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Ren, Y.

Publications and source records attributed to Ren, Y..

At least 55 records · Page 3Linked to original sources

Music Scaffolds Visual Statistical Sequence Learning Through Network-Level Reorganization in the Brain

Statistical learning--the ability to extract patterns from noisy continuous experiences--is fundamental to human cognition. Yet, how contextual factors shape this process remains poorly understood. Music is an important example of such contextual factors, because it is ubiquitous in human experience and provides a rich temporally-structured stimulus that can co-occur with other learning processes. Here we demonstrate that pairing music fundamentally enhances visual statistical learning, and this is correlated with systematic reorganization of large-scale brain networks. Using fMRI and a novel probabilistic sequence learning paradigm, we show that familiar melodies significantly improved participants ability to segment continuous visual streams into events and learn sequential relationships. Neuroimaging analyses revealed that the presence of music fundamentally altered the neural network organization that coordinates learning mechanisms: while sequence learning in silence engaged frontal-parietal networks associated with explicit pattern extraction, providing musical temporal structure as a context shifted learning toward MTL-vmPFC circuits recently implicated in schema-guided memory processing. Machine learning analyses confirmed these architectural differences, with the music condition achieving optimal neural prediction of behavioral performance through distributed connectivity patterns while control condition relied on concentrated processing. Our findings support a Cross-Modal Temporal Scaffolding Theory, demonstrating that structured temporal context signals from one modality (here, music) can create more efficient neural states for sequence processing in another through dual mechanisms: enhanced memory integration through schema-guided learning and reduced demands on explicit control resources. These results identify network-level principles for optimizing statistical learning, with broad implications for understanding how environmental context shapes human learning capacity.

neuroscience↗

Population-level super-pangenome reveals genome evolution and empowers precision breeding in watermelon

Pangenomes are increasingly critical for harnessing crop genetic diversity, yet their resolution and utility are often limited by insufficient sampling of high-quality genome assemblies. Here, we report a population-level watermelon super-pangenome constructed from 138 reference-grade assemblies, including 135 newly generated near-gapless genomes representing all seven watermelon species. The super-pangenome captures approximately one million structural variants (SVs), enabling accurate variant genotyping across ~900 watermelon accessions and substantially expanding variant discovery both across and within species. Broader sampling within the pangenome provides insights into genome evolution among watermelon species and sheds light on the origin of cultivated watermelon. SV-inclusive genome-wide association studies enhance trait mapping resolution and identify a copy number variation upstream of ClFCI1 that regulates flesh color intensity in a dosage-dependent manner. Leveraging this comprehensive variation map, we developed high-accuracy genomic prediction models for 18 agronomic traits. Together, our findings and genomic resources establish a foundational framework for dissecting complex traits and accelerating precision breeding in watermelon, while offering a valuable model for SV-resolved pangenomics in crop species.

plant biology↗

The genome of the early diverged amphioxus, Asymmetron lucayanum, illuminates the evolution of genome architecture and gene repertoires in cephalochordates

Cephalochordates (amphioxus or lancelet) are considered as living proxies for ancestral chordates due to their key phylogenetic position and slow evolutionary rate. The genomes of living amphioxus thus can help to reveal the genetic basis shaping the evolutionary transition from invertebrates to vertebrates. To gain a comprehensive understanding of the genome architecture in amphioxus, here we generate a chromosome-anchored genome assembly for Asymmetron lucaynum, representing the earliest diverging cephalochordate genus. Our results show that Asymmetron has an enlarged genome compared to those of the other four cephalochordate genomes decoded so far (all in the genus Branchiostoma), causing by pervasive expansions of inter-genic transposable elements (TEs). Nevertheless, both macrosynteny and microsynteny remain highly conserved between Asymmetron and Branchiostoma, enabling reconstruction of the ancestral genomic architecture of the Cephalochordate lineage for tracing genome evolutionary process during Deuterostome and Chordate diversification. By coupling developmental transcriptomic analyses, we further show that purifying selection and constraints on co-transcriptional regulation may have contributed to the maintenance of the conserved microsynteny blocks among cephalochordate species. We also examine the evolutionary history of Hox cluster in cephalochordates and vertebrates, and identify species-specific inversions and TE invasions at this important locus in both Asymmetron and Branchiostoma. Finally, we survey key gene families involved in both innate and adaptive immunity (e.g., TLR, NLR, MHC, and RAG) and uncover their plausible ancestry and evolutionary dynamics in chordates. Taken together, our findings illuminate the genome and gene evolution of cephalochordates and provide valuable resources for understanding the early evolution of chordates and the origin of vertebrates.

genomics↗

Dopamine selectively regulates pediatric sclera/choroid interactions through the stimulation of exosome-associated retinoic acid

Postnatal eye growth is critical for healthy vision and yet, how this process is regulated at the cellular level is still unclear. The choroid is thought to play a crucial role in relaying signals from the retina to the sclera to modulate eye growth, but which cells are targeted and how they interact is not known. Using primary cultures of pediatric and adult human choroid and sclera stromal fibroblasts, we investigated the effect of choroid-conditioned medium (CCM) on scleral fibroblasts contractile activity. We show that CCM activates pediatric scleral fibroblast contraction, with age and antero-posterior location differences. Upon exposure to dopamine, a known negative regulator of eye growth, pediatric - but not adult - choroid cells lose their ability to stimulate scleral fibroblasts. Using RNA-Sequencing, we show that dopamine stimulates pathways linked to ribosomal activation, translation and exosome release exclusively in pediatric choroid cells. Removing exosomes from the CCM rescued the ability of dopamine-treated choroid cells to stimulate scleral fibroblasts. We further identify retinoic acid as the active exosome-associated compound preventing scleral fibroblast activation. Mechanistically, we show that CCM stimulates actomyosin-mediated protrusive activity in scleral fibroblasts. This is prevented when scleral cells are exposed to dopamine-CCM, and fully rescued upon exosome removal or ALDH1 inhibition. We thus propose that pediatric choroid stromal cells specifically relay dopamine-mediated retinal signals to the sclera during post-natal eye growth, operating through changes in secretome - including the production of exosome-associated retinoic acid - rather than gene expression changes. SIGNIFICANCEEye size is critical to optimal vision but the exact cellular and molecular mechanisms regulating it are still unknown. Failure to properly regulate postnatal eye growth leads to elongated eyes and myopia. Myopia is expected to affect half of the world population by 2050, with many at risk of blinding complications. Eye growth and homeostasis are supported by the sclera and the choroid, but how the two tissues interact to regulate eye growth is unknown. We use here human cells to demonstrate direct, age-specific, interactions between the two cell types and provide a rationale for the known negative effect of dopamine on eye growth, with significant implications for future studies as well as for the understanding and treatment of myopia.

cell biology↗

Natural gradient Bayesian sampling: an innate algorithm emerges in canonical cortical circuits

AO_SCPLOWBSTRACTC_SCPLOWAccumulating evidence suggests the canonical cortical circuit, consisting of excitatory (E) and diverse classes of inhibitory (I) interneurons, implements Bayesian posterior sampling. However, most of the identified circuits sampling algorithms are simpler than the nonlinear circuit dynamics, suggesting complex circuits may implement more advanced algorithms. Through comprehensive theoretical analyses, we discover the canonical circuit innately implements natural gradient Bayesian sampling, which is an advanced sampling algorithm that adaptively adjusts the sampling step size based on the local geometry of stimulus posteriors measured by Fisher information. Specifically, the nonlinear circuit dynamics can implement natural gradient Langevin and Hamiltonian sampling of uni- and multi-variate stimulus posteriors, and these algorithms can be switched by interneurons. We also find that the non-equilibrium circuit dynamics when transitioning from the resting to evoked state can further accelerate natural gradient sampling, and analytically identify the neural circuits annealing strategy. Remarkably, we identify the approximated computational strategies employed in the circuit dynamics, which even resemble the ones widely used in machine learning. Our work provides an overarching connection between canonical circuit dynamics and advanced sampling algorithms, deepening our understanding of the circuit algorithms of Bayesian sampling.

neuroscience↗

Human fibroblasts from aged individuals exhibit chromosomal instability through replication stress caused by oxidative stress

Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.

cell biology↗

Mechanisms of force transmission on cytokinesis Formin Cdc12 in fission yeast revealed by coiled-coil force sensors

Cytokinesis is a fundamental process in cell division, where an actomyosin contractile ring plays a central role in completing the cell division. Although some experimental and computational efforts have evaluated ring tension and the molecular organization of rings, the mechanisms of force transmission at the molecular level remain unclear. Here, we used our novel coiled-coil force sensors to measure the force distribution along the formin Cdc12, a key cytokinesis protein in fission yeast. Our force measurements revealed that individual formin Cdc12 molecules transmit up to [~]6 pN with distinct mechanisms between the regions upstream and downstream of the formin homology 2 (FH2) domain, which binds the barbed ends of actin filaments. The force transmitted on the N-terminal region before the FH2 domain requires anchoring to a cytokinetic node via the Cdc15 binding region, but is independent of the C-terminal region after FH2. In contrast, the region after the FH2 domain transmits forces independently of the Cdc12s N-terminal region. Force screening using the coiled-coil force sensors found that a region in Cdc12s disordered C-terminal tail can associate with the contractile ring. Altogether, the force measurements with our coiled-coil force sensors allowed us to uncover the mechanisms of force transmission along Cdc12 and characterize new motifs and binding partners.

cell biology↗

Metabolic modulation of intratumoral cholesterol with gut microbiota for the treatment of colorectal cancer

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium, a 4-C-3- producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC.

cancer biology↗

Sexually Dimorphic Circadian Regulation of Eclosion and Clock Gene Expression in a Migratory Moth Spodoptera frugiperda

The circadian clock orchestrates essential behavioral and molecular processes, including the timing of eclosion, one of the most tractable and ecologically relevant outputs of the circadian system. Understanding eclosion timing may offer insights into the circadian clock mechanisms that underlie migratory timing. Here, we characterize the diel and circadian patterns of eclosion and core clock gene expression in the fall armyworm (FAW), Spodoptera frugiperda, a globally distributed migratory moth. Using a custom-designed eclosion monitoring system under both 14 hours light-10 hours dark (L14: D10) and constant darkness (DD) conditions, we observed clear diel eclosion rhythms, peaking shortly after lights-off under L14: D10. Under DD, these rhythms became delayed and damped over three consecutive days, consistent with circadian control. Males exhibited more dispersed emergence patterns and distinct eclosion distributions than females under L14: D10 and DD, suggesting sexually dimorphic timing. Gene expression profiling revealed rhythmic oscillations of five canonical clock genes, cyc, clk, tim, per, cry2, with sex-dimorphic differences in mesor, amplitude, or phase, particularly the mesors of males are higher than those of females in five clock genes under L14: D10. These results provide strong evidence for sexually dimorphic circadian regulation at both behavioral and molecular levels in a migratory insect that recently invaded China, suggesting that sex-dimorphic circadian architecture may contribute to allochronic speciation and ecological strategies such as eclosion and migratory timing in a novel environment. Leveraging the established circadian eclosion rhythm assay, which captures core features of clockwork mechanisms, further investigation may reveal how these sex-based differences contribute to the evolution of circadian function and adaptive traits.

ecology↗

Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery

CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGF{beta}trap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., PDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGF{beta}trap, IL15, or IL12 molecules fused to PDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with PDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with PDL1 fused with TGF{beta}trap or IL15. Further, PDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFN{gamma} production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our PDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.

bioengineering↗

Reduced neural sensitivity to musical tempo despite enhanced neural tracking of musical features in older adults

A substantial body of prior research has focused on how aging affects the neural processing of speech, whereas less is known about how older adults encode naturalistic music. Here, we investigated whether the neural tracking of different features in naturalistic music differs between age groups. Younger and older adults (both sexes) listened to excerpts of naturalistic music with different tempi (1-4 Hz) while electroencephalography (EEG) was recorded. The results show an age-related enhancement of neural responses to sound onsets, suggesting a loss of inhibition in the aged auditory cortex that is thought to arise from peripheral decline. This hyperresponsiveness generalized to the neural tracking of multiple features (amplitude envelope, onsets, beat, and spectral flux) in naturalistic music. Crucially, older adults showed reduced sensitivity of early brain responses (0-130 ms) to tempo: Unlike younger adults, whose neural tracking decreased systematically with increasing tempo, older listeners maintained uniformly enhanced tracking across tempi. Spectral flux best predicted tempo- related changes in EEG activity, but this was reduced in older compared to younger adults. In sum, the current study demonstrates that cortical hyperactivity in aging enhances the tracking of different features during naturalistic music listening but impairs the sensitivity to musical tempo. This dissociation highlights the complex changes and functional consequences of auditory aging related to the processing of naturalistic music. SIGNIFICANCE STATEMENTHow aging affects the encoding of ecologically-valid, naturalistic music is not well understood, although music is an important part of older peoples lives. Here, we used electroencephalography and temporal response function approaches to investigate how younger and older adults encode different features of naturalistic music at different tempi (1 to 4 Hz). The results reveal a fundamental trade-off in the aging auditory system: enhanced neural tracking of acoustic features coexists with declined sensitivity to musical tempo. This dissociation between hyperactivity for feature encoding and impaired temporal sensitivity highlights complex changes in the aged auditory system that can have implications for music perception in older adulthood.

neuroscience↗

De novo design of miniprotein agonists and antagonists targeting G protein-coupled receptors

G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational de novo design methods and a high throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity, and the use of these methods to generate agonists for MRGPRX1, NK1R and CCR5, as well as antagonists for CXCR4, CCR5, OXTR, GLP1R, GIPR, GCGR, PTH1R and CGRPR.. Cryo-electron microscopy data reveals atomic-level agreement between designed and experimentally determined structures for CGRPR- and CXCR4-bound antagonists and MRGPRX1-bound agonists. Our de novo design and screening approach opens new frontiers in GPCR drug discovery and development.

bioengineering↗

Single-cell multiomics reveals disrupted glial gene regulatory programs in Alzheimer's disease via interpretable machine learning

Recent development of single-cell technology across multiple omics platforms has provided new ways to obtain holistic views of cells to study disease pathobiology. Alzheimers disease (AD) is the most common form of dementia worldwide, yet the detailed understanding of its cellular and molecular mechanisms remains limited. In this study, we analyzed paired single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) data from the Seattle Alzheimers Disease Brain Cell Atlas (SEA-AD) Consortium to investigate the molecular mechanisms of AD at a cell-subpopulation-specific resolution focusing on glial cells. We benchmarked various multi-omics integration methods using diverse metrics and built an analytic workflow that enabled effective batch correction and cross-modality alignment, creating a unified cell state space. Through integrative analysis of 26 human brain samples, we uncovered AD-associated gene expression and pathway changes in glial subpopulations and highlighted important transcriptomic and epigenomic signatures via functional inference and interpretable machine learning paradigms, discovering the profound involvement of the Solute Carrier proteins (SLC) family genes in multiple glial cell types. We also identified glial cell-specific regulatory programs mediated by key transcription factors such as JUN and FOSL2 in astrocytes, the Zinc Finger (ZNF) family genes in microglia, and the SOX family of transcription factors in oligodendrocytes. Our study provides a comprehensive workflow and a high-resolution view of how glial regulatory programs are disrupted in AD. Our findings offer novel insights into disease-related changes in gene regulation and suggest potential targets for further research and therapy.

genomics↗

Unveiling Protein-DNA Interdependency: Harnessing Unified Multimodal Sequence Modeling, Understanding and Generation

The interdependent orchestration of proteins, coding DNA sequences (CDS), and adjacent regulatory DNA elements underpins biological functionality, where evolutionary constraints shape codon usage, transcriptional regulation, and structural stability. We present ProDMM, a multimodal framework that deciphers these systemic relationships through unified sequence modeling. Integrating a context-aware encoder with conditional generation, our architecture captures codependent patterns between protein motifs and cis-regulatory syntax. ProDMMs encoder demonstrates superior predictive capabilities in forecasting pathway-level phenotypes and protein expression profiles, outperforming conventional single-modality approaches. Its decoder generates synthetically optimized regulatory elements by resolving spatial dependencies between coding sequences and adjacent non-coding regions, enabling transcriptional fine-tuning unavailable to sequence-agnostic methods. By resolving how localized CDS-NCDS-protein interdependencies propagate to system-level phenotypes, ProDMM establishes a paradigm for holistic biological sequence engineering. This approach enables coordinated optimization of translation efficiency, enzymatic activity, and pathway flux, offering transformative potential for designing tailored biosynthesis systems and advancing sustainable bioproduction strategies.

bioinformatics↗

scWGBS-GPT: A Foundation Model for Capturing Long-Range CpG Dependencies in Single-Cell Whole-Genome Bisulfite Sequencing to Enhance Epigenetic Analysis

Single-cell DNA methylomes are challenging to interpret because of sparse CpG coverage and the complexity of genome-wide sequences. We present scDNAm-GPT, a universal foundation model that uses context-aware CpG tokenization, a Mamba backbone, and cross-attention to capture both local and global DNA methylation patterns. Trained on over one million single cells from 35 human and mouse tissues, scDNAm-GPT enables accurate cell clustering, zero-shot prediction of CpG effects on gene expression, improved trajectory inference, and reference-free deconvolution of cell types from cell-free DNA. The model hierarchically learns regulatory features, and its attention maps highlight functionally relevant regions, demonstrating high biological interpretability. These results establish scDNAm-GPT as a scalable and generalizable framework for single-cell epigenomic analysis, offering new opportunities to dissect epigenetic regulation in health and disease. Code is available at GitHub (https://github.com/ChaoqiLiang/scDNAm-GPT).

bioinformatics↗

Single-cell digital twins identify drug targets and repurposable medicine in Alzheimers disease

Alzheimers disease (AD) is a complex and poorly understood neurodegenerative disorder without sufficiently effective treatments. Novel approaches to identify FDA-approved drugs that may hold potential for mitigating symptoms of AD hold promise for addressing this problem. One such strategy is the use of digital twins (DTs), which are virtual representations of physical entities that facilitate therapeutic target identification by accurately characterizing disease heterogeneities in real time through continuous feedback and dynamic model updates. In this study, we developed a single-cell digital twin (scDT) framework using single-nuclei RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) data from the middle temporal gyrus of 84 donors across 4 degrees of AD neuropathological change (ADNC). We observed differential gene expression for six major cell types intensified at severe ADNC. We also constructed cell type-specific transcription factor (TF)-target gene networks by leveraging peak-to-gene linkages and motif enrichment analyses. By integrating genome-wide association study (GWAS) loci with cell type-specific cis-regulatory DNA elements (CREs), we identified 141 ADNC-associated genes. Using gene set enrichment analysis (GSEA) and network proximity analysis, we identified 13 candidate repurposable drugs that were associated with these ADNC-associated genes. In summary, we constructed a single-cell digital twin (scDT) framework cell type-specific target identification and drug repurposing in AD and other complex diseases if broadly applied.

bioinformatics↗

A Novel COE-D8-Fosfomycin Conjugate Effectively Against First-line Antibiotic Resistant Uropathogenic Escherichia coli

Recurrent urinary tract infections (UTIs) are increasingly associated with antibiotic resistance, posing significant clinical challenges. This study evaluates the antimicrobial efficacy of the membrane-intercalating conjugated oligoelectrolyte COE-D8 against uropathogenic Escherichia coli (UPEC). Among 93 clinical UPEC isolates, over 50% demonstrated resistance to first-line antibiotics, with compound sulfamethoxazole showing the highest resistance (75% at a minimum inhibitory concentration (MIC) >512 g/mL). COE-D8 significantly reduced resistance rates, achieving less than 50% at 32 g/mL and below 5% at 512 g/mL, while demonstrating at least fourfold faster bacterial elimination than standard antibiotics. Mechanistic studies revealed that COE-D8 disrupts bacterial membranes, inducing rapid lysis. However, its cytotoxicity in mammalian cells at 2 g/mL limits clinical application. To address this, a combination therapy with fosfomycin was explored, significantly reducing COE-D8 toxicity by at least fourfold in vitro. In mouse models, fosfomycin co-administration mitigated COE-D8-induced toxicity and prevented mortality at higher doses without compromising antimicrobial efficacy. These findings highlight the potential of COE-D8, particularly in combination with fosfomycin, as a promising strategy to combat antibiotic-resistant UPEC while addressing toxicity challenges.

microbiology↗

Genetically encoded mechano-sensors with versatile readouts and compact size

Mechanical forces are critical for virtually all fundamental biological processes, yet quantification of mechanical forces at the molecular scale in vivo remains challenging. Here, we present a new strategy using calibrated coiled coils as genetically encoded, compact, tunable, and modular mechano-sensors to substantially simplify force measurement in vivo, via diverse readouts (luminescence, fluorescence and analytical biochemistry) and instrumentation readily available in biology labs. We demonstrate the broad applicability and ease-of-use of these coiled coil mechano-sensors by measuring forces during cytokinesis (formin Cdc12) and endocytosis (epsin Ent1) in yeast, force distributions in nematode axons ({beta}-spectrin UNC-70), and forces transmitted to the nucleus (mini-nesprin-2G) and within focal adhesions (vinculin) in mammalian cells. We report discoveries in intracellular force transmission that have been elusive to existing tools.

cell biology↗