Biology subjects

Kim, E.

Publications and source records attributed to Kim, E..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Longitudinal magnetic resonance imaging and spectroscopy in a mouse model of cuprizone-induced demyelination

The cuprizone (CPZ) lesioned mouse is a widely used model of demyelination and remyelination, but most studies rely on histology at terminal timepoints, limiting understanding of disease dynamics. Here, we present a longitudinal multimodal magnetic resonance imaging and spectroscopy (MRI/MRS) study of CPZ-induced pathology, pooling control arms from three independent experiments (n = 40). Mice were imaged at baseline, then exposed to 0.2% cuprizone for 5 weeks and repeatedly imaged at days 24, 35, 49, 63 and 77 after the start of CPZ. Imaging included multiparametric mapping (MPM), diffusion tensor imaging (DTI), tensor-based morphometry (TBM), and single-voxel MRS in the corpus callosum. Histology (MBP, silver, GFAP, Iba1) was performed at selected timepoints for validation. An additional group of 18 CPZ-lesioned mice were imaged ex vivo using a different higher resolution MRI protocol and compared against 19 non-CPZ controls. MPM-derived MTsat{delta} and R1 reductions indicated robust demyelination in the corpus callosum and deep cerebellar nuclei by day 24, expanding to cortex and hippocampus by day 35. Partial recovery was observed by day 77 but changes persisted, consistent with histological evidence. TBM revealed dynamic volumetric alterations, including hippocampal and cerebellar expansion alongside cortical and subcortical shrinkage, persisting beyond CPZ cessation. DTI demonstrated early (days 24-35) decreases in FA and MD, followed by complex trajectories consistent with microstructural disruption and partial repair. MRS detected early increases in GABA, glutamine, taurine, and glutathione, with corresponding decreases in NAA, while inositol showed a biphasic decrease-increase profile, likely reflecting acute astrocytic dysfunction followed by gliosis - neuroinflammatory processes that were corroborated by immunohistochemistry. Together, these results demonstrate that multimodal MRI/MRS sensitively captures widespread, dynamic, and only partially reversible pathology in CPZ-treated mice. Longitudinal imaging provides a non-invasive, translational approach to characterising demyelination, gliosis, and remyelination, offering a powerful alternative to histology for preclinical studies and longitudinal therapeutic screening.

neuroscience↗

bioRxiv2026

ATP8B1-TMEM30B Flippase Activity Maintains Stereocilia Lipid Asymmetry Required for Hearing

Sensory hair cells convert sound-induced vibrations into electrical signals through a process called mechano-electrical transduction (MET). While the protein components of the MET complex are well studied, increasing evidence indicates that MET channel properties are significantly modulated by the surrounding lipid bilayer. The asymmetric distribution of membrane lipids between the inner and outer membrane leaflets is well established to shape membrane mechanics. The recent discovery that the core MET components TMC1 and TMC2 also act as lipid scramblases suggests a direct role for membrane lipid asymmetry in the dynamic shaping of auditory transduction. Because scramblase activity of TMC1/2 disrupts lipid asymmetry, we hypothesized that an opposing flippase may be required to restore and maintain lipid asymmetry. Here, we identify the P4-ATPase ATP8B1 and its chaperone TMEM30B as selectively expressed in outer hair cells (OHCs), enriched in stereocilia, and upregulated following the onset of MET and hearing. Loss of either protein results in elevated auditory brainstem response (ABR) thresholds, phosphatidylserine (PS) externalization, and rapid hair-cell degeneration, demonstrating that lipid homeostasis is crucial for OHC survival. Together, these findings establish ATP8B1 and TMEM30B as key regulators of membrane lipid asymmetry in sensory hair cells and establish TMEM30B as a novel deafness gene.

cell biology↗

bioRxiv2026

SHANK3-CAMSAP2 interaction links synapses to dendritic microtubule organisation in PV neurons

The microtubule cytoskeleton plays an essential role in establishing and maintaining neuronal polarity. In neurons, microtubules are initially generated at the centrosome which gradually loses this role in development. In mature neurons, microtubules are stabilised by the microtubule minus end-binding protein CAMSAP2. How and where microtubule minus ends are anchored within dendrites of mammalian neurons remains an open question. Here, we show that microtubules are directly attached to the postsynaptic density of excitatory synapses through an interaction of CAMSAP2 with the scaffolding protein SHANK3. This process is particularly relevant in parvalbumin-positive GABAergic neurons, in which excitatory synapses are predominantly located directly on the dendritic shaft in direct proximity to microtubules. Notably, this association is strongly enhanced by the Autism Spectrum Disorder (ASD)-associated SHANK3L68P mutation, leading to an increase of synaptic levels of CAMSAP2. This promotes an increased microtubule association with the synapse and alters microtubule dynamics. Downregulation of CAMSAP2 in SHANK3L68P parvalbumin neurons tips the balance between site-specific microtubule stabilisation and dynamics, reshaping dendritic architecture, connecting SHANK3-CAMSAP2 dependent microtubule regulation to synaptic ASD pathology. TeaserInteraction between synapses and microtubules is enhanced in parvalbumin neurons bearing the ASD-associated SHANK3 L68P mutation.

neuroscience↗

bioRxiv2026

Molecular Mechanism of Condensin II auto-repression by NCAPD3 and activation by M18BP1

Human condensin II is a constitutively nuclear molecular motor that initiates chromosome organization in early mitosis. How condensin II is activated specifically in mitosis remains unknown. Here, we describe the molecular mechanism underlying condensin II auto-repression and activation. By determining multiple structural states of condensin II, we discovered that an autoinhibitory tail within the NCAPD3 subunit (NCAPD3Tail) holds the complex in a conformation that is incompatible with DNA capture. Deletion of NCAPD3Tail spontaneously activates condensin II in cells, illuminating its autoinhibitory role in vivo. We further show this translates to increased loop DNA formation by condensin II in vitro. Direct competition for the NCAPD3Tail binding site on condensin II enables the putative activator protein M18BP1 to liberate a key DNA-binding element in the NCAPH2 N-terminus, enabling DNA capture. Unexpectedly, M18BP1 not only relieves autoinhibition but also directly contributes to DNA organization by forming a positively charged loop that enhances DNA-anchoring by condensin II. Together, these findings reveal a bipartite activation mechanism wherein M18BP1 relieves autorepression, and renders condensin II biochemically competent to form stable DNA loops, ensuring highly stringent regulation of mitotic chromosome formation.

biochemistry↗

bioRxiv2026

Extracellular vesicles facilitate the horizontal transfer of drug resistance and stem-like properties between ovarian tumor cells

Ovarian cancer stem cells (CSCs) can seed recurrent drug-resistant disease. Likewise, non-CSCs can acquire CSC phenotypic properties. How this process is orchestrated is of interest to inform how it might be prevented. We tested the hypothesis that ovarian CSC and/or drug-resistant tumor cells confer stem-like properties via extracellular vesicles (EVs). We focused our investigation on how EVs might mediate EZH2 signaling to promote a phenotypic change in drug-sensitive, non-CSCs. To accomplish this, we utilized paired PARP inhibitor-sensitive and - resistant ovarian cancer (OvCa) cell lines, EZH2 knockdown lines, and patient-derived organoids (PDOs) originating from recurrent high-grade serous OvCa. Small EVs isolated from drug-sensitive, CSC and/or drug-resistant enriched cultures, PARP inhibitor (olaparib) resistant lines, or drug-treated (olaparib or carboplatin) lines were cultured with treatment naive or sensitive lines for defined time points. The impact of small EV exposure was determined by assessing cell number, metabolic activity, viability, sphere and colony-forming capacity, ALDH activity, DNA damage, and changes in associated signaling pathways. We found that EVs from CSC or drug-resistant enriched cell fractions communicate CSC-like phenotypes to the more sensitive tumor cells via EZH2 canonical and non-canonical signaling pathways, promoting stemness. We conclude that EV-mediated activation of EZH2 signaling represents a targetable mechanism contributing to stemness-associated drug resistance in OvCa. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/699925v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@6b4ffborg.highwire.dtl.DTLVardef@1501931org.highwire.dtl.DTLVardef@1a5f31aorg.highwire.dtl.DTLVardef@1fb475f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A standardized and reproducible behavioral protocol to elicit visual spatial attention in mice

Understanding how neural activity gives rise to cognitive processes such as selective attention is a fundamental goal of neuroscience. An important but often overlooked advance towards this goal requires the development and sharing of rigorous and reproducible behavioral tasks across labs; this is particularly important given the recent surge in studies of cognition and perception in mice. Here, we developed a standardized training protocol for head-fixed mice to become experts in a psychometric visual contrast detection task in just 17 days. Experts detected stimuli at two distinct spatial locations for several hundred trials per day. As consecutive trials elapsed at either location, the speed, accuracy, and contrast sensitivity of visual perception improved - all hallmarks of spatial attention improving performance, as seen in primates. These findings validate the efficacy of this protocol to reveal multiple aspects of selective spatial attention in mice, establishing a rigorous and reproducible tool for the community.

neuroscience↗

bioRxiv2025

Multiparametric MRI and imaging transcriptomics reveal molecular and cellular correlates of neurodegeneration in experimental multiple system atrophy

Multiple system atrophy (MSA) is an atypical Parkinsonian disorder marked by oligodendroglial -synucleinopathy and selective neurodegeneration. Although MRI can capture regional atrophy and microstructural alterations in MSA brain, the molecular substrates underlying these phenotypes remain poorly defined. Imaging transcriptomics provides a computational framework to relate spatial imaging patterns to brain-wide gene expression. While this approach has been applied to human MSA, interpretation is constrained by limited experimental control and lack of disease-matched molecular validation. Here, we apply imaging transcriptomics in a controlled preclinical setting by integrating high-resolution ex vivo multimodal MRI with transcriptomic mapping in the PLP-Syn mouse model of MSA. Structural and diffusion MRI revealed distinct patterns of regional atrophy and microstructural abnormalities. Atlas-based analyses associated imaging phenotypes to gene programs related to oligodendrocyte biology, energy metabolism, and neuroinflammation, with modality-specific signatures. These associations were supported by independent RNA-sequencing and showed convergence with human MSA findings. Our work benchmarks MRI-transcriptomic relationships in MSA and provides a translational framework for interpreting imaging biomarkers in synucleinopathies.

neuroscience↗

bioRxiv2025

Networks of sexually dimorphic neurons that regulate social behaviors in Drosophila

Neural mechanisms underlying sexually dimorphic social behaviors remain enigmatic in most species. In Drosophila, sexually dimorphic P1/pC1x neurons have been described as a site of sensory integration that regulates mating and aggressive behaviors. We show that the male P1/pC1x population forms a highly intertwined network with male-specific mAL and aSP-a neurons that is poised to regulate male behavior. The 48 P1/pC1x cell types exhibit heterogeneous synaptic connections with a subset receiving strong input from identified sensory pathways. We also describe circuit motifs by which P1 and sexually dimorphic aIPg neurons co-regulate social behaviors. Genetic driver lines for these cell types were generated and used to discover distinct roles for P1/pC1x cell types in promoting social acoustic signaling and male-male interactions. Our results reveal unexpected diversity in the connectivity and behavioral roles of the P1/pC1x cell types and provide essential genetic tools for interrogating their neurophysiological and behavioral functions.

neuroscience↗

bioRxiv2025

A Cross-scale Causal Mapping Framework Pinpoints Macrophage Orchestrators of Balanced Arterial Development

Postnatal pulmonary arteries experience an abrupt surge in flow that demands tightly coordinated remodeling of vascular structure and mechanical compliance. However, the cellular programs orchestrating these multiscale adaptation remain poorly defined, partly due to the absence of analytical tools integrating gene-cell-tissue scales. Here, we present CausaLink, a cross-scale causal mapping framework that predicts how altered gene expression propagates through gene-cell-tissue networks by integrating time-course transcriptomic and tissue morpho-mechanical data. We constructed a single-cell transcriptomic atlas of 11,143 proximal pulmonary artery-derived cells from C57BL/6J mice across five developmental stages (P2, P10, P21, P42, and P84), revealing dynamic lineage transitions and transient mesenchymal population specifying into fibroblasts and smooth muscle cells from P2 to P21. Using this framework, we identified Mgl2 macrophages as central regulators promoting lumen expansion while preventing pathological wall thinning or thickening. To validate these predictions, we established a human induced pluripotent stem cell-derived arterial assembloid enriched in MGLhigh macrophages. In this model, MGLhigh macrophages supported lumen enlargement while maintaining overall wall thickness and induced formation of an adventitia-like fibroblast layer that recapitulated approximately 80% of the native adventitial fraction with balanced collagen-elastin remodeling. By linking predictive modeling to human organoid validation, this study establishes a cross-scale workflow for tracing how gene programs shape vascular architecture, offering mechanistic insights and a foundation for predictive regenerative medicine.

bioengineering↗

bioRxiv2025

Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B

1.Zika virus (ZIKV), a member of the Flaviviridae family, causes significant public health concerns through congenital Zika syndrome and Guillain-Barre syndrome, yet no effective anti-ZIKV drugs or vaccines are available. To address this critical need, we conducted phenotypic, cytopathic effect-based, high-throughput screening followed by medicinal chemistry optimization and discovered novel benzamide anti-ZIKV leads. Current best compounds demonstrated superior potency (EC50 values 40-400 nM, CC50 > 50 {micro}M) compared to NITD-008, the most potent known anti-ZIKV agent. Time-of-addition assays, resistant virus selection studies, and biophysical binding experiments confirmed that NS4B interference constitutes the primary antiviral mechanism. Notably, resistance mutations mapped to the C-terminus of NS4B, distinct from other flavivirus NS4B inhibitors targeting dengue or yellow fever viruses, revealing novel insights into a critical function of the region. These findings establish NS4B as an Achilles heel for flaviviruses and support the development of pan-flavivirus therapeutics targeting this essential viral protein. 2. AUTHOR SUMMARYSince its pandemic spread in 2015-2016, Zika virus infection remains a significant public health threat worldwide. The virus can cause severe brain damage in developing babies and serious neurological complications like Guillain-Barre syndrome in adults. Despite these devastating consequences, we currently lack effective medicines or vaccines to prevent the virus from spreading through communities or from mothers to their unborn children. To address this critical gap, we conducted a large-scale screening of chemical compounds and discovered a promising new class of molecules that can effectively stop Zika virus from replication. Using medicinal chemistry techniques, we were able to make these compounds even more potent against the virus. In follow-up studies, we found that our compounds work by interfering with a specific viral protein called NS4B, which the virus needs to replicate its genome within the cell. Remarkably, other research teams studying related other flaviviruses (e.g., dengue and yellow fever virus) have independently discovered that this same protein is a vulnerable target. Our findings suggest that NS4B represents a universal weakness across the entire flavivirus family, making it an attractive target for developing broad-spectrum antiviral treatments.

microbiology↗

bioRxiv2025

Preselection CD4+CD8+ thymocytes modulate TCR responsiveness following TCRβ selection

Modulation of TCR sensitivity during positive selection is critical to avoid negative selection and direct thymocytes into their appropriate lineage. Thymocytes just prior to positive selection (preselection) are highly responsive to low affinity self-ligands and are also actively rearranging their TCR locus as they await a positive selection signal. Preselection DP thymocytes were thought to be relatively homogeneous and TCR modulation during this stage had not been previously described. Here we provide evidence for progressive gene expression changes within the preselection DP thymocyte population that correlates with a gradual loss of TCR responsiveness and a defect in upregulating TCR target genes associated with the CD4 fate. We relate these observations to the link between positive selection and T cell lineage commitment.

immunology↗

bioRxiv2025

E2f coordinates the proliferation and transdifferentiation of a Sox9+bile duct cell to initiate hepatocellular carcinoma

Disruption of the Rb/E2f interaction is one of the six original hallmarks of cancer and is thought to confer unrestricted proliferative potential to tumor cells. Although E2f is active in almost all cancer cases as a result of this disruption, the consequence of its unrestricted activity for cancer initiation remains mostly unknown. To address this question, we genetically inactivated the entire Rb family of genes (Triple Knock Out, TKO) in specific cell lineages in the liver. Strikingly, this unbiased approach reveals that Rb family inactivation initiates a phenotypically similar hepatocellular carcinoma (HCC) from either periportal hepatocytes or Sox9+ bile duct cells. In the latter population, Rb family inactivation results in unrestricted proliferation as well as the E2f-driven transactivation of the pioneer factor Foxa3, which activates a "periportal hepatocyte-like" metabolic program to ensure transdifferentiation into hepatocytes. Notably, single or compound inactivation of E2f1 and E2f3 in the TKO background is sufficient to suppress Foxa3 expression and HCC initiation, without altering the proliferative status of Sox9+ bile duct cells. Collectively, our results reveal that derepression of a cell cycle gene program and activation of non-cell cycle oncogenic features by E2f are distinct consequences of disrupting the Rb/E2f interaction, and that coordinated activation of these two functions are essential for HCC initiation from a founder liver bile duct cell lineage.

cancer biology↗

bioRxiv2025

Emergence of Genetic Sex Determination in an Environmentally Sex-Determined Animal

The evolution of genetic sex determination (GSD) from environmental sex determination (ESD) remains a fundamental issue in evolutionary biology. However, the mechanisms driving such a transition, particularly in its earliest stages, are largely unknown. Here, we report on a genetic variant in the ESD species, Daphnia pulex, in which structural variations and selection on chromosome have suppressed recombination. This suppression has facilitated the accumulation of antagonistic features of the two chromosome- haplotypes, resulting in heterozygosity and differentiation of the sex-determining gene Dfh on two haplotypes. Consequently, this process has driven the emergence of a mixed-mating system, in which sex determination is jointly regulated by genetic and environmental factors. Additionally, we detected ongoing divergence in chromosomal structure between the two haplotypes at the population level. These findings suggest that processes analogous to early sex-chromosome evolution are occurring in this ESD species, offering novel insights into the molecular mechanisms underlying the emergence of GSD.

evolutionary biology↗

bioRxiv2025

Ubiquitin Receptor-Induced Proximity is Sufficient for Ubiquitin-Independent Targeted Protein Degradation via the 26S Proteasome

The 26S proteasome engages with ubiquitinated substrates primarily through its constituent ubiquitin (Ub) receptors, which initiates a cascade of proteolytic processes. Leveraging this recognition mechanism, we developed a targeted protein degradation (TPD) strategy that recruits substrates directly to the proteasome, thereby bypassing the ubiquitination step. Our proteasome-targeting chimera, Protea-Tac, is a heterobifunctional protein degrader composed of a Ub receptor and an intracellular antibody. This chimera integrates into 26S proteasomes without altering their functional integrity. Localization of target proteins, including c-Fos, BRD4, Flag-TDP43, HA-tau, and GFP-ODC, to the proteasome via Protea-Tac with cognate antibodies resulted in their induced degradation. We demonstrated that this platform is 1) modular, allowing facile switching between targets; 2) Ub-independent; and 3) highly target-specific. Protea-Tac exhibited in vivo anti-tumor efficacy, degrading c-Fos and substantially delaying tumor growth. Overall, these findings identify Protea-Tac as a distinct TPD modality capable of directly degrading intracellular proteins via engineered 26S proteasomes. TeaserProtea-Tac is a heterobifunctional protein degrader that enables Ub-independent TPD, exhibits high specificity and modularity, and demonstrates in vivo applicability.

biochemistry↗

bioRxiv2025

Integrating 12 Spatial and Single Cell Technologies to Characterise Tumour Neighbourhoods and Cellular Interactions in three Skin Cancer Types

Cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and melanoma - the three major skin cancers - collectively comprise over 70% of all cancer cases. Despite their prevalence, much understanding of cellular interactions in the skin cancer microenvironment is needed, both in the outer skin layer where the cancer originates and at the deeper junctional and dermal layers into which it progresses. To address this gap, we integrated 12 complementary spatial and single-cell technologies to generate orthogonally-validated cell signatures, spatial maps, and interactomes for cSCC, BCC, and melanoma. Through comprehensive comparisons and integrating these spatial methods, we provided practical benchmarking guidelines for experimental design and analysis. By identifying keratinocyte cancer cells and melanomas, we found distinct signatures of these cells compared to non-cancer keratinocytes and melanocytes. Spatial integration of transcriptomics, proteomics and glycomics uncovered cancer niches enriched for cancer initiating cells (melanocytes or keratinocytes) and fibroblast and T-cell (MKFT) clusters, with altered tyrosine and pyrimidine metabolism. Ligand-receptor analysis across >700 cell-type combinations and >1.5 million interactions highlighted key roles for CD44, integrins, and collagens, with CD44-FGF2 emerging as a potential therapeutic target. Consistently, melanoma showed strong MFT interactions, validated by Opal Polaris, RNAScope, Proximal Ligation Assay and two additional single-cell spatial platforms (making a total of 14 technologies). For population-scale generalisation, genetic associations from >500,000 individuals were mapped onto spatial skin tissues, identifying SNPs enriched in domains containing melanocytes and T cells and their ligand-receptor pairs, shedding light on functional mechanisms linking genetic heritability to cells within cancer tissue. We built an interactive multiomics resource for exploring spatially-resolved molecular signatures and cellular crosstalk in skin cancer, available at https://skincanceratlas.com.

cancer biology↗

bioRxiv2025

E2f coordinates the cell cycle and cell fate of hematopoietic progenitors to drive stress myelopoiesis

During inflammation, cytokines such as Tnf, Il1{beta} and Il6 stimulate hematopoietic stem and progenitor cells (HSPCs) to proliferate and accelerate the production of inflammatory cells from the myeloid lineage through a process called stress myelopoiesis. Genetic inactivation of repressors of cell cycle activity in HSPCs is sufficient to recapitulate stress myelopoiesis, suggesting that the cell cycle activity and cell fate decision of proliferative HSPCs are coordinated by a cell intrinsic mechanism. However, the nature of this mechanism remains unknown. Here, we show that E2f simultaneously regulates proliferation of HSPCs, repression of alternative cell fates via the activation of Suz12/Ezh2-containing PRC2 complex and promotion of the myeloid fate by enhancing the signaling activity of CD131, the common {beta}chain receptor for {beta}cytokines (i.e. Il3 and Gm-Csf). Accordingly, dual inhibition of Ezh2 and {beta}cytokine signaling activity in a preclinical model of colitis represses stress myelopoiesis and restores colon homeostasis. Our results suggest that dual targeting of {beta}cytokine signaling and Ezh2 activity represents a novel therapeutic strategy to repress the production of pro-inflammatory myeloid cells in a wide spectrum of inflammatory diseases.

cell biology↗

bioRxiv2025

IL-18 inhibition enlarges lesions, necrotic cores and thickens fibrous caps in Jak2V617F clonal hematopoiesis-driven atherosclerosis.

BackgroundInflammasome activation promotes atherosclerosis in clonal hematopoiesis (CH). Active inflammasomes secrete both IL-1{beta} and IL-18. Plasma IL-18 levels are elevated in Jak2VFCH. Genetic deficiency of IL-18 has been shown to reduce atherosclerosis in non-CH murine models. However, whether IL-18 inhibition promotes atherosclerosis in control or Jak2VF CH is unknown. Methods and resultsLdlr-/- mice were transplanted with bone marrow (BM) from Mx1-cre Jak2VF (20%) and wild-type (80%) mice or with control BM, fed a Western-type diet (WTD) for 8, 10 or 16 weeks and administered control or IL-18 IgG from 4 weeks onwards. IL-18 antibody treatment increased plaque collagen content and cap thickness. Unexpectedly, IL-18 antibody treatment increased the size of early lesions and promoted formation of advanced lesions with large necrotic cores in Jak2VF CH mice. IL-18 antibody treatment was associated with diminished interferon (IFN)-{gamma} and AIM2 levels and reduced macrophage pyroptosis especially in Jak2VF CH mice. However, IL-18 antibodies increased cleaved Caspase-3 and TUNEL+ macrophages (indicating increased apoptosis) and reduced efferocytosis. Sc-RNA-seq analysis showed that IL-18 antibody treatment reduced expression of MHC class II genes, a marker of IFN-{gamma} signaling, and of genes mediating efferocytosis (Mertk and Axl), in resident-like macrophage subpopulations in Jak2VF CH mice. Consistently, IFN-{gamma} injection increased Axl and Mertk expression in resident peritoneal macrophages. ConclusionsDespite improvements in collagen and fibrous cap thickness in Jak2VF CH mice, IL-18 antibody treatment increased advanced necrotic lesions, reflecting a shift from pyroptotic to apoptotic cell death coupled with defective efferocytosis, events which were coordinated by reduced IFN-{gamma} signaling. These findings indicate a mixed atherosclerosis phenotype resulting from IL-18 inhibition, advocating for alternative therapeutic strategies. Inhibition of IL-18 has been considered as a novel therapeutic approach to reduce atherosclerosis and stabilize atherosclerotic plaques. We show that IL-18 antibodies have adverse effects on atherosclerotic lesional necrosis, calling this approach into question. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/657754v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@a93b2forg.highwire.dtl.DTLVardef@6cc057org.highwire.dtl.DTLVardef@1c7afc5org.highwire.dtl.DTLVardef@e4da82_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIInflammasome activation produces active IL-1 and IL-18 and worsens atherosclerosis in clonal hematopoiesis (CH) however the contribution of IL-18 is unknown. C_LIO_LIAntibody inhibition of IL-18 increased plaque collagen but also increased early lesion area and late lesions with large necrotic cores in Jak2VF CH mice. C_LIO_LIThere was a reversal of AIM2 inflammasome activation but a switch to apoptosis which along with reduced efferocytosis increased necrosis C_LIO_LIThese events appeared to be coordinated by reduced IFN-{gamma} which increased collagen but also decreased expression of efferocytotic genes. Our studies call into question whether inhibition of IL-18 would stabilize plaques in CH. C_LI

molecular biology↗

bioRxiv2025

An artificial nervous system for communication between wearable and implantable therapeutics

Bioelectronics have transformed our capacity to monitor and treat diseases; however, a lack of micrometer-scale, energy efficient communication options limit these devices from forming integrated networks that enable full-body, sensor driven, physiological control. Inspired by our nervous systems ability to transmit information via ionic conduction, we engineered a Smart Wireless Artificial Nervous System (SWANS) that utilizes the bodys own tissue to transmit signals between wearables and implantables. When SWANS emits signals, it generates voltage gradients throughout the body that selectively turn on implanted transistor switches when exceeding their gate threshold voltages. SWANS implantable communication components maintain syringe-injectable footprints and >15x greater power efficiencies than Bluetooth and Near Field Communication. In vivo studies in rats demonstrate SWANS ability to wirelessly regulate dual hind leg motor control by connecting electronic-skin sensors to implantable neural interfaces via ionic signaling as well as coordinate bioelectronics throughout the epidermal, subcutaneous, intraperitoneal, and gastrointestinal spaces.

bioengineering↗