Biology subjects

Ji, L.

Publications and source records attributed to Ji, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Evasion of Hepatic ILC1 Immunosurveillance Drives Breast Cancer Liver Metastasis

Metastasis, the dissemination of cancer cells to distant organs, is an inefficient process1, yet remains the leading cause of cancer-related mortality2. The cellular barriers and evasion mechanisms governing organ-specific susceptibility remain incompletely understood3-5, hindering the development of effective anti-metastatic therapies6. Here, we show that liver-resident type 1 innate lymphoid cells (ILC1s) constitute an essential immunosurveillance barrier against breast cancer liver metastasis that can be bypassed through either cancer cell intrinsic or host-dependent mechanisms. In a multi-organ metastatic breast cancer patient cohort, liver metastasis occurred later and was associated with poorer survival than lung metastasis, with elevated body mass index emerging as a clinical risk factor. This metabolic vulnerability was recapitulated in mice, where a high-fat diet induced hepatosteatosis and selectively enhanced breast cancer colonization of the liver. Mechanistically, liver and lung colonization were restrained by ILC1s and circulating natural killer (NK) cells, respectively. Following cancer cell challenge, NK cells expanded and activated, employing lytic granule pathways and the death receptor DR5 for clearance, whereas activated ILC1s selectively required high DR5 expression on cancer cells, supported by AP-2a (TFAP2A) mediated transcriptional activation, for effective immunosurveillance. Heterozygous copy number deletion at TNFRSF10B (encoding DR5) in human tumours reduced DR5 expression and predisposed to liver metastasis. Hepatosteatosis further compromised this barrier by reducing IL-15 expression in macrophages, thereby depleting hepatic ILC1s effects reversible with glucagon-like peptide-1 (GLP-1) receptor agonists. Thus, hepatic ILC1s form a critical organ-specific barrier to breast cancer metastasis, vulnerable to both cancer cell-intrinsic DR5 downregulation and host metabolic dysfunction.

immunology↗

bioRxiv2026

Full-Term and Preterm Differences in Human Brain Functional Connectivity Development Across Birth

We possess a limited understanding of how preterm and full-term brains develop during the earliest stages of life, from the fetal to neonatal period, and how they respond to the birth transition. Here, we characterize brain resting-state functional connectivity (RSFC) using over 1000 longitudinal fetal and infant functional MRI scans from 21 to 52 post-conception weeks across birth. By mapping the developmental trajectory of RSFC across this window, we unveil marked divergences in developmental patterns between preterm- and term-born brains at both the global and network levels. When aligned by birth, the full-term group exhibit generally higher RSFC than the preterm group. For selected between-network connections with a significant prematurity effect, full-term cases demonstrate an overall increase in RSFC across age, whereas preterm cases show minimal change or even a decrease in connectivity of these systems. In contrast, when aligned by postconceptional age, the preterm group shows an accelerated increase in RSFC between 30 and 40 weeks. Across comparisons, mode of delivery and sex showed minimal influence on these trajectories. These findings offer novel insight into how prematurity and early exposure to the extrauterine environment alter the developmental trajectories of large-scale neural networks, advancing our understanding of both typical and preterm brain development.

neuroscience↗

bioRxiv2026

Daytime Napping and Associative-Memory Retrieval Speed: An Exploratory Behavioral and EEG Study

Purpose: To test whether a daytime nap was associated with improved associative-recognition performance relative to monitored wakefulness and to determine where any response-time (RT) difference occurred in the RT distribution. Methods: Fifteen healthy students completed nap and wake sessions in a within-participant design. Each session included word-pair learning, immediate recognition, a 60-min interval, and delayed recognition without additional study. Trial-level log RT was the focal outcome; accuracy and electroencephalography (EEG) were complementary outcomes. Results: The RT Condition-by-Time interaction was significant (b = -0.063, 95% CI [-0.117, -0.009], p = .027). Responses were 6.7% faster after the nap (p = .010) but did not change after wakefulness (p = .704), with the difference concentrated among slower responses. Accuracy showed no condition-specific change (p = .401). Nap EEG showed aperiodic spectral slowing and stronger periodic sigma activity, but no EEG measure explained the RT effect. Conclusions: Daytime napping was associated with faster delayed associative recognition, primarily through attenuation of the slowest responses. The exploratory findings warrant larger confirmatory studies.

neuroscience↗

bioRxiv2026

Efficacy profiling of structurally diverse cannabinoid receptor ligands across transducer-coupling assays

The full efficacy range of ligands at CB1 and CB2 (i.e., inverse agonists, neutral agonists, partial agonists, full agonists, and high-efficacy agonists) has been reported collectively across numerous laboratories and assay platforms. Canonical Gi/o and {beta}-arrestin signaling have each been suggested to shape physiological effects differently via different classes of cannabinoid ligands. These prior efficacy classifications, however, were obtained in multiple assay systems, often using indirect, amplified readouts and different reference agonists, making them difficult to compare across ligands. Here we profiled a structurally diverse panel of 22 cannabinoid ligands: synthetic cannabinoid receptor agonists (SCRAs), {Delta}-tetrahydrocannabinol ({Delta}-THC) analogues, endocannabinoid analogues, and antagonists/inverse agonists at CB1 and CB2 receptors using bioluminescence resonance energy transfer (BRET) assays, measuring Gi1 engagement and {beta}-arrestin 2 recruitment and normalizing every response to the reference full agonist CP55,940. At CB1, SCRAs and {Delta}-THC analogues acted as high-efficacy agonists. At CB1, these high-efficacy agonists were also highly efficacious in {beta}-arrestin 2 recruitment. Across the panel, the most consistent trend was a loss of agonist efficacy from CB1 to CB2. Among antagonists, inverse agonists suppressed constitutive CB1 activity more than neutral antagonists. Together, these CP55,940-normalized measurements provide a common efficacy scale and a framework for interpreting pharmacodynamics of CB1 and CB2 cannabinoid receptors.

pharmacology and toxicology↗

bioRxiv2026

Exploratory profiling of defense system signatures in Klebsiella pneumoniae clonal populations

Bacterial defense systems against bacteriophages are critical for bacterial genome stability and fitness, yet their distribution and epidemiological relevance in Klebsiella pneumoniae remain unexplored. We aimed to characterize defense system signatures across major K. pneumoniae clonal lineages and evaluate their utility as genomic signatures for tracking clonal dissemination. Here, we analyzed 6,346 genomes to characterize population structure, defense system signatures, and their coevolution with resistance determinants and plasmid backbones. PopPUNK clustering resolved 146 lineages that stratified into major clonal lineages (G-ST-KL combinations) with distinct resistance and virulence profiles. DefenseFinder and PADLOC identified 320 distinct defense systems, revealing that each clonal lineage harbors a unique defensotype characterized by systematic module replacement rather than stochastic gene loss. Co-occurrence networks further showed that these systems are organized into lineage-specific functional modules, with contrasting architectures even among lineages sharing the same sequence type. Integration of defense, resistance, and plasmid data uncovered strong lineage-specific associations, whereby broad-host-range plasmid backbones acquired distinct defense-resistance payloads in different clonal backgrounds. Geographic and host-niche analyses demonstrated that defense system distribution reflects clonal lineage expansion rather than independent geographic selection, and analysis of 689 Chinese genomes confirmed vertical inheritance of lineage-specific signatures along transmission chains. Collectively, defense systems in K. pneumoniae are organized into lineage-specific defensotypes shaped by synergistic modules and clonal evolutionary dynamics. Defense system profiling provides an additional layer of epidemiological resolution beyond conventional typing and offers practical utility for genomic surveillance, particularly in resource-limited settings where PCR-based detection of conserved systems could serve as a rapid proxy for identifying high-risk K. pneumoniae clones.

bioinformatics↗

bioRxiv2026

The Live Concert of Brains: Performer-Audience Neural Coupling Links Ensemble Coordination to Shared Audience Integration

Collective social events often require coordinated action by one group to become shared experience in another, yet how this transformation is organized across multiple brains remains unclear. Live music provides a tractable model of this problem because ensemble coordination, performer-audience alignment, and shared audience integration unfold within the same event. Here we tested whether performer-audience neural coupling acts as a cross-role neural interface linking ensemble coordination to shared audience integration. We recorded brain activity from a nine-person live performance system, consisting of a fixed three-performer ensemble and four independent audience groups, using synchronized multi-device functional near-infrared spectroscopy hyperscanning across live trio performance sessions. Inter-brain neural coupling was analyzed across three relational layers: performer-performer (PP), performer-audience (PA), and audience-audience (AA) coupling. Behavioral ratings showed strong affective engagement and shared evaluative alignment. Neural coupling during live performance was not expressed as a diffuse increase across channel pairs, but was organized into task-sensitive relational components with interpretable PC-corr network modules. Crucially, path-based mediation analyses revealed that PA components statistically bridged PP coordination and AA coupling, yielding multiple complete and partial PP [->] PA [->] AA pathways. Brain-behavior analyses further suggested that mediation-related PA components were linked to shared performance evaluation and emotional alignment. These findings identify performer-audience coupling as a cross-role neural interface through which coordinated production becomes linked to shared collective reception. Significant StatementHow coordinated actions become shared experiences is a major problem in social neuroscience, yet most studies examine pairs of people. Using live music as a model of group interaction, we found that brain-to-brain alignment was organized across social roles rather than arising as a uniform response to the same event. Performer-audience alignment occupied a bridging position between coordination within the ensemble and integration within the audience. This identifies a systems-level architecture through which collective action may become linked to collective experience. The framework moves multi-brain research beyond dyads and offers a general approach for studying classrooms, public speaking, theater, rituals, and team events, where one group generates structured behavior that another group jointly receives and interprets.

neuroscience↗

bioRxiv2026

Deep Learning Reveals Persistent Individual Signatures in Bat Echolocation Calls of the Greater Leaf-nosed Bat

Intraspecific variation is a prerequisite for natural selection and can manifest in various phenotypic traits, including vocal signals. However, classifying individuals based on their vocalizations, or acoustic individual identification (AIID), remains a significant challenge. This is particularly true for species that use rapidly varying echolocation calls for orientation. Here, we demonstrate that deep learning can overcome the limitation of traditional methods and reveal persistent individual signatures within bat echolocation calls. We recorded echolocation calls from 34 individuals of the greater leaf-nosed bat (Hipposideros armiger) under controlled laboratory conditions, with 19 individuals recorded repeatedly over three months. We show that a convolutional neural network (CNN) dramatically outperforms a traditional method, achieving an average identification accuracy of 84% for single calls and 91% for call sequences. In contrast, the traditional Discriminant Functional Analysis method achieved accuracies of only 39% and 47%, respectively. Through systematically altering the temporal structure of echolocation calls in input sequences, we found that temporal patterning enhances individual classification accuracy, suggesting it contributes to the encoding of individual-specific information. This study revealed that echolocation calls of H. armiger can contain stable, individual identity that were previously undetectable. Our findings highlight the potential of deep learning for non-invasive AIID and provide a methodological basis for future studies aiming to monitor animals in more dynamic environments.

zoology↗

bioRxiv2025

Effects of the Neutral CB1 Receptor Antagonist AM6527 on Spontaneous, Consummatory, and Motivated Behavior in Mice

RationaleThe cannabinoid type-1 receptor (CB1R) signaling pathway plays a central role in regulating motivational and feeding behaviors. Neutral CB1R antagonists represent a promising therapeutic class with potentially fewer adverse effects than inverse agonists, yet their behavioral effects remain incompletely characterized. ObjectivesWe investigated the behavioral profile of AM6527, orally bioavailable neutral CB1R antagonist, across naturalistic and operant paradigms in male mice. To evaluate dopaminergic involvement in AM6527s effects, we employed several pharmacological interventions. ResultsUsing machine learning-based Motion-Sequencing (MoSeq), which parses spontaneous behavior into sub-second syllables, we found that AM6527 did not affect overall speed in an open field, however, it increased the self-directed behaviors and reduced specific locomotor syllables at the highest dose tested. In a naturalistic reward consumption paradigm, AM6527 produced a dose-dependent reduction in milk intake. Operant conditioning paradigms revealed robust suppression of motivated responding on fixed ratio-3 and progressive ratio (PR) schedules for palatable milk reward, with the greatest impact on high-baseline performers under PR conditions. To understand the dopaminergic involvement, we co-administered dopaminergic drugs (targeting D1R, D2R, or dopamine transporter) which resulted in partial rescue of operant responding, indicating dopaminergic and non-dopaminergic contributions to AM6527s observed behavioral effects. ConclusionOur findings suggest that neutral CB1R antagonism suppresses consummatory and motivated behaviors via dopamine-dependent and -independent mechanisms. By leveraging sub-second behavioral analysis with MoSeq, we further reveal distinct changes in spontaneous behavior, underscoring the relevance of CB-based treatments for maladaptive appetitive and motivational states in both psychiatric and metabolic disorder.

neuroscience↗

bioRxiv2025

Single virus lipid mixing study of Sendai virus provides insight into fusion mechanism

Single virus studies have proven useful to interrogate the entry mechanism for several viral families. Here, we employ a fluorescence microscopy-based single virus assay to study the fusion (lipid mixing) of Sendai virus to model membranes, the first for any paramyxovirus to our knowledge. We find that fusion wait times following binding are exponentially distributed, suggesting a single rate-limiting step. Compared to previously studied viruses, fusion is relatively slow (tens of minutes) and inefficient (only a small fraction of virions undergo fusion). Trypsin treatment of the virus or different viral receptors in the target alter the efficiency, although the wait time distribution remains unchanged in both cases. This provides constraints on the fusion mechanism and the identity of the rate-limiting step. Together, our data paints a picture of Sendai virus as a comparatively inefficient and slow fusion "machine" and sets the stage for investigation of other paramyxoviruses.

biophysics↗

bioRxiv2025

Cytochrome b5 reductase 4 efficiently reduces Neuroglobin and Cytoglobin

Cytoglobin and Neuroglobin are heme-containing proteins expressed in most vertebrates, including mammals, with still not completely defined physiological roles. Most of the putative functions of cytoglobin/neuroglobin, such as oxygen binding or nitric oxide dioxygenation, rely on the heme iron being in the ferrous (Fe2+) oxidation state. Therefore, it is very possible that reducing systems are active in the cell to maintain both proteins in the ferrous state. We have previously shown that the cytochrome b5 reductase isoform 3/ cytochrome b5 system, the canonical reductase of hemoglobin and myoglobin, can reduce cytoglobin at very fast rates, consistent with a possible physiological role. However this reducing system is unable to reduce neuroglobin, which to date lacks a validated, physiologically feasible reducing system. Here we have studied the interaction of cytochrome b5 reductase isoform 4 with cytoglobin and neuroglobin and found that cytochrome b5 reductase 4 can reduce cytoglobin at rates comparable to those observed with cytochrome b5 reductase 3/ cytochrome b5. Remarkably, it can also reduce neuroglobin efficiently. Studying different surface mutations of cytoglobin and neuroglobin we note that some cytoglobin mutations, in particular R84E and K116E decrease reduction rates by more than 10-fold, whereas surface mutations in neuroglobin that were shown to impair the interaction of neuroglobin with cytochrome c (E60K/D73K/E87K) show little effect on the reduction rates. We conclude that cytochrome b5 reductase 4 can supplement cytochrome b5 reductase 3/ cytochrome b5 roles for cytoglobin reduction in vivo and is a strong candidate for a physiological role as neuroglobin reductase.

biochemistry↗

bioRxiv2025

Whole genome sequence-based characterization of foodborne Staphylococcus aureus isolated from pork in 2018 and 2023.

This study characterizes the genomic epidemiology of 111 Staphylococcus aureus isolates collected from retail meat in Beijing and Copenhagen during 2018 and 2023 using whole-genome sequencing. Our analysis identified concerning antimicrobial resistance patterns, with methicillin-resistant S. aureus (MRSA) prevalence rising from 19.51% to 24.13% over the study period. The livestock-associated CC398 lineage (27.03% of isolates) demonstrated strong correlations with tetracycline resistance (tetM) and persisted as the dominant clone in Beijing, increasing from 33.33% to 40.91% prevalence. In contrast, we observed the rapid emergence of community-associated CC8 strains in Denmark, reaching 71.43% prevalence by 202327. Virulence profiling revealed MSSA strains frequently carried enterotoxin genes (seg/sei in 55.8% of isolates), while mobile genetic elements like SCCmec IV in ST59-t437 contributed significantly to pathogenicity. Phylogenetic analysis delineated five major clades and highlighted the expansion of multidrug-resistant CC398 strains in Beijing. These findings demonstrate the dynamic evolution of S. aureus at the human-animal interface and emphasize the urgent need for integrated One Health surveillance systems to track resistance gene dissemination. Future research should prioritize investigating zoonotic transmission pathways and the role of horizontal gene transfer in driving the convergence of virulence and resistance traits in foodborne pathogens.

genomics↗

bioRxiv2025

NUSAP1 regulates mitotic processes via KIF2C interaction and AURKA phosphorylation in primary microcephaly

Primary microcephaly (PM) is a neurodevelopmental disorder characterized by a significantly smaller head than normal. Despite the identification of several genes associated with PM subtypes, the etiology remains unclear in a significant proportion of patients. Here, we reported two de novo nonsense mutations in the NUSAP1 gene identified in two independent PM families: c.1209 C>G (p.Tyr403*) and c.1213C>T (p.Gln405*). Nusap1-edited mouse models, designed to mimic Human NUSAP1 mutations, replicated the microcephaly phenotype, characterized by a small brain and thinner cerebral cortex. We demonstrated that Nusap1 was specifically expressed in neural stem/progenitor cells (NSPCs), and the number of NSPCs was significantly reduced in Nusap1-edited mice. In vitro experiments revealed that NUSAP1 mutations disrupted mitotic metaphase chromosome alignment, increased polyploidy, induced cell cycle arrest, and promoted apoptosis. Co-IP confirmed direct interactions between NUSAP1 and KIF2C, and showed that truncating mutations impaired their binding. Furthermore, NUSAP1 rescued the cell cycle arrest and increased apoptosis caused by KIF2C overexpression in NUSAP1 KO HEK293T cells, whereas the mutant truncated protein failed to exert such a rescue effect. We also uncovered an interaction between NUSAP1 and Aurora kinase A (AURKA). Intriguingly, subsequent experiments revealed that AURKA-mediated phosphorylation of NUSAP1 modulates its binding affinity to KIF2C. In conclusion, our findings established NUSAP1 as a novel pathogenic gene for PM. We proposed a model in which AURKA-mediated phosphorylation of NUSAP1 regulates its interaction with KIF2C, balancing spindle microtubule stability and depolymerization to ensure proper sister chromatid segregation. Disruptions in this pathway impair NSPCs mitosis, thereby affecting neocortical development.

genetics↗

bioRxiv2025

CTHRC1 is a new therapeutic target and serum diagnostic biomarker for aortic dissection

Aortic dissection (AD) is a cardiovascular disease with rapid onset and extremely high short-term mortality, currently lacking specific peripheral blood-based biomarkers and effective treatments. Here, our analysis of AD samples from animal models and human patients revealed elevated blood levels of CTHRC1, a protein secreted by vascular fibroblasts. Furthermore, CTHRC1 regulates the phenotypic switch of vascular smooth muscle cells (VSMCs) during arterial remodeling by binding to ADAM9 on the VSMC membrane, activating the ERK1/2 signaling pathway, and promoting a contractile-to-synthetic transition. In Ang-II/BAPN induced mouse models, genetic ablation or antibody-mediated blockade of CTHRC1 effectively prevented AD development. These findings unveil CTHRC1 as a critical regulator of VSMC phenotype and aortic structural integrity via the ERK1/2 pathway, suggesting its potential as a novel serum diagnostic biomarker for AD diagnostic and a promising therapeutic target. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/649636v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@6a3f14org.highwire.dtl.DTLVardef@15353e7org.highwire.dtl.DTLVardef@1a9928forg.highwire.dtl.DTLVardef@1d4ef3d_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefCTHRC1 is aberrantly expressed in aortic adventitial fibroblasts from dissected aortas and function as an exocrine mediator that induces phenotypic switching of vascular smooth muscle cells. A monoclonal antibody targeting CTHRC1 demonstrates therapeutic potential in mouse models of aortic dissection. HighlightsO_LICTHRC1 is highly expressed in aortic adventitial fibroblasts from dissected aortas C_LIO_LICTHRC1 interacts with ADAM9 to induce phenotypic switching of VSMCs C_LIO_LIAn anti-CTHRC1 antibody inhibits aortic dissection formationinvivo C_LIO_LIElevated levels of serum CTHRC1 can be used to identify AD in patients presenting with chest pain C_LI

cell biology↗

bioRxiv2025

Lipidomics profiling identifies β-oxidation as a key process in noise-induced hearing loss

Noise-induced hearing loss (NIHL) is the second leading cause of hearing loss worldwide, and the most common cause in young adults. Despite this burden, the molecular mechanisms by which noise causes damage are poorly understood, and there are no pharmacologic therapies to prevent or reduce noise-induced damage to the inner ear. Here, using targeted and untargeted lipidomics, we show that noise exposure induces changes in fatty acid (FA) and acylcarnitine (CAR) species in the inner ear, a metabolic profile indicative of noise-induced increases in {beta}- oxidation. This conclusion is validated through treatment with Etomoxir, an inhibitor of carnitine palmitoyltransferase 1A, the rate-limiting enzyme of long-chain {beta}-oxidation. Furthermore, we demonstrate that blocking {beta}-oxidation with Etomoxir does not affect hearing in a normal acoustic environment but reduces the extent of hearing loss induced by an intense noise exposure (2 hours, 112 dB SPL, 8-16kHz). Together, our findings provide insights into cochlear energy metabolism and suggest that its modulation could be targeted to reduce NIHL.

neuroscience↗

bioRxiv2025

Multi-Omics Analysis of Wound Microbiome and Staphylococcus aureus in Pressure Ulcer

This study employs a multi-omics approach to investigate the wound microbiome and Staphylococcus aureus in pressure ulcers. Metagenomic sequencing and associated technologies were utilized to examine bacterial populations, identify dominant species, and study biofilm formation in S. aureus through metabolomic and proteomic characteristics. The results revealed a significant reduction in microbial diversity in pressure ulcer samples compared to controls, with Staphylococcus, Corynebacterium, and Klebsiella being the most prevalent genera. Functional prediction analysis indicated differences in pathogenic invasiveness and biofilm formation factors among the groups. The presence of antimicrobial resistance genes was higher in the pressure ulcer group, particularly in Staphylococcus spp. strains. Whole-genome sequencing of 29 S. aureus isolates identified various clonal complexes and spa types, with the majority possessing genes conferring resistance to {beta}-lactam antimicrobials and virulence factors. Histopathological examination and fluorescent in situ hybridization confirmed the presence of S. aureus in biofilm structures. In vitro biofilm formation tests and metabolomic and proteomic analyses provided insights into the interactions between S. aureus strains and their biofilm formation, revealing enriched pathways related to metabolic processes and membrane composition. This research offers a scientific foundation for understanding the colonization patterns of S. aureus biofilms in pressure ulcer wounds.

microbiology↗

bioRxiv2024

The Mechanism Insight into Bacterial Degradation of Pentachlorobiphenyl

Bacterial degradation mechanism for high chlorinated pentachlorobiphenyl (PentaCB) with worse biodegradability has not been fully elucidated, which could limit the full remediation of PCBs-combined pollution. In this research, using enzymatic screening method, a new PentaCB-degrading bacterium M. paraoxydans that has not been reported was obtained. The characteristic of its intracellular enzymes, proteome and metabolome variation during PentaCB degradation were investigated systematically. The results showed that PentaCB (PCB101, 1 mg/L) degradation rate could arrive 23.9% within 4 h till complete degradation within 12 h. The intracellular enzyme compound was optimally active at pH 6.0. The 12 up-regulated characterized proteins involved ABC transporter substrate-binding protein, translocase protein TatA and signal peptidase I (SPase I) indicated that functional proteins for PentaCB degradation were present both in the cytoplasm and outer surface of cytoplasmic membrane. There were also 5 differential metabolites strongly associated with above proteins in which the up-regulated 1, 2, 4-benzenetriol was enriched into the degradation pathways of benzoate, chlorocyclohexane, chlorobenzene and aminobenzoate. Bacterial degradation of PentaCB necessitates transmembrane transport, energy consumption, protein export, biofilm formation and quorum sensing. These findings hold significant theory and application value for PCBs biodegradation.

microbiology↗

bioRxiv2023

Hidden hearing loss in a hereditary peripheral neuropathy: evidence from a mouse model of Charcot Marie Tooth type 1A.

Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds, a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the impact of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL, and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Also, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in CMT1A patients might help develop robust clinical tests for HHL, which are currently lacking.

neuroscience↗

bioRxiv2023

Activating neutrophils by co-administration of immunogenic recombinant modified vaccinia virus Ankara and granulocyte colony-stimulating factor for the treatment of malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive soft-tissue sarcoma with a poor prognosis and is insensitive to immune checkpoint blockade (ICB) therapy. Loss-of-function of the histone modifying polycomb repressive complex 2 (PRC2) components, EED or SUZ12, is one of the main mechanisms of malignant transformation. In a murine model of MPNST, PRC2-loss tumors have an "immune desert" phenotype and intratumoral (IT) delivery immunogenic modified vaccinia virus Ankara (MVA) sensitized the PRC2-loss tumors to ICB. Here we show that IT MQ833, a second-generation recombinant modified vaccinia virus Ankara virus, results in neutrophil recruitment and activation and neutrophil-dependent tumor killing in the MPNST model. MQ833 was engineered by deleting three viral immune evasion genes, E5R, E3L, and WR199, and expressing three transgenes, including the two membrane-bound Flt3L and OX40L, and IL-12 with an extracellular matrix anchoring signal. Furthermore, we explored strategies to enhance anti-tumor effects of MQ833 by co-administration of granulocyte colony-stimulating factor (G-CSF).

immunology↗