Biology subjects

Wu, F.

Publications and source records attributed to Wu, F..

At least 19 recordsLinked to original sources

bioRxiv2026

One lysine, two acyl marks: 2-hydroxyisobutyrylation and acetylation of G6PD differ in outcome and regulation

Lysine 2-hydroxyisobutyrylation is a widespread post-translational modification enriched in enzymes of central carbon metabolism, yet its site-specific biochemical consequences remain poorly defined and usually inferred from amino acid substitutions or heterogeneously modified protein preparations. Using genetic code expansion technology, we generated homogeneous human glucose-6-phosphate dehydrogenase (G6PD) carrying an authentic 2-hydroxyisobutyryl group at nine individual lysine residues. 2-hydroxyisobutyrylation affected G6PD activity in a strongly site-dependent manner: modification within or adjacent to the catalytic pocket (K171, K205, K360), or at the tetramer interface (K288), abolished activity, whereas modification of K386, near the structural NADP+ binding site, reduced catalytic efficiency and destabilized the enzyme. HibK386 G6PD was less oligomeric, while inactive HibK288 G6PD formed stable oligomers, suggesting that in HibK288 G6PD, assembly and catalysis are separable. Molecular dynamics simulations indicated that 2-hydroxyisobutyrylation of K386 reorients the side chain toward the solvent and weakens hydrogen bonding and salt-bridge across the tetramer interface. K386 is also subject to acetylation, allowing the comparison between two acyl groups at one residue; acetylation destabilized G6PD without substantially impairing catalysis, whereas 2-hydroxyisobutyrylation did both, and the two marks were differentially recognized by their erasers. SIRT2 removed both and restored the activity of the purified enzyme, whereas SIRT1 readily deacetylated AcK386 but was a poor de-2-hydroxyisobutyrylase of this position. SIRT2 also de-2-hydroxyisobutyrylated HibK288 G6PD and PKM2 HibK62, but not PKM2 HibK115 or HibK305. Together, these findings identify site-specific 2-hydroxyisobutyrylation as a potent inhibitory modification of G6PD, demonstrate that chemically distinct acylations at the same site can exert different functional effects, and establish deacylase specificity as a function of both modification chemistry and residue context.

biochemistry↗

bioRxiv2026

A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis

The gastroesophageal junction (GEJ) is continuously exposed to refluxed bile acids and microbial perturbations, yet how these environmental cues are converted into persistent oncogenic signaling is unknown. Here we show that bile acid remodeling enriches the oral commensal Prevotella melaninogenica at the GEJ, where bacterial succinate activates both vagal sensory neurons and SUCNR1-expressing tuft cells. Activated tuft cells release 15-deoxy-12,14-prostaglandin J2 (15-d-PGJ2), which sensitizes sensory neurons and sustains nerve remodeling, while neuronal CGRP drives expansion and tuft-cell differentiation of neuro-responsive epithelial progenitors through RAMP1. This self-reinforcing microbiota-neuron-epithelium circuit promotes dysplastic progression, and its genetic or pharmacological disruption, including with the approved CGRP antagonist rimegepant, suppresses tumor development, revealing an interceptable mechanism linking environmental dysbiosis to cancer initiation through neural circuits.

cancer biology↗

bioRxiv2026

SpatialOmicsLab: an integrated research environment for AI co-scientists in spatial transcriptomics

Spatial profiling is moving from method development into a central platform for biological discovery and clinical translation, but analyzing such complex data has become the bottleneck of scientific discovery. Translating spatial transcriptomic measurements into biological insight requires reproducible workflows that integrate diverse analytical methods. Although language-model agents can plan and execute multistep analyses, fragmented data and software ecosystems hinder their use as reliable research assistants. In this study, we introduce SpatialOmicsLab, an integrated research environment for spatial transcriptomics comprising 113 curated computational tools, 63 reference datasets and 4,614 task specifications. We also introduce ST-Coscientist, an AI co-scientist that uses this environment to assemble, execute and refine spatial transcriptomic analyses. Within SpatialOmicsLab, ST-Coscientist outperformed expert-led workflows and other scientific agents across six benchmark settings spanning spatial clustering, cell-type deconvolution and spatially variable gene detection. It constructed alignment-aware workflows for three-dimensional MERFISH data and addressed biological questions by selecting and analysing relevant reference datasets. Procedural memory increased the success rate of integrating and validating additional analytical tools from 48% to 95%. Together, SpatialOmicsLab and ST-Coscientist establish an extensible ecosystem for reproducible spatial transcriptomic research, enabling AI co-scientists to address evolving biological questions with an expanding analytical repertoire.

bioinformatics↗

bioRxiv2026

Simulated microgravity induces aging phenotypes in human organoids

Simulated microgravity provides a controlled perturbation for testing how loss of mechanical load affects human tissues. After 24 hours in rotating-wall vessels, neural, cardiac and tonsil organoids developed tissue-specific transcriptional responses that overlapped published spaceflight datasets, accompanied by higher transcriptomic-age estimates in neural and cardiac models, altered cardiac-organoid contraction dynamics and modified tonsil-organoid antiviral gene-expression signatures. These findings establish a multi-organoid framework for studying acute responses to gravitational unloading.

molecular biology↗

bioRxiv2026

A New Disease Gene for Hypokalemic Periodic Paralysis, KCNA7, Established in a Multigenerational Family

Hypokalemic periodic paralysis (HypoPP) is an inherited skeletal muscle ion channelopathy of CACNA1S or SCN4A characterized by recurrent episodes of weakness, often triggered by rest after exercise or by reduced K+ (carbohydrate ingestion, stress). Here, we describe a multigenerational family in whom a KCNA7 missense variant [c.834A>C (p.Arg278Ser)] co-segregated with susceptibility to recurrent attacks of weakness in association with hypokalemia as low as 1.3 mEq/L and a 40% decrement of the compound muscle action potential after exercise, suggesting an additional HypoPP gene. Arg278 is the outermost positively charged residue (R1) within the S4 transmembrane segment of the voltage-sensor domain of KV1.7, orthologous to the canonical patten of arginine missense mutations at R1 or R2 in S4 segments for HypoPP-mutant CaV1.1 and NaV1.4 channels. To determine the functional consequences of Arg278Ser, we expressed wild-type and mutant KV1.7 channels in Xenopus oocytes and HEK293 cells. Arg278Ser, but not wild-type KV1.7, generated an anomalous inwardly rectifying current at hyperpolarized membrane potentials that was nonselective Na+ or K+, consistent with the anomalous gating pore conductance that causes susceptibility to HypoPP. Other pathogenic variants of KCNA7 have previously been implicated only in inherited cardiac arrhythmias. Collectively, the genetic, structural and electrophysiological findings support KCNA7 Arg278Ser as a pathogenic variant underlying HypoPP and implicate KCNA7 as a disease gene for periodic paralysis, extending the established gating-pore mechanism of HypoPP to KV1.7.

genetics↗

bioRxiv2026

FRESH FROZEN PLASMA-BASED RESUSCITATION LESSENS LUNG INJURY IN MICE WITH ABDOMINAL SEPSIS AND HEMORRHAGIC SHOCK

We have previously shown that fresh frozen plasma (FFP) and fibrinogen have protective effects in mice with hemorrhagic shock through restoration of endothelial syndecan-1 and reversal of endothelial injury. In the current study, we tested the hypothesis that a combined model of abdominal sepsis and hemorrhagic shock would induce endothelial syndecan-1 shedding and lung injury which could be attenuated by both FFP and fibrinogen. C57BL/6 mice underwent cecal ligation and puncture (CLP) followed by hemorrhagic shock (HS) and fluid resuscitation with lactated Ringers (LR), fibrinogen (5 mg/mouse), and FFP, all at 1X shed blood volume. After 24 hours, lung tissues and plasma were harvested for assays. CLP+HS induced an increase in alveolar thickness and decreases in lung syndecan-1 and lung neutrophil granule-enzymes (myeloperoxidase, neutrophil elastase, and MMP9), with reciprocal elevations in plasma syndecan-1 and plasma neutrophil granule-enzymes (myeloperoxidase, neutrophil elastase, and MMP9). All these alterations were significantly attenuated by FFP but not by fibrinogen. Additionally, CLP+HS-induced hypotension at 24 hours was partially reversed by FFP but not by fibrinogen. FFP administration inhibits CLP+HS-induced neutrophil degranulation to prevent syndecan-1 shedding and lung injury. The current study supports that FFP has therapeutic benefit in a combined septic and hemorrhage shock model.

pathology↗

bioRxiv2026

A self-organized geometry sensing oscillator spatially regulates cell division in archaea

Cell division must be tightly regulate in time and space. Many bacteria and eukaryotes employ geometry sensing systems to regulate cell division spatiotemporally. However, how archaea ensure they divide in the right place at the right time is little understood. Here, we report the discovery of a geometry sensing oscillator that determines the division plane in the model haloarcheon Haloferax volcanii, which relies on two tubulin-like proteins, FtsZ1 and FtsZ2, for division. This archaeal oscillator (named as Arco system) is composed of three components, ArcoA, ArcoB and ArcoC, which are a membrane associated Ras superfamily GTPase, a SepF-like protein and an antagonist of FtsZ1, respectively. ArcoA interacts with both ArcoB and ArcoC. ArcoAB sense the geometry of the cell to oscillate between the two cell poles, generating a time-averaged ArcoC gradient which is high at the cell poles but low at the midcell, where FtsZs can assemble into the Z ring to initiate cytokinesis. As a result, deletion of the Arco system caused aberrant FtsZ assembly throughout the cell, leading to irregular division and formation of minicells. Interestingly, the Arco system is globally distributed among archaea and co-occurs with FtsZ1, suggesting that it emerged in the last archaeal common ancestor (LACA). The oscillatory behavior and phenotypes of the archaeal Arco system is remarkably analogous to the bacterial Min system and yet share no protein homology, representing a remarkable example of convergent evolution. Overall, these results suggest that archaea, similar to bacteria and eukaryotes, independently evolved self-organized Turing reaction diffusion systems to sense geometry and spatially regulate cell division.

microbiology↗

bioRxiv2026

Systematic identification of cell division proteins in haloarchaea and the discovery of a membrane anchor for the Z ring

Most archaea rely on the tubulin-like protein FtsZ for division. In the last decade, several novel cell division proteins have been discovered in the model haloarchaeon Haloferax volcanii which contains two FtsZ proteins, FtsZ1 and FtsZ2. However, the composition of this FtsZ-based archaeal divisome is largely uncharacterized. Here, using in vivo crosslinking coupled with immunoprecipitation and mass spectrometry (CLIP-MS), we identified ten proteins that localize to the division site, including wide-spread proteins predicted to be involved in DNA binding and energy metabolism. Deletion analysis indicate that most of these proteins have a modest or minor impact on cell division, but HVO_0399, renamed as Cell Division Protein C (CdpC), is important for cell division and functions as a membrane anchor for FtsZ1. CdpC consists of three domains, an N-terminal domain (NTD) containing an amphipathic helix critical for membrane binding, a long intrinsically disordered linker, and a C-terminal domain (CTD) that binds FtsZ1 with high affinity and likely promotes its polymerization. Notably, both the NTD and CTD of CdpC harbor a zinc finger that is indispensable for its function. Phylogenetic analysis indicates that CdpC sequences evolved fast across haloarchaea, but exhibited high conservation in domain structure and critical residues found in this study. Overall, our study expands the repertoire of candidate division proteins and establishes CdpC as a membrane anchor for FtsZ1 in haloarchaea. These findings pave the way for in-depth studies of arcaheal cell division and broaden the function of zinc finger proteins in archaea.

microbiology↗

bioRxiv2026

Plaque-associated oligodendrocyte proteostatic failure underlies myelin loss in Alzheimers disease

Alzheimers disease (AD) features amyloid-{beta} plaques and tau pathology, yet the mechanism underlying early and clinically significant myelin loss remains unresolved. Here, we report human iPSC-derived forebrain organoids with doxycycline-inducible expression of SOX10, OLIG2, and NKX6-2 (SON), which generate robust, mature oligodendrocytes and compact myelin in vitro and in vivo. Introducing amyloid precursor protein (APP) pathogenic mutations produces extracellular amyloid-{beta} plaques and phosphorylated tau, accompanied by reduced myelin basic protein (MBP) expression and disrupted myelin ultrastructure. Single-cell and spatial transcriptomics combined with amyloid plaque imaging reveal that oligodendrocytes in plaque-dense regions show pathological changes in calcium signaling, immune activation, lipid remodeling, and protein catabolic pathways. Notably, MBP protein is reduced despite elevated myelin-related transcription, suggesting plaque-induced degradation of myelin proteins. Consistent with this, proteasomal inhibition restores MBP protein levels and improves compact myelin ultrastructure in AD organoids. In human AD brain tissue, protein catabolic pathways are similarly upregulated with increasing plaque density. Together, these findings identify plaque-associated oligodendrocyte proteostatic failure as a candidate mechanism of myelin loss and a potential therapeutic pathway in AD.

neuroscience↗

bioRxiv2026

IgGM2: An All-Atom Foundation Model for Adaptive Immune Receptor Design

Accurate immune receptor design requires modeling the coupled variation of aminoacid sequence, full-atom conformation, and target-binding geometry across antibodies, nanobodies, and T-cell receptors (TCRs). Existing methods often address only part of this problem, either by separating structure generation from sequence design, relying on fixed-backbone inverse folding, or focusing on a single receptor class. We introduce IgGM2, a unified all-atom generative framework for immune receptor structure prediction and CDR sequence-structure co-design. IgGM2 follows a structure-to-design strategy: it first learns how immune receptors are positioned around fixed target structures, and then transfers this target-conditioned structural prior to CDR design. Unlike modular design pipelines, IgGM2 jointly generates CDR residue identities and full-atom receptor structures, allowing frame-work geometry to adapt to designed CDRs without separate inverse folding or external sidechain packing. Unlike continuous residue encodings based on virtualatom geometry, IgGM2 keeps sequence prediction explicit while using atom14 placeholders only for full-atom representation. On structure prediction benchmarks, IgGM2 better captures receptor-target spatial relationships than AlphaFold3 on FoldBench and achieves strong performance on TCR-pMHC modeling. On sequence design benchmarks, IgGM2 achieves competitive amino-acid recovery and improves Rosetta-based interface preference metrics, suggesting more favorable generated binding interfaces. These results support IgGM2 as a unified all-atom framework for adaptive immune receptor structure prediction and design.

bioinformatics↗

bioRxiv2026

Spatial synaptic regularization stabilizes learning across biological and artificial neural networks

How the spatial organization of synapses contributes to stable learning remains a fundamental question in neuroscience. Using the H01 electron microscopy connectome of human temporal cortex, we found that dendritic spines clustered morphologically, whereas synaptic weights followed a center-elevated, surround-suppressed arrangement along dendrites. A regularized Hebbian model formalized this spatial signature, showing that strong synapses lower the probability that neighboring synapses reach high-weight states. Translating this principle into Spatial Synaptic Regularization (SSR) reduced forgetting and stabilized learning across diverse artificial networks and tasks, including continual visual learning, large language-model knowledge editing, and parameter-efficient adaptation of vision-language models, by preserving high-rank, low-overlap representations. These findings identify spatial synaptic organization as an unrecognized dimension for stabilizing learning and show that structural connectomics can yield actionable AI methods.

neuroscience↗

bioRxiv2026

Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis

Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown. Here, we show that vagal sensory neurons acquire a durable, experience-dependent state following gastric injury or Helicobacter pylori infection, leading to enhanced regeneration, metaplasia, and tumor progression upon re-injury. This neuronal program is stable, functionally transferable, and sufficient to drive epithelial responses in vivo. Mechanistically, injury-activated ILC2s establish sensory neuronal memory through IL-13-dependent epigenetic remodeling, inducing SMYD4-mediated H3K4 trimethylation and promoting CGRP-dependent activation of gastric epithelial cells. Together, our findings support a model in which tissue memory is not restricted to epithelial or immune compartments but emerges through coordinated long-term adaptations across multiple cellular systems. Within this framework, sensory neurons provide a persistent substrate for recall responses, linking prior inflammatory experience to sustained epithelial plasticity and cancer susceptibility. HIGHLIGHTSO_LISensory neurons function as a durable compartment of tissue memory. C_LIO_LICGRP-RAMP1 signaling couples neuronal memory to gastric stem cells. C_LIO_LIILC2-derived IL-13 establishes sensory neuronal memory programs. C_LIO_LISMYD4-mediated H3K4me3 stabilizes long-term neuronal memory. C_LIO_LINeuronal memory promotes gastric regeneration and tumor susceptibility. C_LI

cancer biology↗

bioRxiv2026

Single-cell learning in Stentor coeruleus is governed by a fractional-order low-pass filter

Single cells display a range of complex behaviors normally associated with a nervous system, including basic forms of learning like habituation. The giant ciliate Stentor coeruleus habituates to mechanical stimuli and shows many of the hallmark features characteristic of habituation in animal cells. When Stentor cells are mechanically stimulated by a predator or other stimuli, an action potential fires and leads to calcium-dependent contraction. When the same cell is repeatedly stimulated, it becomes less likely to respond, thus showing habituation. While the molecular basis of habituation in Stentor is not yet known, it has been shown to involve CaMKII, which also plays a key role in learning in neurons. The presence of an action potential, the role of calcium in the response, and the involvement of CaMKII in habituation, all suggest a potential deep conservation of learning mechanisms between single-celled protists and the neurons of animals. A number of different models have been proposed to explain habituation in a single cell but existing data in Stentor are unable to clearly rule out any of these models or favor others. Here we report a frequency domain analysis of habituation in which we measure the response probability of Stentor cells to pulsatile stimuli delivered at a range of frequencies. We find that the Bode plot of the frequency response resembles a classic low pass filter, with a flat passband at low frequencies, a clear corner frequency, and a linear roll-off. However, unlike standard low pass filter, the roll-off occurs with a slope of -30dB/decade, thus showing a fractional-order behavior. None of the existing models for habituation in Stentor, at least in their current form, predict this form of the frequency response, leading us to look for other explanations. We tested, and ruled out, a model based on a refractory period associated with the re-extension of cells following contraction. Inspired by methods used in analog circuit design to approximate fractional order systems using conventional lumped devices, we developed a model in which a series of distinct molecular species, such as different multimeric complexes of CaMKII, acting in parallel to inhibit the response, produce a fractional-order effect. The fractional order behavior of habituation in Stentor resembles the fractional-order behavior of adaptation in neurons, further supporting the idea that neurons may employ similar mechanisms for learning as were already present in unicellular eukaryotes prior to the evolution of metazoa.

cell biology↗

bioRxiv2026

Distinct senescent β-cell senotypes differentially drive islet aging and dysfunction

Biological aging greatly impacts the bodys ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell-resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20-80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34-69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A senescent cells (SnCs) exhibit loss of {beta}-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive (CDKN2A) from a maladaptive (CDKN1A) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

cell biology↗

bioRxiv2026

HDAC6 and SSAT2 orchestrate acetyllysine metabolism and protein homeostasis

Lysine acetylation is a prevalent and dynamic posttranslational modification, yet the metabolic fate and physiological role of free N {varepsilon}-acetyl-L-lysine (AcK) remain unclear. Here, we identify opposing enzyme-catalyzed reactions linking lysine/AcK homeostasis to protein stability. We show that the first catalytic domain of HDAC6 stereospecifically deacetylates free AcK, establishing HDAC6 as an N {varepsilon}-acyl-lysine deacylase. AcK functions both as a recyclable lysine reservoir and as a signaling metabolite that elevates -tubulin acetylation and suppresses cell migration. Conversely, SSAT2 acetylates free lysine in cells and undergoes substrate-dependent C-terminal autoacetylation. We demonstrate that C-terminal lysine acetylation constitutes a reversible proteasomal degradation signal that promotes SSAT2 degradation and may extend to additional proteins bearing a terminal lysine. Stabilization of SSAT2 by HDAC6-dependent deacetylation, together with intricate regulation affected by substrate availability, reveals a novel mechanism that couples amino acid recycling to cytoskeletal dynamics and proteostasis.

biochemistry↗

bioRxiv2026

Integrative Single-Cell and Multi-Cohort Analysis of the Netrin-1 Signaling Pathway Reveals Divergent Prognostic Trends and Sex-Dimorphic Associations in Glioblastoma

BackgroundThe Netrin-1 dependence receptor pathway plays critical roles in neural development, but its expression landscape and prognostic significance in glioblastoma (GBM) remain poorly characterized. MethodsSingle-cell RNA-seq data from 148,019 cells across 34 tumors (Neftel et al., 2019) were analyzed to map Netrin-1 pathway gene expression across GBM cellular states. Differential gene expression and pathway enrichment analyses were performed on NEO1-defined subpopulations. Bulk RNA-seq survival analysis was conducted across three independent GBM cohorts TCGA (n=106), CGGA mRNAseq_325 (n=137), and CGGA mRNAseq_693 (n=237), totaling 480 patients. Primary analysis used continuous Cox regression (per-SD hazard ratios); meta-analysis employed fixed-effects inverse-variance weighting. ResultsIn GBM single-cell data, Netrin-1 pathway genes showed state-specific enrichment --NEO1, DCC, NTN1, and RGMB were predominantly expressed in oligodendrocyte-precursor (OPC) and neural-progenitor (NPC) states. Cells positive for NEO1 were enriched for neural differentiation programs (nervous system development, p=9.6x10-; Axon Guidance, p=2.8x10-), whereas NEO1-negative cells were dominated by ribosomal/translational and immune activation programs. In the 3-cohort survival meta-analysis, NTN1 (Netrin-1 ligand) emerged as the sole gene reaching meta-analytic significance as a risk factor (Meta HR=1.163 per SD, 95% CI 1.056-1.281, p=0.0021, I{superscript 2}=0%, 3/3 cohorts concordant), while DCC and RGMB showed directionally consistent protective trends (DCC: Meta HR=0.938, 95% CI 0.858-1.025, p=0.156; RGMB: Meta HR=0.979, 95% CI 0.881-1.087, p=0.686; both 3/3 cohorts concordant). NEO1 itself did not independently predict survival (Meta HR=1.008, 95% CI 0.885-1.147, p=0.910). After Bonferroni correction for 10 genes tested (threshold p<0.005), only NTN1 met strict significance. In exploratory sex-stratified analysis of a single cohort (CGGA 693, n=237), NEO1 and NTN1 exhibited female-specific risk enhancement (NEO1: HR=1.417, p=0.014; NTN1: HR=1.249, p=0.019), with minimal effects in males. UNC5B showed context-dependent risk in MGMT-unmethylated tumors (HR=1.331, p=0.037). These sex-dimorphic findings require independent validation. ConclusionsThe Netrin-1 pathway exhibits divergent prognostic trends in GBM, with NTN1 as a risk factor and DCC trending toward protection--consistent with the dependence receptor model. These findings, which should be interpreted as hypothesis-generating, nominate NTN1 as a candidate therapeutic target and highlight the potential importance of sex-stratified evaluation in future Netrin-1-directed trials. Independent replication in larger cohorts is warranted.

cancer biology↗

bioRxiv2026

Near-Infrared-II Chemo-Optogenetics for Deep-Brain Stimulation

Precise activation of ion channels enables fine-tuned control of neuronal excitability, providing a powerful strategy for dissecting and modulating neural circuits. Although optogenetics offers high spatiotemporal neuronal manipulation with cell-type specificity, its reliance on visible light (400-650 nm) limits tissue penetration to millimeter depths, restricting applications in deep-brain stimulation. Here we report a near-infrared-II (NIR-II)-sensitive calcium channel, HaloNeu, created by genetically fusing a circularly permuted HaloTag (cpHaloTag) to the thermo-sensitive transient receptor potential vanilloid 1 (TRPV1) and covalently conjugating NIR-II photothermal nanotransducers (HPN). The HaloNeu enables non-invasive neuromodulation at depths up to 1.0 cm at ultralow laser power ([~]60 mW/cm2) and up to 5.0 cm under the safe exposure limit ([~]1 W/cm2) with 1064 nm laser illumination. Remarkably, HaloNeu maintains stable, on-demand neuron-specific modulation for over two months in vivo, providing sustained activation of ventral tegmental area (VTA) circuits and effective alleviation of Parkinsonian symptoms in mouse models. These results establish HaloNeu as a robust and versatile platform for cell-type-specific, deep-tissue, and chronic neuromodulation, with broad implications for neuroscience and neurotherapeutics.

neuroscience↗

bioRxiv2026

Deciphering the epitranscriptomic code of RNA degradation with nanopore direct RNA sequencing

The precise regulation of RNA degradation is crucial for gene expression homeostasis, yet how multiple molecular features coordinate on a single transcript remains poorly understood. Here, we use nanopore direct RNA sequencing (DRS) to simultaneously track alternative isoforms, m6A modifications, and poly(A) tail dynamics at single-molecule resolution during a time course of RNA decay. We show that m6A regulates RNA degradation in a stoichiometry-dependent manner, where modification levels quantitatively modulate decay kinetics. Mechanistically, m6A is functionally coupled to deadenylation, promoting accelerated poly(A) tail shortening and coordinated RNA turnover. At the isoform level, we identify regional m6A clusters (RMCs) as structural elements that associate with isoform-selective degradation and remodel protein-coding potential. Furthermore, transcript splicing architecture is associated with distinct m6A deposition patterns, suggesting that gene structure encodes RNA decay kinetics through m6A-mediated regulation. A machine learning model integrating these multi-modal features highlights the central contribution of m6A and deadenylation in shaping RNA decay, while revealing substantial regulatory heterogeneity across transcripts. Collectively, our study deciphers the multi-layered, cooperative principles of RNA degradation and provides an epitranscriptomic perspective for understanding how RNA fate is encoded at the single-molecule resolution.

bioinformatics↗