The truncated constitutive active form of protein kinase C (PKC) called protein kinase M (PKM) plays a role in long-term memory maintenance in vertebrate and invertebrate models. Previously we have shown that the Aplysia Kidney/Brain protein (KIBRA) stabilizes the atypical PKM Apl III, but not the classical PKM Apl I in Aplysia neurons. Expression of Aplysia KIBRA with changes in the proposed atypical PKM binding site does not stabilize PKM Apl III and erases forms of plasticity supported by PKM Apl III. Here, we have examined biomolecular fluorescence complementation (BIFC) between KIBRA variants and PKM Apl III in Aplysia neurons. These KIBRA variants include: the KIBRA with changes in the proposed atypical binding site noted above; a splicing variant that stabilizes PKM Apl I, but not PKM Apl III; and several mutations identified in mammalian WW and C2 domain containing protein 3 (WWC3, a member of the chordate-specific expansion of the KIBRA family) associated with cancer or neurodevelopmental disorders. Surprisingly, we find that some KIBRA variants show BIFC with PKM Apl III but do not stabilize PKM Apl III. We used models of protein-protein interactions (AlphaFold 3) to gain insights into the discrepancy between BIFC and stabilization of PKMs by KIBRA and KIBRA variants and suggest a model where stabilization is linked to stable inhibition of PKMs by KIBRA.
Oral squamous cell carcinoma (OSCC) represents the most prevalent primary malignant neoplasm within the head and neck region. The elevated rates of recurrence and metastasis, coupled with resistance to conventional therapies, significantly compromise patient prognosis, thereby necessitating the identification of novel molecular regulatory targets. N6-methyladenosine (m6A) modification emerges as the most widespread post-transcriptional RNA modification in eukaryotic organisms. This modification operates through a dynamic regulatory network involving methyltransferases (Writers), demethylases (Erasers), and recognition proteins (Readers), which collectively orchestrate precise regulation of RNA functionality and are intricately involved in oncogenic processes. Current research indicates that m6A modification and its associated regulatory factors exhibit aberrant dysregulation in OSCC. By modulating critical biological processes such as tumor cell proliferation, invasion, metastasis, autophagy, ferroptosis, and the characteristics of OSCC tumor stem cells, these modifications influence both the progression and therapeutic responsiveness of OSCC. This article systematically reviews the core regulatory mechanisms of m6A modification, focusing on its functional effects and molecular pathways in the malignant progression of OSCC. It summarizes the clinical translational value of m6A regulatory factors as diagnostic and prognostic biomarkers as well as targets for targeted therapy, and outlines future research directions in this field, aiming to provide important theoretical references for the precision diagnosis and treatment of OSCC. 口腔鳞状细胞癌（OSCC）是头颈部最常见的原发恶性肿瘤，其高复发、高转移率及治疗耐药严重影响患者预后，亟须挖掘新的分子调控靶点。N6-甲基腺苷（m6A）修饰是真核生物中最主要的RNA转录后修饰方式，通过甲基转移酶、去甲基化酶与识别蛋白构成的动态调控网络，精准调控RNA功能，并广泛参与肿瘤生物学进程。现有研究表明，m6A修饰及其调控因子在OSCC中异常失调，可通过调控肿瘤细胞增殖、侵袭、转移、细胞自噬、铁死亡及OSCC肿瘤干细胞特性等关键生物学过程，影响OSCC的发生发展与治疗应答。本文系统综述m6A修饰的核心调控机制，重点阐述其在OSCC恶性进展中的功能效应与分子通路，总结m6A调控因子作为OSCC诊断、预后标志物及靶向治疗靶点的临床转化价值，展望该领域未来研究方向，旨在为OSCC的精准诊疗提供重要理论参考。.
N6-methyladenosine (m6A) is one of the most important RNA modifications and is widely distributed across mRNAs and non-coding RNAs. Its deposition, removal, and recognition are dynamically regulated by a set of proteins, including methyltransferases (writers), demethylases (erasers), and binding proteins (readers). Through these regulators, m6A modifications influence key aspects of RNA metabolism, including stability, splicing, nuclear export, and translation efficiency, dynamically regulating cell fate. Protein lactylation is a reversible post-translational modification occurring on lysine residues of both histones and non-histones, with lactate or lactyl-CoA serving as the substrate. Lactylation modulates protein properties, including structure, function, and activity, thereby influencing gene expression. RNA m6A modifications and protein lactylation significantly regulate the biological behaviors of tumors, including proliferation, invasion, metastasis, metabolic reprogramming, immune evasion and treatment resistance. In recent years, their crosstalk has garnered increasing attention. On one hand, m6A regulatory proteins can be regulated by lactylation, either directly or via histone lactylation-mediated epigenetic regulation. On the other hand, m6A modifications may promote protein lactylation by regulating glycolysis and lactate production. This bidirectional interaction forms a regulatory loop that influences tumor progression. This review summarizes the emerging role of the crosstalk between RNA m6A modification and protein lactylation in tumor progression.
Protein lysine lactylation (Kla) is a newly identified post-translational modification (PTM), in which lactyl groups are transferred to specific lysine residues in proteins. As a crucial intermediary between cellular metabolism and epigenetic regulation, Kla immensely increases the functional diversity of the proteome. This intriguing modification extends beyond histones to non-histone proteins, signaling molecules, enzymes, and substrates. In addition to enzymatic L-lactylation utilizing lactate as a lactyl donor and involving enzymes including writers (lactyltransferases), readers (lactylation-binding enzymes), erasers (delactylases), and lactyl-coenzyme A (lactyl-CoA) synthases, non-enzymatic D-lactylation derived from the glyoxalase II substrate S-D-lactoylglutathione (SLG) has also been identified. Emerging evidence underscores the molecular significance of Kla, including gene transcriptional activation, protein stability, enzyme activity, protein‒protein interactions, protein subcellular translocation, crosstalk with other PTMs, RNA modification, epigenetic instability, and phase separation, in orchestrating diverse biological processes. Functionally, Kla plays a fundamental role in physiology, such as somatic cell reprogramming, as well as embryonic, neural, and cochlear development, by regulating gene expression, cell cycle progression, and signal transduction. Conversely, dysregulated Kla renders extensive impacts on the pathogenesis of various diseases, including cancer, neuropsychiatric disorders, cardiovascular and ophthalmic diseases, and immunoinflammatory and metabolic dysregulation, through modulating immune homeostasis, metabolic adaptation, and epigenetic remodeling. This review systematically elucidates the molecular regulatory mechanisms and biological significance of Kla while comprehensively summarizing its involvement in both physiology and pathology. Furthermore, we emphasize the translational potential of Kla as a diagnostic or prognostic biomarker and therapeutic target, offering novel insights for future research and development of innovative therapeutic strategies.
This study aims to synthesize qualitative evidence on the lived experiences and perceived support needs of suicide-bereaved family members, including extended relatives. A qualitative systematic review and quote-based thematic meta-synthesis was conducted. Searches were undertaken in PubMed, Scopus, and Web of Science. Eligible studies were primary qualitative research published in English involving family members bereaved by suicide. Methodological quality was appraised using the JBI Critical Appraisal Checklist for Qualitative Research, and confidence in each synthesized finding was assessed using GRADE-CERQual. Verbatim participant quotations extracted from findings/results sections were analyzed using Braun and Clarke's thematic analysis, guided by Doka's disenfranchised grief as a sensitizing framework, with inductive coding for data not captured by the lens. Twenty-seven studies were included. Six cross-cutting themes described suicide bereavement as layered disenfranchisement: (1) stigma and anticipatory judgment prompting secrecy and withdrawal; (2) relational erasure through silence and loss of permission to name the deceased; (3) institutional non-recognition and lack of navigable postvention pathways; (4) moral injury and persistent culpability; (5) embodied, trauma-like distress and enduring existential suffering; and (6) legitimacy repair through peer support, compassionate witnessing, continuing bonds, and meaning-making. Synthesized support needs converged on stigma-competent and culturally safe care, permission-based communication, proactive coordinated pathways, trauma-informed long-term follow-up with attention to suicide risk, and accessible, tailored peer support. Suicide bereavement among family members is frequently shaped by social, relational, and institutional disenfranchisement, with important implications for designing proactive, culturally safe, and longitudinal postvention that addresses both symptom burden and social-ecological barriers. Silence erases the deceased and removes permission to name and remember.System non-recognition excludes families and leaves no clear postvention pathway.Stigma and system gaps amplify guilt, sustaining moral injury and isolation.
This study explores the experiences of formula-feeding mothers in Israel as they navigate their maternal identity within a hegemonic infant-feeding discourse that promotes exclusive breastfeeding. While extensive research has focused on the benefits of breastfeeding, limited qualitative attention has been given to the lived experiences of formula-feeding mothers. Drawing on Adrienne Rich's concept of institutionalized motherhood, this study positions the lack of formula-related support as a disciplinary mechanism targeting mothers who deviate from institutional norms. Based on in-depth semi-structured interviews of 31 educated, middle-class Jewish mothers who primarily or exclusively formula fed, we offer a theoretical contribution by illuminating how institutionalized motherhood constructs 'good mothering' through prescribed maternal foodwork (i.e., breastfeeding), thereby perpetuating the stigmatization of formula feeding. The formula warning label is examined as a manifestation of institutionalized motherhood that, according to participants' accounts, undermines the legitimacy of formula feeding and casts doubt on mothers' competence and reasoning for using it. Empirically, the study contributes to the limited qualitative literature on formula-feeding mothers' experiences. Positioned as marginalized, at times ideologically deviant autonomous agents, the women offer critical insights into the inequities of support systems, the persistence of social stigma, and the role of shame and judgment in shaping maternal identity through feeding practices. Four key findings emerged: (a) the label perpetuates the perception of formula as harmful; (b) it triggers feelings of inadequacy and self-doubt; (c) it erases the diversity of reasons behind formula use; and (d) it reinforces hierarchical feeding norms. This study contributes to matricentric feminism by exposing how rigid hierarchical feeding prescriptions shape maternal identity through shame and regulation. Findings point to the importance of developing a more supportive, inclusive discourse that acknowledges maternal agency and diverse infant-feeding experiences.
Culinary Medicine (CM) is positioned by physician leaders as an innovative, interdisciplinary model addressing the long-neglected role of food and nutrition in clinical healthcare. Yet its institutional rise recenters medical authority and erases the feminized and racialized expertise that had led dietary care for over 100 years. This article critiques CM as a case study in epistemic erasure and medical dominance, examining how professional and institutional hierarchies shape which knowledge is recognized as legitimate. Drawing on frameworks of racial capitalism, epistemic injustice, and feminist standpoint theory, this article finds that CM devalues and marginalizes dietetics and ignores community-based models of nutritionally tailored meals, despite decades of success. By framing CM as novel, the origins, knowledge, and expertise informing culinary-focused dietary care is recoded through male- and physician-dominated institutions. CM's implementation often reproduces structural biases, including racialized gatekeeping through biometric eligibility and the dismissal of cultural foodways. While CM holds potential for addressing diet-related health disparities, it must confront the exclusionary logics it reproduces to truly achieve health equity. CM must center the expertise of those historically excluded, particularly women, communities of color, and community-based practitioners, to build equitable, interprofessional models that prioritize professional humility and structural transformation over institutional prestige to improve population health.
Lysine lactylation (Kla) is a lactate-derived post-translational modification that has emerged as a critical metabolic-epigenetic regulator linking cellular metabolic states to innate immune signaling. The cGAS-STING pathway, a central cytosolic DNA-sensing mechanism essential for antiviral defense, antitumor immunity, and inflammatory regulation, is profoundly influenced by the metabolic milieu. However, the precise role of lactylation in modulating this pathway remains to be systematically synthesized. This review aims to comprehensively analyze the molecular mechanisms by which lysine lactylation regulates the cGAS-STING signaling axis, and to discuss the pathophysiological implications and therapeutic potential of targeting this modification in diseases ranging from autoimmunity and neuroinflammation to cancer. A comprehensive review of the relevant literature was conducted to summarize the biochemical basis of lactylation (including writers, erasers, and readers) and to systematically examine emerging evidence demonstrating direct and indirect regulation of cGAS-STING components by lactylation. Studies involving site-specific modifications, disease models, and therapeutic interventions were collated and analyzed. Lactylation directly targets core pathway components-cGAS at residues such as K21, K131, K156, K162, K275, and K409, and STING-altering their stability, enzymatic activity, DNA-binding capacity, phase separation, and downstream signaling outputs. Depending on context, lactylation exerts dual effects: it stabilizes cGAS and amplifies type I interferon responses in autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis) and hypoxic-ischemic encephalopathy, but promotes cGAS degradation or suppresses STING activity in cancer (lung adenocarcinoma, glioblastoma) and neuropathic pain, thereby facilitating immune evasion or pain sensitization. Indirectly, lactylation modulates cytosolic DNA ligand availability by influencing mitochondrial DNA release (via HMGB1, VDAC1, Arg1, DRP1) or DNA repair (via KU70). The discovery of specific lactyltransferases (AARS1/2, p300) and delactylases (SIRT1-3, HDAC1-3) establishes lactylation as a dynamic, enzymatically controlled process. Lactylation functions as a pivotal metabolic-immune checkpoint that fine-tunes cGAS-STING signaling in a cell-type- and disease-specific manner. Targeting the lactylation regulatory axis-by inhibiting pathogenic lactylation to restore anti-tumor immunity or enhancing it to dampen deleterious inflammation-offers a novel immunometabolic therapeutic strategy for autoimmune disorders, chronic infections, neurodegeneration, and cancer.
The discourse surrounding surrogacy portrays pregnancy as a temporary process, depicting surrogates as neutral "carriers" whose involvement concludes at birth. This narrative minimizes gestation's biological significance despite evidence of its lasting effects on both women and children. We interviewed 47 retired Israeli surrogates using thematic analysis to examine how they navigate biological experiences. Surrogates employ frameworks that dismiss gestational bio-ties and emphasize genetic kinship, empowering their act of giving by rendering gestation inconsequential. This framework benefits surrogates, intended parents, and the industry by allowing narratives that overlook certain bio-ties. Two instances challenge this: bodies "talking back" through biological disruptions and intended mothers confronting surrogates about lasting bio-imprints on their babies. These challenges produce "embodied dissonance"-biology clashing with social expectations-and lead to "collaborative biologies," forcing recognition of connections the dominant framework erases. This study addresses bio-ties in surrogacy, paving the way for new frameworks reflecting human reproduction's complexities.
Lactate, once considered merely the product of glycolysis, is now recognized as both a metabolic fuel and a signaling molecule with broad physiological and pathological roles. The landmark discovery of lysine lactylation in 2019 unveiled a novel, direct mechanism through which lactate regulates cellular function. This dynamic post-translational modification, installed by "writers" enzymes and removed by "erasers," modulates the activity of histone and non-histone proteins, thereby influencing gene transcription, metabolism, and signal transduction. In reproductive biology, lactylation may represent an important regulator of fundamental processes including gametogenesis, embryo development, implantation, and placentation. Notably, aberrant lactylation is increasingly implicated in the pathogenesis of diverse reproductive disorders such as polycystic ovary syndrome, asthenozoospermia, ovarian cancer, preeclampsia, and recurrent pregnancy loss. This review systematically synthesizes current knowledge on the molecular mechanisms and functional significance of lactylation within the reproductive system, under both physiological and pathological contexts. Furthermore, we discuss the translational potential of targeting the lactylation pathway for novel therapeutic strategies and highlight key directions for future research.
Achieving aggregation-induced emission (AIE) in polymers via in situ, real-time generation of chemically explicit emissive motifs, while simultaneously enabling programmable 4D (time-/sequence-dependent) luminescence, remains challenging. Herein, we report a facile platform that converts nonemissive polymer precursors into AIE-active materials through photo-triggered radical reactions that dynamically construct thiocarbonyl (C = S) motifs in polymer backbones. Two kinetically programmable modules are established by molecular design: Switch 1 affords a metastable C = S motif with reversible write-read-erase behavior, and can further evolve into a stabilized thiobenzophenone-like state under prolonged irradiation; Switch 2 yields a more stable C = S motif featuring delayed-write and write-fix characteristics. Spectroscopic evidence supports the radical pathway and reversible/stable C = S formation. By substituent engineering of diphenylmethane-derived cores and sulfur-containing groups, the emission is rationally tuned across the full visible range, supported by quantum-chemical simulations correlating color with frontier-orbital gaps. Leveraging orthogonal control of activation and erasure kinetics via photoinitiators and oxygen-free atmospheres, we demonstrate two modes of 4D fluorescence encryption with time-gated decryption and time-window decoding. This work shifts AIE polymer design from "preinstalled AIEgens" to writable covalent emissive motifs, providing a scalable strategy for smart luminescent coatings and advanced information-security materials.
Dynamically tunable surface textures offer a powerful route to spatiotemporally regulate surface and interfacial properties, enabling emerging applications ranging from adaptive optics to soft robotic manipulation. However, achieving programmable, reversible, and spatiotemporal modulation of surface texture remains a fundamental challenge. Here, we present a photothermal-actuated liquid crystal elastomer bilayer that enables reversible, on-demand spatiotemporal modulation of surface textures through dynamically emerging and propagating wrinkles. Using direct laser writing or projected light fields, programmable and self-erasable wrinkle patterns are generated for dynamic information encoding. This spatiotemporal wrinkling enables object manipulation across diverse geometries, including uphill transport and navigation along predesigned paths. By coupling wrinkle-driven motion with thermally reversible dynamic bonding, the bilayer further enables assembly and disassembly of dynamic polymers, as well as cargo transportation. This work demonstrates spatiotemporally programmable wrinkling as a powerful mechanism for dynamic modulation of surface textures, establishing a versatile platform for multifunctional and reconfigurable smart surfaces.
In the 19th and early 20th centuries, many fetuses and infants were collected for anatomical study. Yet little research has explored their origins or the ethical implications of holding and using these individuals in teaching and research. This paper reviews the literature on fetal and infant skeletal collections and presents a case study from the W. D. Trotter Anatomy Museum in Aotearoa New Zealand that uses the lens of biopower and necropolitics to examine the acquisition and use of these individuals in anatomical education. This model highlights how societal and institutional powers and medicine regulate reproductive bodies and determine the perceived worth of fetuses and infants within specific cultural, historical, and medical contexts. This case study shows that individuals were often acquired from marginalized populations-unwed parents, the impoverished, and institutionalized women-whose reproductive autonomy was politically and socially negated. The paper explores how biopower and the necropolitics of reproduction in colonial New Zealand operated to control populations and individuals. Biopower and the necropolitics of reproduction were enacted through eugenic sentiment, structural inequality in healthcare, alongside medical and institutional control over the living and the dead. This contributed to higher infant mortality for marginalized mothers and infants, a loss of autonomy over the fate of deceased bodies, and the suppression of grief. The anatomization of fetuses rendered them objects of scientific value, whilst simultaneously erasing their personhood and socio-historical context, thus extending the structural violence their families experienced during life into their postmortem "life" history (necro-violence).
Tumour drug resistance remains a major hurdle in cancer treatment, with post-translational modifications (PTMs) playing a pivotal role in this process. Lysine lactylation (Kla), a newly identified PTM, is tightly associated with the Warburg effect, where tumour cells favour glycolysis even under aerobic conditions, resulting in excessive lactate accumulation. As a key substrate for Kla, this surplus lactate leads to markedly elevated Kla levels in tumours. This review systematically outlines the molecular mechanisms of Kla, including its biochemical definition, enzymatic regulation, metabolic cross-talk and feedback mechanisms within tumour reprogramming. Furthermore, we comprehensively discuss how Kla promotes tumour drug resistance through diverse mechanisms: activating DNA damage repair pathways, mediating epigenetic regulation and gene expression reprogramming, remodelling the tumour microenvironment (TME) to facilitate immune evasion and disrupting the balance between cell survival and apoptosis. Additionally, we analyse Kla's context-specific characteristics and mechanisms in drug resistance across distinct cancer types, such as breast, colorectal, lung and pancreatic cancer. Notably, we further expand the discussion to the spatial and clonal heterogeneity of Kla within the same tumour, including the divergent Kla profiles between hypoxic tumour cores and oxygen-rich tumour peripheries, the distinct Kla status of circulating tumour cells compared with primary tumour sites, and the specific Kla signatures that distinguish drug-resistant clones from drug-sensitive counterparts, key biological features that are critical for understanding Kla-driven drug resistance but have been largely understudied. Finally, we explore potential Kla-targeted therapeutic strategies, including inhibition of key lactate-metabolising enzymes, modulation of lactyltransferase activity and combination therapies, while discussing current challenges and future directions. By unravelling these Kla-driven mechanisms, this review provides a novel metabolic-epigenetic axis for overcoming cancer therapeutic resistance. Kla serves as a metabolic-epigenetic switch governed by writer-eraser-reader regulatory systems, directly connecting the Warburg effect to diverse forms of tumour drug resistance. Pharmacological modulation of Kla offers an innovative precision therapeutic approach to reverse drug resistance and enhance clinical prognosis across various malignancies. Lysine lactylation (Kla) functions as a metabolic-epigenetic switch that directly links the Warburg effect to tumour drug resistance via the writer-eraser-reader regulatory framework Kla promotes drug resistance through four interconnected mechanisms: DNA damage repair activation, epigenetic reprogramming, immune microenvironment remodelling, and anti-apoptotic pathway engagement. Intratumoural Kla exhibits profound spatial and clonal heterogeneity, with distinct Kla profiles in hypoxic tumour cores, oxygen-rich peripheries, circulating tumour cells, and drug-resistant clones. Kla-targeted therapeutic strategies-including inhibition of lactate-metabolising enzymes, modulation of lactyltransferase/delactylase activity, and combination therapies-offer a novel precision approach to reverse drug resistance.
The ability to continuously adjust hand movements using visual information is critical for success in many everyday tasks. To further characterize the age-related decline in visuomotor processes, here we investigated a task in which participants had to track with the hand, by means of a joystick, a visual target whose position was updated at different rates on a screen (from 1.5 to 240 Hz). This procedure was selected to grade the necessity for online control. As the target refresh rate increased, the need to continuously update hand motor commands became greater. We also manipulated gaze contingency and asked participants to perform this tracking task under gaze-free and gaze-fixed conditions, a procedure chosen to assess the contribution of eye movements and peripheral vision. The comparison between 30 older (71 yrs, 17 females) and 28 younger (21 yrs, 17 females) participants revealed detrimental effects of aging on tracking accuracy, notably through greater mean cursor-target distance and lag. Importantly, temporally realigning hand and target signals did not erase the gap in tracking performance between young and older participants. Moreover, we noticed that the effect of age was greater under higher target refresh rates and gaze-free conditions. Finally, sex/gender differences were found in each age group with men generally outperforming women. Overall, we interpret these observations as evidence that the age-related decline in manual tracking is driven by both slower and less accurate visuomotor loops, particularly when eye movements are engaged.
Skin fibrosis encompasses a spectrum of disorders, including hypertrophic scars, keloids, systemic sclerosis and lymphedema, that arise from distinct initiating insults but converge on persistent fibroblast activation, immune dysregulation and excessive extracellular matrix deposition. Although inflammatory, metabolic and mechanical abnormalities are increasingly recognized in these diseases, the mechanisms through which these signals are integrated into sustained profibrotic transcriptional programs remain incompletely understood. Histone modifications provide a dynamic and potentially reversible regulatory layer that links changes in the tissue microenvironment to chromatin accessibility and gene expression. In this Review, we summarize the major classes of histone modifications implicated in skin fibrosis, including acetylation, methylation, lactylation and selected non-canonical modifications. We discuss how their writers, erasers and readers regulate fibroblast activation, immune-cell dysfunction and profibrotic signaling pathways, and compare the available evidence across pathological scars, systemic sclerosis and lymphedema. Current evidence is most extensive for acetylation-related mechanisms, whereas the effects of histone methylation are highly dependent on the modified locus, cell type and experimental context. Histone lactylation provides an emerging mechanistic link between glycolytic reprogramming, lactate accumulation and profibrotic transcription, although its broader importance across cutaneous fibrotic diseases remains to be established. We further evaluate inconsistencies among experimental studies, limitations in causal interpretation and the translational challenges associated with targeting histone-modifying enzymes and chromatin readers. These challenges include limited cell-type specificity, non-histone effects, systemic toxicity and inadequate delivery to fibrotic tissues. Future integration of longitudinal, cell-resolved and spatial epigenomic approaches may help define disease-specific chromatin programs and facilitate the development of more precise biomarkers and targeted antifibrotic therapies.
Osteoclasts, through their excessive production, are the primary cause of postmenopausal osteoporosis. However, the influence of metabolism on osteoclastogenesis remains poorly understood. This study reveals that protein lactylation plays a critical role in osteoclast differentiation. The ovariectomized (OVX) mouse model was used to investigate osteoporosis by examining glycolysis and lactate levels during osteoclast differentiation. Bone resorption was assessed through histomorphometric analysis. The effects of elevating lactate levels were tested both endogenously via exercise and exogenously through sodium lactate (NaLac) administration. Protein lactylation, focusing on histone modifications, was analyzed, and key osteoclastogenesis genes, including cathepsin K (Ctsk), matrix metalloproteinase 9 (Mmp9), and matrix metalloproteinase 12 (Mmp12), were quantified. The enzymes responsible for lactylation and delactylation were identified through cleavage under targets and tagmentation (CUT&Tag) and RNA-Seq analyses. Our findings showed that glycolysis and lactate levels were reduced during osteoclast differentiation in the OVX model, despite increased bone resorption. Elevating lactate through exercise or sodium lactate supplementation increased protein lactylation and mitigated OVX-induced bone loss. Mechanistically, lactate enhanced histone H3 lysine-18 lactylation (H3K18la), which suppressed osteoclast differentiation by downregulating key osteoclastogenesis genes like Ctsk, Mmp9, and Mmp12. Alanyl-tRNA synthetase 1 (AARS1) was identified as the lactylation "writer" that mediates H3K18la, with sirtuin 6 (SIRT6) acting as an "eraser" in a regulatory circuit. Lactate suppresses osteoclast differentiation and alleviates osteoporosis through histone H3K18 lactylation, which downregulates osteoclastogenic genes including Ctsk, Mmp9, and Mmp12. The dynamic regulation of H3K18la involves AARS1 as the lactylation "writer"and SIRT6 as an "eraser". This study reveals an epigenetic mechanism by which lactate regulates osteoclast function and suggests that exercise-induced lactate elevation or lactate supplementation may represent a viable therapeutic strategy for postmenopausal osteoporosis.
Many plant species can propagate asexually or be regenerated in vitro; but asexual offspring are more likely to maintain environmentally induced epigenetic marks, for instance, inheritance of the prolonged cold-induced 'vernalized state' in overwintering plants through asexual reproduction. Here we demonstrate that 'vernalized state' is reprogrammed during Arabidopsis asexual propagation through somatic embryogenesis. This overturns a long-standing idea, that the vernalized state could not be reset through asexual reproduction, and provides a strategy to erase parental effects on offspring during asexual reproduction.
'Smart tattoos' based on stimulus-responsive nanoparticles have emerged as a promising platform for intradermal biosensing and dynamic optical interfaces, yet translation to safe and sustained use in human skin remains largely untested. We report a pilot clinical evaluation of Magic Ink, a rewritable photochromic tattoo ink comprising nano-engineered pigments that switch reversibly between nearly colorless and magenta states under visible and ultraviolet light, enabling permanent intradermal tattoos to be visually erased and restored on demand. Preclinical studies established third-party-verified sterility and non-cytotoxicity, confirmed nanoparticle size/morphology and shear-thinning rheological behavior suitable for intradermal delivery, and demonstrated robust photochromic performance with rapid switching kinetics and high fatigue resistance. In a paired, within-subject study, 11 participants received matched Magic Ink and commercial 'Standard Ink' control tattoos. Healing outcomes were assessed by clinical inspection (days 7 & 21), participant surveys through day 21, and longitudinal photographic documentation over five months. No adverse events were observed (0/11 per group). Dermatologist assessments and participant-reported symptoms of pain, redness, and itch did not differ significantly between Magic Ink and Standard Ink tattoos. Magic Ink tattoos remained nearly imperceptible in the deactivated state yet became readily visible upon UV activation after at least one year in vivo, demonstrating durable retention of photoswitchable function in human skin. These results indicate that photo-rewritable tattoo nanomaterials can function as tolerable intradermal implants over the timescales examined, and support their further evaluation for dynamic or 'disappearing' tattoos in medical (e.g., radiotherapy treatment localization and biopsy site marking in dermatology), cosmetic and paramedical (e.g., permanent makeup and micropigmentation), and body art applications.
We show that a single Hodgkin-Huxley (HH) neuron with Pyragas-type delayed feedback control (DFC) can store multiple symbols as stable periodic orbits, where the specific orbit is selected by tuning the DFC gain K and time delay τ. Sweeping the (K,τ) parameter plane at fixed bias current Ibias = 10.0 μA/cm2 reveals 207 orbit types across 12 topological categories, with inter-spike interval (ISI) means from 5.9 to 56.9 ms. We establish: (i) a write protocol that reliably locks orbits with 13.9 ms median settling time; (ii) a novel Pattern-Oriented Limit-cycle Decoder (POLD) that reads orbits at 100% accuracy from only five observed ISIs (1200 trials across 12 orbits; Wilson 95% CI: 99.7-100%); (iii) a complete single-symbol write-read-erase (W-R-E) cycle with 100% read accuracy, 92% erase verification, and no decay over hold durations up to 50 s; and (iv) a fully validated 12-symbol memory capacity with a read-discriminable upper bound of 67 symbols (11.2× over rate coding; write viability confirmed only for the conservative 12-symbol subset). Reliable orbit addressing needs delay precision of ±2%, which constitutes a write-precision specification and not a fundamental capacity limit. These findings show that parametric delayed feedback is a viable mechanism for limit-cycle-based information storage in conductance-based spiking neurons. The biological interpretation is analogical, not direct: the ±2% delay-precision requirement exceeds what has been demonstrated for biological autaptic variability, and the orbit-coded memory framing is best understood as a computational proof-of-principle aimed at neuromorphic engineering, not as a claim about biological working memory.