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Li, W.

Publications and source records attributed to Li, W..

At least 19 recordsLinked to original sources

Preclinical Development and Safety of Laterally Spreading Dual AAV.SPR-MYO7A Vectors for the Treatment of Usher Syndrome Type 1B

Usher syndrome type 1B (USH1B), caused by mutations in MYO7A, is the most severe form of Usher syndrome and accounts for more than 50% of USH1 cases. Affected patients are born profoundly deaf with vestibular dysfunction and develop progressive retinitis pigmentosa, for which no approved treatment exists. The MYO7A coding sequence exceeds the packaging capacity of adeno-associated virus (AAV), the gold standard vector for retinal gene therapy. To overcome this, we developed dual AAV hybrid and overlap platforms to reconstitute full-length MYO7A expression in photoreceptors and retinal pigment epithelium. Modification of cDNA split points, and reduction of non-coding sequence yielded optimized vector pairs that produced higher full-length MYO7A levels with substantially reduced truncated protein. Packaging in the laterally spreading AAV.SPR capsid enabled supraphysiological MYO7A expression in cynomolgus macaques at macular and distal retinal sites without requiring foveal detachment, an important safety consideration for USH1B patients with remaining central vision. A six-month GLP toxicology study confirmed that ATSN-301, an AAV.SPR-based dual vector reconstituting MYO7A driven by the smCBA promoter, was well tolerated at all doses, with a No Observed Adverse Effect Level established at 1.2E11 vg/eye, supporting its clinical advancement for USH1B.

genetics↗

Efficient recovery of transgene-free edited tobacco using the transgene self-elimination system via de novo regeneration

Elimination of integrated editing constructs remains a major challenge for generating transgene-free progeny in plant genome editing based on Agrobacterium-mediated regeneration. Here, we adapted the Transgene Killer CRISPR (TKC) concept to tobacco and established the transgene self-elimination system, in which CRISPR/Cas9 is coupled with developmentally regulated BARNASE cassettes. Three pU3TR-derived vectors carrying DLL-, OsRP3- or PHAS-driven Barnase regenerated normally after leaf-disc transformation. The DLL construct pEB138 showed the highest T editing frequency, with 56 of 69 independent T plants (81.16%) carrying mutations at one or both NtDFR target loci. Under a stringent lineage-level screen in which up to 48 T progeny were tested per T line, 36 of 43 pEB138 lineages (83.72%) yielded uniformly marker-negative progeny for the three assayed T-DNA markers, compared with 0 of 7 lineages transformed with the parental pU3TR vector. The platform also supported recovery of dfr mutants with altered flower pigmentation and NtA622-edited lines with reduced nicotine accumulation. Moreover, introduction of DLL-iBarnase into the independent pDC45 editing backbone did not impair shoot regeneration, and representative NtBBL progeny showed markedly reduced nicotine content together with loss of the selectable cassette. These results demonstrate that BARNASE-assisted transgene elimination can be integrated with Agrobacterium-mediated de novo regeneration in a dicot, enabling one-step recovery of transgene-free edited tobacco progeny.

molecular biology↗

Janusein and EB Cooperate to Enhance Microtubule Plus-end Catastrophe

Microtubule (MT) plus ends are organized by end-binding (EB) proteins, yet how EB-associated factors modulate the transition from growth to catastrophe remains incompletely understood. Using spatially resolved proximity proteomics, we identified Janusein (ZC2HC1A) as a conserved, poorly characterized MT-associated protein (MAP). At low expression levels, Janusein tracked MT plus ends and reduced EB comet velocity; at higher levels, it redistributed to the MT lattice and was associated with MT bundling and widespread MT loss. Loss of Janusein resulted in spindle defects in human cells. In vitro, Janusein alone facilitated MT elongation through its C-terminal fragment, but promoted MT catastrophe through its N-terminal fragment in the presence of EB proteins. Molecular dynamics simulations and mutational analyses suggest that an N-terminal loop may perturb lateral contacts between adjacent MT protofilaments. Together, these findings identify Janusein as an unconventional MAP that functionally cooperates with EB proteins to promote MT catastrophe.

cell biology↗

Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MECP2 gene, currently lacks effective treatments. The motor cortex is a pivotal hub in RTT and autism spectrum disorders, and its impairments contribute to motor, social, and cognitive deficits. Here we examined the effects of repetitive transcranial magnetic stimulation (rTMS) targeting motor area in non-human primate of RTT (MECP2-mutant monkey) and investigated neuromolecular basis underlying therapeutic effects. We identified a new treatment target, ventral premotor cortex (PMv), for RTT and found that following a 20-day rTMS course, several behavioral and functional connectivity measures showed directional changes. Neuroimaging analyses confirmed that rTMS induced reorganization of large-scale functional connectivity with enhanced functional integration between the somatomotor and the salience networks and normalized coupling between the motor cortex and both the thalamus and the anterior cingulate cortex. Notably, single-nucleus RNA sequencing revealed that rTMS triggered cell-type-specific transcriptional reprogramming: it rescued pathological hyperactivity of excitatory neurons by restoring the expression and regulatory networks of immediate early genes (e.g., FOS, EGR1) and corrected dysregulated intercellular signaling (e.g., NRG, WNT). These findings indicate that targeting motor cortical areas with brain stimulation may treat RTT, which warrants further clinical validation.

neuroscience↗

Practical Identifiability of a Minimal Adaptive Learning-Gain Model for Binary Feedback: A Simulation Study

Social learning is jointly determined by several computationally distinct quantities, namely baseline belief (prior mean), sensitivity to feedback (learning gain), and the temporal uncertainty of belief (drift), which are rarely separated in empirical designs. Here we systematically characterise the practical identifiability and predictive adequacy of a minimal four-parameter adaptive learning-gain model of binary feedback: a latent belief v_t about the probability of a positive outcome is carried forward deterministically between observations while an internal confidence-precision state decays by a per-trial amount omega, and the belief is updated by a learning gain lambda from a deterministic prior mean mu with initial confidence precision sigma; sigma, omega and lambda are model-defined internal quantities, not validated psychological constructs. The simulated process is self-reinforcing: the same latent state both generates the binary outcome and represents the learner's belief, so the model does not represent inference about an independently evolving social environment. The study is therefore an analysis of a phenomenological adaptive filter under a specified binary stochastic process: its update equations are deliberately chosen rather than derived from the Bernoulli-logistic likelihood, and it does not reduce to a standard hierarchical Gaussian filter. Using fixed-seed simulation studies, we report four findings. First, joint maximum-likelihood recovery is poor. On the 24-condition parameter grid at T=80 (100 independent replications per condition), the belief mean mu shows comparatively smaller errors but is still not reliably recovered; sigma and omega show near-zero tolerance-based recovery that stays at most 0.002 across tolerance thresholds of 0.3, 0.6 and 1.0 transformed units, whereas lambda recovery is low but not near-zero and increases with tolerance (0.078, 0.182 and 0.263 at tolerances 0.3, 0.6 and 1.0). Boundary convergence is strongest for sigma (upper bound) and omega (lower bound), whereas lambda boundary solutions are not uniform across grid conditions. In a separate single-parameter-vector experiment that varies trial length (T in {40, 80, 120, 240, 480}), extending the sequence alone does not repair recovery of the positive parameters, including lambda. Tolerance recovery concerns point estimates only; calibrated interval coverage is not evaluated and is not substituted by a flat profile or a boundary estimate. Second, profile-likelihood and trade-off diagnostics show flat likelihood regions for sigma and omega, with an asymmetric profile for lambda that constrains its upper range but is uninformative over its low range; the flat sigma-omega geometry replicates in a second, low-gain regime (a within-study replication, not a claim across the full condition grid), whereas the exact steepness of the lambda profile is regime-dependent. Three optimisers converge to the same boundary solution, and the fitted estimates cannot reliably rank individual simulated subjects either. These patterns support weak practical identifiability under the tested design, not structural non-identifiability; no formal structural identifiability analysis is performed, so a structural claim is not made. Third, a fitting-parity audit found and corrected a return-order defect in the fixed-gain candidate: its fitted parameters were returned with sigma and omega interchanged, which artificially raised that candidate's fitted block loss. Under the corrected fit, overall block discrimination is 67/150 = 0.45 under the original wider bounds and 72/150 = 0.48 under common fitting bounds matched to the proposed model (56 common forecast observations per dataset, each scored exactly once, with an automated index check confirming no fit-forecast overlap and no look-ahead), modestly above the 0.33 chance level; a calibrated permutation test that preserves the asymmetric winner marginals is significant (p = 0.0011 and p < 0.001). This above-chance accuracy is almost entirely attributable to Rescorla-Wagner (0.88-0.90 correct), whereas the adaptive filter and its nested fixed-gain restriction remain heavily confused (row-wise accuracies 0.18-0.22 and 0.24-0.36, neither significant), and the result is robust to the fitting bounds (row-wise p-values are descriptive and uncorrected; none of this establishes model equivalence). Fourth, across 50 independent held-out datasets the model shows no predictive advantage over a training-set empirical-frequency baseline (the paired 95% confidence interval spans zero under both normal-approximation and bootstrap estimation; the proportion of datasets won is not used as evidence of superiority), and a paired ablation shows no consistent predictive gain from the added update components and no improvement in parameter stability; no predictive advantage over this empirical-frequency baseline has therefore been demonstrated.

neuroscience↗

Cardiomyocyte Identity Crisis Without Regenerative Re-entry: A Multi-Scale Atlas of Incomplete Dedifferentiation and Intercellular Communication Rewiring in the Infarcted Human Heart

Background: Adult mammalian hearts regenerate poorly after myocardial infarction (MI) because cardiomyocytes largely, though not absolutely, exit the cell cycle during postnatal maturation, yet the molecular logic connecting maturation, disease-associated dedifferentiation, and intercellular communication remains unclear. Methods: Public single-cell and single-nucleus transcriptomes of developing, adult, and infarcted human and mouse hearts (55,342 cardiomyocytes) are integrated with Visium spatial transcriptomics to reconstruct a cross-species maturation trajectory, a directional ligand-receptor communication atlas, and rare-event proliferation counts with donor-aware statistics. Results: MI cardiomyocytes show a partial identity erosion -- a stress-associated myosin isoform switch, collapse of the ventricular identity factor IRX4, and maturation-score decline -- without regenerative proliferative re-entry and without fetal transcription-factor re-activation; cycling nuclei remained exceedingly rare (<0.03%), a state corroborated by chromatin accessibility and human genetics, with only the MYC regulon passing transcriptome-wide correction. Inferred communication reorganization was confined to non-myocyte compartments and did not exceed donor-label permutation nulls; cardiomyocytes remained net receivers without gaining signalling authority. IRX4 knockdown in human iPSC-derived cardiomyocytes recapitulated this identity loss, including stress-gene induction and elevated NT-proBNP secretion, and IRX4 overexpression attenuated the adrenergic stress response in IRX4-intact cardiomyocytes (orthogonal rescue untested). Conclusions: These findings support a model of state-relationship decoupling, in which an intracellular cardiomyocyte identity crisis and an intercellular niche rewiring proceed independently -- a decoupling we define operationally and test with donor-level null models and equivalence bounds -- and may help explain the limited success of regenerative strategies that target either layer alone.

bioinformatics↗

Tumbly: An Open-Source Home-Cage Device for Time-Restricted Feeding in Mice

Time-restricted feeding (TRF) is a common tool for studying metabolism, circadian rhythms, aging, and neurodegeneration. Here, we describe a new device called Tumbly, an automated device for performing TRF studies in mouse home-cages. Tumbly controls access to rodent diets at user-set times via a programmable servo-driven food hopper. Tumbly is also battery powered and compatible with multiple types of vivarium home-cages, due to a removable faceplate that can be customized to fit different cage dimensions without modification. Finally, Tumbly is open-source and affordable, with all design files available online, allowing researchers to build and customize it. As a validation test, we deployed Tumbly in two labs at separate institutions, one with singly housed mice (n = 6, within-subject) and one with group-housed mice (n = 22, between-group). We measured daily body weight and food intake. In both labs, mice on an 8-hour TRF schedule maintained their body weight and ate similar amounts of food compared to ad libitum feeding. Our quantified error rates were also low, with no device failures over >1000 hours of operation. We conclude that Tumbly provides a reliable, low-cost option for running TRF studies in mice.

neuroscience↗

OmniRE-seq: A Dual-Method Framework for Decoding RNA Editing Dynamics in Disease and Therapy

RNA editing is a widespread post-transcriptional modification involved in transcriptome diversity and disease regulation. However, its quantification remains technically challenging. We present OmniRE-seq, a dual-framework combining RE-seq for bulk and scRE-seq for single-cell RNA-seq data, enabling multi-level quantification, differential analysis, and functional annotation of RNA editing. Using RE-seq, we profile editing alterations across diverse contexts -- including murine sepsis, MDS, drug-treated melanoma, and colorectal cancer -- demonstrating the utility of locus-, gene-, and burden-level metrics in capturing biologically meaningful differences. scRE-seq further resolves cell-type-specific editing patterns by aggregating cells of shared identity into pseudo-bulk units (Spots), enhancing editing signal while preserving cellular resolution in colorectal cancer. Integrated bulk and single-cell analysis identified convergent editing signals and therapeutic targets, exemplified in a mouse model of thymic atrophy treated with Ganoderma lucidum spores. Together, OmniRE-seq offers a standardized and scalable toolkit for dissecting RNA editing landscapes across resolution levels, advancing both mechanistic discovery and translational application in precision medicine.

bioinformatics↗

Small-molecule ACOD1 inhibition attenuates colitis and tumor growth through a shared myeloid mechanism, diverging from genetic deletion

Aconitate decarboxylase 1 (ACOD1), the enzyme responsible for synthesis of the immunometabolite itaconate, is widely regarded as an anti-inflammatory brake on tissue damage based on Acod1-deficient mice and itaconate supplementation expermiments. ERG344, a small-molecule ACOD1 inhibitor, suppressed itaconate synthesis in endotoxemic mice and in inflamed colonic mucosa and, contrary to genetic-deletion studies, attenuated acute DSS colitis in an ACOD1-dependent manner. ERG344 treatment was associated with reduced influx of immature monocytes early on and accumulation of mature neutrophils. In syngeneic tumor models, ERG344 prolonged survival and increased tumor-infiltrating lymphocytes and antigen-presenting dendritic cells. Across murine and human colitis scRNA-seq datasets and a ten-model syngeneic tumor atlas, ACOD1 marked interferon-stimulated immature monocytes and maturing neutrophils, and tracked with SOD2 and CD274 independently of interferon and NF-{kappa}B signaling. ACOD1 appears to act through a common myeloid recruitment and maturation mechanism, making pharmacological ACOD1 inhibition a viable therapeutic strategy in colitis and cancer.

pharmacology and toxicology↗

Feed-based delivery of plasmid DNA using milk-derived extracellular vesicle-polyethylenimine complexes enables hepatic transgene expression in goldfish

Oral administration through feed offers a non-invasive, cost-effective, and scalable approach for gene delivery in aquaculture. However, gastrointestinal degradation and intestinal barriers severely limit the oral delivery of plasmid DNA (pDNA). In this study, we developed a ternary nanocarrier composed of bovine milk-derived extracellular vesicles (MEVs), polyethylenimine (PEI), and pDNA (MPPs) to investigate its potential for functional gene delivery to the goldfish (Carassius auratus) liver (hepatopancreas). The resulting MPPs exhibited a relatively uniform particle size, high pDNA loading efficiency, and protection against nuclease-mediated degradation. Formulation optimization in HEK293T cells identified an MEV:PEI:pDNA mass ratio of 16.7:4.1:1, which supported robust EGFP reporter expression. Following oral administration of DiD-labeled MEVs through feed, fluorescence signals were detected in the goldfish hepatopancreas within 2 h and remained detectable at 6 h. After a single feeding of MPP-containing feed, hepatic luciferase mRNA expression peaked at 24 h and gradually declined to near-baseline levels by 72 h. During 14 consecutive days of feeding, luciferase protein expression was detectable from day 3, with progressively increased protein abundance and enzymatic activity observed on days 7 and 14. Collectively, these findings demonstrate the feasibility of feed-based MPP administration for inducing functional transgene expression in the goldfish hepatopancreas, providing a promising foundation for developing non-invasive nucleic acid delivery strategies in aquaculture.

molecular biology↗

Pan-cancer nucleosome landscapes reveal tumor heterogeneity and inform cell-free DNA-based detection

Background: Nucleosome positioning and occupancy are fundamental features of chromatin organization, yet their variation across human cancers and potential utility for noninvasive cancer detection remain poorly characterized. Methods: We systematically characterized nucleosome organization across 410 primary tumors spanning 23 cancer types using ATAC-seq, establishing a high-confidence pan-cancer nucleosome atlas validated by independent MNase-seq data. We characterized shared and cancer-type-enriched nucleosome patterns, investigated their associations with tumor heterogeneity and regulatory alterations, and evaluated tissue-derived nucleosome signatures for cancer classification and detection using circulating cell-free DNA (cfDNA). Results: The atlas identified shared and cancer-type-enriched nucleosomes associated with distinct regulatory programs. Notably, nucleosome occupancy provided information complementary to chromatin accessibility for tumor stratification and revealed molecular heterogeneity within individual cancers, including subgroups associated with Basal-like breast cancer. In hepatocellular carcinoma, differential nucleosome analysis revealed cancer-associated chromatin remodeling involving regulatory pathways, transcription factor motifs, and candidate genes. Importantly, tissue-derived nucleosome signatures were detectable in cfDNA, enabling classification among three cancer types (AUROC = 0.877) and colorectal cancer detection (AUROC = 0.930), with an AUROC of 0.773 in an independent validation cohort. We also developed OncoNucAtlas, a publicly accessible database facilitating exploration of these nucleosome landscapes. Conclusions: Our study cancer-associated nucleosome organization as a complementary source of epigenomic information and demonstrates the potential of tissue-derived nucleosome signatures for cfDNA-based cancer detection. The pan-cancer atlas provides a resource for investigating tumor heterogeneity and developing noninvasive cancer detection approaches.

bioinformatics↗

Neural Representations of Visual Anagrams in Macaque Inferotemporal Cortex

Visual recognition requires stable representations of object identity despite large changes in the retinal image. Yet this stability must be selective: some transformations change not only how an image looks, but also what object it appears to depict. Visual anagrams highlight this challenge: a single image can resemble two different objects at different orientations, such as an elephant and a rabbit. Here, we asked how macaque inferotemporal (IT) cortex represents such transformations. We recorded large neuronal populations while presenting visual anagrams and unambiguous exemplars of their two interpretations across rotations. Neurons preferring one exemplar tended to prefer anagram orientations supporting the corresponding interpretation. At each of the two interpretation-relevant canonical angles, population responses more closely resembled those to the matching exemplar than those to the nonmatching exemplar. This matching advantage persisted when both exemplars were presented at the alternative canonical angle. Decoders trained exclusively on exemplars across rotations also tracked the shifts in anagram representations. Visual models showed anagram-exemplar alignment as well, with stronger alignment in models with greater relative shape preference. These findings suggest that transformation tolerance in IT is sensitive to what an image appears to depict, while relative shape preference is associated with similar representational organization in visual models.

neuroscience↗

BioMod: Biological Module Tokenization for Single-Cell Foundation Modeling

Single-cell foundation models typically represent cells as flat sequences of individual genes, requiring higher-order biological organization to be inferred implicitly from sparse expression profiles. Similar to the evolution from character-level to semantic tokenization in natural language processing,we hypothesize that cellular states can be more efficiently represented using biologically meaningful intermediate units. Here we present BioMod, a 50-million-parameter single-cell foundation model that introduces biological modules as representation units between genes and cells. BioMod constructs an overlapping vocabulary of 660 biological modules derived from curated pathways and data-driven gene programs, replacing thousands of gene-level inputs with compact module representations. Pretrained on approximately 73 million human cells using high-ratio module masking with an asymmetric decoder, BioMod achieves state-of-the-art performance across cell-type annotation, zero-shot batch integration, perturbation-response prediction and drug-response forecasting while maintaining a compact architecture that enables efficient inference on a single GPU. Module-level analyses further demonstrate that BioMod captures biologically meaningful cellular programs and preserves pathway-level organization.

bioinformatics↗

Filling the Missing Puzzle: Integrating Interaction and Evolutionary Information to Enhance Protein Fitness Prediction in Inverse Folding

Protein inverse folding, which infers compatible amino acid sequences from a given backbone structure, is central to rational protein design. Current methods rely largely on sequence recovery rate as the evaluation metric, emphasizing structural compatibility but seldom addressing function. Yet functional activity depends on the proper network of non-covalent interactions-protein-ligand contacts being a prime example. We argue that function-oriented protein design is governed by three complementary constraints: structural, interaction, and evolutionary, none of which are handled in a unified manner by existing pretrained models. To bridge this gap, we introduce zPolaron, a graph neural network built on protein-ligand complexes for functional protein design. zPolaron represents residues and ligand atoms as a heterogeneous graph and jointly encodes structural, interaction, and evolutionary information by fusing physical-interaction-enhanced graph representations with ESM-2 embeddings. Across multiple fitness prediction benchmarks, zPolaron outperforms all baselines, with gains evident across structural, interaction, and evolutionary dimensions. Wet-lab experiments further confirm its utility in functional enzyme screening and design: the optimized CalA6-D205A-S160G mutant achieves a 17.84-fold improvement in activity, while the CalB-I121M mutant yields a 1.91-fold increase. Together, these results show that integrating interaction and evolutionary information fills the missing puzzle of inverse folding, enhancing protein fitness prediction beyond structural compatibility. zPolaron is available at https://github.com/zelixirSH/zPolaron.

bioinformatics↗

Multilayer analysis reveals extensive hidden population complexity in a dairy starter microbiome comprising few species

The genomic and epigenomic complexity of microbiomes with low species richness remains poorly characterized. Here, we integrated 111 non-redundant isolate genomes with deep long-read metagenomics to investigate an undefined mesophilic dairy starter. Closely related isolates harboured distinct combinations of features associated with fermentation traits and phage defence, including surface polysaccharide genotypes, plasmids, prophages, defence systems, and methylation profiles. Metagenomics revealed additional elements and inferred host associations. However, the limited overlap between approaches across core-genome lineages and accessory repertoires underscored complementary but incomplete recovery, to the extent that the dominant metagenomic cell wall polysaccharide genotype (29.6% abundance) was absent from isolates. Metagenomic methylation signatures supported 36 species-level plasmid-host assignments, corroborated by isolate genomes in nine of ten testable cases. Our findings revealed extensive combinatorial diversity hidden from either approach alone, providing a plausible molecular basis for phage resilience, while likely representing only a lower bound on population complexity.

microbiology↗

CryoFAST: A Fab-Aided Cryo-EM Workflow for High-Resolution Structure Determination of Sub-50-kDa Protein Targets

Single-particle cryo-electron microscopy (cryo-EM) plays an increasingly important role in structure-based drug discovery (SBDD) by revealing target protein-ligand interactions at the molecular level, but its application has largely focused on large- and medium-sized protein complexes. Many therapeutically important targets are smaller than 50 kDa and remain highly challenging for cryo-EM analysis because of low signal-to-noise ratios and difficulties in particle alignment. Here, we describe cryoFAST, an integrated workflow that couples ligand-compatible Fab discovery and structure-guided computational maturation with biochemical triage, fiducial-complex assembly, and single-particle cryo-EM. Through phage-display screening and/or AI-guided design, we developed high-affinity Fab binders of approximately 50 kDa that stabilize the target without disrupting ligand-target interactions and then assembled Fab-target complexes for cryo-EM analysis. Using the therapeutically relevant extracellular domain (~20 kDa) of interleukin-4 receptor (IL-4R) as a proof of concept, we determined its cryo-EM structure at 2.74 Angstrom resolution and established a framework for elucidating ligand-binding modes. This workflow provides a practical, efficient, and potentially broadly applicable route to the structural characterization of small protein targets that are otherwise challenging to study. By extending the applicability of cryo-EM to high-value but technically challenging small targets, cryoFAST may open new opportunities for structure-based drug discovery.

biophysics↗

Engineered Chimeric Proteins Functionally Replace ALS-causing Endogenous FUS and TDP-43 to Improve Neuronal Health

Mislocalization and aggregation of the RNA-binding proteins (RBPs) FUS and TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), contributing to combined loss- and gain-of-function toxicity. Here, we present a protein engineering strategy that appends optimized anti-aggregation motifs to FUS and TDP-43, thereby enhancing their nuclear localization and solubility, and enabling functional replacement of disease-associated proteins. We show that these engineered chimeric RBPs reduce levels of aggregation-prone endogenous proteins through autoregulatory mechanisms. In addition, chimeric FUS and TDP-43 recapitulate key nuclear functions, including DNA repair and mRNA processing. Notably, chimeric FUS restores neurite outgrowth in diseased iPSC-derived neurons, while chimeric TDP-43 suppresses cryptic exon inclusion in patient-derived fibroblasts. Collectively, these results demonstrate that engineered chimeric RBPs can rebalance RBP homeostasis by simultaneously addressing protein aggregation and mislocalization, thus mitigating RBP-associated loss- and gain-of-function toxicity, highlighting a generalizable strategy for therapeutic protein replacement in neurodegenerative disease.

neuroscience↗

The Effective Visual Acuity of Butterflies in Flight

The spatial visual acuity of an eye is determined by both the spatial sampling density of the retina and the angular sensitivity of individual photoreceptors. In insect compound eyes, these are respectively characterised by the interommatidial angle, {Delta}{varphi}, and photoreceptor acceptance angle, {Delta}{rho}. During movement, however, finite photoreceptor integration times cause retinal image motion to broaden the effective acceptance angle, potentially degrading spatial resolution beyond its anatomical limit. This problem is especially acute in flying insects, which experience large rotational velocities during locomotion and must actively stabilise gaze to limit retinal image motion. Butterflies present a particularly demanding case because their flight is characterised by large, wingbeat-coupled thoracic oscillations. Here, we quantify how gaze stabilisation limits motion blur in freely flying Monarch butterflies Danaus plexippus by combining free-flight kinematic reconstruction of the head and thorax with separate intracellular measurements of photoreceptor acceptance angles and integration times from quiescent butterflies. We found that, without head compensation, thoracic oscillations would broaden the effective photoreceptor acceptance angle from its quiescent value of 2.17{degrees} to 9.38{degrees} during take-off. Compensatory head movements substantially reduced this motion-induced broadening, limiting the effective acceptance angle to 5.28{degrees}. Nevertheless, this 2.4-fold broadening of effective photoreceptor acceptance angle represents a substantial degradation of spatial acuity in flight, highlighting motion blur as an important constraint on the visual ecology of flying butterflies.

neuroscience↗