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Advancing cell-based influenza vaccine production: from clonal MDCK selection to robust and intensified upstream processes
No full textIn situ Structural Evolution of Transition Metal-Based Electrocatalysts Probed by Electrochemical Atomic Force Microscopy
No full textElectrocatalysis presents a promising pathway for sustainably converting intermittent renewable energy into value-added chemicals and fuels, while simultaneously mitigating environmental pollutants such as carbon dioxide (CO2) and nitrate (NO3-). Despite its potential, the practical deployment of key electrocatalytic processes, including the CO2 electroreduction reaction (CO2RR), NO3- reduction reaction (NO3RR), and oxygen evolution reaction (OER), remains limited by challenges in achieving high selectivity, activity, and long-term stability. These performance metrics are intrinsically linked to the catalyst’s surface structure, which evolves under reaction conditions. While catalyst surface reconstruction driven by dynamic processes can facilitate the in situ formation of active sites, excessive or uncontrolled restructuring may compromise catalyst stability. Moreover, such structural transformations can be reversible, complicating post-reaction characterization due to a possible relaxation back to the resting state. To overcome these challenges, in situ and operando surface-sensitive techniques with high spatial resolution are essential for directly visualizing local structural and morphological changes at the solid-liquid interface and decoupling their impact on catalytic performance from bulk properties. However, the intense gas evolution associated with many electrocatalytic reactions imposes significant obstacles to in situ surface characterization. Beyond merely capturing these structural transformations, it is critical to elucidate the fundamental factors governing surface evolution and to establish their correlation with catalytic activity, selectivity, and stability. Such insights are vital for the rational design of efficient and robust electrocatalysts, as well as for developing strategies to actively control catalytic properties under operando conditions. This thesis investigates Co- and Cu-based model electrocatalysts in the form of thin films and single-crystals, which enable precise control over surface properties while minimizing the intrinsic complexity of the catalytic system. By combining these well-defined model systems with advanced in situ and operando characterization techniques, particularly electrochemical atomic force microscopy (EC-AFM), this work elucidates how initial electrode faceting, local chemical environment, and applied potential govern the in situ morphological and structural evolution of electrocatalysts under reaction conditions, spanning mesoscopic to atomic length scales. This includes having a key role on determining how long is needed till the active state is created or a "steady-state" is achieved. Building on these insights into catalyst surface structural evolution, the thesis further explores surface pre-functionalization with organic modifiers as a strategy to regulate in situ restructuring and other critical properties, ultimately enhancing catalytic performance. The findings presented in this thesis challenge conventional interpretations and theoretical models based on static surfaces assumptions and contribute to establishing reliable correlations between catalyst properties, in situ surface structures, and catalytic behavior. EC-AFM is demonstrated as a powerful and versatile technique for advancing mechanistic understanding of transition metal (oxide)-based heterogeneous electrocatalysts. Its broader applicability to the study of functional materials under operational electrocatalytic conditions is also highlighted
Braess’ Paradox in Enzyme Kinetics: Asymmetry from Population Balance without Direct Cooperativity
No full textThe ATPase ABCE1, a member of the ubiquitous ATP-Binding Cassette protein superfamily, is essential in eukaryotic and archaeal ribosome recycling. It comprises a pair of homologous nucleotide-binding domains (NBDs), each containing a consensus nucleotide-binding site (NBS), where ATP hydrolysis takes place. Each of these sites can be in either an open or closed conformation. Despite the near symmetry of the two NBDs, and quite unexpectedly, their hydrolysis kinetics are highly asymmetric. While substitution of the catalytic glutamate (E238Q) in NBSI reduced the overall turnover rate of the ATPase by a factor of 2, as one might expect, the corresponding substitution in NBSII (E485Q) shows a so far unexplained 10-fold increase. To address this issue, we used Markov models to study how such a drastic asymmetry can arise. Specifically, we asked whether this observation can be explained without previously proposed direct allosteric interactions, such as electrostatic interactions, between the two NBSs. Indeed, using a Bayesian approach, we found Markov models that quantitatively predict the experimentally observed kinetics, as well as additional steady-state ATP occupancy data, both without such direct allosteric interaction. In particular, our results show that the observed remarkable asymmetry is fully explained by the structure-induced property that opening and closing always involves both NBSs. These models can explain the unexpected fast kinetics of the mutant of NBSII in terms of a drastic population shift due to the mutation, which circumvents a kinetic trap state that slows wild-type kinetics. Our Bayesian Markov approach may help to quantitatively explain similar nonintuitive Braess-type kinetics also in other enzymes where chemical/conformation coupling is essential
Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells
No full textMutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule KRAS inhibitors have emerged as promising cancer therapeutics, yet resistance development remains a major hurdle. To overcome this challenge, we explored rational combination strategies aimed at enhancing therapeutic efficacy and durability. We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Similar synergistic effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress growth of KRAS-G12D-mutant PDAC cells. Mechanistically, the combinations induced sustained cell cycle arrest, marked by reduced RB phosphorylation, decreased E2F1 expression, and increased levels of CDKN1B/p27. Deletion of CDKN1B largely reversed the growth-inhibitory effect, highlighting its essential role in mediating the observed synergy. In an orthotopic, immunocompetent mouse model of PDAC, MRTX1133 significantly reduced tumor growth and extended survival; however, despite its ability to suppress RB phosphorylation, Palbociclib failed to enhance these effects. Single-cell RNA sequencing suggested that Palbociclib treatment induces tumor vascularization, perhaps contributing to the lack of drug synergy observed in vivo. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of placing combination therapies into a suitable context
The AURORA Survey: Robust Helium Abundances at High Redshift Reveal a Subpopulation of Helium-enhanced Galaxies in the Early Universe
No full textWe present the first robust helium (He) abundance measurements in star-forming galaxies at redshifts 1.6 less than or similar to z less than or similar to 3.3 using deep, moderate-resolution JWST/NIRSpec spectroscopy from the AURORA survey. We establish a high-z He sample consisting of 20 galaxies with multiple high-signal-to-noise-ratio (>5 sigma) He i emission-line detections, including the critical near-infrared lambda 10833 line. This is the first study at high redshift leveraging lambda 10833 to break degeneracies between temperature, electron density, optical depth, and He+/H+, enabling reliable He abundance determinations in the early Universe. We use a custom Markov Chain Monte Carlo framework incorporating direct-method electron temperature priors, extended optical depth (tau lambda 3890) model grids up to densities of 106 cm-3, and simultaneous fits of the physical conditions and He i/H i line ratios to derive ionic He+/H+ abundances. Most of the AURORA galaxies follow the extrapolated z similar to 0 He/H-O/H trend, indicating modest He enrichment by z similar to 2-3. However, we identify a subpopulation of four galaxies that exhibit elevated He mass fractions (Delta Y > 0.03) without corresponding enhancements in N/O or alpha-elements (similar to 20% of the sample). This abundance pattern is inconsistent with enrichment from asymptotic giant branch stars, but favors early He enrichment from very massive stars (M greater than or similar to 100M circle dot), which can eject He-rich, N-poor material via stellar winds and binary stripping in young stellar populations. We speculate that these elevated-He systems may represent an early phase of globular cluster (GC) formation where N enrichment is still lagging behind He production. This work demonstrates the power of JWST multi-line He i spectroscopy for tracing early stellar feedback, enrichment pathways, and GC progenitor signatures in the high-redshift Universe
First Mapping of Prebiotic Molecule CH2NH in a Prestellar Core
No full textWe present the first spatially resolved map of methanimine (CH2NH) in the prestellar core L1544 using the IRAM 30 m telescope. The 20,2-10,1 line at 127 GHz was mapped with 20 '' resolution (similar to 2800 au), revealing extended CH2NH emission across the core. The peak line intensity coincides with the well-known c-C3H2 peak, while the integrated intensity peaks between the HNCO and dust continuum peaks due to broader linewidths in the latter region. Column densities of CH2NH are similar to(0.5-1.4x)1012 cm-2, corresponding to fractional abundances of 5 x 10-11-1 x 10-10, with a trend decreasing from the southern, carbon-chain rich region to the dust and HNCO peak in the north. Comparison with complementary molecular maps and the gas-grain chemical model of Sipil & auml; et al. suggests that neutral-neutral gas-phase reactions and dissociative recombination dominate in the outer carbon-chain shell. This study demonstrates that CH2NH, a simple nitrogen- and carbon-bearing molecule previously detected with pointed observations in other cold cores, is present and spatially extended in the evolved prestellar core L1544. This indicates that prebiotic nitrogen-carbon chemistry continues efficiently up to the onset of gravitational collapse, providing key constraints for astrochemical models and the early stages of chemical complexity leading to amino acids
COSMOS2025: The COSMOS-Web galaxy catalog of photometry, morphology, redshifts, and physical parameters from JWST, HST, and ground-based imaging
No full textWe present COSMOS2025, the COSMOS-Web catalog of photometry, morphology, photometric redshifts, and physical parameters for more than 700 000 galaxies in the Cosmic Evolution Survey (COSMOS) field. This catalog is based on our James Webb Space Telescope 255 h COSMOS-Web program, which provides deep near-infrared imaging in four NIRCam (F115W, F150W, F277W, F444W) and one MIRI (F770W) filter over the central similar to 0.54 deg(2) (similar to 0.2 deg(2) for MIRI) in COSMOS. These data are combined with ground- and space-based data to derive photometric measurements of NIRCam-detected sources using both fixed-aperture photometry (on the space-based bands) and a profile-fitting technique on all 37 bands spanning 0.3 mu m to 8 mu m. We provide morphology for all sources from complementary techniques including profile fitting and machine-learning classification. We derive photometric redshifts, physical parameters, and non-parametric star formation histories from spectral energy distribution (SED) fitting. The catalog has been extensively validated against previous COSMOS catalogs and other surveys. Photometric redshift accuracy measured using spectroscopically confirmed galaxies out to z similar to 9 reaches sigma(MAD) = 0.012 at m(F444W) < 28 and remains at sigma(MAD) less than or similar to 0.03 as a function of magnitude, color, and galaxy type. This represents a factor of similar to 2 improvement at 26 AB mag compared to COSMOS2020. The catalog is approximately 80% complete at log(M-star/M-circle dot) similar to 9 at z similar to 10 and at log(M-star/M-circle dot) similar to 7 at z similar to 0.2, representing a gain of 1 dex compared to COSMOS2020. COSMOS2025 represents the definitive COSMOS-Web catalog. It is provided with complete documentation, together with redshift probability distributions, and it is ready for scientific exploitation today
Circumplanetary Disk Candidate in the Disk of HD 163296 Traced by Localized Emission from Simple Organics
No full textAtacama Large Millimeter/submillimeter Array observations suggest that the disk of HD 163296 is being actively shaped by embedded yet unseen protoplanets, as indicated by numerous gas and dust substructures consistent with planet-disk interaction models. We report the first detection of simple organic molecules, HCN and C2H, tracing a candidate circumplanetary disk (CPD) in the HD 163296 system, located at an orbital radius of R = 88 +/- 7 au and azimuth phi = 46(degrees) +/- 3(degrees) (or R = 0 ''., PA = 350(degrees) in projected sky coordinates), and originating near the midplane of the circumstellar disk. The signature is localized but spectrally resolved, and it overlaps with a previously reported planet candidate, P94, identified through kinematic perturbations traced by CO lines. We propose a scenario in which the observed chemical anomalies arise from increased heating driven by the forming planet and ongoing accretion through its CPD, facilitating the thermal desorption of species that would otherwise remain frozen out in the disk midplane, and potentially triggering the activation barriers of chemical reactions that lead to enhanced molecular production. Based on a first-order dynamical analysis of the HCN spectrum from the CPD-isolated with a 7 sigma significance-we infer an upper limit on the planet mass of 1.8M(Jup), consistent with predictions from CO kinematics and constraints from direct imaging studies. By comparing the CPD sizes derived from our models with theoretical expectations where the CPD radius corresponds to roughly one-third of the planet's Hill radius, we favor CPD gas temperatures T > 150 K, planet masses M-p < 1.0M(Jup), and CPD radii R-CPD < 2 au
