Biology subjects

Ramakrishnan, A.

Publications and source records attributed to Ramakrishnan, A..

At least 19 recordsLinked to original sources

bioRxiv2026

KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics

Histone H3 Gln 5 serotonylation (H3Q5ser) is a recently identified epigenetic modification in brain that modulates reader interactions with adjacent H3 Lys 4 trimethylation (H3K4me3) to promote transcriptional permissiveness. However, whether H3K4me3Q5ser and its associated binding proteins regulate neurodevelopmental gene expression programs remains unknown. Here, we identified the catalytically inactive Lysine methyltransferase 2E (KMT2E) as a reader of combinatorial H3K4me3Q5ser. KMT2E preferentially binds H3K4me3Q5ser over H3K4me3 alone, and enriches at broad chromatin domains marking actively transcribed neurodevelopmental loci. Notably, heterozygous variants in KMT2E have been implicated in ODLURO syndrome, a recently characterized neurodevelopmental disorder (NDD). To identify the molecular mechanisms underlying ODLURO syndrome, we generated a Kmt2e transgenic mouse model that reproduces behavioral, physiological, and cellular endophenotypes associated with this and other NDDs. Furthermore, we observed that KMT2E mediates these effects by recruiting the NCoR/HDAC3 repressor complex to H3K4me3Q5ser-marked loci to restrict spreading of co-localized H3 Lys 9 acetylation (H3K9ac). Inhibition of aberrant H3K9ac spreading was sufficient to rescue transcriptional dysregulation in Kmt2e haploinsufficient neurons. These findings thus establish KMT2E as a critical reader of H3 serotonylation during neurodevelopment and provide mechanistic insights into the pathogenesis of ODLURO syndrome.

neuroscience↗

bioRxiv2026

State-dependent aperiodic EEG dynamics track cortical network reorganization in chronic epilepsy

Aperiodic (1/f-like) EEG activity has rapidly become a popular noninvasive marker of cortical network state, proposed to index excitation-inhibition (E/I) balance and increasingly applied across neurological and psychiatric disorders. However, whether this approach remains reliable in the pathological brain, where disease progressively reorganizes neural networks, alters signal morphology, and drives continuous transitions between cortical states has yet to be systematically established.Using a medication-free genetic model of chronic epilepsy (Lafora disease; Epm2a-- mice), we tracked the aperiodic component of the cortical EEG across resting wakefulness, isoflurane anesthesia, and PTZ-induced seizures of graded severity, asking how a single spectral marker behaves as the brain moves between states. Epileptic mice exhibited systematically steeper aperiodic exponents than controls, an effect that persisted after removal of interictal epileptiform discharges and was replicated using independent time-resolved spectral parameterization. Slopes steepened predictably under GABAergic anesthesia, supporting the interpretation that aperiodic activity captures biologically meaningful state transitions beyond simple contamination by pathological waveforms. Across seizure phases, the aperiodic exponent varied systematically, however, the exponent flattened during ictal activity in step with the dominant discharge morphology, revealing that pathological waveform shape itself is a substantial contributor to seizure-state exponent changes. Together, these findings indicate that aperiodic EEG dynamics reflect a combination of chronic network-state reorganization and waveform-shape-driven spectral distortion, with their relative contributions varying across brain states. These results support spectral parameterization as a sensitive approach for tracking pathological neural activity in chronic epilepsy while delineating its interpretive boundaries in the presence of pathological waveforms.

neuroscience↗

bioRxiv2026

Effects of dopamine and serotonin on persistence for delayed rewards in humans

People often must decide how long to continue waiting for rewards that will arrive at an uncertain time in the future. We propose that these persistence decisions involve weighing the benefits of continued waiting against opportunity costs of waiting, a balance that may shift over time. This framework suggests that persistence decisions share neural mechanisms with foraging decisions, which require ongoing comparisons between a current resource and possible alternatives. Dopamine and serotonin have been proposed to play opposing roles in foraging, with dopamine promoting exploration and serotonin promoting exploitation. Here we investigated their roles in persistence. In a within-subjects, double-blind, placebo-controlled study in young adults (n = 42), we examined the effects of increasing dopamine with L-dopa and increasing serotonin with escitalopram. We predicted that L-dopa would decrease persistence and escitalopram would increase it. Participants also completed patch-foraging, time perception, risk tolerance, and temporal discounting tasks to explore potential mechanisms of drug effects on persistence. Escitalopram increased persistence, after adjusting for the effects of anxiety and condition order, such that participants waited longer for rewards after taking the serotonergic drug. L-dopa did not influence persistence. In exploratory analyses controlling for age, however, L-dopa reduced persistence and increased exploration in foraging.

neuroscience↗

bioRxiv2026

Trait anxiety drives premature disengagement despite intact opportunity-cost sensitivity

Anxiety has been linked to difficulty sustaining engagement with ongoing tasks, even when continued engagement would yield greater rewards, yet the underlying mechanisms remain unclear. Here we examined how trait anxiety shapes sequential foraging decisions using a patch-leaving task grounded in the Marginal Value Theorem (MVT), a normative framework for explore-exploit decisions previously used to reveal altered computations in conditions such as problem gambling and attention-deficit hyperactivity disorder. Across two independent cohorts, participants adjusted patch residence times according to environmental opportunity costs, indicating preserved sensitivity to task structure irrespective of anxiety levels. Despite this, individuals with higher trait anxiety consistently left patches earlier and accrued fewer rewards. Drift diffusion modeling revealed that these deviations arose from reduced reward-driven evidence accumulation, rather than impaired environmental sensitivity or altered learning: trait anxiety reliably reduced the drift rate governing continued exploitation, providing a computational account of premature disengagement. This effect remained robust after accounting for pupil-linked arousal and baseline stress biomarkers, including salivary -amylase and cortisol, which independently constrained decision dynamics. Together, these findings identify reduced reward-evidence accumulation as a core mechanism through which anxiety promotes premature disengagement from rewarding environments.

neuroscience↗

bioRxiv2026

Attenuation of value-to-evidence translation drives biased decision making in anxiety and depression

Anxiety and depression are globally prevalent conditions associated with maladaptive decision making. However, whether affective symptoms primarily amplify threat avoidance or dampen motivational drive remains debated, and behavioural studies yield inconsistent findings. Here we show that both anxiety and depression impair the fundamental cognitive process of translating objective value into decision evidence. Across independent cohorts from the US and India, participants evaluated risky gambles while we assessed choice behaviour and the centroparietal positivity, an EEG marker of accumulating decision evidence. Prospect theory parameters, like risk and loss aversion, showed little association with symptom severity. Conversely, hierarchical drift-diffusion modelling revealed that higher symptom scores predicted attenuated value sensitivity during evidence accumulation, whereas decision caution remained intact. This reduction in value sensitivity suggests internalizing symptoms disrupt choice at the value-to-evidence interface, offering a unified mechanism underlying biased decision making in affective disorders.

neuroscience↗

bioRxiv2026

Quinone reductase 2 reads H3 serotonylation to support neuronal maturation

Histone H3 Gln5 serotonylation (H3Q5ser) is a recently described posttranslational modification1 that plays important roles in guiding transcriptional permissiveness in brain and peripheral systems2-5. H3Q5ser has been implicated in diverse physiological and pathological processes ranging from neural differentiation1 to sensory processing6, circadian rhythmicity7, stress responsivity8, placental gene regulation9, and tumorigenesis10-19. Since H3Q5ser can occur in combination with H3 Lys4 trimethylation (H3K4me3), most mechanistic studies to date have focused on H3Q5sers roles in modulating H3K4me3 reader interactions, where it has been shown to potentiate TAF3/TFIID binding to H3K4me31,20,21 and inhibit the recruitment of K4me3 demethylases21; however, whether H3 serotonylation functions as an autonomous chromatin signaling mark through dedicated reader proteins has remained unknown. Here, using a combination of proteomic-, structural-, molecular-, epigenomic-, and cellular-based approaches, we demonstrate that the Quinone reductase 2 (QR2) enzyme reads H3Q5ser independently of H3K4me3. CRISPR-Cas9-mediated disruption of H3 serotonylation or QR2s binding to the mark in human induced pluripotent stem cell-derived neurons impairs the establishment of neuronal transcriptional programs, alters synaptic connectivity, and disrupts electrophysiological maturation. These findings thus uncover an H3 serotonylation-dependent chromatin signaling axis that is essential for human neurodevelopment.

molecular biology↗

bioRxiv2026

A shared transcriptional network in the nucleus accumbens supports resilience to chronic stress across sex.

Although chronic stress increases the risk for depression, only a subset of exposed individuals develop psychiatric illness. The biological mechanisms that protect against depression remain incompletely understood, particularly at the molecular level. Here, we identify a transcriptional network in the nucleus accumbens (NAc), a central brain reward region, that supports stress resilience in both sexes and demonstrate the causal contribution of key hub genes. Using chronic social defeat stress, RNA-seq, and co-expression network analysis, we find sex-specific but overlapping gene modules linked to resilience, anchored by shared hub genes embedded within a common network architecture. Overexpression of these hub genes in stress-naive mice confers stress protection and induces a transcriptional state that is discrete from both susceptible and resilient profiles. These findings position resilience as a structured and targetable molecular phenotype and provide a basis for investigating sex-informed mechanisms of stress adaptation.

neuroscience↗

bioRxiv2026

Anxiety Selectively Impairs Reward Learning Under Uncertainty, While N3 Sleep Recalibrates It

Adapting to uncertain environments requires distinguishing stochastic variability from genuine environmental change, yet how anxiety and sleep shape this process remains unclear. Using a probabilistic reversal-learning task that simultaneously manipulated stochasticity and volatility, we show that high trait anxiety selectively impairs reward learning in stable but noisy environments, despite preserved sensitivity to true volatility. Computational modeling revealed that anxious individuals misattribute stochastic fluctuations to environmental change, resulting in elevated reward learning rates and impaired evidence accumulation. In a second experiment combining task performance with overnight sleep EEG, greater N3 sleep was associated with reduced learning rates and improved evidence accumulation. These findings identify a selective computational mechanism underlying anxiety-related learning deficits and suggest N3 sleep as a state-dependent pathway for recalibrating adaptive learning under uncertainty.

neuroscience↗

bioRxiv2025

Environmental Conflict Modulates Pavlovian Bias

Pavlovian avoidance enables rapid defensive responding but can undermine goal-directed behaviour when it overrides instrumental control, a tendency amplified in anxiety. Whether such biases can be flexibly and rapidly modulated by environmental structure remains unknown. Here we show that global conflict in the environment can suppress Pavlovian avoidance and enhance instrumental choice, particularly in individuals high in trait anxiety. One hundred and sixteen participants completed a sequential approach-avoidance task in which three options differed in reward-punishment conflict, and blocks varied the frequency of high-conflict encounters. In low-conflict environments, participants exhibited pronounced and misplaced avoidance of objectively safe, no-conflict options indicating that choices are not determined by local contingencies alone but are tuned to broader environmental context. Interestingly, increasing environmental conflict reduced this maladaptive avoidance: approach to safe options increased, and reinforcement-learning and drift-diffusion modelling revealed higher reward sensitivity and drift rates alongside reduced lapse and Pavlovian bias parameters. These effects were strongest in high-anxious individuals, whose behaviour shifted markedly toward that of low-anxious peers. Crucially, benefits depended on the frequency of conflict encounters and were not elicited by cue-outcome reversals or increased punishment probability alone. Furthermore, a modified Go/NoGo task replicated global conflict-dependent improvements on Pavlovian-incongruent trials. Together, these results demonstrate that global environmental conflict can rapidly recalibrate the balance between Pavlovian and instrumental systems, attenuating maladaptive avoidance and disproportionately aiding anxious individuals. We propose that conflict-driven arousal dynamics, plausibly mediated by LC-NE mechanisms, promote this adaptive reconfiguration of defensive and goal-directed control. Significance statementAvoiding danger is essential for survival, but sometimes our automatic fear responses make us avoid things that are actually safe and potentially rewarding. This problem is especially common in people with anxiety, where avoidance can become rigid and limit everyday functioning. In this study, we discovered that the broader structure of the environment, not just the immediate situation, can strongly influence these automatic reactions. When the environment contained more frequent conflicts or difficult choices, people actually became less avoidant, even toward options that were completely safe. Their decisions became more goal-directed, and this shift was especially strong in individuals with high anxiety, whose behaviour began to resemble that of low-anxiety individuals. These results show that anxious individuals can be more flexible and their behaviour can be rapidly improved by changing the surrounding context. This challenges assumptions about how rigid avoidance tendencies are and suggests ways to reduce maladaptive avoidance without relying solely on long or intensive training. By revealing how environmental structure can rebalance automatic fear responses and deliberate decision-making, this work opens avenues for designing interventions and potentially therapies that harness contextual factors to support more adaptive behaviour in anxiety.

neuroscience↗

bioRxiv2025

Guidance receptor-mediated mechanocompliance of GBM cells facilitates immune-silent invasion

The lethality of glioblastoma (GBM) stems from diffuse infiltration and immune evasion, two hallmarks traditionally studied separately. Here, we identify as unifying mechanism how GBM cells utilize guidance receptors Plexin-D1 and Plexin-B2 to gain mechanocompliance, i.e., the ability to deform and remodel membrane/cytoskeleton during confined migration without triggering immune activation. We show that PLXND1 upregulation marks invasive fronts and predicts poor survival of glioma patients. Through live-cell imaging in microchannels, intracranial xenografts, single-nucleus transcriptomics, and lipidomics we demonstrate that Plexin-D1/B2 enable GBM cells to retract tumor microtubes (TMs), traverse constrictions, and escape microglial surveillance. Single and especially double deletion of PLXND1 and B2 resulted in TM overgrowth, membrane instability, and susceptibility to cell fragment shedding, leading to impaired migration and a shift to activation of tumor-associated myeloid cells. Our findings thus reveal a molecular strategy used by GBM cells to penetrate through interstitial space while escaping immune surveillance. SIGNIFICANCEPlexin-mediated mechanocompliance underlies the invasive yet immune-silent behavior of GBM cells, exposing a vulnerability that could be therapeutically exploited by forcing invading tumor cells into a mechanically fragile, immunogenic state.

cancer biology↗

bioRxiv2025

Passive muscle forces in Drosophila are large but insufficient to support a flys weight

Movement of a limb is shaped by active forces generated by muscle contraction but also by passive forces within individual muscles and joints. In small animals such as insects, the contribution of passive forces to limb movement can match the active forces. However, most measurements of passive forces are limited to the femur-tibia joint in large insects. Here we take advantage of genetic tools in Drosophila to measure passive torques at multiple joints in the flys leg. We genetically inactivate all the motor neurons to assess passive forces. We find that the passive torques are well approximated by a linear spring, i.e., the passive torques linearly increase with angular deviation from the rest angle. The torques are much larger than the gravitational torque due to the leg itself. We estimate that the passive torques are seventy times smaller than necessary to support the weight of the animal. We also inactivated all the motor neurons in a freely standing fly and found that, as predicted from the model, the fly falls when the motor neurons are inactivated. We found that the height at which a fly stands, and, therefore the active forces vary. The flys height affects the time to initiate a fall. The time it takes for the fall is consistent with the active forces decaying with a time constant of [~]100 ms. Thus, although passive forces are strong and will have a large effect on limb kinematics, they are not strong enough to support the weight of the fly.

neuroscience↗

bioRxiv2025

OctopusV and TentacleSV: a one-stop toolkit for multi-sample, cross-platform structural variant comparison and analysis

Structural variants (SVs) significantly influence genomic variability and disease, but their accurate analysis across multiple samples and sequencing platforms remains challenging. We developed OctopusV, a tool that standardizes ambiguous breakend (BND) annotations into canonical SV types (inversions, duplications, translocations) and integrates variant calls using flexible set operations, such as union, intersection, difference, and complement, enabling cohort-specific variant identification. Together with TentacleSV, an automated pipeline, OctopusV provides an end-to-end solution from raw data to final callsets. Evaluations show improved precision, recall, and consistency, highlighting its value in cancer genomics and rare disease diagnostics. Both tools are available at https://github.com/ylab-hi/OctopusV and https://github.com/ylab-hi/TentacleSV.

bioinformatics↗

bioRxiv2024

Leg compliance is required to explain the ground reaction force patterns and speed ranges in different gaits

Two simple models - vaulting over stiff legs and rebounding over compliant legs - are employed to describe the mechanics of legged locomotion. It is agreed that compliant legs are necessary for describing running and that legs are compliant while walking. Despite this agreement, stiff legs continue to be employed to model walking under the assumption that the compliance of the leg during walking is high enough to be considered stiff. Here we study gait choice and walk-to-run transition in a biped with compliance and show that the principles underlying gait choice and transition are completely different from stiff legs. Two findings underpin our conclusions: First, at the same speed, step length, and stance duration, multiple gaits that differ in the number of leg contraction cycles are possible. Among them, humans and other animals choose the (normal) gait with M-shaped vertical ground reaction forces (vGRF) not just because of energy considerations but also constraints from forces. Second, the transition from walking to running occurs because of three factors: vGRF minimum at mid-stance characteristic of normal walking, synchronization of horizontal and vertical motions during single support, and velocity redirection during the double support. The insight above required an analytical approximation of the double spring-loaded pendulum (DSLIP) model describing the intricate oscillatory dynamics that relate single and double support phases. Additionally, we also examined DSLIP as a quantitative model for locomotion and conclude that DSLIP speed-range is limited. However, insights gleaned from the analytical treatment of DSLIP are general and will inform the construction of more accurate models of walking.

neuroscience↗

bioRxiv2024

3D Brain Vascular Niche Model Captures Invasive Behavior and Gene Signatures of Glioblastoma

Glioblastoma (GBM) is a lethal brain cancer with no effective treatment; understanding how GBM cells respond to tumor microenvironment remains challenging as conventional cell cultures lack proper cytoarchitecture while in vivo animal models present complexity all at once. Developing a culture system to bridge the gap is thus crucial. Here, we employed a multicellular approach using human glia and vascular cells to optimize a 3-dimensional (3D) brain vascular niche model that enabled not only long-term culture of patient derived GBM cells but also recapitulation of key features of GBM heterogeneity, in particular invasion behavior and vascular association. Comparative transcriptomics of identical patient derived GBM cells in 3D and in vivo xenotransplants models revealed that glia-vascular contact induced genes concerning neural/glia development, synaptic regulation, as well as immune suppression. This gene signature displayed region specific enrichment in the leading edge and microvascular proliferation zones in human GBM and predicted poor prognosis. Gene variance analysis also uncovered histone demethylation and xylosyltransferase activity as main themes for gene adaption of GBM cells in vivo. Furthermore, our 3D model also demonstrated the capacity to provide a quiescence and a protective niche against chemotherapy. In summary, an advanced 3D brain vascular model can bridge the gap between 2D cultures and in vivo models in capturing key features of GBM heterogeneity and unveil previously unrecognized influence of glia-vascular contact for transcriptional adaption in GBM cells featuring neural/synaptic interaction and immunosuppression.

bioengineering↗

bioRxiv2024

antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8 T cell cytotoxicity after traumatic brain injury

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking 4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/596673v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@97311aorg.highwire.dtl.DTLVardef@18a86borg.highwire.dtl.DTLVardef@d9162forg.highwire.dtl.DTLVardef@3f8d06_HPS_FORMAT_FIGEXP M_FIG C_FIG Aged brains after TBI comprise two pools of CD8+ T cells. The aged brain has long been resided by a population of CD8+ T cells thats exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8+ T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8+ T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.

immunology↗

bioRxiv2024

Differential gene expression and chromatin accessibility in the rat medial prefrontal cortex mediating individual variability in vulnerability to opioid use

We characterized gene transcriptional activity in the medial prefrontal cortex of rats associated with individual differences in vulnerability to three distinct phases of opioid use disorder (OUD). Resilient rats showed many more changes in canonical pathway activity than Vulnerable rats in models of both early and advanced OUD, involving passive opioid exposure and opioid self-administration (SA), respectively. The Resilient/Vulnerable phenotype was also associated across phases with functionally specific gene networks, including those mediating epigenetic, neuroimmune, and neuroplasticity function. In contrast, we identified two phase-specific effects. First, differential activity of a myelination-related gene network was associated with Resilience/Vulnerability measured after passive morphine exposure. Second, expression of the calmodulin-inhibitor Pcp4, a gene recently implicated in a rat opioid SA GWAS analysis, was associated with Resilience/Vulnerability measured after SA but not after passive morphine exposure. Thus, we have identified both general and phase-specific transcriptional signatures involved in OUD vulnerability across its trajectory. TeaserAdaptations in the brain transcriptome are associated with resilience and vulnerability to opioid use disorder.

neuroscience↗

bioRxiv2023

Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome

Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (SERT/SLC6A4). SERT deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in early embryonic brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.

molecular biology↗

bioRxiv2023

Aryl hydrocarbon receptor restricts axon regeneration of DRG neurons in response to injury

Neurons must balance stress responses with regenerative demands following injury, but the mechanism is unclear. Here, we identify the aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, as a key regulator of this stress-growth switch. We show that ligand mediated AhR signaling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models. Mechanistic studies revealed that axotomy-induced AhR activation in dorsal root ganglion (DRG) neurons enforces proteostasis and stress-response programs to preserve tissue integrity. In contrast, AhR ablation redirects the neuronal response toward elevated de novo translation and pro-growth signaling, enabling axon regeneration. This growth-promoting effect required HIF-1, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response (ISR) and DNA hydroxymethylation to rewire neuronal injury programs. Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis, and metabolic signaling to control the balance between stress adaptation and axonal repair.

neuroscience↗