Biology subjects

Jang, H.

Publications and source records attributed to Jang, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Reference normalizations of Effort-To-Compress across length, alphabet size, and composition

Comparing finite symbolic complexity requires an explicit reference. Effort-To-Compress (ETC) counts the recursive pair substitutions needed to reduce a symbolic sequence to a constant. Its conventional normalization with L - 1 leaves systematic dependence on sequence length L and alphabet size k, confounding comparisons across datasets. We derive certified lower bounds for ETC and show that, for L [≥] k [≥] 2, the ceiling L - 1 is attainable if and only if L [≤] k2 + k + 1. For fixed k [≥] 2, the global ensemble mean and maximum ETC grow as {Theta}k(L/ logk L) as L [->] {infty}. These support two normalized ETC coordinates. Global-ensemble normalized ETC (nETC) maps a certified lower bound to zero and the uniform ensemble mean at the same L and k to one. Composition-conditioned normalized ETC (cETC) uses corresponding references restricted to the observed symbol composition. In Potts chains, nETC substantially reduced dependence on length and alphabet size. cETC further reduced differences associated with unequal symbol frequencies, while retaining sensitivity to temporal dependence. In human chromosome 22, the exploratory predictor nETC - cETC outperformed LZ76 in distinguishing CpG islands and long interspersed nuclear elements from genomic background with AUROC of 0.947 and 0.848. Matched references therefore enable interpretable comparisons of symbolic complexity across sequence lengths, alphabet sizes, and compositions.

bioinformatics↗

bioRxiv2026

Predicting conformational changes induced by biomolecular interactions

Biomolecular interactions trigger structural changes of protein complexes essential for cellular signaling, regulation, and drug action. Modern co-folding models can now generate detailed structures of multi-component complexes directly from sequence. However, recent evaluations reveal that they frequently fail to capture specific conformational states induced by a ligand or partner. Here, we show that explicitly modeling the structural transition from an unbound to a bound state, rather than generating the bound complex alone, better resolves these interaction-induced states. Our generative learning framework, K-Fold, transforms independently predicted unbound component priors into an assembled complex through an ultrafast diffusion bridge, operating entirely without multiple sequence alignments. By eliminating co-evolutionary dependencies, K-Fold accurately recovers non-coevolved interfaces in antibody-antigen and targeted-degrader complexes, as well as ligand-directed regulatory states in GPCRs and kinases. Furthermore, by coupling this diffusion bridge with diverse monomeric equilibrium ensembles, K-Fold provides a computationally tractable foundation for sampling complex multi-state landscapes without retraining. These results demonstrate that formulating molecular assembly as an explicit structural transition moves structure prediction beyond static geometries toward capturing biomolecular dynamics.

molecular biology↗

bioRxiv2026

An auto-generated ADP-ribosyl-cysteine degron drives DTX2-dependent turnover of PARP7

The mono-ADP-ribosyltransferase PARP7 exerts negative feedback on androgen receptor (AR) signaling by generating an ADP-ribosyl-cysteine degron on AR that marks it for degradation. Here we show that the protein half-life of PARP7 is set by cysteine auto-ADP-ribosylation, providing a mechanism for temporal control of its feedback on AR-dependent transcription in prostate cancer cells. ADP-ribosyl-cysteine in the PARP7 catalytic domain constitutes a degron read by the E3 ligase DTX2, driving PARP7 polyubiquitination and proteasomal degradation. Thus, the same E3 is used to degrade both PARP7 and its substrate AR. Using label-free mass spectrometry, we identify the AP-1 factor c-JUN as a PARP7 substrate and show that ADP-ribosylated c-JUN accumulates upon DTX2 depletion. ADP-ribosyl degron formation is dependent on NAD+ availability since depleting NAD+ pharmacologically or under hypoxia prevents degron formation and stabilizes PARP7 in a catalytically constrained state that compromises its feedback activity. Correlations between PARP7 expression and hypoxia signatures in prostate tumors, together with sensitivity to the PARP7-selective inhibitor RBN-2397 across cancer lines, nominate hypoxic, NAD+ depleted contexts as heightened vulnerability to PARP7-targeting agents. Marking transcription factors for degradation by covalent ADP-ribosylation is emerging as a distinct mode of transcriptional control.

biochemistry↗

bioRxiv2026

Engineered mRNA-packaging virus-like particles enable efficient and precise mitochondrial base editing in vitro and in vivo

Mitochondrial DNA (mtDNA) base editors (mtBEs) are promising tools for studying and correcting pathogenic mtDNA mutations. However, the application of mtBEs is often hindered by substantial mtDNA-wide off-target editing that accumulates with prolonged mtBE expression resulting from plasmid DNA or viral delivery. To overcome this limitation, we developed mtBE-VLPs, a virus-like-particle (VLP) platform for transiently delivering mtBEs in vitro and in vivo with minimal off-target effects. While canonical protein-packaging VLPs yielded undetectable mtDNA base editing, engineered mRNA-packaging VLPs enabled efficient but transient mtBE cargo delivery. By iteratively engineering mRNA-packaging VLP compositions, we improved mtBE-VLP-mediated base editing efficiencies from less than 1% to greater than 50% across multiple target mtDNA loci in bulk populations of treated cultured cells. To further improve the packaging and delivery of certain mtBEs, we developed a strategy to selectively reduce mtBE cargo expression in VLP producer cells but not transduced cells, which increased VLP-mediated base editing efficiencies for certain mtBEs by 7.1-fold. Compared to plasmid DNA delivery in vitro, mtBE-VLPs exhibited equivalent on-target editing but 23- to 41-fold lower mtDNA-wide off-target editing, highlighting the improved editing specificity offered by transient mtBE delivery. mtBE-VLPs efficiently installed a pathogenic mtDNA mutation in mouse embryonic fibroblasts (88% efficiency) and corrected a pathogenic mtDNA mutation in a human patient-derived cell line (41% efficiency). Additionally, a single subretinal injection of mtBE-VLPs yielded 6-20% (average 12%) mtDNA base editing in the mouse retinal pigment epithelium with minimal mtDNA-wide off-target editing. These findings establish mRNA-packaging mtBE-VLPs as promising vehicles for efficient and precise mitochondrial base editing via transient mtBE delivery.

bioengineering↗

bioRxiv2026

Single-cell multi-ancestry regulatory map of systemic lupus erythematosus

Integrating genomic and single-cell transcriptomic profiles from patient cohorts can uncover regulatory effects underlying genetic associations with disease. Here we present SLEmap, a multi-ancestry single-cell expression quantitative trait locus (sc-eQTL) map generated from peripheral blood mononuclear cells from 281 patients with systemic lupus erythematosus (SLE). We identified 18,608 independent eQTLs in 5,656 genes, of which 149 signals in 66 genes colocalized with SLE GWAS loci. Nearly half of these colocalizations were detected exclusively through cell type-level analyses, highlighting the importance of cellular context for interpreting disease-associated genetic variation. Multi-ancestry data identified regulatory signals robust across diverse ancestral backgrounds and improved signal resolution. Most colocalizations were undetectable in sc-eQTLs from a healthy cohort (OneK1K), with novel SLE colocalizations highlighting disease-relevant regulatory mechanisms across distinct cell types, including the NF-{kappa}B pathway. These findings demonstrate the value of disease-specific, multi-ancestry single-cell regulatory maps for resolving the genes and cellular mechanisms underlying disease-associated genetic variation.

genetics↗

bioRxiv2026

Low-intensity focused ultrasound pulsation along the anterior-posterior thalamic axis differentially modulates the latency of reporting conscious visual experience

Background: Transcranial low-intensity focused ultrasound (LIFU) neuromodulation can alter human task performance depending on target and acoustic configurations. However, single behavioral endpoints cannot locate effects within multistep tasks, and predefined target labels ignore acoustic variations. Objective: To determine whether thalamic LIFU affects visual categorization or subsequent subjective report latency and whether the effects vary with target, acoustic parameter, and beam location. Methods: Sixty healthy adults were randomized to 70% or 5% duty cycle (DC70 or DC5) and received sonication on four left thalamic targets with matched pulse repetition frequency (10 Hz) and temporal-average intensity (0.72 W/cm2). Behavioral models tested target-by-DC interactions in categorization (RT1) and subjective report (RT2) latencies. Spatial analyses correlated focal spot coordinates and voxel-wise intensity from 179 acoustic simulations to baseline-adjusted RT2. Results: The target-by-DC interaction was detected for RT2 but not RT1. At the ventroposterior thalamic target, adjusted RT2 was 55.9 ms longer under DC70 than DC5. More anterior focal spots shortened RT2 under DC70 but increased RT2 under DC5. Correlation between intensity and adjusted RT2 significantly differed between DC70 and DC5 in 18.8% of thalamic voxels. These voxels formed an anterior mediodorsal-motor set and a posterior pulvinar-dominant set. Conclusions: The latency of reporting conscious visual experience, but not categorization latency, was affected by thalamic LIFU. This effect varied jointly with anterior-posterior target engagement and acoustic configuration. Analyzing sequential reaction times separately and treating field variation as an anatomical variable revealed associations not fully captured by a single endpoint or predefined target labels.

neuroscience↗

bioRxiv2026

Multimodal optical imaging reveals spatial metabolic heterogeneity in the aging retina

Understanding how aging reshapes retinal metabolism requires methods that can resolve molecular and structural changes across the retinas highly organized cellular layers. Here, we applied a nonlinear multimodal imaging platform that integrates fluorescence lifetime imaging microscopy (FLIM), second-harmonic generation (SHG), hyperspectral stimulated Raman scattering (HS-SRS), and deuterium oxide-based stimulated Raman scattering (DO-SRS) to map age-associated metabolic and compositional alterations in young and aged mouse retinas. FLIM analysis of the outer nuclear layer (ONL) revealed increased free NADH and NADPH fractions in aged retinas, consistent with reduced oxidative phosphorylation and enhanced lipid anabolic activity. SHG imaging of the sclera showed pronounced age-related remodeling of collagen organization, including increased fiber density, elevated anisotropy, and the emergence of densely crosslinked bundles in the central sclera. DO-SRS further demonstrated elevated lipid turnover in rod photoreceptor outer segments and the retinal pigment epithelium (RPE) with aging which was confirmed by lipidomic analysis. Complementary HS-SRS analysis revealed reduced triacylglycerol and cholesterol content together with localized sphingosine accumulation in the RPE. Together, these findings provide a spatially resolved view of metabolic remodeling in the aging retina and establish multimodal optical imaging as a powerful framework for studying alterations associated with age-related retinal disease.

bioengineering↗

bioRxiv2026

Single-Cell Mapping of Malignant Signaling Networks Guides Drug Combinations

Single-cell breast cancer atlases reveal malignant, immune, and stromal diversity; however, how the recurrent signaling pathways drive untreated malignant-cell states and could inform combination therapy remains unclear. Here, we analyzed 15,753 malignant cells from untreated primary breast tumors using a cell-resolved network framework. Individual transcriptomes were projected onto a protein-protein interaction network, partitioned into Leiden communities, and annotated by pathway enrichment. Pathway recurrence was evaluated against matched null models preserving community size, protein-network degree, and gene detection rate. Before null correction, recurrent pathways included PI3K/AKT, MAPK, JAK/STAT, and HIF-1 (hypoxia-inducible factor 1) signaling. After correction, HIF-1 emerged as the dominant recurrent signal across patients, indicating convergence of diverse upstream pathways on a shared hypoxia- and stress-adaptive malignant-cell program. The recurrent JAK/STAT, cAMP, glucagon, oxytocin, and thyroid hormone signaling suggest inflammatory, metabolic, and endocrine crosstalk. These findings support rational drug combinations targeting HIF-1 together with upstream PI3K/AKT/mTOR, MAPK, or JAK/STAT signaling.

bioinformatics↗

bioRxiv2026

Loss of TAFAZZIN leads to perturbation of amino acid metabolism and reduction of collagen synthesis

Barth syndrome is a life-threatening genetic disorder caused by mutations in the TAFAZZIN (TAZ) gene, which disrupt remodeling of cardiolipin in mitochondria. The disease is associated with cardiac and skeletal myopathy, neutropenia, fatigue, and metabolic dysfunction. Previous studies showed that loss of TAZ decreases pyruvate dehydrogenase activity, reduces glucose flux into the TCA cycle, and impairs fatty acid metabolism. To test the hypothesis that amino acid (AA) metabolism may be altered to compensate for these deficiencies, we characterized AA metabolism in TAZ-deficient mouse myoblasts (TAZ-KO). Levels of branched-chain amino acids (BCAAs) were reduced, while proline levels were increased in TAZ-KO cells. Levels of proline dehydrogenase and glutamate dehydrogenase, which convert proline to TCA cycle intermediates, were increased. 13C5-proline isotope tracing demonstrated elevated conversion of proline into glutamate and TCA cycle intermediates. SILAC analysis using [U-13C6, 15N2]-Lys and [U-13C6]-Arg revealed decreased synthesis of collagen and proteins associated with extracellular matrix (ECM). Gene expression and protein analyses revealed reduced collagen expression, lower total collagen content, decreased collagen crosslinking enzymes, decreased proline hydroxylation and reduced synthesis of new collagen and cell-adhesion proteins. SILAC analysis using [U-13C6, 15N2]-proline also showed diminished incorporation of proline into newly synthesized ECM proteins. Together, our findings reveal that loss of TAZ leads to increased proline catabolism to the TCA cycle, decreased incorporation of proline into collagen, and impaired collagen synthesis and ECM remodeling.

cell biology↗

bioRxiv2026

NDUFA4L2 rescues hyperoxia-induced migration defects in retinal endothelial cells by reversing isocitrate dehydrogenase flux blockade

Retinopathy of prematurity (ROP) is caused by hyperoxic exposure of prematurely born infants. The mouse model of oxygen-induced retinopathy (OIR) recapitulates pathological features of both phase I and phase II ROP. We here looked at the retinal proteins that change in response to hyperoxia in phase I of the mouse model of OIR. Using tandem mass tag labeled proteomics, we found several differentially expressed proteins (DEPs) in phase I of OIR. Of all the DEPs, we investigated the role of previously unknown protein NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2). NDUFA4L2 protein and its paralog NDUFA4 are both mitochondrial complex I proteins; however, here we demonstrate that NDUFA4L2 changes in both phases of OIR, with no changes in its paralog NDUFA4, implying its unique function in pathophysiology of the disease. We demonstrate that NDUFA4L2 is an oxygen-sensitive protein and regulates retinal endothelial cell migration by rescuing isocitrate dehydrogenase flux impaired by hyperoxia in phase I of OIR.

biochemistry↗

bioRxiv2026

Reorganization of Human Brain Waves Across Diverse States of Consciousness

Brain waves are ubiquitous phenomena of human brain activity. As they propagate, they coordinate neural communication, shaping conscious perception. Understanding how brain waves unfold across space and time is thus critical for uncovering the neural mechanisms that support and suppress consciousness. Here, we analyzed data from the Human Connectome Project alongside multiple independent human datasets of various states of consciousness collected during non-rapid eye movement sleep, propofol anesthesia, and psychedelic states produced by lysergic acid diethylamide, N,N-dimethyltryptamine, psilocybin, nitrous oxide, and ketamine. We then applied complex principal component analysis to map spatiotemporal propagation patterns of blood oxygen level-dependent activity across the human brain, under these diverse states of consciousness. We identified four dominant motifs of wave propagation: a global synchronized wave supporting unimodal-transmodal propagation, an anti-correlated unimodal-transmodal wave, an anti-correlated task-positive/task-negative wave, and an anti-correlated visual-somatomotor wave. Among them, the global wave exhibited the most pronounced state-dependent reconfiguration: in diminished states (sleep and anesthesia), the time needed for the wave to propagate across brain regions consistently increased and the distribution of regional contributions to the waves power became more spatially concentrated and heterogeneous across individuals, indicating slower, more fragmented, and less stereotyped dynamics. In contrast, propagation duration decreased under psychedelic states, reflecting accelerated global wave dynamics alongside a trend towards more spatially distributed and uniform regional contributions, consistent with a more integrated global wave propagation pattern. Beyond this global mode, diminished states slowed propagation primarily along the unimodal-transmodal axis, whereas psychedelic states selectively accelerated propagation along the task-positive/task-negative axis. Together, our findings reveal that diminished (sleep and anesthesia) and psychedelic states alter the spatiotemporal structure of wave propagation across the brain in opposite and distinct ways, providing a unifying account of how macroscale brain dynamics are dynamically reshaped under pharmacological and endogenous perturbations of consciousness.

neuroscience↗

bioRxiv2026

The structural basis of RanGAP1 regulation and catalysis in nuclear transport

RanGAP1 promotes GTP hydrolysis of nuclear pore complex (NPC) transport complexes at the cytoplasmic face. A disordered linker connects its catalytic GAP domain to the C-terminal sumoylation domain, anchoring into NPCs cytoplasmic filaments. This arrangement raises the question of how these distinct functions are coordinated within a crowded cellular environment. Using atomistic molecular dynamics simulations, we show that RanGAP1 adopts an autoinhibited conformation, where the C-terminal domain masks the catalytic GAP domain. Sumoylation allosterically relieves this autoinhibition, enabling GTP-bound Ran access to the GAP domain. In the cytosol, Ran-GTP/RanBP1 can bind a less populated open conformation of RanGAP1, providing a backup mechanism for GTP hydrolysis in Ran. Importantly, we observe that Arg191 of human RanGAP1 inserts into the GTP-binding pocket of Ran and directly interacts with the {gamma}-phosphate, consistent with a canonical arginine finger. This observation contrasts with earlier models derived from yeast RanGAP and suggests that human RanGAP1 may follow a catalytic mechanism similar to classical small GTPase regulators like NF1. Together, these findings provide a framework of RanGAP1, linking autoinhibition, sumoylation, spatial organization at the NPC, and the catalytic mechanism. They also highlight how conformational regulation and post-translational modification coordinate efficient GTP hydrolysis in Ran during nuclear transport.

biophysics↗

bioRxiv2026

Age-related morphological changes in the C57BL/6J mouse calvaria: implications for stereotaxic neurosurgery

The mouse skull serves as the coordinate framework for stereotaxic neurosurgery, yet whether aging alters surgically critical calvarial geometry has not been examined. We measured three parameters in large cohorts of young (2-3 months) and aged (23-30 months) male and female C57BL/6J mice: bregma-lambda distance and the dorsoventral depth at rostral-lateral (X = {+/-} 2.5 mm, Y = 0) and caudal-lateral (X = {+/-} 2.5 mm, Y = -0.65 mm) calvarial sites. Bregma-lambda distance was significantly reduced with aging in both sexes. Similarly, the rostral-lateral calvaria showed age-related flattening in both male and female mice. The more caudal-lateral site showed smaller but significant age-related flattening, with males exhibiting significantly greater reductions than females. Aging increased caudal-lateral shape variability while reducing bregma-lambda distance variability in males. On the contrary, aging reduced rostral-lateral shape variability in females. These findings demonstrate that the mouse skull undergoes significant, spatially non-uniform, and sexually dimorphic remodeling into old age, where skull shrinks along the midline and flattens more significantly at the rostral than caudal plane. Stereotaxic protocols designed for young adult mice may systematically misestimate skull geometry in aged animals. Age-stratified reference data should be incorporated into stereotaxic practice for aged rodent models.

neuroscience↗

bioRxiv2026

How Functional Variants Reconfigure the Rac2 Conformational Landscape

Rac2, a member of the Rho family of small GTPases, is a fundamental regulator of essential cellular processes. Pathogenic substitutions near and within the Switch II region, specifically D57N and E62K, have been implicated in oncogenesis and immunodeficiency. Despite their proximity, D57N is characterized as a loss-of-function mutation, while E62K is a constitutively active, gain-of-function mutation. In this study, we addressed several critical questions: (i) the structural basis of their altered cellular functions, (ii) how these variants rearrange the conformational ensemble, and (iii) the subsequent impact on cellular signaling networks. Using molecular dynamics (MD) simulations, we characterized the conformational dynamics of these Rac2 variants in GDP- and GTP-bound states. Our results demonstrate that Rac2D57N predominantly adopts an inactive-like conformation, regardless of the bound nucleotide. GTP binding is insufficient to induce the canonical active state in this mutant. Conversely, Rac2E62K maintains a nucleotide-dependent toggle, appearing inactive when bound to GDP and active when bound to GTP. Additionally, we examined the assembly of these variants with the regulator p50-RhoGAP. In the wild-type complex, GAP binding facilitates a shift toward a near-transition-state ensemble. In stark contrast, both the D57N and E62K complexes remain sequestered in a ground-ON state configuration, effectively trapping the GTPase and hindering GAP-mediated hydrolysis. While both Rac2 mutations result in immune system dysfunction, the underlying mechanisms are opposite: inactive vs. overactive. This work provides a high-resolution, mechanistic framework for understanding how localized perturbations in the switch loops landscape dictate systemic cellular outcomes.

biophysics↗

bioRxiv2026

Label free multimodal optical imaging of metabolic heterogeneity in aging by integrating SRS, MPF, FLIM, and SHG

Cellular metabolism is governed by the coordinated organization of macromolecules, including lipids and proteins, together with redox-active cofactors such as NADH and FAD. However, resolving these biochemical features quantitatively and spatially at subcellular resolution remains challenging because no single imaging modality can capture molecular composition, redox state, and tissue architecture simultaneously without labeling. Here, we present MANIFEST (Multimodal Analysis of Nonlinear Imaging for Functional Endogenous Spatial correlaTion), a label-free imaging platform that integrates stimulated Raman scattering (SRS), second harmonic generation (SHG), multiphoton fluorescence (MPF), and fluorescence lifetime imaging microscopy (FLIM) with their spatial correlation. MANIFEST combines chemical imaging of lipids with autofluorescence- and lifetime-based quantification of NADH and FAD metabolism, enabling spatially resolved analysis of metabolic heterogeneity at organelle and tissue-compartment levels. We apply this framework to four distinct aging or disease models: amyloid-beta-treated tri-cultured brain cells, high-fat diet mouse liver, human non-ischemic cardiomyopathy tissue, and aging mouse retina. Across these systems, MANIFEST reveals disease-associated lipid remodeling, redox imbalance, disrupted metabolic zonation, collagen reorganization, and layer-specific metabolic changes. By integrating complementary nonlinear optical modalities into a single label-free platform, MANIFEST provides an extensible, proof-of-concept platform for high-resolution metabolic phenotyping in complex biological systems and offers new opportunities for studying disease mechanisms, aging biology, and metabolism-driven tissue pathology.

bioengineering↗

bioRxiv2026

Long-lived yeast-derived lipids promote longevity via regional and systemic metabolic remodeling

Aging is marked by a progressive breakdown of intestinal integrity and metabolic homeostasis, which together drives systemic decline in physiology and reduces lifespan. Here, we found that dietary lipids extracted from a genetically engineered long-lived yeast strain robustly extend lifespan in Drosophila and further uncovered the mechanisms using deuterium oxide-probed stimulated Raman scattering microscopy to image metabolic dynamics and single nucleus RNA sequencing (scRNA-seq) to unveil the underlying pathways. These yeast lipids are enriched in shorter, more saturated fatty acids and phospholipids as revealed by Raman spectroscopy and lipidomics, contributing to increased membrane order and reduced lipid storage. Functionally, targeted dietary supplementation with these lipid components synergistically prolongs fly lifespan. We show that these lipids reverse age-related declines in gut lipid droplet abundance, enhance membrane lipid incorporation, and increase de novo lipid synthesis, thereby improving epithelial structural integrity and barrier function. snRNA-seq identifies transcriptional remodeling in metabolically active enterocytes, including upregulation of autophagy and protein turnover genes, alongside reduction of unsaturated fatty acid biosynthesis. In the brain, dietary lipids orchestrate a dual metabolic strategy--promoting energy conservation and enhanced signaling across most neuronal and glial populations, while selectively boosting mitochondrial function in memory-critical Kenyon cells. All these leads to the enhancement of gut-to-glia communication, particularly through EGFR and FGFR pathways. Finally, analysis of our data with the Fly Metabolic Analysis Pipeline (FLY-MAP) reveals that yeast lipids restructure gut metabolic modules to coordinate energy production, redox balance, and nutrient flexibility. Our study uncovers a cross-kingdom mechanism of metabolic longevity regulation, paving the way for leveraging yeast-derived nutritional components to support tissue homeostasis and promote healthy aging.

molecular biology↗

bioRxiv2026

Opposing Network Patterns of Integration-Segregation in Psychedelic and Sedated States of Consciousness

Understanding the relationship of conscious states to large-scale brain dynamics remains a central challenge in neuroscience. Here, diverse pharmacological and physiological perturbations--including psychedelic states, sleep, and propofol sedation--were used to examine integration-segregation organization of brain networks across altered states of consciousness in humans using functional MRI. Across analyses, psychedelic and sedative states exhibited a robust "mirror-image" pattern of integration and segregation. Psychedelics were characterized by increased large-scale integration and reduced segregation of brain network interactions, whereas sleep and propofol sedation showed the opposite configuration. These opposing integration-segregation patterns were consistently indexed by complementary measures of functional connectivity, network topology, and interaction complexity, capturing non-redundant dimensions of large-scale brain organization. Importantly, this mirror-image organization generalized across multiple spatial levels and reliably differentiated conscious states in an unbiased, data-driven manner. Together, these findings demonstrate that psychedelic and sedated states are characterized by systematic and opposing shifts in large-scale integration and segregation, with implications for mechanisms of consciousness.

neuroscience↗

bioRxiv2025

Cellular Mechanisms Underlying Melanoma Brain Metastasis

Brain metastasis is a major contributor to melanoma-related mortality, arising from both genomic alterations and dynamic adaptations to the brain microenvironment. Tumor cells must cross the blood-brain barrier and exploit brain-specific signaling and metabolic landscapes to establish metastases. Brain metastases display molecular and phenotypic programs distinct from other organs, reflecting pre-existing and acquired mutations during progression. We analyzed primary melanoma, metastatic melanoma, and metastatic brain tumors genomic datasets to identify mutated proteins and signaling pathways that are common to or distinct among these tumor types. Our comprehensive computational analyses uncovered key pathways and proteins associated with brain metastasis. Brain metastases exhibit unique mutational landscapes and convergent alterations in neurotrophin, MAPK, and PI3K/AKT signaling compared with primary and metastatic melanoma. Proteins especially frequent in brain metastases pathways support survival, proliferation, and adaptation in the brain microenvironment. Pharmacology-wise, rational strategies such as combining c-KIT and VEGFR inhibitors can suppress converging oncogenic pathways and mitigate resistance in advanced melanoma. Co-targeting neurotrophin receptors with MAPK pathway members, particularly in combination with BRAF inhibitors, appears a promising approach for treating melanoma brain metastases. Our findings underscore the molecular heterogeneity of melanoma brain metastases, shaped by interconnected signaling networks, and reveal therapeutic targets that may diverge from those in other metastatic sites.

bioinformatics↗