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Phase boundaries promote chemical reactions through localized fluxes
One of the hypothesized functions of biomolecular condensates is to act as chemical reactors, where chemical reactions can be modulated, i.e., accelerated or slowed down, while substrate molecules enter and products exit from the condensate. Similarly, the components themselves that take part in the architectural integrity of condensates might be modified by active (energy consuming, non-equilibrium) processes, e.g., by ATPase chaperones or by kinases and phosphatases. In this work, we study how the presence of spatial inhomogeneities, such as in the case of liquid–liquid phase separation, affects active chemical reactions and results in the presence of directional flows of matter, which are one of the hallmarks of non-equilibrium processes. We establish the minimal conditions for the existence of such spatial currents, and we furthermore find that these fluxes are maximal at the condensate interface. These results propose that some condensates might be most efficient as chemical factories due to their interfaces rather than their volumes and could suggest a possible biological reason for the observed abundance of small non-fusing condensates inside the cell, thus maximizing their surface and the associated fluxes.
The false evidence rate: An approach to frequentist error rate control conditioning on the observed <i>P</i> value
A P value is conventionally interpreted either as a) the probability by chance of obtaining more extreme results than those observed or b) a tool for declaring significance at a prespecified level. Both approaches carry difficulties: b) does not allow users to make inferences based on the data in hand, and is not rigorously followed by researchers in practice, while (a) is not meaningful as an error rate. Although P values retain an important role, these shortcomings are likely to have contributed significantly to the scientific reproducibility crisis. We introduce the concept of defining long-run frequentist error rates given the observed data, allowing researchers to make accurate and intuitive inferences about the probability of making an error after proposing that the null hypothesis is false. As one approach, we define the false evidence rate (FER) as the probability, under the null hypothesis, of observing a hypothetical future P value providing evidence toward the alternative hypothesis suggested by the observed P value, which we define as a false positive. FERs are much more conservative than their corresponding P values, consistent with studies demonstrating that the latter do not effectively control error rates across the scientific literature. To obtain an FER below 5%, one needs to obtain a P value below approximately 5 × 10 − 5 , while a P value of 5% corresponds to an FER of about 25%.
Atomistic dynamics of elimination and substitution driven by entrance channel
E2 elimination and SN2 substitution reactions are of central importance in preparative organic synthesis due to their stereospecificity. Herein, atomistic dynamics of a prototype reaction of ethyl chloride with hydroxide ion are uncovered that show strikingly distinct features from the case with fluoride anion. Chemical dynamics simulations reproduce the experimental reaction rate and reveal that the E2 proceeding through a direct elimination mechanism dominates over SN2 for the hydroxide ion reaction. This unexpected finding of a pronounced contribution of direct reaction dynamics, even at a near-thermal energy, is in strong contrast to the complex-mediated indirect mechanism for the fluoride case that characterizes the low-energy ion–molecule reactions. The entrance channel structures are found to be crucial and the differences are attributed to subtle changes in the hydrogen-bonding interaction of the approaching reactants. This effect presents in E2/SN2 reactions of different bases and alkyl halides and might play a role in complex chemical networks and environments.
Cluster perturbation theory. XI. Excitation-energy series using a variational excitation-energy function
Traditionally, excitation energies in coupled-cluster (CC) theory have been calculated by solving the CC Jacobian eigenvalue equation. However, based on our recent work [Jørgensen et al., Sci. Adv. 10, eadn3454 (2024)], we propose a reformulation of the calculation of excitation energies where excitation energies are determined as a conventional molecular property. To this end, we introduce an excitation-energy function that depends on the CC Jacobian and the right and left eigenvectors for the Jacobian eigenvalue problem. This excitation-energy function is variational with respect to the right and left eigenvectors but not with respect to the cluster amplitudes. Instead, the cluster amplitudes satisfy the cluster-amplitude equations, and we set up an excitation-energy Lagrangian by adding to the excitation-energy function the cluster-amplitude equations with an undetermined multiplier for each cluster-amplitude constraint. The excitation-energy Lagrangian is variational in all its parameters. Based on the variational property of the Lagrangian, we have determined two quadratically convergent excitation-energy series: the total-order cluster-perturbation (tCP) and variational cluster-perturbation (vCP) excitation-energy series. Calculations of the excitation energies of three small molecules have shown that the vCP series is to be preferred over the tCP series. The test calculations have been carried out for CPS(D) expansions [targeting the CC singles-and-doubles (CCSD) wave function from the CC singles wave function] and the CPSD(T) expansion [targeting the CC singles-doubles-triples (CCSDT) wave function from the CCSD wave function]. For the S(D) and SD(T) orbital excitation space calculations, we obtain in the second vCP iteration excitation energies with a mean deviation from CCSD excitation energies of about 0.04 eV for the S(D) orbital spaces, and for the SD(T) orbital space calculation, we obtain a mean deviation from the CCSDT excitation energies of 0.001 eV.
Molecular engineering charge transfer and triplet exciton formation in donor–acceptor cocrystals
Organic donor–acceptor (D–A) cocrystals are gaining attention for their potential applications in optoelectronic devices. This study explores the dynamics of charge transfer (CT) and triplet exciton formation in various D–A cocrystals. By examining a series of D–A cocrystals composed of coronene (COR), peri-xanthenoxanthene (PXX), and perylene (PER) donors paired with N,N-bis(3′-pentyl)perylene-3,4:9,10-bis(dicarboximide) (PDI), naphthalene-1,4:5,8-tetracarboxy-dianhydride (NDA), or pyrene-4,5,9,10-tetraone (PTO) acceptors, using transient absorption microscopy and time-resolved electron paramagnetic resonance spectroscopy, we find that the strength of the CT interaction influences the nature and yield of triplet excitons produced by CT state recombination. In particular, in the PER-PDI, COR-PTO, and PER-PTO cocrystals, localized triplet excitons are lower in energy than the CT state. By contrast, no localized triplet excitons are available to the CT states of the PXX-NDA, PER-NDA, and PXX-PTO cocrystals, and as a result, the CT states rapidly decay to ground state with no triplet formation. Moreover, density functional theory calculations show that the transition between delocalized CT states to a triplet state localized to a single donor or acceptor unit provides the source of spin–orbit coupling necessary when the triplet states are energetically accessible. These findings provide insights into the design of molecular materials with tailored exciton properties for optoelectronic applications.
Increasing pesticide diversity impairs soil microbial functions
Pesticide application is essential for stabilizing agricultural production. However, the effects of increasing pesticide diversity on soil microbial functions remain unclear, particularly under varying nitrogen (N) fertilizer management practices. In this study, we investigated the stochasticity of soil microbes and multitrophic networks through amplicon sequencing, assessed soil community functions related to carbon (C), N, phosphorus (P), and sulfur (S) cycling, and characterized the dominant bacterial life history strategies via metagenomics along a gradient of increasing pesticide diversity under two N addition levels. Our findings show that higher pesticide diversity enriches the abundance of bacterial specialists and opportunists capable of degrading or resisting pesticides, reducing the proportion of bacterial generalists in the absence of N addition. These shifts can complicate multitrophic microbial networks. Under increased pesticide diversity, selective pressure may drive bacteria to streamline their average genome size to conserve energy while enhancing C, N, P, and S metabolic capacities, thus accelerating soil nutrient loss. In comparison, N addition was found to reduce bacterial niche differentiation at higher pesticide diversity, mitigating the impacts of network complexity and functional traits associated with pesticide diversity, ultimately alleviating soil nutrient loss. Our results reveal the contrasting impacts of pesticide diversity on microbial functions under different N input scenarios and emphasize that strategic N fertilizer management can mitigate the ecological effects of pesticide use in agricultural systems.
Harsh criticism and unreasonable expectations worsen PhD students’ mental health
The role of spin diffusion in endogenous metal ions DNP
The sensitivity of solid state nuclear magnetic resonance spectroscopy can be enhanced via dynamic nuclear polarization (DNP) using unpaired electrons as polarizing agents. In metal ions based (MI)-DNP, paramagnetic metal ions are introduced as dopants into inorganic materials serving as endogenous polarizing agents. Having polarizing agents as part of the structure enables signal enhancements within the bulk of the material. Nuclear spins can be hyperpolarized either directly through their coupling to the polarizing agent or via homonuclear spin diffusion. In this work, we addressed what are the factors determining the relative sizes of the spin pools polarized by each of these two mechanisms and how changing their contribution to the polarization process affects the experimental outcome. Experimentally, we adjusted the spin diffusion rate through modifying the isotope ratio 6Li/7Li in otherwise identical samples, Li4Ti5O12 doped with paramagnetic Fe(III). DNP experiments on samples with typical content of polarizing agents for MI-DNP, corroborated by simulations, evidenced that while the efficiency of spin diffusion has large effects on the polarization buildup times, the enhancements remain largely unaffected.
Daily briefing: Pluto-Charon duet started with a gravitational ‘kiss-and-capture’
Size-dependent phase change in energy storage materials: Comparing the impact of solid-state wetting and of coherency stress
Coherent phase transformations in interstitial solid solutions or intercalation compounds with a miscibility gap are of practical relevance for energy storage materials and specifically for metal hydride or lithium-ion compound nanoparticles. Different conclusions on the size-dependence of the transformation conditions are reached by modeling or theory focusing on the impact of either one (internal, solid-state-) critical-point wetting of the nanoparticle surface or coherency constraints from solute-saturated surface layers. We report a hybrid numerical approach, combining atomistic grand canonical Monte Carlo simulation with a continuum mechanics analysis of coherency stress and modeling simultaneously wetting and mechanical constraints. When the ratio between chemical and misfit-strain-related contributions to the solute-solute interaction energy takes values realistic for interstitial solutions—which are typical for energy storage materials—we find that the impact of solid-state wetting is weak and that of coherency stress is dominant. Specifically, mechanical interaction can act to reduce the phase transformation hysteresis at small system size, and it can make the solid more binding for solute, thereby reducing the “plateau” chemical potential at phase coexistence. We present equations for the impact of coherency stress on the size-dependence of upper consolute temperature, plateau chemical potential, and charging/discharging hysteresis.
Recognized Outstanding Reviewers for <i>Circulation</i> in 2024
Phase transitions in chromatin: Mesoscopic and mean-field approaches
By means of a minimal physical model, we investigate the interplay of two phase transitions at play in chromatin organization: (1) liquid–liquid phase separation within the fluid solvating chromatin, resulting in the formation of biocondensates; and (2) the coil–globule crossover of the chromatin fiber, which drives the condensation or extension of the chain. In our model, a species representing a domain of chromatin is embedded in a binary fluid. This fluid phase separates to form a droplet rich in a macromolecule (B). Chromatin particles are trapped in a harmonic potential to reproduce the coil and globular phases of an isolated polymer chain. We investigate the role of the droplet material B on the radius of gyration of this polymer and find that this radius varies nonmonotonically with respect to the volume fraction of B. This behavior is reminiscent of a phenomenon known as co-non-solvency: a polymer chain in a good solvent (S) may collapse when a second good solvent (here B) is added in low quantity and expands at higher B concentration. In addition, the presence of finite-size effects on the coil–globule transition results in a qualitatively different impact of the droplet material on polymers of various sizes. In the context of genetic regulation, our results suggest that the size of chromatin domains and the quantity of condensate proteins are key parameters to control whether chromatin may respond to an increase in the quantity of chromatin-binding proteins by condensing or expanding.
A signaling molecule from intratumor bacteria promotes trastuzumab resistance in breast cancer cells
Emerging evidence indicates that intratumor bacteria exist as an active and specific tumor component in many tumor types beyond digestive and respiratory tumors. However, the biological impact and responsible molecules of such local bacteria–tumor direct interaction on cancer therapeutic response remain poorly understood. Trastuzumab is among the most commonly used drugs targeting the receptor tyrosine-protein kinase erbB-2 (ErbB2) in breast cancer, but its resistance is inevitable, severely limiting its clinical effectiveness. Here, we demonstrate that the quorum-sensing signaling molecule N-(3-oxo-dodecanoyl) homoserine lactone (3oc), a chemical compound released by Pseudomonas aeruginosa ( P. aeruginosa ), one tumor-resident bacteria with a relative high abundance in breast cancer, promotes breast cancer cell resistance to trastuzumab. Mechanically, 3oc directly leads to spontaneous dimerization of the transforming growth factor β (TGF-β) type II serine/threonine kinase receptor on the cell membrane in a ligand-independent manner. The 3oc-induced TGF-β signaling subsequently triggers ErbB2 phosphorylation and its downstream target activation, overcoming the inhibition effect of trastuzumab on ErbB2. With specific real-time qPCR, fluorescence in situ hybridization imaging, and liquid chromatography ionization tandem mass spectrometry analyses of clinical samples, we confirmed that P. aeruginosa and its signaling molecule 3oc exist in breast cancer tissues and there is a clinical correlation between P. aeruginosa colonization and trastuzumab resistance. This work expands the biological functions of intratumor bacteria in cancer treatment responsiveness and provides a unique perspective for overcoming trastuzumab resistance.
Global Rounds Afghanistan: A Critical Overview of Cardiovascular Medicine
Analytical derivative approaches for vibro-polaritonic structures and properties. I. Formalism and implementation
Vibro-polaritons are hybrid light–matter states that arise from the strong coupling between the molecular vibrational transitions and the photons in an optical cavity. Developing theoretical and computational methods to describe and predict the unique properties of vibro-polaritons is of great significance for guiding the design of new materials and experiments. Here, we present the ab initio cavity Born–Oppenheimer density functional theory (CBO-DFT) and formulate the analytic energy gradient and Hessian as well as the nuclear and photonic derivatives of dipole and polarizability within the framework of CBO-DFT to efficiently calculate the harmonic vibrational frequencies, infrared absorption, and Raman scattering spectra of vibro-polaritons as well as to explore the critical points on the cavity potential energy surface. The implementation of analytic derivatives into the electronic structure package is validated by a comparison with the finite-difference method and with other reported computational results. By adopting appropriate exchange–correlation functionals, CBO-DFT can better describe the structure and properties of molecules in the cavity than CBO-Hartree–Fock method. It is expected that CBO-DFT is a useful tool for studying the polaritonic structures and properties.
Partial PdAu nanoparticle embedding into TiO <sub>2</sub> support accentuates catalytic contributions from the Au/TiO <sub>2</sub> interface
Despite the broad catalytic relevance of metal–support interfaces, controlling their chemical nature, the interfacial contact perimeter (exposed to reactants), and consequently, their contributions to overall catalytic reactivity, remains challenging, as the nanoparticle and support characteristics are interdependent when catalysts are prepared by impregnation. Here, we decoupled both characteristics by using a raspberry-colloid-templating strategy that yields partially embedded PdAu nanoparticles within well-defined SiO 2 or TiO 2 supports, thereby increasing the metal–support interfacial contact compared to nonembedded catalysts that we prepared by attaching the same nanoparticles onto support surfaces. Between nonembedded PdAu/SiO 2 and PdAu/TiO 2 , we identified a support effect resulting in a 1.4-fold higher activity of PdAu/TiO 2 than PdAu/SiO 2 for benzaldehyde hydrogenation. Notably, partial nanoparticle embedding in the TiO 2 raspberry-colloid-templated support increased the metal–support interfacial perimeter and consequently, the number of Au/TiO 2 interfacial sites by 5.4-fold, which further enhanced the activity of PdAu/TiO 2 by an additional 4.1-fold. Theoretical calculations and in situ surface-sensitive desorption analyses reveal facile benzaldehyde binding at the Au/TiO 2 interface and at Pd ensembles on the nanoparticle surface, explaining the connection between the number of Au/TiO 2 interfacial sites (via the metal–support interfacial perimeter) and catalytic activity. Our results demonstrate partial nanoparticle embedding as a synthetic strategy to produce thermocatalytically stable catalysts and increase the number of catalytically active Au/TiO 2 interfacial sites to augment catalytic contributions arising from metal–support interfaces.
Response by Sun et al to Letter Regarding Article, “Piezo1-Mediated Neurogenic Inflammatory Cascade Exacerbates Ventricular Remodeling After Myocardial Infarction”
The bcc coating of Lennard-Jones crystal nuclei vanishes with a change of local structure detection algorithm
Since the influential work of ten Wolde, Ruiz-Montero, and Frenkel [Phys. Rev. Lett. 75, 2714 (1995)], crystal nucleation from a Lennard-Jones fluid has been regarded as a paradigmatic example of metastable crystal ordering at the surface of a critical nucleus. We apply seven commonly used local structure detection algorithms to characterize crystal nuclei obtained from transition path sampling simulations. The polymorph composition of these nuclei varies significantly depending on the algorithm used. Our results indicate that one should be very careful when characterizing the local structure near solid–solid and solid–fluid interfaces. Particles near such interfaces exhibit a local structure distinct from that of bulk fluid or bulk crystal phases. We argue that incorporating outlier detection into the local structure detection method is beneficial, leading to greater confidence in the classification results. Interestingly, the bcc coating nearly disappears when adopting a machine learning method with outlier detection.
Effects of the Nonsteroidal MRA Finerenone With and Without Concomitant SGLT2 Inhibitor Use in Heart Failure
BACKGROUND: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. METHODS: FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses. RESULTS: Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60–1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74–0.98]; P interaction =0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76–0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point. CONCLUSIONS: The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04435626.