Biology subjects

Cai, A.

Publications and source records attributed to Cai, A..

9 recordsLinked to original sources

bioRxiv2026

Biologically inspired alignment reveals distributed and directionally asymmetric correspondence between rat and human cortices

Rodent models enable causal interrogation of brain circuits, but translating their systems-level organization to humans requires correspondence beyond one-to-one anatomical homology. Guided by the view that cortical areas are characterized by their relationships within distributed functional networks, we developed BrainMapping, a biologically inspired framework for aligning rat and human cortex using resting-state functional MRI. The framework combined a shared representation with optimal transport to derive probabilistic, bidirectional maps. These alignments revealed distributed, many-to-many correspondences that generalized to held-out subjects and preserved functional connectivity architecture, cortical gradients, and graph topology. Organizational preservation was directionally asymmetric. Human-to-rat mapping preserved organization more uniformly across rat cortical systems, whereas rat-to-human mapping showed stronger preservation in human association-related networks than in primary sensory and motor networks. The maps recovered literature-consistent default-mode and salience-system correspondences and generated testable non-canonical predictions. These findings provide a framework for expressing rat functional organization in human functional-network coordinates.

neuroscience↗

bioRxiv2025

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 M). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated [~]24 hours post-infection significantly reduced log10 viral RNA copies/mLxday area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

microbiology↗

bioRxiv2024

Oxytocin receptor controls distinct components of pair bonding and development in prairie voles

Oxytocin receptor (Oxtr) signaling influences complex social behaviors in diverse species, including social monogamy in prairie voles. How Oxtr regulates specific components of social attachment behaviors and the neural mechanisms mediating them remains unknown. Here, we examine prairie voles lacking Oxtr and demonstrate that pair bonding comprises distinct behavioral modules: the preference for a bonded partner, and the rejection of novel potential mates. Our longitudinal study of social attachment shows that Oxtr sex-specifically influences early interactions between novel partners facilitating the formation of partner preference. Additionally, Oxtr suppresses promiscuity towards novel potential mates following pair bonding, contributing to rejection. Oxtr function regulates coordinated patterns of gene expression in regions implicated in attachment behaviors and regulates the expression of oxytocin in the paraventricular nucleus of the hypothalamus, a principal source of oxytocin. Thus, Oxtr controls genetically separable components of pair bonding behaviors and coordinates development of the neural substrates of attachment.

neuroscience↗

bioRxiv2023

RNA polymerase sliding on DNA can couple the transcription of nearby bacterial operons

DNA transcription initiates after an RNA polymerase (RNAP) molecule binds to the promoter of a gene. In bacteria, the canonical picture is that RNAP comes from the cytoplasmic pool of freely diffusing RNAP molecules. Recent experiments suggest the possible existence of a separate pool of polymerases, competent for initiation, which freely slide on the DNA after having terminated one round of transcription. Promoter-dependent transcription reinitiation from this pool of post-termination RNAP may lead to coupled initiation at nearby operons, but it is unclear whether this can occur over the distance- and time-scales needed for it to function widely on a bacterial genome in vivo. Here, we mathematically model the hypothesized reinitiation mechanism as a diffusion-to-capture process and compute the distances over which significant inter-operon coupling can occur and the time required. These quantities depend on previously uncharacterized molecular association and dissociation rate constants between DNA, RNAP and the transcription initiation factor{sigma} 70; we measure these rate constants using single-molecule experiments in vitro. Our combined theory/experimental results demonstrate that efficient coupling can occur at physiologically relevant{sigma} 70 concentrations and on timescales appropriate for transcript synthesis. Coupling is efficient over terminator-promoter distances up to [~] 1, 000 bp, which includes the majority of terminator-promoter nearest neighbor pairs in the E. coli genome. The results suggest a generalized mechanism that couples the transcription of nearby operons and breaks the paradigm that each binding of RNAP to DNA can produce at most one messenger RNA. SIGNIFICANCE STATEMENTAfter transcribing an operon, a bacterial RNA polymerase can stay bound to DNA, slide along it, and reini-tiate transcription of the same or a different operon. Quantitative single-molecule biophysics experiments combined with mathematical theory demonstrate that this reinitiation process can be quick and efficient over gene spacings typical of a bacterial genome. Reinitiation may provide a mechanism to orchestrate the transcriptional activities of groups of nearby operons.

biophysics↗

bioRxiv2020

In vitro analysis of colistin and ciprofloxacin antagonism of Pseudomonas aeruginosa phage PEV2 infection activities

Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections. In the clinic, phage therapy often is used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial activities, such as DNA and protein synthesis, which also are required for phage infection processes. Resulting antagonistic impacts of antibiotics on phages nevertheless are not commonly determined in association with phage therapy studies using standard, planktonic approaches. Here we assess the antagonistic impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new virion production activities of Pseudomonas aeruginosa podovirus PEV2, using a broth culture, optical density-based lysis profile assay. Though phage-antibiotic combinations were more potent in reducing cell viability than phages or antibiotics alone, colistin substantially interfered with phage PEV2 bacteriolytic and virion-production activities at minimum inhibitory concentration (MIC). Ciprofloxacin, by contrast, had no such impact at 1x MIC or 3x MIC. At higher but still clinically relevant concentrations (9x MIC) burst sizes were still significant (~30 phages/infected bacterium). We corroborated these lysis profile results by more traditional measurements (colony forming units, plaque forming units, one-step growth experiments) and two other P. aeruginosa phages. To our knowledge this is the first study in which detailed antibiotic impact on P. aeruginosa phage infection activities has been determined under conditions similar to those used to determine antibiotic MICs and could point especially to ciprofloxacin as a minimally antagonistic phage therapy co-treatment of P. aeruginosa infections.

microbiology↗

bioRxiv2019

Regeneration of dorsal spinal cord neurons after injury via in situ NeuroD1-mediated astrocyte-to-neuron conversion

Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors. We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimers disease by overexpressing a single neural transcription factor NeuroD1 via retroviruses. Here we demonstrate regeneration of dorsal spinal cord neurons from reactive astrocytes after SCI via adeno-associated virus (AAV), a more clinically relevant gene delivery system. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency ([~]95%). Interestingly, NeuroD1-converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate of conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model, allowing future studies of evaluating this reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift for spinal cord repair using in vivo astrocyte-to-neuron conversion technology to generate functional neurons in the grey matter.

neuroscience↗

bioRxiv2019

A new GABAergic projection from the BNST onto accumbal parvalbumin neurons controls anxiety

The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs). Here, we show that PV activity within the nucleus accumbens shell (sNAc) is required for producing anxiety-related avoidance when mice are under anxiogenic situations; sNAcPV neurons exhibited high excitability in chronically stressed mice model, which generated excessive maladaptive avoidance behavior in an anxiogenic context. We also discovered a novel GABAergic projections from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAcPV neurons; optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNSTGABA [Formula] sNAcPV synapses, which in turn explains the hyperexcitability of sNAcPV neurons on stressed models; therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to anxious state.\n\nOur findings reveal the coordination between BNST and NAc through an inhibitory architecture in controlling of anxiety-related response and provide a neurobiological basis for therapeutic interventions in pathological anxiety.

neuroscience↗

bioRxiv2018

EXOSOME RELEASE PROMOTES INFLAMMATORY RESOLUTION IN ACTIVATED AND AGED MICROGLIA

Proper regulation of inflammatory responses is critical for effective function of microglia, in both physiological and disease states. While the mechanisms that drive microglia activation are well characterized, the pathways leading to inflammatory resolution and immune homeostasis have yet to be fully elucidated. Using RNA interference, pharmacological inhibition and genetic knockout mouse model approaches, we show that exosome release promotes immune homeostasis in activated and aged microglia. We demonstrate that induction of anti-inflammatory pathways enhances release of exosomes containing immune proteins and microRNAs. Functionally, inhibition of exosome release alters trafficking of exosome cargo, such as miR-155, in activated microglia resulting in increased cellular retention of these cargo molecules. Concordantly, we identify increased miR-155 activity leading to sustained activation of pro-inflammatory pathways as a potential mechanism underlying impaired inflammatory resolution due to inhibition of microglia exosome release. Similarly, inhibition of augmented exosome release in aged microglia exacerbates inflammatory activation, demonstrating conservation of the immune modulatory effects of exosome release in microglia. Taken together, our study identifies exosomes as novel components of an anti-inflammatory mechanism utilized by activated and aged microglia to restore immune homeostasis.

neuroscience↗

bioRxiv2018

Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion

Nerve injury often causes neuronal loss and glial proliferation, disrupting the delicate balance between neurons and glial cells in the brain. Recently, we have developed an innovative technology to convert internal reactive glial cells into functional neurons inside the mouse brain. Here, we further demonstrate that such glia-to-neuron conversion can rebalance neuron-glia ratio and reverse glial scar back to neural tissue. Specifically, using a severe stab injury model in the mouse cortex, we demonstrated that ectopic expression of NeuroD1 in reactive astrocytes significantly reduced glial reactivity and transformed toxic A1 astrocytes into less harmful astrocytes before neuronal conversion. Importantly, astrocytes were not depleted after neuronal conversion but rather repopulated due to its intrinsic proliferation capability. Remarkably, converting reactive astrocytes into neurons also significantly reduced microglia-mediated neuroinflammation. Moreover, accompanying regeneration of new neurons together with repopulation of new astrocytes, blood-brain-barrier was restored and synaptic density was rescued in the injury sites. Together, these results demonstrate that glial scar can be reversed back to neural tissue through rebalancing neuron:glia ratio after glia-to-neuron conversion.

neuroscience↗