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Theoretical limits for sensing through phase separation
Biomolecular condensates form on timescales of seconds in cells upon environmental or compositional changes. Condensate formation is thus argued to act as a mechanism for sensing such changes and quickly initiating downstream processes, such as forming stress granules in response to heat stress and amplifying cyclic GMP-AMP synthase enzymatic activity upon detection of cytosolic DNA. Here, we study a dynamical model of droplet nucleation and growth to demonstrate how phase separation allows cells to discriminate small concentration differences on finite, biologically relevant timescales. We propose optimal sensing protocols, which use the sharp onset of phase separation. We show how, given experimentally measured rates, cells can achieve rapid and robust sensing of concentration differences of 1 % on a timescale of minutes, offering an alternative to classical biochemical mechanisms.
HSCs/MPPs as cells of origin with altered differentiation hierarchy impairing immunomicroenvironment in <i>PML::RARA</i> and <i>CBFα/β</i> fusion AML
The theoretical possibility for leukemia stem cells (LSCs) to produce both leukemia blasts and dysfunctional immune cells remains underexplored. Here, we investigate three major fusion transcription factor (fTF)-driven acute myeloid leukemia (AML) subtypes [ RUNX1(CBFα)::RUNX1T1 , PML::RARA , and CBFB::MYH11 ] using two optimized single-cell RNA-sequencing technologies to trace fTF expression in 24 de novo AML patients. We demonstrate that the fTFs are widely expressed not only in leukemia blasts but also in differentiated myeloid and lymphoid cells, indicating hematopoietic stem cells or multipotent progenitors (HSCs/MPPs) as LSCs that propagate altered cellular differentiation hierarchies, including immune cells. DNA-FISH confirms the presence of fTFs in T lymphoid and erythroid cells, and targeted sequencing of secondary mutations in sublineages of cells corroborates hierarchical and stepwise leukemogenesis. By tracking RUNX1::RUNX1T1 -expressing cells in patients with or without relapse post–frontline chemotherapy, we highlight the necessity of eradicating LSCs to achieve sustained long-term complete remission and restore a functional immune system capable of suppressing residual disease over time. Comparative single-cell transcriptome analyses further reveal that fTFs are associated with AML subtype-specific differentiation defects in both innate and adaptive immune compartments, suggesting an altered landscape of immune cell–cell communication networks that may facilitate the survival and proliferation of leukemic blasts. Through the examination of intercellular communications among various putative fTF + and normal cell populations, we developed a ligand–receptor (L–R)-based risk-scoring model with independent prognostic value. Collectively, these findings provide insights into the cells of origin of LSCs and the implications of fTF expression for the immune landscape of AML.
Carbon–phosphorus exchange rate constrains density–speed trade-off in arbuscular mycorrhizal fungal growth
Symbiotic nutrient exchange between arbuscular mycorrhizal (AM) fungi and their host plants varies widely depending on their physical, chemical, and biological environment. Yet dissecting this context dependency remains challenging because we lack methods for tracking nutrients such as carbon (C) and phosphorus (P). Here, we developed an approach to quantitatively estimate C and P fluxes in the AM symbiosis from comprehensive network morphology quantification, achieved by robotic imaging and machine learning based on roughly 100 million hyphal shape measurements. We found that rates of C transfer from the plant and P transfer from the fungus were, on average, related proportionally to one another. This ratio was nearly invariant across AM fungal strains despite contrasting growth phenotypes but was strongly affected by plant host genotype. Fungal phenotype distributions were bounded by a Pareto front with a shape favoring specialization in an exploration–exploitation trade-off. This means AM fungi can be fast range expanders or fast resource extractors, but not both. Manipulating the C/P exchange rate by swapping the plant host genotype shifted this Pareto front, indicating that the exchange rate constrains possible AM fungal growth strategies. We show by mathematical modeling how AM fungal growth at fixed exchange rate leads to qualitatively different symbiotic outcomes depending on fungal traits and nutrient availability.
Neurotensin in the extended amygdala maintains wakefulness in novel environments
Animals remain awake in unfamiliar environments to assess potential safety threats, a process involving changes in neuronal activity within sleep–wake regulatory brain regions. However, the specific circuits and neurotransmitters involved remain poorly understood. Here, we show that neurotensin (NTS) peptides in corticotropin-releasing factor (CRF) neurons of the lateral part of the interstitial nucleus of the posterior limb of the anterior commissure (IPACL) play a key role in maintaining wakefulness in response to environmental changes. Activation of IPACL CRF neurons increased wakefulness, whereas their inhibition or deletion of NTS reduced wakefulness in novel environments. These neurons are activated in response to exposure to a novel environment and project primarily to the substantia nigra pars reticulata (SNr) and release NTS, which modulates wakefulness. These findings suggest that NTS signaling from IPACL CRF neurons to the SNr is essential for sustaining wakefulness in unfamiliar or changing environments.
Molecular assemblies and pharmacology of cerebellar GABA <sub>A</sub> receptors
GABA A receptors (GABA A Rs) mediate fast inhibitory neurotransmission in the brain and are assembled from 19 subunit isoforms into multiple pentameric assemblies. Although α1-containing GABA A Rs are broadly expressed and are pharmacologically important, the molecular diversity of native α1-based assemblies in specific brain regions remains incompletely understood. Here, we use immunofluorescence, mass spectrometry, and cryogenic electron microscopy (cryo-EM) to characterize the spatial distribution, subunit composition, and structural architecture of native α1-containing GABA A Rs in the rat cerebellum. Confocal microscopy reveals robust colocalization of α1 and γ2 subunits across cerebellar layers, including prominent labeling at glomerular synapses. Biochemical purification and proteomic analysis identify a range of α, β, and γ subunits, along with abundant α6 and δ subunits. Using cryo-EM and automated subunit identification, we resolve eight α1-containing receptor assemblies, including the first structure of α6-containing receptors. We further determine the binding mode of the α6-selective pyrazoloquinolinone modulator PZ-II-029 at the α + /γ – interface, showing ligand-induced expansion of the entire extracellular domain (ECD). Together, our study defines the structure and subunit composition of the α1-containing cerebellar GABA A Rs and elaborates the molecular interactions between native receptors and pyrazoloquinolinone, thereby laying the groundwork for brain region and subunit-specific pharmacology.
Ultrasonic vocal communication of negative affective states in laboratory mice
Anxiety disorders are the most common mental disorders, resulting in substantial social and economic costs stemming from reduced productivity. Pharmacotherapy is the most widely used treatment for these disorders, and effective improvement requires a reliable animal model of human anxiety. Although communication in rats using ultrasonic vocalizations (USVs) has been reported as a biologically valid animal model of human anxiety, an equivalent model in mice has not yet been established. To identify such USVs, we conducted physiological, behavioral, and pharmacological experiments using ddY strain mice. Ultrasonic sine waves within a limited frequency range enhanced anxiety levels in male mice. When female mice were exposed to ethologically stressful situations, they emitted a specific type of USV that was not only quantitatively abundant and qualitatively distinct but also within a frequency range that induced increased anxiety in male mice. Playback of these female USVs induced anxiety-related affective changes in male mice. We believe that these findings represent a step toward demonstrating ultrasonic vocal communication of negative affective states in laboratory mice. This study offers a foundation for developing mouse models using USVs as a tool to understand the pathogenic mechanisms of human anxiety disorders and to develop neuropharmacological therapies.
EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity
Polycomb Repressive Complex 2 (PRC2) facilitates the formation of facultative heterochromatin, instrumental to tissue specific gene expression. PRC2 catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3), which is targeted for chromatin compaction by PRC1. Importantly, PRC2-associated cofactors regulate its distinct activities, as in the case of MTF2 and JARID2 that direct PRC2 to specific chromatin nucleation sites based on preferred DNA-binding motifs. Here, we investigated EPOP whose role in regulating PRC2 was not well-defined. We find that both EPOP and MTF2 stimulate PRC2 histone methyltransferase (HMT) activity in vitro. Unlike MTF2, EPOP is ineffectual in PRC2 chromatin recruitment as evidenced by an EED-rescue system in vivo but promotes H3K27me3 deposition de novo in cooperation with MTF2 and JARID2. Binding assays using reconstituted dinucleosome substrates revealed that similar to MTF2, EPOP promotes PRC2 chromatin-binding activity in a distinct DNA-sequence-dependent manner (GCN-rich and GA-rich, respectively). Thus, EPOP and MTF2 in conjunction with JARID2 foster PRC2-mediated HMT activity at chromatin sites comprising cofactor-preferred DNA-binding sequences during the formation of H3K27me3-chromatin domains.
Variable thresholds for phosphorylation targets of the ERK signaling pathway
Cell fates regulated by ERK respond to different thresholds of signaling strength. In mammalian cells, conditions that activate ERK to submaximal levels are sufficient to sustain proliferation, survival, and transformation, while stimuli that activate ERK to very high levels often lead to cell death or cell cycle arrest. But while this “Goldilocks effect” is well known, the mechanisms have never been fully explained. In particular, threshold responses have been shown at the level of transcription and cell state changes, but whether phosphorylation responses upstream of these events also respond to thresholds is unknown. Here, we used mass spectrometry-based phosphoproteomics to ask if molecular events in the ERK pathway respond to different thresholds of signaling strength, by quantifying changes in phosphorylation of pathway targets against the occupancy of the two activating phosphosites in ERK. The results show that most phosphorylation events track ERK activation faithfully, responding linearly with increasing 2P-ERK occupancy. But some sites respond nonlinearly, reaching maximal phosphorylation when 2P-ERK exceeds lower thresholds (10 to 40%), or increasing substantially after 2P-ERK exceeds higher thresholds (>60%). Low threshold sites are found on transcriptional repressors that facilitate proliferation when inactivated by ERK/ribosomal s6 kinase (RSK) phosphorylation. By contrast, high threshold sites are found on proteins that are recruited to double-stranded DNA breaks and mediate DNA repair. Measurement of phosphorylation occupancies also revealed unexpected differences between cell states not apparent from inhibitor fold-changes. Our findings demonstrate that signaling thresholds exist at the level of the phosphoproteome, providing potential mechanisms for regulating cellular responses to pathway strength.
Probabilistic mapping and automated segmentation of human brainstem white matter bundles
Brainstem white matter (WM) bundles are essential conduits for neural signals that modulate homeostasis and consciousness. Their architecture forms the anatomic basis for brainstem connectomics, subcortical circuit models, and deep brain navigation tools. However, their small size and complex morphology, compared to cerebral WM, makes mapping and segmentation challenging in neuroimaging. As a result, fundamental questions about brainstem modulation of human homeostasis and consciousness remain unanswered. We leverage diffusion MRI tractography to create BrainStem Bundle Tool (BSBT), which automatically segments eight WM bundles in the rostral brainstem. BSBT performs segmentation on a custom probabilistic fiber map using a convolutional neural network architecture tailored to detect small anatomic structures. We demonstrate BSBT’s robustness across diffusion MRI acquisition protocols with in vivo scans of healthy subjects and ex vivo scans of human brain specimens with corresponding histology. BSBT also detected distinct brainstem bundle alterations in patients with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and traumatic brain injury through tract-based analysis and classification tasks. Finally, we provide proof-of-principle evidence for the prognostic utility of BSBT in a longitudinal analysis of traumatic coma recovery. BSBT creates opportunities for scalable mapping of brainstem WM bundles and investigation of their role in a broad spectrum of neurological disorders.
Correction: An experimental investigation of the drift ratio and its influencing factors in mechanical draft wet cooling towers
Hydration gradients drive lipid self-segregation
Evaporation from a multicomponent aqueous mixture not only establishes a hydration gradient but may also lead to composition gradients in the other components. Here, we show that such a gradient induces a strong segregation between two phospholipids that differ only in the saturation of their acyl chains. Using high-resolution confocal Raman microscopy combined with small- and wide-angle X-ray scattering, we simultaneously resolve local composition and structure along the evaporation direction. We find that the saturated phospholipid, dipalmitoyl phosphatidylcholine (DPPC), accumulates near the air–liquid interface, while the unsaturated phospholipid, dioleoyl phosphocholine (DOPC), is displaced toward a more hydrated intermediate region, resulting in a complete inversion of their initial proportions. This nonmonotonic lipid gradient reflects the different water swelling capacities of the L β′ and L α lamellar phases favored by DPPC and DOPC, respectively. Despite the system being out of equilibrium, the segregation is quantitatively captured by a description based on local equilibrium chemical potentials and multicomponent diffusion with cross-coupling. Our findings identify hydration gradients as a robust driver of lipid segregation and establish a general framework for predicting transport and organization in evaporating soft-matter systems.
Assessment of radiological risks in soils from different land use types within southwest Nigeria
Hierarchical friction memory leads to subdiffusive configurational dynamics of fast-folding proteins
Proteins often exhibit subdiffusive configurational dynamics, the origins of which are still unresolved. We investigate the impact of non-Markovian friction and the free-energy landscape on the dynamics of fast-folding proteins in terms of the mean squared displacement (MSD) and the mean first-passage-time (MFPT) of the folding reaction coordinate. We find the friction memory kernel from published molecular dynamics simulations to be well-described by a hierarchical multiexponential function, which gives rise to subdiffusion in the MSD for times shorter than the longest memory time, while for longer times the confining free-energy landscape produces subdiffusion. Thus, for a wide range of times, friction memory effects in fast-folding proteins dominate the scaling behavior of the MSD compared to effects due to the folding free-energy landscape. As a consequence, Markovian models are insufficient to fully capture the folding dynamics, as quantified by the MSD and the MFPT, even when including coordinate-dependent friction. Our results demonstrate the importance of memory effects in protein folding and conformational dynamics and explicitly show that subdiffusion in fast-folding protein dynamics originates mainly from memory effects, not from the free-energy landscape and not from coordinate-dependent friction.
Enhanced diabetes prediction using pre-trained CNNs, LSTM, and conditional GAN on transformed numerical data
How earthquakes organize stress
Stress is not uniform in the Earth. Therefore, we must use natural experiments to measure the distribution of stresses and related quantities, rather than single values. For instance, dynamic triggering shows that faults are uniformly distributed over their loading cycles in Southern California. The probability that a fault ruptures across a barrier measures the in situ energy distribution. Fault roughness reflects the distribution of strength. These natural experiments produce observable distributions that are surprisingly consistent and suggest some degree of self-organization in the Earth’s crust. Once established, the functional form of the distributions can be used to track changes in response to earthquakes as well as to distinguish fundamentally different fault systems. Transient fault locking before stress release in laboratory experiments can be interpreted as a consequence of self-organization of fault stress. The robust self-organization of multiple variables in earthquake systems suggests that the most consequential mechanical outcome of earthquakes may be the redistribution of stress and the strain energy associated with it. The low friction on a fault during seismic slip as inferred by temperature measurements of the Tohoku earthquake is consistent with dissipation playing a secondary role to this redistribution process. Through stress redistribution and interaction, subduction zone faults tend to synchronize, perhaps due to their geometric simplicity, while the continental system of Southern California cannot synchronize, perhaps due to the complexity of the fault network. Earthquakes organize stress in the crust and produce a suite of well-defined, consistent distributions.
Enhancement of essential oil yield and quality of basil (Ocimum basilicum L.) via intercropping system, AMF and PGPR
Integration of fear learning and fear expression across the dorsoventral axis of the hippocampus
Classically, the dorsal and ventral hippocampus are thought to play distinct roles in fear conditioning, with the dorsal hippocampus primarily handling information about environmental cues and contexts, and the ventral hippocampus more involved in emotional processing. Both functions are essential for the learning and expression of conditioned fear responses, but how these processes are integrated remains largely unexplored. In this study, we simultaneously recorded single-unit activity from the dorsal and ventral hippocampus during fear conditioning in male rats to identify the neural dynamics that may underlie these processes and their integration. As fear expression emerged, shifts in neural firing patterns were observed in both regions, with a stronger shift in ventral hippocampal activity, as expected. However, contrary to the prevailing view of the ventral hippocampus as central to anxiety and fear regulation, surprisingly, fear expression-related neuronal responses were more predominant in the dorsal hippocampus. In contrast, ventral hippocampal neuronal activity was more closely linked with the acquisition of conditioned fear. These features were combined in cell assemblies that emerged during fear conditioning, composed of both dorsal fear expression-responsive neurons and ventral fear learning-responsive cells. These multifactorial engrams, distributed along the hippocampal dorsoventral axis, provide a potential substrate for integrating fear acquisition and expression, thereby coordinating associative learning.
Field-tunable charge confinement in III–V layered nanowire-array superlattices
Bridging unpaired single-cell multimodal data for integrative analyses with SuperMap
Current single-cell profiling technologies enable the capture of multiple cellular modalities, providing valuable insights into complex biological systems. While a substantial amount of single-cell multimodal data has been generated and accumulated, most of these datasets are unpaired, characterized by distinct feature spaces and a lack of cell-wise correspondence. The absence of explicit linkages between modalities poses a fundamental challenge for data integration and interpretation. To address this, we introduce SuperMap, a statistical learning method designed for the integrative analyses of unpaired multimodal data. SuperMap directly learns cross-modal mappings from unpaired data to effectively bridge and link different modalities, facilitating a variety of downstream analysis tasks. Comprehensive benchmarking and real-world applications demonstrate the superior performance of SuperMap in enhancing cell-type identification, improving diagonal integration, enabling regulatory analysis, and revealing epigenomic priming events to specify cell differentiation directions for trajectory inference.