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MultistageOT: Multistage optimal transport infers trajectories from a snapshot of single-cell data
Single-cell RNA-sequencing captures a temporal slice, or a snapshot, of a cell differentiation process. A major bioinformatical challenge is the inference of differentiation trajectories from a single snapshot, and methods that account for outlier cells that are unrelated to the differentiation process have yet to be established. We present MultistageOT ( https://github.com/dahlinlab/MultistageOT ), a generalized optimal transport-based framework that models cell differentiation in a single snapshot as a series of intermediate cell transitions. MultistageOT employs multiple transport stages to establish temporal progression within the snapshot—overcoming limitations with the classic bimarginal formulation of optimal transport. Moreover, our multistage framework uses global information across all cells and differentiation stages to infer coherent trajectories from initial to terminal states. This allows MultistageOT to infer individual outlier cells that are unrelated to the analyzed differentiation process—an essential mechanism for preventing the inference of spurious or biologically implausible trajectories. We benchmark MultistageOT on snapshot data of cell differentiation, showing significantly improved fate prediction accuracy over state-of-the-art bimarginal optimal transport and demonstrating MultistageOT’s unique ability to detect outlier cells.
Fluoride triggers lysis in <i>Streptococcus mutans</i> by inhibition of the Clp protease complex, leading to an unabated competence cascade
Fluoride has long been known to possess antimicrobial properties. For many bacteria, the toxic effects of fluoride are reversible. However, fluoride has also been shown to trigger lysis and cell death in many other diverse bacterial species, including dental pathogens. The underlying molecular mechanisms responsible for fluoride-induced cell lysis have not been established. Using Streptococcus mutans as a model, we show that fluoride elicits an uncontrolled stress response characterized by upregulation of competence pathways and extensive cell wall degradation. While controlled and limited autolysis under stress is an adaptive response, we show that expression of the competence-associated alternative sigma factor ComX is prolonged under fluoride stress, relative to other stressors. Using in vitro and in vivo analyses, we show that fluoride disrupts the typical tight temporal control of ComX by specifically inhibiting assembly and activity of Clp ATPases responsible for its proteolytic degradation. Unchecked, ComX upregulates bacteriocins and autolysins, while simultaneously suppressing immunity peptide expression via a 6S RNA-mediated mechanism. Thus, fluoride subverts cellular mechanisms to turn off competence pathways that are induced under cellular stress, causing irreversible damage to the cell wall and ultimately cell death. Phenylalanine partially restores Clp protease assembly and activity, providing a rationale for the frequent presence of a gene encoding chorismate mutase in fluoride-responsive operons. Together, our findings reveal the molecular mechanism of fluoride-dependent lysis in bacteria, fifty years after this phenomenon was first reported. These pathways could be exploited to potentiate the antimicrobial effects of oral fluoride.
A balance between glycitein and glyceollins governed by isoflavone 6-hydroxylase confers soybean resistance to <i>Phytophthora sojae</i>
Isoflavonoids, predominantly found in legumes, are specialized metabolites with antioxidant properties that benefit both plant resilience and human health. Using metabolic genome-wide association studies (mGWAS), we identified the cytochrome P450 gene ( Glyma.11g108300 ), GmIF6H1 , as a key determinant of glycitein biosynthesis in soybean [ Glycine max (L.) Merr.]. Biochemical assays together with in planta stable-isotope tracing demonstrated that GmIF6H1 catalyzes the 6-hydroxylation of daidzein, establishing a previously unrecognized and predominant biosynthetic route for glycitein. A single amino acid substitution in GmIF6H1 accounts for the domestication-associated reduction of glycitein-type isoflavonoids. Upon Phytophthora sojae infection, (malonyl)glycitins undergo sustained deglycosylation to release glycitein aglycone, underscoring its defensive role. Strikingly, both loss- and gain-of-function alleles increase susceptibility to P. sojae , indicating that precise tuning of GmIF6H1 expression is essential for effective resistance. Metabolite profiling further reveals complementary daidzein-centered defense strategies: Glycitein-type isoflavonoids (via daidzein 6-hydroxylation) function as phytoanticipins, whereas glyceollins (via daidzein 2’-hydroxylation) act as inducible phytoalexins. Together, these findings clarify the biosynthetic origin of the glycitein and underscore the synergistic action of glycitein and glyceollins in pathogen resistance, offering opportunities for engineering disease-resilient soybean cultivars.
Biological fidelity: The engine driving the neuromorphic renaissance
Reward-driven adaptation of movements requires strong recurrent basal ganglia–cortical loops
The basal ganglia (BG) are a collection of subcortical nuclei involved in motor control, sensorimotor integration, and procedural learning. They play a key role in the acquisition and adaptation of movements, a process driven by dopamine-dependent plasticity at cortico-striatal projections, which serve as BG input. However, BG output is not necessary for executing many well-learned movements. This raises a fundamental question: How can plasticity at BG input contribute to the acquisition and adaptation of movements which execution does not require BG output? Existing models of BG function often neglect the feedback dynamics within cortico-BG-thalamo-cortical circuitry and do not capture the interaction between the cortex and BG in movement generation and adaptation. In this work, we address the above question in a theoretical model of the BG-thalamo-cortical multiregional network, incorporating anatomical, physiological, and behavioral evidence. We examine how its dynamics influence the execution and reward-based adaptation of reaching movements. We demonstrate how the BG-thalamo-cortical network can shape cortical motor output through the combination of three mechanisms: i) the diverse dynamics emerging from its closed-loop architecture, ii) attractor dynamics driven by recurrent cortical connections, and iii) reinforcement learning via dopamine-dependent cortico-striatal plasticity. Our study highlights the role of the cortico-BG-thalamo-cortical feedback in efficient visuomotor adaptation. It also suggests a mechanism for early-stage acquisition of reaching movements through motor babbling. More generally, our model explains how the BG-cortical network refines motor output through its intricate closed-loop dynamics and dopamine-dependent plasticity at cortico-striatal synapses.
New reconstruction of DAN5 cranium (Gona, Ethiopia) supports complex emergence of Homo erectus
MBNL loss of function in smooth muscle as a model for myotonic dystrophy associated gastrointestinal dysmotility
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of Mbnl1 and Mbnl2 to model and investigate myogenic mechanisms contributing to GI dysmotility in DM1. Mice with Mbnl knockout exhibited delayed GI transit of small and large bowel in vivo and increased smooth muscle contractile tone of jejunum and colon segments ex vivo. Smooth muscle from the jejunum and colon showed no histopathology suggesting an intrinsic defect and contained increased phosphorylation of the 20 kDa myosin light chain (Mlc20), consistent with increased contraction. RNA sequencing of mouse and human DM1 GI samples enriched for smooth muscle revealed conserved misregulated alternative splicing of transcripts associated with the regulation of Mlc20 phosphorylation and smooth muscle contraction. These findings demonstrate that Mbnl knockout disrupts the regulation of contraction dynamics and causes GI smooth muscle hyperactivity, suggesting that therapeutics that reduce GI contractile activity may improve DM1 GI symptoms.
Strain engineering of single-site Cu on SWCNTs for highly efficient diene cyclopropanation
The inferred functional connectome underlying circadian synchronization in the mouse suprachiasmatic nucleus
Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the suprachiasmatic nucleus (SCN). Although anatomical, molecular, and genetic approaches have revealed diverse SCN cell types, how network-level wiring enables their synchronization remains unclear. To overcome the challenges of inferring functional connectivity from fixed tissue, we developed Mutual Information & Transfer Entropy (MITE), an information-theoretic framework to infer directed cell–cell connections with high fidelity from long-term live-cell imaging. Recording and analyzing 3,290 h of clock gene expression from 8,261 SCN neurons across 17 mice, we uncovered a highly conserved, sparse SCN network organized into two asymmetrically coupled modules: dorsal and ventral. Connectivity analyses revealed five functional SCN cell types independent of neurochemical identity. Notably, only ~30% of vasoactive intestinal peptide neurons exhibited Hub-like connectivity, classifying them as Generators and Broadcasters of synchrony signals. Other spatially stereotyped cell types consistently identified as Bridges, Receivers, or Sinks. Simulations based on MITE-inferred connectomes recapitulated emergent SCN dynamics, including recovery from desynchrony and the daily dorsal-to-ventral phase wave of gene expression. Together, these results demonstrate that MITE enables precise mapping of cellular network topology, revealing the circuit logic and key cell types that mediate circadian synchrony across space and time in the mammalian SCN.
Quantum thermalization must occur in translation-invariant systems at high temperature
Abstract Quantum thermalization describes how closed quantum systems can effectively reach thermal equilibrium, resolving the apparent incongruity between the reversibility of Schrödinger’s equation and the second law of thermodynamics. Despite its ubiquity and conceptual significance, the precise conditions that give rise to quantum thermalization are still not well understood. After nearly a century of efforts, we have yet to find a complete mathematical proof that an effective statistical description naturally emerges the underlying quantum dynamics in generic settings. Here, we prove that quantum thermalization must occur in any qubit system with local interactions under three conditions: (i) high effective temperature, (ii) translation invariance, and (iii) no perfect resonances in the energy spectrum. Specifically, we show that a typical, low-complexity pure state drawn from any ensemble with large entropy and well-defined effective temperature becomes locally indistinguishable from a Gibbs state upon unitary evolution. In this setting, our rigorous results prove the widely anticipated notion that statistical physics should be understood as an emergent phenomenon, explicitly derived from the first principles of quantum mechanics.
Correction for Jang et al., Lipid raft proteomics identify endothelial myosin-9 (MYH9) as a regulator of low-density lipoprotein transcytosis and atherosclerosis
Rapid culture-free diagnosis of clinical pathogens via integrated microfluidic-Raman micro-spectroscopy
Abstract Antimicrobial resistance (AMR) is a critical global health challenge, demanding rapid and accurate diagnostics to guide timely antimicrobial therapy. Current diagnosis is hindered by prolonged culturing and difficulties detecting low pathogen loads. Here, we present a culture-free diagnostic platform that integrates microfluidics, Raman micro-spectroscopy, and deep learning to deliver “sample-to-report” testing within 20 min. The microfluidic enrichment system employs dialysis-dielectrophoresis (DEP) technology to rapidly isolate pathogens directly from clinical samples with a detection limit as low as <2 colony forming unit (CFU)/ml. Combining a single-cell Raman fingerprint database of 342 clinical isolates from 29 bacterial and 7 fungal species with a 1D ResNet deep learning model, our approach achieved 95.1% accuracy in lab settings. Validated in a 305-patient clinical study involving primary urine and other clinical samples, it demonstrated 95.4% agreement with traditional culture methods and 98.5% sensitivity in diagnosing infections. While broader validation is needed for clinical implementation, the integrated, rapid diagnosis pipeline, as well as broad-spectrum detection, offer a promising solution for next-generation diagnostics for combating AMR.
We need transparency standards for social media research that involves companies
Integrating a host biomarker with a large language model for diagnosis of lower respiratory tract infection
Abstract Lower respiratory tract infections (LRTI) are a leading cause of mortality and are challenging to diagnose in critically ill patients, as non-infectious causes of respiratory failure can present with similar clinical features. We develop an LRTI diagnostic method combining the pulmonary transcriptomic biomarker FABP4 with electronic medical record text assessment using the large language model Generative Pre-trained Transformer 4. In a cohort of critically ill adults, a combined classifier incorporating FABP4 expression and large language model electronic medical record analysis achieves an area under the receiver operating characteristic curve (AUC) of 0.93 ± 0.08 and an accuracy of 84%, outperforming FABP4 expression alone (0.84 ± 0.11) and large language model-based analysis alone (0.83 ± 0.07). By comparison, the medical team admission diagnosis has an accuracy of 72%. In an independent validation cohort, the combined classifier yields an AUC of 0.98 ± 0.04 and accuracy of 96%. This study suggests that integrating a host biomarker with large language model analysis can improve LRTI diagnosis in critically ill adults.
CDCA7 facilitates MET1-mediated CG DNA methylation maintenance in centromeric heterochromatin via linker histone H1
DNA methylation is a conserved epigenetic modification essential for maintaining genome stability. However, how methyltransferases maintain CG methylation within compact chromatin, including centromeres, remains unclear. In humans, CDCA7 is necessary for the inheritance of DNA methylation at juxta-centromeres. Mutations that impair its ability to bind chromatin result in Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) syndrome, characterized by centromeric instability. To investigate whether CDCA7 function is conserved, we identified two Arabidopsis thaliana orthologs, CDCA7α and CDCA7β . The loss of both copies results in CG hypomethylation at pericentromeric regions and centromeric satellite repeat arrays. Machine learning analysis suggested that heterochromatic nucleosomes, with enrichment of H1, H2A.W, and H3K9me2, depend heavily on CDCA7 proteins for CG methylation maintenance of the associated DNA. Loss of H1 restores heterochromatic DNA methylation in cdca7α cdca7β mutants, indicating that CDCA7α and CDCA7β mainly remodel H1-containing nucleosomes for methyltransferases to access DNA. Notably, in h1.1 h1.2 mutants, CG methylation shows a significant increase in centromeres, which reveals a new inhibitory role of H1 in DNA methylation maintenance within satellite repeat arrays. Centromeric DNA hypermethylation is lost in h1.1 h1.2 cdca7α cdca7β quadruple mutants, demonstrating that CDCA7α and CDCA7β can act independently of H1 to enhance MET1 activity at nucleosomes. Overall, these findings establish CDCA7α and CDCA7β as conserved regulators of DNA methylation within heterochromatin and centromeric satellite repeat arrays.
Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer
Endogenous forms of ATP–ATP <sup>4−</sup> and MgATP <sup>2−</sup> —orchestrate distinct pathophysiological signaling via biased activation of P2X3 receptors
P2X receptors, a family of ATP-activated ion channels, encompass subtypes P2X1–7, which are expressed in both homo- and heterotrimeric forms across various tissues. These receptors play crucial roles in pathophysiological processes such as synaptic transmission, nociception, cough, and taste perception. Extracellular ATP exists as both MgATP 2− and ATP 4− , with P2X3 responding to both. The evolutionary rationale for two nearly identical ligands and their distinct signaling potential remains unclear. While previous structural studies suggest a uniform ATP recognition mechanism for two endogenous ATP forms, we propose that MgATP 2− and ATP 4− activate P2X3 through distinct mechanisms, leading to differential physiological and pathological outcomes. Using mutagenesis, voltage-clamp fluorometry, and small molecule interventions, we identify divergent interactions of ATP 4− and MgATP 2− with P2X3, despite binding to the same orthosteric pocket. In P2rx3 D158A/D158A transgenic mice, which selectively impair MgATP 2− activation, we find that MgATP 2− modulates ammonia-induced cough frequency without affecting complete Freund’s adjuvant-induced inflammatory pain or sweet taste preference. P2rx3 −/− mice show deficits in all three responses. The allosteric inhibitor aurintricarboxylic acid selectively modulates ATP 4− and MgATP 2− effects, resulting in distinct antitussive and analgesic outcomes in vivo. These findings uncover a mechanism of P2X3 activation by its endogenous ligands, diverging from previous structural models and resembling the biased activation mechanisms observed in G-protein-coupled receptors, offering insights for P2X3-targeted therapeutics.