Browse Articles

Intracellularly coupled oscillators for synthetic biology

Volatile and non-volatile pathogen cues shape host extracellular vesicles production in pre-infection response

Abstract In natural environments, animals encounter pathogen-derived chemicals long before infection occurs. How such anticipatory cues influence extracellular vesicle (EV) dynamics, which are central to immune regulation, intercellular communication, and stress responses, remains unknown. Using Caenorhabditis elegans , we show that pathogen-derived volatile and non-volatile compounds trigger distinct EV pathways through separate sensory and molecular mechanisms. Non-volatile secretome components, including the tripeptide Ile-Pro-Pro, activate immune-dependent EV production, whereas volatile metabolites elicit immunity-independent EV formation. Both responses require sensory input from ASK, ADL, and AWC neurons and converge on a neural circuit involving RMG, AIB, and AIA interneurons. GPCRs SRI-19, SRI-36/39, and SRR-6 mediate non-volatile responses, with SRR-6 acting in the intestine to regulate muscle EVs release. Notably, pre-exposure to pathogen volatiles enhances offspring survival during subsequent infection in an SRI-19–dependent manner, suggesting a predictive, intergenerational benefit of pathogen detection. In summary, our findings uncover that pathogen-derived chemical cues shape host EV production via specialized sensory circuits, revealing how animals anticipate infection and prime protective physiological responses.

Single cell profiling framework reveals metabolic subpopulations as drivers of bioproduction heterogeneity

Abstract Heterogeneity within clonal cell populations remains a critical bottleneck within bioprocess engineering, notably by undermining bioproduction yields. Efforts to mitigate its impact have, however, been hampered by technological difficulties quantifying metabolism at the single-cell level. Here, we propose a framework based on single-cell biosensor analysis that enables robust characterisation of cell’s metabolic states, leveraging it to detect and isolate isogeneic heterogeneity in response to environmental perturbations and within microbial cell factories. We identify acute and gradual glucose depletion to induce differentiation of metabolically distinct subpopulations and reveal these subpopulations to exhibit differential production capabilities, with lower intracellular pH subpopulations exhibiting enhanced product accumulation within violacein-producing strains but reduced yields within lycopene-producing strains. Lastly, we highlight galactose cultivation as a method to modulate subpopulation dynamics towards higher-producing lycopene phenotypes. Altogether, our research provides insights into subpopulation differentiation and establishes promising avenues for the engineering of more robust and higher-producing strains.

Overlooked deforestation from global mining activities in the 21st century

Microwave spectroscopy of partially and fully deuterated HCl dihydrate clusters

A detailed understanding of water’s remarkable ability to solvate small molecules is a central theme in chemistry. In this work, we have identified 12 new partially and fully deuterated isotopologues of the hydrochloric acid dihydrate cluster, (H2O)2 · HCl, by chirped-pulse Fourier transform microwave spectroscopy. We also performed high-level ab initio calculations relevant to the structure and dynamics of the cluster. The observation of singly substituted isotopologues at each unique hydrogen position enables a more detailed experimental characterization of the geometry than was possible previously. In addition, an analysis of splittings in the spectrum that are caused by population of more than one vibration-tunneling level enables a detailed characterization of hydrogen bond-breaking bifurcation tunneling motions that occur in the complex. Not only do our results confirm theoretical predictions about hydrogen atoms that are permuted by the tunneling motions—they also provide experimental evidence for concerted large-amplitude motions of other atoms. Finally, an analysis of the chlorine nuclear quadrupole coupling tensor suggests that the HCl bonding character might be influenced to a small extent by isotopic substitution of atoms involved in the Cl–H⋯O hydrogen bond due to zero-point vibrational effects.

Eye movements during free viewing to maximize scene understanding

Abstract What humans look at and do when freely viewing a scene is not well understood. We measure observer eye movements under different instructions while participants view a customized set of image pairs containing small visual alterations that greatly change scene interpretation (Winograd images). We show that free-viewing fixations resemble those of observers describing scenes but differ from those of observers counting or searching for objects. Fixations are more often directed toward people and objects whose removal most alters scene interpretation, rather than toward the most salient or meaningfully judged regions (meaning maps), or objects perceived to be grasped or gazed at. Small image changes that modify scene understanding (Winograd images), but not salience or meaning maps, alter fixation patterns. By instructing observers to describe scenes while fixating on objects either relevant or irrelevant to scene understanding, we demonstrate that free-viewing eye movements are functionally important for accurate scene comprehension. Thus, an important human default task of free viewing eye movements is to comprehend scenes.

Overcoming surface energy to control Cu3N epitaxial growth

Crystal orientation control during copper nitride (Cu3N) epitaxial growth was achieved using reactive DC magnetron sputtering. Both the (100)-orientation and (111)-orientation were observed readily from x-ray diffraction measurements for Cu3N thin films grown on single-crystal MgO(100), MgO(111), SrTiO3(100), and sapphire(0001) substrates. The Cu3N(111) surface energy is greater than that of Cu3N(100), suggesting that the Cu3N(111) orientation has a lower formation probability than the Cu3N(100) orientation. To control the influence of surface energy, thin film growth parameters related to the thermodynamics and kinetics of epitaxial thin film growth were tuned. The growth of single (111)-oriented Cu3N epitaxial thin films, which have a higher surface energy orientation, was achieved on MgO(111) substrates. The optical bandgaps of the single (111)-oriented Cu3N epitaxial thin film were 1.80 eV for direct transition and 0.82 eV for indirect transition, indicating the formation of a reasonable electronic structure in single (111)-oriented Cu3N epitaxial thin films with higher surface energy.

Risk of major adverse cardiovascular events with aripiprazole versus olanzapine, quetiapine, and risperidone in severe mental illness: a target trial emulation

Abstract Initiating aripiprazole as antipsychotic monotherapy rather than olanzapine, quetiapine, or risperidone, might prevent/delay major adverse cardiovascular events (MACEs) over the long-term in people diagnosed with severe mental illness. Using Clinical Practice Research Datalink data, we emulated a trial of aripiprazole versus olanzapine, quetiapine, and risperidone in 20,404 patients 2005–2014. Primary outcome was five-year MACE risk (composite of hospitalisation for acute myocardial infarction or stroke and cardiovascular death). Here we show that patients initiating aripiprazole had a similar five-year MACE risk as those initiating olanzapine (risk ratio: 1.03, 95% CI, 0.78-1.32), quetiapine (1.02, 95% CI, 0.72-1.32), and risperidone (0.88, 95% CI, 0.67-1.17). Risk was lower among patients initiating and continuing aripiprazole versus risperidone (0.58, 95% CI, 0.39-0.84). For patients at clinical equipoise, antipsychotic selection does not appear to significantly impact risk of the most severe, long-term cardiovascular events. However, further research is needed to replicate our finding of increased risk with continued risperidone use versus aripiprazole.

Ultrafast charge-carrier localization and separation dynamics in CdS nanowires wrapped in C3N5 nanosheets

Nanowires are broadly used in photocatalytic and photoelectrochemical applications due to advanced encapsulation techniques and the large surface area of nanowire networks. However, future sustainable nanotechnologies depend on our ability to harness ultrafast charge-carrier dynamics in emerging nanowires. In this work, we combine time-resolved terahertz spectroscopy (TRTS) and time-resolved photoluminescence (TRPL) to explore ultrafast charge-carrier dynamics in CdS nanowires wrapped in C3N5 nanosheets. Our fluence-dependent TRTS results reveal that the photoexcited charge-carrier dynamics are consistent with the Drude–Smith model and not the plasmon model or the Bruggeman effective medium theory. We find that CdS nanowires possess bulk-like short-range (<14 nm) charge-carrier mobilities that are unaltered by post-growth encapsulation with C3N5 nanosheets. In situ encapsulation is observed to reduce the short-range mobility in the CdS nanowire core. The Drude–Smith localization parameters indicate that the nanowires are fully depleted, even at our highest photoexcitation densities. In turn, photoexcited holes are rapidly transported to the nanowire surface, which affects our TRTS and TRPL lifetimes. We simultaneously model the TRTS and TRPL lifetimes with a 1D diffusion model that contains hot-carrier cooling, intrananowire charge-carrier diffusion, surface recombination, bimolecular recombination, and charge-separation. Our model reveals that sub-nanosecond charge-separation can prolong carrier lifetimes into nanosecond timescales and that post-growth encapsulation increases surface recombination at the CdS–C3N5 interface. Since this has been linked to increased photocatalytic efficiency, our model provides a direct link between the ultrafast carrier dynamics and solar-driven photocatalytic efficiency in CdS nanowires and explains recently observed control over photocatalytic pathways.

Antibiotic use and survival from breast cancer: A population-based cohort study in England and Wales

Abstract The role of the gut microbiota in carcinogenesis is increasingly being acknowledged. Recent studies in multiple breast cancer mouse models have found that antibiotics, by altering the gut microbiota, can accelerate tumour growth. In humans, a recent cohort study restricted to triple negative breast cancer showed that breast cancer patients using a greater number of antibiotics had markedly worse survival. These studies have raised concerns about repeated antibiotic use in breast cancer patients. In this Registered Report, we investigated whether breast cancer patients using oral antibiotics had increased breast cancer-specific mortality. In population-based cohorts (n = 44,452), we did not observe a statistically significant association between antibiotic prescriptions after diagnosis and breast cancer-specific mortality (adjusted HR = 1.07 95% CI 0.87, 1.33) apart from prescriptions of 12 or more antibiotics (adjusted HR = 1.62 95% CI 1.31, 2.01). This association was weaker after adjustment for infections (adjusted HR = 1.44 95% 1.14, 1.81), when restricted to antibiotics within five years (adjusted HR = 1.33 95% 0.95, 1.84), and was similar for deaths from other causes (adjusted HR = 1.69 95% 1.19, 2.41). Frequent antibiotic users had higher cancer-specific mortality but the attenuation of associations in sensitivity analyses, and similar findings for other causes of death, suggest this increase may reflect residual confounding. Protocol registration: The Stage 1 protocol for this Registered Report was accepted in principle on 7 November 2023. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.24746721.v1 .

Strong intermolecular coupling protects delocalization and transport of organic exciton-polaritons against static excitation energy disorder

Direct intermolecular interactions, being short-range and, hence, strongly dependent on local disorder, are commonly neglected in simulations of organic exciton-polaritons, and molecules are only indirectly linked through the cavity electromagnetic field, irrespective of intermolecular separations. Whereas accounting for direct intermolecular interactions has presumably little effect on the properties of organic exciton-polaritons in many experimental systems, disregarding these interactions might no longer be valid in systems with a certain degree of structural ordering, such as organic crystals, conjugated polymers, or molecular aggregates. In these systems, intermolecular couplings are comparable to the experimentally achieved collective light–matter coupling strengths and, therefore, may modify the properties of polaritons compared to those in weakly interacting molecular systems. To test this, we incorporate nearest-neighbor excitonic couplings into the multi-mode Tavis–Cummings Hamiltonian and perform numerical simulations of polariton delocalization and transport. The simulation results suggest that negative, or J-aggregate-type, coupling alters the energetics of lower polariton states such that these states become more robust against static excitation energy disorder. This results in better transport properties, in particular in less velocity renormalization and the transition from ballistic transport to diffusion occurring at larger exciton fractions than in the absence of excitonic coupling. In contrast, positive, or H-aggregate-type, coupling makes the lower polariton states more sensitive to disorder and deteriorates their propagation. These findings emphasize the importance of intermolecular interactions as a control parameter for achieving long-range excitation energy transfer in optical microcavities.

A protein complex in the extreme distal tip of vertebrate motile cilia controls their organization, length, and function

Fast methods for multisite charge transfer processes. I. Constrained, state averaged CASSCF(1,n) and CASSCF(2n − 1,n) simulations

We design a dynamically weighted state-averaged constrained complete active space self-consistent field (DW-SA-cCASSCF) algorithm to treat electrons or holes moving between n molecular fragments (where n can be larger than 2). Within such a so-called eDSCn/hDSCn approach, we consider configurations that are mutually single excitations of each other, and we apply a generalized set of constraints to tailor the method for studying charge transfer problems. The constrained optimization problem is efficiently solved using a DIIS-SQP algorithm, thus maintaining computational efficiency. We demonstrate the method for a finite Su–Schrieffer–Heeger chain, successfully reproducing the expected exponential decay of diabatic couplings with distance. When combined with a gradient, the current extension immediately enables efficient nonadiabatic dynamics simulations of complex multi-state charge transfer processes.

Fruquintinib plus sintilimab in patients with advanced endometrial cancer with mismatch-repair proficient status: a multicenter, single-arm, phase Ib/II trial

Fast methods for multisite charge transfer. Processes II. Analytic nuclear gradients and nonadiabatic dynamics for cCASSCF(1,n) and cCASSCF(2n-1,n) wavefunctions

We derive and implement analytic nuclear gradients and derivative couplings for a constrained complete active space self-consistent field with a small active space designed to model electron or hole transfer. Using a Lagrangian formalism, we are able to differentiate both the CASSCF energy and the constraint (which is required for smooth surfaces over a wide range of parameter space), and the resulting efficient algorithm can be immediately applied to nonadiabatic dynamics simulations of charge transfer processes. Here, we run initial surface-hopping simulations of a proton coupled electron transfer event for a phenoxyl–phenol system.

Neoadjuvant serplulimab combined with chemotherapy for resectable oesophageal squamous cell carcinoma: a single-arm, phase 2 trial

Water-modulated structure and dynamics in aqueous choline chloride-polyol deep eutectic solvents: Insights from molecular dynamic simulations

Understanding how water modulates the structure and dynamics of deep eutectic solvents (DESs) is essential for their rational design, yet their complex structuring in aqueous environment remains poorly understood. Here, we have performed molecular dynamic simulations to investigate structural organization, hydrogen-bond (H-bond) network, and water dynamics of aqueous DESs (ADESs) composed of choline chloride and three polyols, erythritol, xylitol, and sorbitol, at 0, 25, 50, and 75 wt. % of water, respectively. These polyols are deliberately chosen as H-bond donors because they possess an increasing number of hydroxyl groups. Radial distribution functions and cluster size distributions reveal various micro-structures formed inside ADESs. Their dependence on water content and on alcohol identity reflects a complex interplay of interactions. Alcohol–alcohol clustering decreases with increasing water content; however, water–water clustering shows a non-monotonic dependence. The normalized H-bond counts with varying water wt. % can explain the underlying alcohol dependency. The water dynamics is further investigated through tetrahedral order parameter, H-bond relaxation times, self-diffusion coefficients, and rotational time correlation functions. These reveal a progressive recovery of bulk-like water structure and dynamics from a confined environment with increasing water content, a well-known transition of “water in DESs” to “DESs in water.” Such effects directly influence solvent behavior, viscosity, and hydration properties, which are critical for biocatalysis. The results highlight the importance of tuning DES composition to control water-mediated structuring for chemical and biological applications.

Mechanosensitive dynamics of lysosomes along microtubules regulate leader cell emergence during collective cell migration

An enhanced adaptive image steganography method using block skin-maps and the integer S-transform

Is MRSF-TDDFT suitable for cyclobutanone dynamics? The role of higher energy states in surface hopping simulations

Modeling photochemical reactions remains a significant challenge due to the need for accurate descriptions of multiple excited states and their couplings with nuclear vibrations. Despite considerable advances in the field, the predictive power of current methodologies is still not fully established. Motivated by the recent Journal of Chemical Physics prediction challenge on cyclobutanone photochemistry, we simulated the photochemistry of the excitation of cyclobutanone by a 200 nm laser pulse using decoherence-corrected fewest-switches surface hopping, with a specific focus on the electronic structure method: mixed-reference spin-flip (MRSF) TDDFT. This promising method allows the description of S1–S0 conical intersections due to the ground state being a response of two triplet reference states, without the problem of spin contamination associated with regular spin-flip TDDFT. The simulated results show several decay pathways, most commonly through a ring opening S2/S1 conical intersection, resulting in the various photoproducts of carbon monoxide with some variation of C3 species, as well as the formation of ethene and ketene. Our simulations indicate that including higher-lying electronic states is essential to capture the diabatic trapping of the initial Rydberg 3s character, facilitated by an S3/S2 conical intersection. We emphasize the importance of carefully selecting the number of electronic states in the dynamical manifold. Comparison with XMS-PT2 confirms the presence of an S3/S2 conical intersection, although with a different topology and geometry closer to the Franck–Condon region. We also highlight the sensitivity of MRSF-TDDFT results to the choice of functional and the need for further validation of its conical intersection topologies to extend the method’s applicability in nonadiabatic dynamics.