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Gao, S.

Publications and source records attributed to Gao, S..

At least 19 recordsLinked to original sources

Individual Differences in Sustained Attention Tune Semantic Abstraction in Neural Encoding of Narratives

Neural encoding modeling for narrative comprehension -- using LLM embeddings to predict the temporal dynamics of neural activation -- is widely used to evaluate how well the brain represents certain semantic information. This approach, however, typically collapses semantic representation into a scalar fidelity score aggregated across participants, overlooking potentially rich individual differences and qualitative differences in naturalistic neural representations. In the current study, we addressed this gap by investigating how neural semantic encoding varies across individuals with sustained attention, and whether this difference is qualitative in addition to quantitative. Using fMRI data from 49 participants listening to an audiobook, Le Petit Prince, in English, we trained encoding models with GPT-2 embeddings at varying layers and forecasting lengths. Encoding models trained on high-level embeddings (from the 8th layer of GPT-2) showed significant brain-LLM alignment in 73 of 122 cortical and subcortical ROIs, concentrated in the temporal cortex and the default mode network. Functional connectivity strength in a validated connectome-based predictive model of sustained attention correlated with encoding performance in 18 ROIs, most strongly in the insula and in control and attention networks, with no ROI showing significant opposite relationship. Decomposing semantic information by levels of abstraction showed that the neural signature of sustained attention was selectively associated with a greater proportion of high-level gist information encoded in the frontoparietal and attention networks, while the opposite relationship emerged for proportion of low-level information. Sustained attention scores further predicted stronger predictive coding of upcoming narrative content across multiple networks across the whole brain (control, default mode, salience/ventral attention, limbic, and somatomotor networks). These findings suggest that sustained attention does not uniformly amplify neural semantic encoding, but instead shifts neural representations toward more compressed, gist-level formats that support anticipation of upcoming content. Individual differences in brain-LLM alignment can be a signature of representational strategy rather than noise, with potential utility for cognitive phenotyping.

neuroscience↗

Complex enzyme active site scaffolding by iteratively detuned catalytic guidance

De novo enzyme design requires sequences whose structures reproduce prescribed catalytic geometries. This remains challenging for active sites that couple multiple catalytic residues, cofactors and substrates. Here we introduce the Catalytic Guidance Engine (CaGE), which optimizes designed sequences to satisfy complex sets of functional constraints by alternating constraint guided structure prediction trajectories with sequence design, gradually fading the strength of the constraint information over cycles to nudge the designed sequence towards satisfying all the constraints. We train RF3 to accept atom-pair distances and other design conditions, and use classifier-free guidance to fade their influence over multiple design cycles. We also develop training-free motif guidance protocols which operate at inference time by directly adjusting selected atoms towards the design target geometry during diffusion sampling. CaGE improves catalytic-motif geometry across a diverse enzyme benchmark and yields sequences that recover complex target active sites in independent AF3 predictions. We experimentally demonstrate the power of CaGE by designing active enzymes with complex catalytic sites: a nonheme-iron design positions four active-site residues around an iron centre and a transition-state ligand, and a PLP-dependent design positions four catalytic residues around a PLP cofactor with multiple functional groups. Active site substitutions and a 2.7[A] crystal structure support the designed mechanisms and structures. Thus, CaGE provides a route to functional de novo enzymes with complex active sites.

bioengineering↗

Thalamic Dysconnectivity and Negative Symptoms in Schizophrenia Spectrum Disorder

Background and Hypothesis Negative symptoms in schizophrenia spectrum disorder (SSD) are associated with poor functional outcomes and reduced quality of life; however, effective treatments remain limited. A better understanding of the underlying brain mechanisms is needed to develop better treatments. Neuroimaging studies implicate multiple brain networks in negative symptoms, though findings remain heterogeneous, potentially reflecting the multidimensionality of both symptoms and brain networks. Larger, more systematic dissections are required to identify the key hub(s) underlying negative symptoms. Study Design Structural MRI data from 394 participants (210 SSD, 184 healthy controls [HC]) were analyzed to identify cortical thickness and subcortical volume demonstrating both SSD-HC differences and associations with negative symptoms measured by the Brief Negative Symptom Scale (BNSS). Regions meeting both criteria were selected as seeds for resting-state functional connectivity analyses in 143 SSD patients to examine association with negative symptoms and their subdomains. Study Results The thalamus was the only region demonstrating significant structural abnormalities both in SSD and an association with BNSS total score (p-FDR<0.05). Functional-network-defined thalamic subregions were subsequently examined. Several thalamic hypoconnectivities were significantly corresponded with negative symptoms, involving thalamic subregions associated with the cortical default mode, somatosensory, medial temporal, and dorsal attention networks (p=0.001, corrected<0.05). Blunted affect showed the most extensive thalamic connectivity alterations, involving the striatum, cerebellum, and temporoparietal junction/superior temporal sulcus (TPJ-STS). Thalamic hypoconnectivity with TPJ-STS was also associated with overall negative symptoms and anhedonia. Conclusions This study identifies the thalamus as a central hub of negative symptom-related dysfunction in SSD and highlights specific thalamic subnetworks as potential targets for circuit-based interventions.

neuroscience↗

SLC25A28 is a synthetic lethal vulnerability in nucleotide excision repair-deficient cancers

Approximately 10% of bladder, upper urinary tract, and endometrial cancers harbor deleterious somatic alterations in nucleotide excision repair (NER) pathway genes. Although platinum-based chemotherapy is the standard treatment for NER-deficient tumors, its utility is limited by nephrotoxicity, motivating alternative strategies that avoid direct DNA targeting. Here, we employed a genome-wide CRISPR-Cas9 screen to identify synthetic lethal vulnerabilities in NER-deficient cancer cells. An ERCC4-null RT112/84 bladder cancer cell line was generated and validated by Sanger sequencing and Western blotting, and functional NER deficiency was confirmed using a host cell reactivation assay. Parallel screens in ERCC4-deficient and isogenic wild-type cells. nominated SLC25A28 as the top-ranked synthetic lethal candidate in ERCC4-deficient cells, an interaction further supported by DepMap dependency. Clonogenic assays confirmed that loss of SLC25A28 selectively impaired cell viability in cells deficient for ERCC2, ERCC3, ERCC4, or ERCC5 and inducible knockout selectively suppressed ERCC4-deficient xenograft growth in-vivo. Mechanistically, RNA sequencing followed by gene set enrichment analysis revealed enrichment of oxidative stress-related pathways, including cellular responses to reactive oxygen species (ROS) and DNA damage signatures, upon SLC25A28 loss. These transcriptional changes are consistent with increased oxidative stress and DNA damage, placing heightened demand on NER-mediated repair. Direct measurement confirmed increased intracellular ROS. Collectively, our nominates SLC25A28 as a previously unrecognized synthetic lethal vulnerability in NER-deficient cancers and implicate mitochondrial iron homeostasis as a candidate metabolic dependency that may be targeted independently of platinum-based chemotherapy.

cancer biology↗

Deep-learning-based design of an orthogonal self-labeling protein from K-Ras(G12C)

Self-labeling protein (SLP) tags enable versatile labeling of proteins in live cells, yet only two SLPs are commonly used, limiting multiplexing. Here, we repurposed the oncoprotein K-Ras(G12C) and its covalent inhibitors to create a third, orthogonal SLP system. We used a deep-learning-based approach to radically redesign the sequence of K-Ras(G12C) while preserving its covalent-inhibitor binding pocket. Our top design, LUCI-tag, is a 19 kDa, monomeric, thermostable SLP that rapidly and covalently reacts with commercially available K-Ras(G12C) inhibitors bearing diverse payloads. Unlike existing SLPs, LUCI-tag exhibited payload-agnostic labeling kinetics, outperforming HaloTag7 and SNAP-tag for a negatively charged payload. X-ray crystal structures of drug-bound and drug-free LUCI-tag showed the design was structurally accurate and contained a preorganized inhibitor-binding pocket that could explain its rapid labeling kinetics. Proteomics and cell-signaling experiments confirmed LUCI-tag is biologically inert. LUCI-tag enabled rapid, wash-free, live-cell imaging and simultaneous three-color multiplexed experiments with HaloTag7 and SNAP-tag. This work establishes LUCI-tag as an immediately useful orthogonal SLP and demonstrates that covalent drug-target pairs can be repurposed into a broadly applicable platform for protein labeling.

bioengineering↗

Linoleic Acid-Lyso PG Axis promoting lipid droplet-mitochondria tethering by stabilizing Noncanonically Mitochondrial PPAR β/δ to Ameliorate Microglial Dysfunction in subarachnoid hemorrhage

Background Microglial lipid handling and mitochondrial failure contribute to brain injury after subarachnoid hemorrhage (SAH), but the lipid signals coupling these processes remain unclear. We investigated whether linoleic acid (LA) restores microglial homeostasis through lysophosphatidylglycerol 16:0 (LPG[16:0]) and peroxisome proliferator-activated receptor-{delta} (PPAR{delta}). Methods Cerebrospinal fluid metabolomics included 30 patients with aneurysmal SAH and 10 control participants. Mechanisms were examined in a blood-injection mouse model and hemoglobin-exposed primary mouse microglia using targeted lipidomics, RNA sequencing, mitochondrial and phagocytosis assays, pharmacological perturbation, fractionation, coimmunoprecipitation, thermal shift analysis, and structural modeling. Behavioral outcomes were evaluated by open-field, Y-maze, and Morris water-maze testing. Results; CSF LA was higher in SAH and discriminated the groups within this cohort (area under the curve, 0.9967 [95% CI, 0.9859-1.000]; P<0.001). LA attenuated inflammatory activation and restored phagocytosis, mitochondrial membrane potential, respiration, and ATP production in hemoglobin-exposed microglia. LA restored PLA2G15-associated LPG(16:0), which phenocopied these effects. Transcriptomic and inhibitor analyses identified PPAR{delta} as a downstream effector. LPG(16:0) increased PPAR{delta} stability, and fractionation and protease protection identified a PPAR{delta} pool on the cytosolic face of the outer mitochondrial membrane. PPAR{delta} associated with PLIN2 and CPT1A, promoted lipid droplet-mitochondria apposition, and supported fatty acid oxidation. In mice, LA reduced neuroinflammatory injury and partially improved anxiety-related behavior and spatial memory.

neuroscience↗

TEDDY: An integrative workflow for TE-chimeric isoform reconstruction and systematic characterization of TE-dependent transcriptional regulation

Transposable elements (TEs) substantially expand transcriptional regulation and complexity. Despite advances in sequencing technologies, the systematic interrogation of TE-dependent transcripts across diverse samples and platforms remains limited. Here we introduce TEDDY, a computational workflow for large-scale reconstruction, quantification and regulatory inference of TE-dependent isoforms. Using TEDDY, we resolved the landscape of TE-dependent isoforms in mammalian preimplantation development, revealing a conserved pattern of stage-specific isoform generation via species-specific TE exonization. We reconstruct a TE-dependent regulatory network underlying pluripotent-to-totipotent transition wherein key transcription factors are driven by TE-derived promoters and validated experimentally. Within this network, Arid3a, a novel regulator nominated by TEDDY, was functionally validated as essential for totipotency establishment and early development. Further application of TEDDY to hepatocellular carcinoma identified recurrence-associated prognostic isoforms, underscoring their clinical relevance. Benchmarking establishes TEDDY's accuracy and efficiency with unique capabilities in full-length isoform recovery, cross-sample and -platform analysis, visualization, and TF-TE-gene network reconstruction, making TEDDY applicable across diverse biological contexts.

genomics↗

K2P Channels Regulate Presynaptic Organisation through a Membrane Potential-Independent Mechanism

Neuronal ion channels have well-established effects on synaptic plasticity, in many cases by influencing pathways that depend on membrane excitability. Here we find that a C. elegans two-pore domain potassium (K2P) channel, TWK-40, regulates presynaptic organisation through a membrane potential-independent mechanism. Instead, this mechanism depends on TWK-40's effects on intracellular potassium levels. Loss-of-function mutations in TWK-40 lead to excessive presynaptic protein accumulation, while gain-of-function mutations lead to depleted presynaptic components and cause synaptic transmission deficits. These abnormalities are phenocopied by transporter mutations that mimic TWK-40's effects on intracellular potassium concentration, but not by sodium channel mutations that mimic its effects on membrane excitability. This indicates that cytoplasmic potassium promotes presynaptic assembly. This process depends on the PYK-1 pyruvate kinase, a potassium-sensitive enzyme, and three transcription factors. These findings establish a new pathway linking neuronal potassium homeostasis to the control of presynaptic organisation and synaptic function.

molecular biology↗

Knee Joint Biomechanics During Lunges at Different Tibial Angles and External Loads: A Musculoskeletal Analysis with Finite Element Insights

ObjectiveThis study investigates knee joint biomechanics during lunges under varying tibial angles and external loads using musculoskeletal modeling and finite element analysis. The goal is to provide a biomechanical basis for understanding knee loading patterns and optimizing sports training and rehabilitation. MethodsTwenty-six healthy young men performed lunges under tibial inclination angles relative to the ground (60{degrees} and 90{degrees}) and two external load conditions (bodyweight and an additional 98 N external load). Kinematic and kinetic data were captured using motion capture and force plates. Musculoskeletal models were used to estimate joint moments, range of motion, and stiffness, with data analyzed using two-way repeated-measures ANOVA. Finite element analysis was performed at 90{degrees} tibial angle to evaluate tissue stress and displacement. ResultsThe joint moment at a 60{degrees} tibial angle was much higher than at a 90{degrees}. External load showed significant effects on knee stiffness, with lower rotational stiffness in the horizontal plane (P < 0.001) and lower coronal plane stiffness at 90{degrees} (P = 0.012) under the 98 N external-load condition, indicating reduced resistance to angular displacement in these planes. Under the 90{degrees} tibial-angle condition with external load, peak stress and displacement were concentrated in the posterior horn of the meniscus, with a maximum displacement of 3.12 mm. ConclusionThe anterior tilt of the tibia increased sagittal-plane knee loading, while external load mainly reduced joint stiffness in the coronal and horizontal planes. Under the 90{degrees} loaded condition, the concentration of stress and displacement in the posterior horn of the meniscus suggests a mechanically unfavorable loading pattern rather than direct evidence of injury risk. These findings may provide useful biomechanical information for load management during lunge-based training and rehabilitation.

bioengineering↗

Dithionite quenching of NBD-labeled lipids reveals artificial lipid droplet purity and neutral lipid surface accessibility

Artificial lipid droplets (aLDs) provide a controllable platform for studying lipid biochemistry, but their use is limited by contamination with other membrane structures and the lack of quantitative methods to assess sample purity. Here, we establish dithionite quenching of NBD-labeled lipids as a simple approach to evaluate aLD purity. The approach relies on dithionites ability to selectively quench NBD fluorophores exposed in the phospholipid monolayer of aLDs and in the outer leaflet of liposome bilayers, but not those protected within the inner leaflet of liposome bilayers. Consistent with liposome contamination, bulk aLD preparations exhibit incomplete quenching, which can be separated by sucrose gradient centrifugation into liposome-like and droplet-enriched populations based on quenching behavior. Guided by this assay, sonication conditions were optimized to increase aLD purity and reduce liposome contamination. A biotin-streptavidin immobilization strategy further enabled stable imaging of individual aLDs. Finally, we applied dithionite quenching to probe the accessibility of neutral lipids within aLDs. This revealed hydrophobicity-dependent quenching kinetics of neutral lipids, with less hydrophobic diacylglycerols showing greater surface exposure within aLDs than more hydrophobic triacylglycerols and cholesterol esters. Taken together, these establish dithionite quenching of NBD-labeled lipids as a simple quantitative method for assessing aLD purity and demonstrate its utility for studying lipid accessibility.

biochemistry↗

Myeloid Suclg2 deficiency attenuates aortic dissection by reshaping succinate-associated macrophage remodelling

BackgroundSuccinate has emerged as an immunometabolic mediator of cardiovascular diseases. However, the enzymatic mechanisms linking macrophage succinate metabolism to aortic dissection remain incompletely understood. This study investigated whether Suclg2, which encodes the GDP-forming {beta}-subunit of succinyl-CoA ligase, regulates succinate-associated macrophage remodelling and aortic dissection progression. MethodsSuclg2 expression was examined in BAPN-induced AD and human acute type A aortic dissection tissues by Western Blot and immunofluorescence. Myeloid- and smooth muscle cell-specific Suclg2 conditional knockout mice were subjected to BAPN treatment to evaluate survival, aortic outcomes, histological injury and aortic morphology. Aortic RNA-seq was used to discover transcriptional changes. Bone marrow-derived macrophages were analysed under basal, M1-like and M2-like conditions to assess macrophage-intrinsic transcriptional responses. Plasma succinate levels and untargeted metabolomic profiles were further examined. ResultsSuclg2 was increased in murine and human dissected aortas and partially localized to CD68 cells. Myeloid Suclg2 deletion markedly reduced BAPN-induced aortic rupture and dissection, whereas smooth muscle cell Suclg2 deletion did not confer comparable protection. Aortic transcriptomic analysis showed that myeloid Suclg2 deficiency attenuated inflammatory adhesion and matrix-destructive programmes. In macrophages, Suclg2 deletion did not induce a simple M1/M2 polarization shift; instead, it remodelled lipid-handling, phagolysosomal, adhesive and matrix-remodelling pathways across stimulation states. Metabolic profiling showed reduced circulating succinate and broader changes in central carbon, lipid-associated, nucleotide and redox-related metabolites after myeloid Suclg2 deletion. ConclusionsMyeloid Suclg2 is a succinate-associated immunometabolic regulator of aortic dissection. Its deficiency protects against aortic dissection by reshaping macrophage inflammatory-remodelling programmes and the systemic metabolic environment.

Cell Biology↗

Phase-tuned interfacial condensates drive transcellular access

Nanocondensates occupy mesoscopic scale in both spatial scale and thermodynamic state, and the mesoscopic scale is central to structure-function conversion in living systems. However, how the dual mesoscopic properties of nanocondensates support biological function remains unclear because their small size and rapid dynamics hinder direct observation in living cells. Here we construct nanocondensates in situ at the cell-membrane interface and observe them permeating membranes within seconds, diffusing freely, exiting cells within minutes, re-entering neighbouring cells and traversing multilayered barriers. We report the first observation of this phenomenon and term it nanocondensate tunnelling. We find that nanocondensates cross membranes without membrane enclosure, preserving their wetting characteristics after passage. Theoretical and ultrastructural analyses support a transient-pore model linking this behaviour. We exploit nanocondensate tunnelling to transport small molecules, siRNA and antibodies across cellular barriers, and small molecules and siRNA across a multilayered corneal barrier, demonstrating its functional capacity for intercellular transfer. Our results suggest that nanocondensate tunnelling represents a previously undescribed mode of intercellular transfer. Nanocondensate tunnelling provides a physical basis for biologics delivery and a testable framework for investigating unresolved biological phenomena such as viral permeation.

bioengineering↗

Physics-Driven Zero-Shot Reconstruction of Isotropic 3D Fluorescence Microscopy under Undersampled Acquisition

Three-dimensional (3D) imaging represents the development of next generation of fluorescence microscopy. However, routine axial down-sampling makes isotropic resolution unrealistic. Here, we propose DeepUI, a physical zero-shot framework designed to achieve isotropic 3D fluorescence images from a low axial sampling rate. DeepUI fully leverages the intrinsic characteristics of 3D images through physics-guided degradation, which incorporates spatial-frequency joint learning to generate a scaled optical transfer function, combined with noise degradation and an up-sampling branch. Typically requiring just 5 minutes for training and 0.5 minutes for high-throughput and fast prediction, we demonstrate the superior performance of DeepUI to get isotropic results, and the exclusivity to axial down-sampling conditions, even in more challenging conditions, including defocused background, noise, and resolution blur.

bioinformatics↗

Lineage tracing and live-cell imaging reveal that NeuroD1 does not reprogram microglia into neurons

In situ glia-to-neuron conversion induced by a single transcription factor is a promising regenerative strategy for treating central nervous system injuries and neurodegenerative diseases. Previous studies reported that NeuroD1 can induce microglia-to-neuron cross-lineage conversion and improve recovery after brain injury. However, these findings remain controversial. To examine the ability of NeuroD1 in inducing microglia-to- neurons conversion, we employed virus-free genetic lineage tracing systems to specifically induce NeuroD1 expression in microglia, and track the cell fate of NeuroD1-expressing cells at multiple timepoints. Meanwhile, we longitudinally monitored NeuroD1-expressing microglia via two-photon imaging, and characterized their transcriptional profile by single-cell RNA sequencing. All observations across these methods revealed that NeuroD1-expressing cells retained their microglia identity, and cannot convert into neurons, no matter under physical and injury conditions. Instead, sustained expression of NeuroD1 facilitated microglia apoptosis in vivo. Collectively, our findings provide strong evidence that NeuroD1 alone is sufficient to induce microglia-to neuron conversion. This study further highlighted the importance of rigorous lineage-tracing and cell fate mapping strategies for validating in situ glia-to-neuron conversion.

neuroscience↗

Population-scale Y chromosome assemblies reveal recurrent remodeling within constrained architectures

The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.

genomics↗

The Regional Vulnerability Index (RVI) as a Neuroimaging-Based Biomarker for Autism: Associations with Likelihood, Cognition, and Longitudinal Social Outcomes

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with symptoms spanning cognitive, social and behavioral domains and leading to lifelong challenges. Autism is heritable but specific genetic and environmental factors that shape its early neurodevelopmental trajectory remain unknown. Despite the clinical variability, neuroimaging findings from Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA)-ASD consortium identified stable and replicable patterns of cortical and subcortical differences that were consistent with those reported by an independent consortium, the Cognitive Genetics Collaborative Research Organization (COCORO) in Japan. Here we developed and evaluated a regional vulnerability index (RVI), a similarity metric that quantifies how closely a persons brain resembles the specific pattern of an individual with autism. RVI-ASD is based on combining the regional effect sizes for regional brain measurements published by the ENIGMA-ASD group with microstructural white matter integrity differences reported by COCORO. RVI-ASD showed significantly higher effect size for case-control differences relative to any individual brain measure (d=0.30 vs. d=0.01-0.21) in individuals with autism, particularly in the adolescent-to-adult sample (N=2,577; Mean age = 16.1; SD=5.0). We next calculated RVI-ASD in the baseline and follow-up (ages 10 and 12) data from normally developing participants of the ABCD study (N=4,201). We tested the longitudinal stability, heritability, genotype-by-age interaction and sensitivity of RVI-ASD to known factors and cognitive measurements. RVI-ASD were stable on the 2-year follow up (ICC=0.76-0.92); showed significant heritability (h{superscript 2}=0.55-0.83, p<10-16) but was not affected by gene-by-age interaction. RVI-ASD showed significant positive correlation with paternal age, while correlation with maternal age was non-significant. Baseline and follow-up RVI-ASD were negatively correlated with cognitive measures including total, fluid and crystallized intelligence (r=-0.09 to -0.11, p<10-6). RVI-ASD scores tracked with core autism phenotypes including poor eye contact and rigid routines (p < .01). In a sub-sample of children with symptoms of autism (N=20), we found that earlier age of symptom onset was strongly correlated with higher White Matter RVI (r = -0.61), linking early behavioral emergence to the neuroanatomical signature. Longitudinal changes in subcortical RVI-ASD are significantly correlated with change in social functioning. The RVI-ASD is a neuroimaging-based biomarker linked to stable and reproducible brain patterns in autism. RVI-ASD allows researchers to study associations with factors associated with the likelihood for autism and cognition across large and inclusive non-clinical samples, thus moving beyond simple case-control models to understand the biological pathways of autism.

neuroscience↗

Connectome-based spatial statistics enabling large-scale population analyses of human connectome across cohorts

Large-scale population analyses of structural connectome organization remain challenging because of cross-subject alignment, pathway interpretability and computational burden. No widely adopted standard exists for systematic evaluation across processing methods. We developed connectome-based spatial statistics (CBSS), a scalable framework for anatomically aligned and functionally informed quantification of white-matter microstructure that yields atlas-defined pathways organized into 13 functional networks. Using data from 56,510 UK Biobank participants together with five independent lifespan cohorts, we evaluated the streamline-, voxel- and network-level measures in the aspects of reliability, heritability, structure-function coupling, cognitive and behavioral prediction, brain aging patterns and lifespan trajectories across cohorts. The systematic evaluation workflow compares population-level white-matter representations across methods, spatial scales, tasks and datasets. The results support CBSS as a common connectome reference for large-scale, cross-cohort diffusion MRI studies.

neuroscience↗

Z-TAC enables custom and combinatorial degradation of cell surface proteins

Cell-surface degrader platforms typically require target-specific engineering and have therefore been applied to a relatively small set of protein targets. Here we report Z-TAC, a strategy that enables plug-and-play conversion of existing IgG antibodies into cell-surface protein degraders. Across multiple targets from distinct protein families, Z-TAC induced efficient and sustained degradation of both individual receptors and receptor combinations. For a multi-pass membrane receptor lacking selective antagonists, Z-TAC mediated complete receptor degradation and functional inhibition, demonstrating the ability of this platform to overcome the limitations of conventional pharmacological approaches. This study delineates a generalizable and scalable strategy for functional perturbation of the cell-surface proteome.

bioengineering↗