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In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1–3. Studies of human and mouse GSDM pores reveal the functions and architectures of 24–33 protomers assemblies4–9, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing >50 protomers. We determine a 3.3 Å cryo-EM structure of a Vitiosangium bGSDM in an active slinky-like oligomeric conformation and analyze bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, our results support a stepwise model of GSDM pore assembly and suggest that a covalently bound palmitoyl can leave a hydrophobic sheath and insert into the membrane before formation of the membrane-spanning β-strand regions. These results reveal the diversity of GSDM pores found in nature and explain the function of an ancient post-translational modification in enabling programmed host cell death.
Background: Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remains poorly understood.
Results: We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results show that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on genomic features as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons. These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.
Conclusions: Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.
Predator-prey interactions are vital for organismal survival. They shape anti-predator mechanisms and often depend on sensory abilities. Tadpoles use chemical cues, such as injury cues (alarm cues), to assess predation risks and modify their life-history, morphology, and behaviours accordingly. However, the prevalence of chemically mediated anti-predator responses in species with distinct ecological niches (e.g. within phytotelmata) remains unknown, hindering our understanding of the ecological significance and evolution of alarm substances. Therefore, our study aimed to investigate chemically mediated anti-predator responses in tadpoles of two Neotropical poison dart frogs, Ranitomeya sirensis and Epipedobates anthonyi (and compare their responses to two Palearctic model organisms, Rana temporaria and Bufo bufo, which are known to utilise alarm substances). Through behavioural bioassays, we exposed predator-naïve tadpoles to extracts of each species (i.e. con- and heterospecific cues), including water as a control (i.e. five treatments per species). We assessed changes in their activity before and after stimulus introduction. Our results show that E. anthonyi did not respond to any of the stimuli, whereas R. sirensis displayed increased activity levels exclusively in response to conspecific cues, but not to heterospecific cues. With this, our findings suggest a specialized recognition system in R. sirensis, potentially directed at conspecific competitors but likely unrelated to anti-predator mechanisms. In contrast, E. anthonyi may be insensitive to injury cues or utilize alternative sensory modalities to respond to acute predation events. This study sheds light on the chemical alarm response system of Neotropical poison dart frog tadpoles, providing foundational understanding of how dendrobatids react to injury cues. It prompts questions about the ecological significance and evolutionary implications of chemical communication in species facing extreme resource limitation during development and underscores the importance of comparative research for understanding chemical communication in diverse aquatic ecosystems.
Purpose: To evaluate intermediate and long-term visual outcomes and safety of a phakic intraocular posterior chamber lens with a central hole (ICL V4c) for myopic eyes.
Methods: Retrospective, consecutive case study of patients that uneventfully received a ICL V4c for myopia correction, with a 5-year postoperative follow-up. Department of Ophthalmology, Goethe University Frankfurt, Germany.
Results: From 241 eyes that underwent ICL implantation, we included 45 eyes with a mean age at surgery of 33 years ± 6 (18–48 years), with a 5 years follow-up. CDVA improved from 0.05logMAR ± 0.15 CDVA preoperatively to − 0.00 ± 0,07 at 5 years and did not change significantly from 3 to 5 years’ time (p = 0.266). The mean spherical equivalent (SE) improved from -10.13D ± 3.39 to − 0.45D ± 0.69. The change in endothelial cell count showed a mean decrease of 1.9% per year throughout the follow-up. Safety and efficacy index were 1.16 and 0.78, respectively. Cataract formation was seen in 2 of 241 eyes (0.8%), but in none of the 45 eyes that finished the 5-year follow-up.
Conclusions: Our data show a good intermediate and long-term stability, efficiency, and safety of ICL V4c phakic lenses in myopic eyes comparable to other known literature.
The category of abelian varieties over Fq is shown to be anti-equivalent to a category of Z-lattices that are modules for a non-commutative pro-ring of endomorphisms of a suitably chosen direct system of abelian varieties over Fq. On full subcategories cut out by a finite set w of conjugacy classes of Weil q-numbers, the anti-equivalence is represented by what we call w-locally projective abelian varieties.
We consider ground state solutions u ∈ H2(RN) of biharmonic (fourth-order) nonlinear Schrodinger equations of the form ¨2u + 2au + bu − |u| p−2u = 0 in RN with positive constants a, b > 0 and exponents 2 < p < 2∗, where 2∗ = 2N N−4 if N > 4 and 2∗ = ∞ if N ≤ 4. By exploiting a connection to the adjoint Stein–Tomas inequality on the unit sphere and by using trial functions due to Knapp, we prove a general symmetry breaking result by showing that all ground states u ∈ H2(RN) in dimension N ≥ 2 fail to be radially symmetric for all exponents 2 < p < 2N+2 N−1 in a suitable regime of a, b > 0. As applications of our main result, we also prove symmetry breaking for a minimization problem with constrained L2-mass and for a related problem on the unit ball in RN subject to Dirichlet boundary conditions.
ABC transporters are found in all organisms and almost every cellular compartment. They mediate the transport of various solutes across membranes, energized by ATP binding and hydrolysis. Dysfunctions can result in severe diseases, such as cystic fibrosis or antibiotic resistance. In type IV ABC transporters, each of the two nucleotide-binding domains is connected to a transmembrane domain by two coupling helices, which are part of cytosolic loops. Although there are many structural snapshots of different conformations, the interdomain communication is still enigmatic. Therefore, we analyzed the function of three conserved, charged residues in the intra-cytosolic loop 1 of the human homodimeric, lysosomal peptide transporter TAPL. Substitution of D278 in coupling helix 1 by alanine interrupted peptide transport by impeding ATP hydrolysis. Alanine substitution of R288 and D292, both localized next to the coupling helix 1 extending to transmembrane helix 3, reduced peptide transport but increased basal ATPase activity. Surprisingly, the ATPase activity of the R288A variant dropped in a peptide-dependent manner while ATPase activity of wildtype and D292A was unaffected. Interestingly, R288A and D292A mutants did not differentiate between ATP and GTP in respect of hydrolysis. However, in contrast to wildtype TAPL, only ATP energized peptide transport. In sum, D278 seems to be involved in bidirectional interdomain communication mediated by network of polar interactions while the two residues in the cytosolic extension of TMH3 are involved in regulation of ATP hydrolysis, most likely by stabilization of the outward facing conformation.
Der Artikel bietet eine Analyse von John A. Williams' Roman "Clifford's Blues" (1999), der in der Form eines fiktiven, von einem afroamerikanischen Jazz-Musiker geschriebenen Tagebuchs von der Inhaftierung im Konzentrationslager Dachau erzählt. Der Roman lässt sich nicht nur als mit den Mitteln der Fiktion arbeitender Beitrag zur Geschichte der Verfolgung Schwarzer Menschen im Nationalsozialismus verstehen, sondern auch als selbst transatlantisches, vermeintlich historisches Zeitzeugnis, das aus einer ungewöhnlichen Perspektive die Thematik eines unsteten Archivs verflochtener Gewalt- und Exilerfahrungen beleuchtet. Das Augenmerk der Analyse liegt einerseits auf den Chancen eines solchen Archivs: Der Roman zeigt Möglichkeiten diasporischer Gemeinschaftsbildung und beschreibt die transatlantische Perspektive des Protagonisten als Ressource für das Erkennen von Kontinuitäten der Unterdrückung wie auch für das Ableiten von alltäglichen Widerstandsstrategien. Andererseits werden ausgehend vom Kunstgriff der Herausgeberfiktion und von Dokumenten aus dem Nachlass Risiken und Widersprüche des hier entworfenen Archivs diskutiert. Es wird gezeigt, dass dieses zwar auf Transnationalität zielt, jedoch teilweise der Rückbindung an ein lokales Moment bedarf.
The article discusses the University Library Frankfurt am Main’s current exhibition focusing on the background of and the systematic search for looted assets in the library holdings as part of a wider provenance research project. It offers an overview of various topical areas reaching from initial changes in 1933 to raids throughout Europe by Nazi organisations and restitution procedures during the post-war period. The scope and first findings of the provenance research project will also be addressed.
By analyzing 𝑒+𝑒− annihilation data with an integrated luminosity of 2.93 fb−1 collected at the center-of-mass energy √𝑠=3.773 GeV with the BESIII detector, we present the first absolute measurements of the branching fractions of twenty Cabibbo-suppressed hadronic 𝐷0(+) decays involving multiple pions. The highest four branching fractions obtained are ℬ(𝐷0→𝜋+𝜋−𝜋0) = (1.343±0.013stat±0.016syst)%, ℬ(𝐷0→𝜋+𝜋−2𝜋0) = (1.002±0.019stat±0.024syst)%, ℬ(𝐷+→2𝜋+𝜋−𝜋0) = (1.165±0.021stat±0.021syst)%, and ℬ(𝐷+→2𝜋+𝜋−2𝜋0) = (1.074±0.040stat±0.030syst)%. The 𝐶𝑃 asymmetries for the six decays with highest signal yields are also determined and found to be compatible with zero.
Using a sample of (448.1±2.9)×106 𝜓(3686) decays collected with the BESIII detector at BEPCII, we report an observation of Ξ− transverse polarization with a significance of 7.3𝜎 in the decay 𝜓(3686)→Ξ− ¯Ξ+ (Ξ−→Λ𝜋−, ¯Ξ+→¯Λ𝜋+, Λ→𝑝𝜋−, ¯Λ→¯𝑝𝜋+). The relative phase of the electric and magnetic form factors is determined to be ΔΦ=(0.667±0.111±0.058) rad. This is the first measurement of the relative phase for a 𝜓(3686) decay into a pair of Ξ−¯Ξ+ hyperons. The Ξ− decay parameters (𝛼Ξ−, 𝜙Ξ−) and their conjugates (𝛼¯Ξ+, 𝜙¯Ξ+), the angular-distribution parameter 𝛼𝜓, and the strong-phase difference 𝛿𝑝−𝛿𝑠 for Λ𝜋− scattering are measured to be consistent with previous BESIII results.
Luminosities and energies of e⁺e⁻ collision data taken between √s=4.61 GeV and 4.95 GeV at BESIII
(2022)
From December 2019 to June 2021, the BESIII experiment collected about 5.85 fb−1 of data at center-of-mass energies between 4.61 GeV and 4.95 GeV. This is the highest collision energy BEPCII has reached so far. The accumulated e+e− annihilation data samples are useful for studying charmonium(-like) states and charmed-hadron decays. By adopting a novel method of analyzing the production of Λ+cΛ¯−c pairs in e+e− annihilation, the center-of-mass energies are measured with a precision of ∼0.6 MeV. Integrated luminosities are measured with a precision of better than 1\% by analyzing the events of large-angle Bhabha scattering. These measurements provide important inputs to the analyses based on these data samples.
A common element of market structure analysis is the spatial representation of firms’ competitive positions on maps. Such maps typically capture static snapshots in time. Yet, competitive positions tend to change. Embedded in such changes are firms’ trajectories, that is, the series of changes in firms’ positions over time relative to all other firms in a market. Identifying these trajectories contributes to market structure analysis by providing a forward-looking perspective on competition, revealing firms’ (re)positioning strategies and indicating strategy effectiveness. To unlock these insights, we propose EvoMap, a novel dynamic mapping framework that identifies firms’ trajectories from high-frequency and potentially noisy data. We validate EvoMap via extensive simulations and apply it empirically to study the trajectories of more than 1,000 publicly listed firms over 20 years. We find substantial changes in several firms’ positioning strategies, including Apple, Walmart, and Capital One. Because EvoMap accommodates a wide range of mapping methods, analysts can easily apply it in other empirical settings and to data from various sources.
Regulators worldwide have been implementing different privacy laws. They vary in their impact on the value for advertisers, publishers and users, but not much is known about these differences. This article focuses on three important privacy laws (i.e., General Data Protection Regulation [GDPR], California Consumer Privacy Act [CCPA] and Personal Information Protection Law [PIPL]) and compares their impact on the value for the three primary actors of the online advertising market, namely, advertisers, publishers and users. This article first compares these three privacy laws by developing a legal strictness score. It then uses the existing literature to derive the effects of the legal strictness of each privacy law on each actor’s value. Finally, it quantifies the three privacy laws’ impact on each actor’s value. The results show that GDPR and PIPL are similar and stricter than CCPA. Stricter privacy laws bring larger negative changes to the value for actors. As a result, both GDPR and PIPL decrease the actors’ value more substantially than CCPA. These value declines are the largest for publishers and are rather similar for users and advertisers. Scholars and practitioners can use our findings to explore ways to create value for multiple actors under various privacy laws.
For many services, consumers can choose among a range of optional tariffs that differ in their access and usage prices. Recent studies indicate that tariff-specific preferences may lead consumers to choose a tariff that does not minimize their expected billing rate. This study analyzes how tariff-specific preferences influence the responsiveness of consumers’ usage and tariff choice to changes in price. We show that consumer heterogeneity in tariff-specific preferences leads to heterogeneity in their sensitivity to price changes. Specifically, consumers with tariff-specific preferences are less sensitive to price increases of their preferred tariff than other consumers. Our results provide an additional reason why firms should offer multiple tariffs rather than a uniform nonlinear pricing plan to extract maximum consumer surplus.
Digitale Technologien begünstigen den Einsatz einer dynamischen Preisgestaltung, also von Preisen, die für ein prinzipiell gleiches Produkt unangekündigt variieren. Dabei werden in der öffentlichen Diskussion unterschiedliche Ausgestaltungsformen dynamischer Preise oftmals vermischt, was eine sinnvolle Analyse der Vor- und Nachteile der dynamischen Preisgestaltung erschwert. Das Ziel des Beitrags ist die Darstellung der ökonomischen Grundlagen und die Diskussion sowie Klassifikation der Ausgestaltungsmöglichkeiten der dynamischen Preisgestaltung. Darüber hinaus erfolgt eine Bewertung der Vor- und Nachteile der dynamischen Preisgestaltung aus Käufer- und Verkäufersicht. Abschließend werden Implikationen für die betriebswirtschaftliche Forschung diskutiert.
Thought to be monotypic for decades, the only species in the goosefish genus Lophiomus Gill, Lm. setigerus (Vahl), shows a wide range of morphological variation and is distributed widely in the Indo-West Pacific (IWP). In this study, datasets for two mitochondrial and two nuclear genes sequences obtained from samples of Lophiomus collected in different localities across the IWP were constructed and analyzed to explore the phylogeny and species diversity within the genus. Our integrated approach with multiline evidence unveiled an unanticipated richness of at least six delimited species of Lophiomus. Herein, based on materials already available from museums and new specimens obtained primarily through the Tropical Deep-Sea Benthos program surveying IWP benthic fauna, we formally describe three new species: Lm. immaculioralis sp. nov., Lm. nigriventris sp. nov., and Lm. carusoi sp. nov. Also, we resurrect Lm. laticeps stat. rev. from synonyms of Lm. setigerus. These species can be diagnosed by genetics, body coloration, patterns on the floor of the mouth, peritoneum pigmentation, morphometric measurements, and meristic counts of cranial spines, dorsal-fin spines, and pectoral-fin and pelvic-fin rays from each other and from Lm. setigerus. The species Lm. setigerus, as well as the genus Lophiomus, are re-described accordingly based on the new results. Amended identification keys to the four extant lophiid genera and to species of Lophiomus are also provided.
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
Climate change affects ecosystems worldwide and is threatening biodiversity. Insects, as ectotherm organisms, are strongly dependent on the thermal environment. Yet, little is known about the effects of summer heat and drought on insect diversity. In the Mediterranean climate zone, a region strongly affected by climate change, hot summers might have severe effects on insect communities. Especially the larval stage might be sensitive to thermal variation, as larvae—compared to other life stages—cannot avoid hot temperatures and drought by dormancy. Here we ask, whether inter-annual fluctuations in Mediterranean moth diversity can be explained by temperature (TLarv) and precipitation during larval development (HLarv). To address our question, we analyzed moth communities of a Mediterranean coastal forest during the last 20 years. For species with summer-developing larvae, species richness was significantly negatively correlated with TLarv, while the community composition was affected by both, TLarv and HLarv. Therefore, summer-developing larvae seem particularly sensitive to climate change, as hot summers might exceed the larval temperature optima and drought reduces food plant quality. Increasing frequency and severity of temperature and drought extremes due to climate change, therefore, might amplify insect decline in the future.