grade 3, 54.8%; grade 4, 19.0%; grade 5, 11.7%), OPLL (26.2%), SS (grade 0, 7.7%; grade 1, 42.3%; grade 2, 26.2%; grade 3, 23.8%), UD (39.1%), ED (normal, 69.0%; focal defect, 9.7%; corner defect, 11.7%; erosion, 6.9%; sclerosis, 2.8%), and FD (normal, 48.8%; narrowing, 27.0%; hypertrophied, 24.2%). The interrelationship of degenerative parameters showed close relation between UD, SS, DD, OPLL, Mc. ED, and CS has partial relation with degenerative finding. FD only has relation with UD, and Mc. Conclusion Our results may indicate that FD is a degeneration that occurs independently, rather than as a result of other degenerative factors.
The role of epidermal turgor in stomatal interactions following a local perturbation in humidity

Humidity in a small area of a Vicia faba L. leaf was perturbed with a flow of dry air from an 80 µm (inside diameter) needle, while the remainder of the leaf was maintained at high and constant humidity. The influence of the needle flow on the humidity at the leaf surface was quantified by using a spatially explicit dewpoint hygrometer to observe condensation patterns. When the dry air from a needle was applied to the leaf, stomata within the influence of the needle opened within the first few minutes of the perturbation, and local epidermal turgor pressure declined within the same time frame. When the needle flow was removed from the leaf, these responses were reversed, but with more variable kinetics. Stomata and epidermal cells outside the influence of the needle flow, which were exposed to a constant and high humidity, showed similar, but smaller, responses when the needle flow was applied to the leaf. Since the opening of these stomata should have had only a small effect on transpiration (because of the high humidity), it is likely that the reduction in epidermal turgor was the cause (rather than the result) of the stomatal opening. The magnitude of the turgor response was only loosely related to the distance from the needle flow up to distances of almost 400 μm. The data support the idea that neighbouring stomata can interact through the influence of transpiration on epidermal turgor.
DOES DIFFERENTIAL SUSCEPTIBILITY TO PREDATION IN TADPOLES STABILIZE THE BOMBINA HYBRID ZONE

Despite substantial divergence, the European toads Bombina bombina and Bombina variegata (Anura: Discoglossidae) interbreed freely wherever their parapatric distributions adjoin. Natural selection that stabilizes the resulting hybrid zones should rest in part on the adaptation to different breeding habitat of the pure taxa. While B. bombina lays its eggs in semipermanent ponds, B. variegata is a typical puddle breeder. Here, we investigate whether selection for rapid larval development in B. variegata has resulted in the loss of effective antipredator defenses, thus excluding this species from predator-rich ponds. We collected adults from four populations in Romania (two for each taxon) and reared the offspring from four crosses per population in the laboratory either in the presence or in the absence of caged odonate predators (Aeshna cyanea). In predation trials, we found no taxon difference in mortality rate among tadpoles that had been reared with predators. The resilience of B. variegata tadpoles may have been due to their remarkable phenotypic plasticity. In both taxa, predator presence led to the development of a higher tail fin, which has been shown to reduce predation rates in other amphibians. This response was much stronger in B. variegata than in B. bombina. Moreover, differences between the two B. variegata populations in terms of laboratory predation rates and levels of plasticity correlated with predator abundance at the collection sites so as to suggest local adaptation in predator defenses. Finally, delayed metamorphosis in the predator-induced morphs of both taxa implies a cost to the defense. Given the heterogeneity of temporary habitat in terms of desiccation rate and predator occurrence, the greater amount of phenotypic plasticity in B. variegata fits predictions of life history theory. At the same time, our results leave the question unresolved as to why this species avoids ponds.
Respuesta barotrópica de los golfos norpatagónicos argentinos forzados por mareas y vientos

This work presents the results of a high resolution three dimensional non-linear barotropic hydrodynamic model used to examine the response of three north Patagonian gulfs in Argentina (San Matias, SMG; Nuevo, NG; and San Jose, SJG) forced by tides and idealized patterns of surface winds. The structure of the circulation induced by the dominant winds (Westerly) in all three gulfs consists of two independent gyres: one anticyclonic gyre in the west with an intense southward coastal flow and weaker return flow in the middle of the gulfs and one cyclonic gyre in the east that, in the SMG's case, connects with the shelf. The other two gulfs (NG and SJG) have much more restricted connections with the exterior. The inclusion of tidal dissipation effects reduces the intensity of the gyres, but the general spatial pattern of the circulation remains. Increasing the wind magnitude mainly intensifies the anticyclonic gyre and the cross-shelf transport through the SMG mouth and deepens the surface Ekman layer. If the gulfs are forced with meridional winds, the circulation splits into two gyres whose sense of circulation depends on the wind direction: a northern cyclonic (anticyclonic) gyre and a southern anticyclonic (cyclonic) gyre for Southerly (Northerly) winds. When the gulfs are forced simultaneously by tides and winds, the residual tidal currents dominates the general circulation and contributes to a greater dynamical isolation of the gulfs from the exterior shelf.
A PHYLOGENY OF THE BRACHYOPOIDEA (TEMNOSPONDYLI, STEREOSPONDYLI)

Abstract In the thirty years since the last comprehensive review of the Brachyopidae many new brachyopid genera have been described and several different phylogenies proposed. This paper provides revised diagnoses of the Brachyopidae, their sister taxon, the Chigutisauridae, and the Brachyopoidea, erects a new higher taxon, Brachyopomorpha to include stem brachyopoids, and reviews the status of all material referred at one time to these taxa. In it we present revised illustrations of the first described member of the Brachyopidae and clarify parts of the morphology of it and other members of the Brachyopoidea including especially the mandible and postcranial skeleton. A new genus and species, Vigilius wellesi, is proposed for the skull of Hadrokkosaurus bradyi as the holotype of H. bradyi, a mandible, cannot be positively associated with the skull. A phylogenetic analysis including most taxa and all putative outgroups confirms the Chigutisauridae as sister group to the Brachyopidae, forming the Brachyopoidea. Bothriceps australis becomes a sister taxon to the Brachyopoidea. Xenobrachyops allos and Keratobrachyops australis are the most plesiomorphic members of the Brachyopidae and Chigutisauridae respectively.
Growth and development in the subtropical copepod Acrocalanus gibber

Growth rates of the subtropical copepod Acrocalanus gibber were measured in field incubations. Prosome length of adult females was correlated with rearing temperature, but variation in condition of copepods masked any correlation of temperature with carbon and nitrogen content. The resulting N-specific growth rates (GN) were log-linear and ranged from 0.4'9 to 0.72 d-l at temperatures of 24.4-29.2"C. Highest growth rates occurred in the middle of the temperature range, but no re- lationship between GN and temperature could be established, although molting rate and generation time were correlated with temperature. Growth rate was negatively related to chlorophyll a con- centration and was independent of particulate C and N. Nitrogen-specific egg production, measured either from wild-caught females or from females produced in the incubations, never exceeded 0.28 d-l (representing only 46% of GN) and was frequently near zero. In this respect, juvenile growth was less food-limited than was adult growth (measured as egg production). The measured duration of A. gibber developmental stages, particularly copepodite stages 1 and 5, varied in laboratory experiments, apparently as a result of variation in food composition. Molting rate, copepod weight, and the resulting growth rates appear to be influenced by food quality.
Verification of Nuclear Magnetic Resonance Characterization of Traditional Homeopathically Manufactured Metal (Cuprum metallicum) and Plant (Gelsemium sempervirens) Medicines and Controls

Abstract Background Nuclear magnetic resonance (NMR) proton relaxation is sensitive to the dynamics of the water molecule, H2O, through the interaction of the spin of the proton (1H) with external magnetic and electromagnetic fields. NMR relaxation times describe how quickly the spin of 1H, forced in a direction by an external electromagnetic field, returns to a normal resting position. As a result, such measurements allow us potentially to describe higher structuring of water in homeopathic medicines. Objective The purpose of the present study was to verify whether specific NMR relaxation times could be measured in full lines of cH dynamizations of a metal (copper) and of a plant substance (Gelsemium sempervirens), compared with a solvent control, a potentized lactose control and a control prepared by simple dilution, in three production lines. It is aimed at verification of a previous publication (2017) on two new manufacturing lines of the same starting material and controls. Materials and Methods To monitor dilution and potentization processes, measurements of 1H spin-lattice T1 and spin-spin T2 relaxation times were used. T1 and T2 relaxation times were measured at 25°C with a spin analyser working at a frequency of 20 MHz. To account for its possible role as a confounding factor, free oxygen was also measured in all samples, using a MicroOptode meter. Results When the values of the three production lines were pooled, a statistically significant discrimination of NMR relaxation times between the medicines and their controls was confirmed. We found for copper cH and Gelsemium sempervirens cH a highly significant influence of the starting material (p = 0.008), a highly significant influence of level of dilution (p < 0.001), and a significant influence of the O2 concentration (p = 0.04). Conclusions We have evidence of an obvious retention of a specific magnetic resonance signal when a substance (lactose, copper, Gelsemium) is diluted/potentized in pure water. This means that homeopathic solutions cannot be considered to be pure water. O2 is a covariant and not an explanatory variable: this factor itself is too weak to explain the NMR signal specificities in potentized samples. Homeopathic dilutions may thus have a specific material configuration governed not only by the potentized substance but also by the chemical nature of the containers, the chemical nature of dissolved gases and even by the electromagnetic environment. This sensitivity of homeopathically prepared medicines to electromagnetic fields may be amplified by the processes routinely applied during their preparation; because it occurs only when a dynamization has been performed, we may call this phenomenon “dynamic pharmacy”.