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Target class repurposing across membrane transporter families provides privileged ligands to address specific and undruggable pharmacological targets
No full textAltogether, 60–70% of the ATP-binding cassette (ABC) and solute carrier (SLC) transporters can currently not be targeted by drugs, despite their involvement in human diseases. The design of potential drug candidates relies on hit identification and subsequent optimization with regard to selectivity and specificity. However, these workflows ultimately fail if no hit molecules can be found. We pursued a strategy of rational discovery of hit molecules for ‘undruggable’ ABC and SLC transporters based on polypharmacology as an alternative approach in the drug development repertoire. The 42 most polypharmacological ABC transporter modulators were profiled against eight specific (NAT, DAT, and SERT) and polyspecific (OCT1–3, MATE1–2K) SLCs. The general hit rate increased expectedly with the degree of polyspecificity, ranging from 0 to 9.52% (NAT, DAT, SERT) to 19.0–52.4% (OCT1–3, MATE1–2K). Striking was the hit rate for potent drugs, which was highest for the specific transporter SERT (75.0%); additionally, pranlukast (PRA) could also be identified as common substrate of NAT, DAT, SERT, and MATE2K. The polypharmacology of drugs correlated with their potency, and a higher degree of polypharmacology against ABCs was reflected in a higher degree of polypharmacology against SLCs. Some compounds mediated between both specific and polyspecific transporters which could be underpinned by the identification of common molecular features (‘privileged structures’). The polypharmacology of selected drugs could be transferred to ABCA1 and Oatp1d1, two transporters for which almost no modulators have been reported before. This strategy provided privileged ligands with high potency at high hit rates to challenge transporter undruggability
Airborne particulates and brain health: the role of PM2.5 in blood-brain-barrier dysfunction
No full textAmbient particulate matter (PM), especially fine and ultrafine particles, has emerged as a significant environmental risk factor for neurological disorders, largely through its impact on the blood-brain barrier (BBB) and the neurovascular unit. This review summarizes current evidence on how PM affects BBB integrity, emphasizing the coordinated and cell-specific responses that drive neurovascular dysfunction. Upon systemic or neural translocation, PM induces oxidative stress and inflammation in endothelial cells, disrupting tight junctions (TJs), enhancing permeability, and upregulating adhesion molecules (e.g. ICAM-1 and VCAM-1), which facilitate immune cell infiltration. Pericytes contribute to these processes in a stage-dependent manner, promoting BBB leakage through detachment and inflammation in acute settings while participating in later reparative processes such as angiogenesis and neurogenesis. Astrocytes respond to PM exposure by adopting a reactive phenotype, releasing pro-inflammatory cytokines and reactive oxygen species that exacerbate barrier disruption and impair neurovascular coupling. Microglia act as central mediators of neuroinflammation, releasing cytokines that weaken TJs and perpetuate endothelial dysfunction. These mechanisms are further modulated by particle properties and host-related factors including age, metabolic status, and pre-existing comorbidities. The resulting cascade of BBB impairment and neuroinflammation underscores the multifaceted nature of PM-induced neurotoxicity and identifies potential cellular targets for intervention
Progression-free survival with darolutamide and docetaxel vs. androgen receptor pathway inhibitors vs. docetaxel in metastatic hormone-sensitive prostate cancer: a real-world multicenter retrospective study
No full textImproved bioclimatic variables from regional climate models: a comparative analysis of three classic bias adjustment methods and a novel adjustment approach
No full textBioclimatic variables (BCVs) play an important role in understanding ecological dynamics and species distribution under climate variability and change. This research assesses the effectiveness of three bias adjustment methods—Linear Scaling (LSC), Empirical Quantile Mapping (EQM), and Quantile Data Mapping (QDM)—on improving BCVs from Regional Climate Models (RCMs) over Europe, with ERA5-Land as reference dataset. Among the methods tested, EQM slightly stands out for its ability to accurately adjust temperature and precipitation variables, as well as BCVs. However, the different with the two other bias-correction methods is marginal. RCMs were not effective in representing interactive BCVs, especially the mean temperature of the wettest quarter (BIO8) and the mean temperature of the driest quarter (BIO9) and significant residual bias remains after the application of bias adjustment methods. A key innovation of this study was the application of a static quarter/month adjustment in conjunction with EQM, which significantly improved the representation of interactive BCVs. This novel approach effectively addressed seasonal and spatial discrepancies, aligning modeled climate patterns more closely with observed data, thereby improving the model’s ecological relevance. The finding of this study contributes to a more nuanced understanding of ecological dynamics under climate change, offering valuable insights for species distribution modelling based on BCVs
Zur abfallwirtschaftlichen Entwicklung im produzierenden Gewerbe der Bundesrepublik Deutschland
No full textDegradation of lithium-ion batteries: a meta-analysis
No full textThe transition toward sustainable energy systems requires reliable and durable energy storage technologies, with lithium-ion batteries (LIBs) being central to electrification and the integration of renewables. However, the decline in capacity per cycle, referred to as the degradation rate (DegRate), decreases the lifetime and performance of LIBs, thereby limiting their ecological and economic benefits. To address this, we conducted the first meta-analysis of LIB degradation, drawing on 146 studies and 917 effect sizes. The analysis accounts for the heterogeneity in reported DegRates using explanatory variables grouped into battery differences, experiment-, measurement-, and publication-specific categories. Across studies, we found a median DegRate of 0.04%/cycle, with cut-off charge voltage and temperature emerging as the dominant influencing factors. Using meta-regression, we quantify the effects of these explanatory variables. Furthermore, we establish a forward-looking quantitative benchmark: under extreme cold (0 °C) and very high charge cut-off voltages, model-implied mean DegRates for graphite-based systems reach 0.68–1.41%/cycle (14–29 cycles). For promising Si-based chemistries, the benchmark is more prospective with model-implied mean DegRates of 0.98–1.71%/cycle (11–20 cycles), with higher uncertainty in these sparsely covered regimes, as reflected in the confidence intervals. This study highlights critical gaps in the experimental matrix and, rather than relying on a single estimate, establishes quantitative benchmarks for LIB degradation that serve as a reference for future research, particularly for combinations of operating conditions that have not yet been experimentally explored
Mathematikdidaktik – quo vadis? Eine Fragensammlung
No full textEs werden eine Reihe von Fragen bezüglich der Schwerpunkte der Mathematikdidaktik zur Diskussion gestellt
BPS2026 – Controlling multiphase coacervate wetting and self-organization by interfacial proteins [Abstract]
No full textCharacterization of polyconvex isotropic functions
No full textPolyconvexity is an important concept in the analysis of energies related to elasticity. A function W:Rd×d→R is called polyconvex if it can be written as a convex function in the minors of the argument. We show that for isotropic functions it suffices to consider diagonal matrices. For d=3, this leads to a dimension reduction for the convex representative of W from R19 to R7. Moreover, we present a new result for the polyconvexity of functions formulated in the principal invariant of the left or right stretch tensor
