Biology subjects

LI, Q.

Publications and source records attributed to LI, Q..

8 recordsLinked to original sources

bioRxiv2026

Bumetanide Strengthens Residual Brain Bladder Communication After Spinal Cord Injury

Neurogenic bladder is one of the most disabling consequences of spinal cord injury (SCI), yet it remains unclear whether residual brain bladder communication persists after injury and can be therapeutically strengthened. Here, we integrated analysis of a clinical SCI cohort with studies in a mouse model that recapitulates key features of human neurogenic bladder. SCI markedly impaired both descending and ascending limbs of the spinobulbospinal micturition reflex, reducing bladder responses evoked by stimulation of the pontine micturition center (PMC) and bladder filling-induced activation of the periaqueductal gray. Despite this marked functional impairment, pseudorabies virus tracing, optogenetics, and machine learning assisted three dimensional imaging revealed persistent bladder connected neurons within the spared thoracic interlesion region. Neurons within this region remained responsive to descending PMC input, identifying the interlesion network as a candidate substrate for residual brain bladder communication. Early continuous intrathecal bumetanide improved urinary storage and emptying, enhanced descending PMC to bladder and ascending bladder to brain signaling, and increased the functional engagement of bladder-connected thoracic neurons without increasing urine production. Bumetanide also increased transsynaptic labeling between the bladder and PMC, consistent with enhanced polysynaptic brain bladder connectivity. Together, these findings indicate that brain bladder communication is not completely lost after SCI and may be supported by a functionally compromised residual spinal network that remains amenable to therapeutic reinforcement. Targeting spared autonomic circuitry may therefore provide a strategy for improving bladder function after SCI.

neuroscience↗

bioRxiv2025

Tryptophan Chemistry Driven by a Widespread Cytochrome P422 Enzyme Family

Tryptophan serves as a versatile biosynthetic precursor across living organisms. While heme-binding proteins (HBPs) mediate key reactions in tryptophan transformation, the full diversity of HBPs remains largely unexplored. Here, we developed the novel Cofactor-Integrative Structural Inspector (CISSspector) to systematically identify HBPs in the extensive extant microbial genomic sequence database, which revealed several uncharacterized HBP families. We experimentally characterized one of the most prominent families, the cytochrome P422 (formerly DUF6875) family, distributed throughout the prokaryotes and eukaryotes. Strikingly, we discovered that this enzyme family orchestrates four chemically distinct and biochemically unprecedented transformations, with regioselectivity, including N1-, C6-, and C7-hydroxylations and intramolecular C-S bond formations. Notably, the discovery of enzymes capable of Trp N1- and C7-hydroxylation addresses a long-standing gap in the natural enzyme arsenal. Structural analysis of the representative cytochrome P422 enzyme Mc170 revealed a structurally unique HBP fold in which conserved residues form a substrate "clamp" that positions the tryptophan indole ring for selective modification. Our work unveils a hidden enzymatic repertoire of HBPs, expands the known landscape of tryptophan metabolism, and establishes an artificial intelligence-augmented framework for discovering cryptic enzymes with broad implications for synthetic biology and natural product discovery.

biochemistry↗

bioRxiv2025

Functional Specialization for Language Processing in Inferior Frontal Regions During Early Childhood: Evidence from functional near-infrared spectroscopy individual functional channels of interest approach

SignificanceEarly language acquisition represents a fundamental achievement in cognitive development, yet the neural mechanisms underlying this process remain debated, particularly whether specialized language circuits exist from early life or emerge gradually through development. AimTo investigate functional specialization for language processing in bilateral inferior frontal regions during early childhood, examining whether language-selective regions are distinct from domain-general cognitive networks in toddlers aged 2-4 years. ApproachUsing functional near-infrared spectroscopy (fNIRS) with an innovative functional Channel of Interest (fCOI) approach, we conducted two experiments involving adults (N=20) and toddlers (N=22, ages 2-4 years) who completed language processing and cognitive control tasks. ResultsWe demonstrated early functional specialization in the language-selective region of left inferior frontal gyrus, which showed selective responses to linguistic content while remaining insensitive to cognitive demand manipulations in both age groups. However, language selectivity in the homologous right hemisphere region was present only in adults. The multiple demand regions showed complementary patterns, with right-hemispheric selectivity for cognitive control emerging early. ConclusionsThese findings provide evidence for early neural specialization of language processing in the left hemisphere, while revealing ongoing development in right hemispheric organization. Our results support models of early language-specific neural circuits rather than gradual differentiation from domain-general mechanisms, while highlighting the protracted development of language organization.

neuroscience↗

bioRxiv2025

Immunogenicity of Rabies Virus G-Protein mRNA Formulated with Muscle Targeting Lipid Nanoparticles in Mice

Rabies is a preventable zoonotic disease caused by the rabies virus (RABV) with a high mortality rate. Most vaccines on the market or under development have issues such as a low single-dose neutralization titer, complex processes, and high costs. During the COVID-19 pandemic, the successful development of mRNA vaccines has opened up a new avenue for preventive vaccines. As a new technology, mRNA has higher scalability. In this study, we designed an mRNA encoding the RV-G protein, encapsulated by our own muscle targeting lipid nanoparticles (LNP), and evaluated the expression of the RV-G protein in vitro, its immunogenicity, and its protection against virus infection in vivo. The results showed that RV-G mRNA was significantly expressed in vitro. High Virus-IgG binding titers and Virus-neutralizing antibody titers (VNT) were induced by immunization with RV-G mRNA-LNP. Additionally, our results show that the RV-G mRNA vaccine is better than commercially available vaccines in mice.

pharmacology and toxicology↗

bioRxiv2024

Efficacy and safety of an mRNA-based RSV preF vaccine in preclinical studies

The transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between virus and the target cell membrane. During the fusion process, F protein transits from a metastable state (prefusion, preF) to a stable state after merging of virus and cell membranes (postfusion, postF). The majority of highly neutralizing antibodies induced by natural infection or immunization targets the preF form, making it the preferred antigen for vaccine development. Here, we evaluate the mRNA vaccine candidate, STR-V003, which encapsulates the modified mRNA encoding the preF protein in lipid nanoparticles (LNPs). This vaccine demonstrated robust immunogenic in both mice and cotton rats. STR-V003 induced high levels of neutralizing antibodies and RSV preF-specific IgG antibodies, and significantly reduced the RSV viral loads in the lung and nose tissue of challenged animals. In addition, STR-V003 did not have obvious enhancement of lung pathology without causing vaccine enhanced disease (VED). The repeated dose general toxicology studies and local tolerance studies of STR-V003 were evaluated in rats. Therefore, STR-V003 has an acceptable safety profile and robust protective immunity against RSV, and has been approved by the FDA to enter phase I clinical study (NCT06344975).

pharmacology and toxicology↗

bioRxiv2024

Hippocampal sharp wave ripples mediate generalization and subsequent fear attenuation via closed-loop brain stimulation in rats

The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD.

neuroscience↗

bioRxiv2022

Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression

Although the etiology of major depressive disorder remains poorly understood, impairment of gamma oscillations recently emerged as a potential biomarker for major depression. The olfactory bulb (OB) is a major source of brain wide gamma oscillations and bulbectomy is an animal model for depression. Here we demonstrate that chemogenetic suppression of OB neuronal activity or temporally suppressing the OB to pyriform cortex synaptic transmission decreased gamma oscillation power in multiple brain areas associated with depression-like behaviors. To assess the hypothesized link between depression and diffuse depression of gamma oscillations, we employed gamma phase-dependent closed loop neuromodulation of cortical areas, paced by the native OB output. This procedure alleviated depressive-like behaviors in animals and suggests that restoring gamma oscillations may improve depression in humans. One Sentence SummaryRole of limbic gamma oscillations in depression

neuroscience↗

bioRxiv2019

TSG-6 in extracellular vesicles from canine mesenchymal stem/stromal is a major factor in relieving DSS-induced colitis

Mesenchymal stem/stromal cell (MSC)-derived extracellular vesicles (EV) have been reported to be beneficial against dextran sulfate sodium (DSS)-induced colitis in mice. However, the underlying mechanisms have not been fully elucidated. We hypothesize that the tumor necrosis factor--stimulated gene/protein 6 (TSG-6) in EVs is a key factor influencing the alleviation of colitis symptoms. DSS-induced colitis mice (C57BL/6, male, n = 6-8/group) were intraperitoneally administered EVs (100 ug/mice) on day 1, 3, and 5; colon tissues were collected on day 10 for histopathological, qRT-PCR, western blot, and immunofluorescence analyses. In mice injected with EV, inflammation was alleviated. Indeed, EVs regulated the levels of pro- and anti-inflammatory cytokines, such as TNF-, IL-1{beta}, IFN-{gamma}, IL-6, and IL-10 in inflamed colons. However, when injected with TSG-6 depleted EV, the degree of inflammatory relief was reduced. Furthermore, TSG-6 in EVs plays a key role in increasing regulatory T cells (Tregs) in the colon. In conclusion, this study shows that TSG-6 in EVs is a major factor in the relief of DSS-induced colitis, by increasing the number of Tregs in the colon.

cell biology↗