Biology subjects

Wu, J.

Publications and source records attributed to Wu, J..

At least 433 records · Page 24Linked to original sources

bioRxiv2023

The Synaptic Architecture of Layer 5 Thick Tufted Excitatory Neurons in the Visual Cortex of Mice

The neocortex is one of the most critical structures that makes us human, and it is involved in a variety of cognitive functions from perception to sensory integration and motor control. Composed of repeated modules, or microcircuits, the neocortex relies on distinct cell types as its fundamental building blocks. Despite significant progress in characterizing these cell types 1-5, an understanding of the complete synaptic partners associated with individual excitatory cell types remain elusive. Here, we investigate the connectivity of arguably the most well recognized and studied excitatory neuron in the neocortex: the thick tufted layer 5 pyramidal cell 6-10 also known as extra telencephalic (ET) 11 neurons. Although the synaptic interactions of ET neurons have been extensively explored, a comprehensive characterization of their local connectivity remains lacking. To address this knowledge gap, we leveraged a 1 mm3 electron microscopic (EM) dataset. We found that ET neurons primarily establish connections with inhibitory cells in their immediate vicinity. However, when they extend their axons to other cortical regions, they tend to connect more with excitatory cells. We also find that the inhibitory cells targeted by ET neurons are a specific group of cell types, and they preferentially inhibit ET cells. Finally, we observed that the most common excitatory targets of ET neurons are layer 5 IT neurons and layer 6 pyramidal cells, whereas synapses with other ET neurons are not as common. These findings challenge current views of the connectivity of ET neurons and suggest a circuit design that involves local competition among ET neurons and collaboration with other types of excitatory cells. Our results also highlight a specific circuit pattern where a subclass of excitatory cells forms a network with specific inhibitory cell types, offering a framework for exploring the connectivity of other types of excitatory cells.

neuroscience↗

bioRxiv2023

Respiration and growth of Paracoccus denitrificans R-1 with nitrous oxide as an electron acceptor

In the nitrogen biogeochemical cycle, the reduction of nitrous oxide (N2O) to N2 by N2O reductase, which is encoded by nos gene cluster, is the only biological pathway for N2O consumption. However, the capability and mechanisms of microbial N2O reduction are poorly understood. In this study, we investigated the ability to obtain energy for growth of Paracoccus denitrificans R-1 by coupling the oxidation of various electron donors to N2O reduction. This strain has strong N2O reduction capability, and the average N2O reduction rate was 5.10{+/-}0.11x10-9 mol{middle dot}h-1{middle dot}cell-1 under anaerobic condition at 30 using acetate as the electron donor in a defined medium. This reduction was accompanied by the stoichiometric consumption of acetate over time when N2O served as the sole electron acceptor and the reduction can yield energy to support microbial growth, suggesting that microbial N2O reduction is an electron transport process. Cu2+, silver nanoparticles, O2, and acidic conditions can strongly inhibit the reduction, whereas NO3- or NH4+ can promote it. Genomic analysis showed that the gene cluster encoding N2O reductase of P. denitrificans R-1 was composed of nosR, nosZ, nosD, nosF, nosY, and nosL, and nosZ, which was identified as clade I. The respiratory inhibitors test indicated that the pathway of electron transport for N2O reduction was different from that of the traditional electron transport chain for aerobic respiration. These findings suggest that modular N2O reduction by P. denitrificans R-1 is linked to the electron transport chain and energy conservation, and that dissimilatory N2O reduction is a form of microbial anaerobic respiration. IMPOETANCEIn the nitrogen biogeochemical cycle, the reduction of N2O to N2 by N2O reductase, which is encoded by nos genes, is the only biological pathway for N2O consumption. However, the capacity and mechanisms of microbial N2O reduction are poorly understood. We investigated the ability to obtain energy for growth of Paracoccus denitrificans R-1 by coupling the oxidation of various electron donors to N2O reduction. Our study showed that the nosZ type I bacterium, P. denitrificans R-1, can respire N2O as the sole electron donor. Thus, the modular N2O reduction process of clade I denitrifiers not only can consume N2O produced by themselves but can also consume the external N2O generated from non-denitrification biological or abiotic pathways under suitable conditions, which is critical for controlling the release of N2O from ecosystems into the atmosphere.

microbiology↗

bioRxiv2023

A molecularly distinct cell type in the dmPAG regulates intermale aggression behaviors in mice

BackgroundThe periaqueductal gray (PAG) is a central hub for regulation of aggression, while little is known on the circuitry and molecular mechanisms that govern this regulation. We investigate the role of a distinct cell type, Tachykinin 2-expressing (Tac2+) neurons, located in the dorsomedial PAG (dmPAG), in modulating aggression in mice. MethodsWe combined activity mapping, in vivo Ca2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. ResultsWe reveal that the dmPAGTac2 neurons were selectively activated during fighting behaviors. Activation of the dmPAGTac2 neurons evoked, while inhibition or genetic ablation of the dmPAGTac2 neurons suppressed fighting behaviors. TRAP profiling of dmPAGTac2 neurons revealed that fighting behaviors specifically induced enrichment of serotonin-associated transcripts to the dmPAGTac2 neurons. Last, we validated these findings by selectively delivering pharmacological agent into the dmPAG and reversed the behavioral outcomes induced by chemogenetic manipulation. ConclusionsWe identify that the dmPAGTac2 neuron can regulate mouse aggressive behavior and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/562724v3_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@afc876org.highwire.dtl.DTLVardef@91e355org.highwire.dtl.DTLVardef@1e41e43org.highwire.dtl.DTLVardef@17ef3f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Enhanced K Na 1.1 Channel Underlies Cortical Hyperexcitability and Seizure Susceptibility after Traumatic Brain Injury

Pathogenic variants of the sodium-activated potassium channel KNa1.1, have been reported in multiple epileptic disorders. However, whether and how KNa1.1 channel is involved in epileptogenesis after traumatic brain injury (TBI) remains unknown. Firstly, we used behavioral monitoring and EEG recording to examine physiological property, spontaneous seizure activity, and seizure susceptibility after TBI. We explored the changes of KNa1.1 channel following TBI, including changes of subcellular distribution and expression pattern. Meanwhile, we performed patch-clamp recording to detect the neuronal excitability. Furthermore, we built TBI model using kcnt1-/- mice and compared seizure activity with those on wild- type mice. We found severity-dependent seizure susceptibility in different degree of injured mice. Meanwhile, increased neuronal expression of KNa1.1 channel, especially in inhibitory neurons, around the lesion was also observed following TBI with increased neuronal excitability including reduced firing rate of interneurons and imbalanced excitation and inhibition (E/I). Although the maximum frequency of action potential of kcnt1-/- neurons was increased, kcnt1-/- mice displayed decreased seizure susceptibility to the pentylenetetrazole (PTZ) after TBI. Taken together, this study suggests that pathologically enhanced expression and abnormally distributed KNa1.1 channel after TBI contribute to disputed E/I and seizure susceptibility, which might provide a potential therapeutic target on the epileptogenesis after TBI.

neuroscience↗

bioRxiv2023

Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig.

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression of UGT2B31 in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.

genetics↗

bioRxiv2023

Microglia facilitate and stabilize the response to general anesthesia

General anesthesia leads to a loss of consciousness and an unarousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.

neuroscience↗

bioRxiv2023

Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration

Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M- deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration. One Sentence SummaryIRAK-M is a protective molecule and promising therapeutic target for macular degeneration

immunology↗

bioRxiv2023

Gene transfer among viruses substantially contributes to gene gain of giant viruses

Horizontal gene transfers (HGTs) integrate all forms of life and viruses into a vast network of gene flow, which facilitates the transmission of genes beyond vertical inheritance and enhances genomic evolution. HGT is known to occur between closely related viruses. We hypothesized that there is frequent HGT among nucleocytoviruses, a group of diverse but evolutionarily related DNA viruses encoding hundreds to thousands of genes. However, the frequency of viral HGT (vHGT) has not been systematically investigated for nucleocytoviruses. We reconciled over 4,700 gene trees with a robust viral species tree that contains 195 reference viral genomes mainly from cultivation as a reference to infer evolutionary events, including gene gains (gene duplication, origination, and vHGT) and losses. The inferred evolutionary scenarios revealed that the genomes of these viruses have undergone numerous gene gain and loss events, with vHGT representing 28% to 42% of gene gain events in each viral order. By integrating the evolutionary paths of multiple viruses, our data suggest that vHGT is crucial for nucleocytovirus evolution.

evolutionary biology↗

bioRxiv2023

Piezo1 agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associates with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1+/-:5xFAD transgenic Alzheimers disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

neuroscience↗

bioRxiv2023

Hidden HCN channels permit pathway-specific synaptic amplification in L2/3 pyramidal neurons

Layer 2/3 pyramidal cells (L2/3 PCs) play a crucial role in cortical information transfer. Although the dendritic arbors of L2/3 PCs are impressive, they often lack the distinct anatomical compartments characteristic of deeper L5 PCs. For example, many L2/3 PCs do not display an apparent distal tuft region. However, L2/3 PCs receive inputs from both thalamic (bottom-up) and cortical (top-down) inputs, which preferentially synapse onto their proximal and distal dendrites, respectively. Nonuniform organization of channels and NMDA receptors in L2/3 dendrites could serve to independently modulate these information streams to affect learning and behavior, yet whether L2/3 PC dendrites possess this capability has not been established. Here we found a previously unappreciated, non-uniform HCN channel distribution in L2/3 PCs, allowing for pathway-specific gating of NMDA receptor recruitment at bottom-up (proximal) but not top-down (distal) synapses. HCN availability shifted depending on developmental stage and neuromodulation, suggesting that the gain of thalamic and cortical-cortical signals in L2/3 may be independently modified in vivo across different timescales.

neuroscience↗

bioRxiv2023

Cardiomyocyte-specific Loss of Glutamyl-prolyl-tRNA Synthetase Leads to Disturbed Protein Homeostasis and Dilated Cardiomyopathy

Glutamyl-prolyl-tRNA synthetase (EPRS1), an aminoacyl-tRNA synthetase (ARS) ligating glutamic acid and proline to their corresponding tRNAs, plays an essential role in decoding proline codons during translation elongation. The physiological function of EPRS1 in cardiomyocytes (CMs) and the potential effects of CM-specific loss of EPRS1 remain unknown. Here, we found that heterozygous Eprs1 knockout in CMs does not cause any significant changes in CM hypertrophy induced by pressure overload, while homozygous knockout leads to dilated cardiomyopathy, heart failure, and lethality at around 1 month after Eprs1 deletion. Transcriptomic profiling of early-stage Eprs1 knockout hearts suggests a significantly decreased expression of multiple ion channel genes and an increased gene expression in proapoptotic pathways and integrated stress response. Proteomic analysis shows decreased protein expression of multi-aminoacyl-tRNA synthetase complex components, fatty acid, and branched-chain amino acid metabolic enzymes, as well as a compensatory increase in cytosolic translation machine-related proteins. Immunoblot analysis indicated that multiple proline-rich proteins were reduced at the early stage, which might contribute to cardiac dysfunction of Eprs1 knockout mice. Taken together, this study demonstrates the physiological and molecular outcome of loss-of-function of EPRS1 in vivo and provides valuable insights into the potential side effects on CMs resulting from the EPRS1-targeting therapeutic approach.

pathology↗

bioRxiv2023

High-fidelity Image Restoration of Large 3D Electron Microscopy Volume

Volume Electron Microscopy (VEM) is an essential tool for studying biological structures. Due to the challenges of sample preparation and continuous volumetric imaging, image artifacts are almost inevitable. Such image artifacts complicate further processing both for automated computer vision methods and human experts. Unfortunately, the widely used Contrast Limited Adaptive Histogram Equalization (CLAHE) can alter the essential relative contrast information about some biological structures. We developed an image-processing pipeline to remove the artifacts and enhance the images without CLAHE. We apply our method to VEM datasets of a Microwasp head. We demonstrate that our method restores the images with high fidelity while preserving the original relative contrast. This pipeline is adaptable to other VEM datasets.

bioinformatics↗

bioRxiv2023

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-cage Behavior

Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, [~]6-7 months and [~]12 months of age, malin deficient mice ("KO") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

neuroscience↗

bioRxiv2023

Nuclear Lipid Droplets Exit to the Cytoplasm: A Novel Mechanism of non-nuclear pore-dependent material exchange

In cellular biology, the extrusion of large molecular complexes from the nucleus has consistently represented a considerable challenge. In this investigation, we reveal a hitherto unexplored mechanism facilitating the efflux of nuclear lipid droplets (nLDs) from the nucleus directly into the cytoplasm, a process integral to comprehending cellular processes and nuclear dynamics. Through high-throughput sequencing, immunoprecipitation, and immunofluorescence experimentation, we demonstrated that the type I nucleoplasmic reticulum engages with nLDs, enabling the dynamic protein Rab8as transfer to the nLDs and fostering their translocation to the nuclear membrane. Phosphorylation of LMNA/C at the S392 site, adjacent to the nLD-nuclear membrane contact site, induces local depolymerization of lamins, creating an aperture that enables gradual nuclear exit of nLDs. Following this, nLDs, carrying DNA fragments, are released into the cytoplasm through budding and subsequently undergo autophagy-mediated degradation. Furthermore, we demonstrate that RhoA-PKC signaling enhances nLD movement and LMNA/C phosphorylation, while its inhibition impedes nuclear nLD efflux. Our groundbreaking investigation illuminates non-nuclear pore-dependent mechanisms of material exchange and offers fresh perspectives on nuclear metabolic pathways. In Brief O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/556761v1_ufig1.gif" ALT="Figure 1"> View larger version (107K): org.highwire.dtl.DTLVardef@38a213org.highwire.dtl.DTLVardef@1898caorg.highwire.dtl.DTLVardef@d7270forg.highwire.dtl.DTLVardef@14582a2_HPS_FORMAT_FIGEXP M_FIG C_FIG In this study, Jin et al. elucidate a novel mechanism for the expulsion of nuclear lipid droplets (nLDs) from the nucleus. They demonstrate that the activation of RhoA within the nucleus recruits Rab8a to the surface of nLDs. Concurrently, PKC phosphorylation triggers the phosphorylation of LMNA/C at the S392 site, leading to a localized depolymerization of lamins. This creates an aperture that allows for the gradual exit of nLDs from the nucleus. The efflux process of nLDs involves three sequential steps: rupture of the nuclear fibril layer, fusion of nLDs with the inner nuclear membrane (INM), and subsequent fusion with the outer nuclear membrane (ONM). This enables nLDs to enter the cytoplasm, shedding light on a previously unknown process of large molecular entity expulsion from the nucleus.

molecular biology↗

bioRxiv2023

New tree shrew Parkinson's model: a cost-effective alternative to monkey models

The surge in demand for experimental monkeys has led to a rapid increase in their associated costs. Consequently, there is a growing need for the development of a cost-effective model for Parkinsons disease (PD) that exhibits all core clinical and pathological phenotypes of PD. Evolutionarily, tree shrews (Tupaia belangeri) are much closer to primates in comparison to rodents and share more similar PD-related brain structures and movement ability with monkeys. As such, tree shrews represent an ideal small animal species for modeling PD. To develop a tree shrew PD model, we used the 1-Methyl-4-phenylpyridinium (MPP+) metabolite, derived from the well-established PD modeling drug 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to induce lesions in the dopaminergic neurons of the unilateral substantia nigra. After determining the optimal modeling dosage, the tree shrews consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms closely resembled the ones observed in PD monkeys and included bradykinesia, rest tremor, postural instability, and apomorphine-induced rotations, a classic phenotype of unilateral PD models. Immunostaining showed a significant loss of dopaminergic neurons (approximately 95%) in the substantia nigra on the lesioned side of the brain, a crucial pathological marker of PD. Further cytomorphological analysis revealed that the size of nigral dopaminergic neurons in tree shrews exceeded that of rodents and more closely approximated that of macaques. Based on the principle that structure determines function, the morphological similarity between tree shrews and monkeys may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, this study successfully developed a PD model in a small animal species that faithfully recapitulated the classical clinical symptoms and key pathological indicators of PD monkeys. In addition to the well-recognized monkey models, the tree shrew model provides a novel avenue for the evaluation of PD treatments and underlying mechanisms.

neuroscience↗

bioRxiv2023

Protein Kinase Structure and Dynamics: Role of the αC-β4 Loop

Although the C-{beta}4 loop is a stable feature of all protein kinases, the importance of this motif as a conserved element of secondary structure, as well as its links to the hydrophobic architecture of the kinase core, has been underappreciated. We first review the motif and then describe how it is linked to the hydrophobic spine architecture of the kinase core, which we first discovered using a computational tool, Local Spatial Pattern (LSP) alignment. Based on NMR predictions that a mutation in this motif abolishes the synergistic high-affinity binding of ATP and a pseudo substrate inhibitor, we used LSP to interrogate the F100A mutant. This comparison highlights the importance of the C-{beta}4 loop and key residues at the interface between the N- and C-lobes. In addition, we delved more deeply into the structure of the apo C-subunit, which lacks ATP. While apo C-subunit showed no significant changes in backbone dynamics of the C-{beta}4 loop, we found significant differences in the side chain dynamics of K105. The LSP analysis suggests disruption of communication between the N- and C-lobes in the F100A mutant, which would be consistent with the structural changes predicted by the NMR spectroscopy.

molecular biology↗

bioRxiv2023

The ubiquitin ligase UBR-1 regulates the synaptic strength between the GABAergic and glutamatergic signaling

Excitation/Inhibition (E/I) balance is carefully maintained by the nervous system. Neurotransmitter GABA has been reported to be co-released with its sole precursor, another neurotransmitter glutamate. The genetic and circuitry mechanisms to establish the balance between GABAergic and Glutamatergic signaling have not fully elucidated. C. elegans DVB is a classically defined excitatory GABAergic motoneuron that drives the expulsion step in defecation motor program. We show that in addition to UNC-47, the vesicular GABA transporter, DVB also expresses EAT-4, a vesicular glutamate transporter. UBR-1, a conserved ubiquitin ligase, regulates the DVB activity by suppressing a bidirectional inhibitory glutamate signaling. Loss of UBR-1 impairs the DVB Ca2+ activity and the expulsion frequency. These impairments are fully compensated by the knock-down of EAT-4 in DVB. Further, glutamate-gated chloride channels GLC-3 and GLC-2/4 receive DVBs glutamate signals to inhibit DVB and enteric muscle, respectively. These results implicate an intrinsic cellular mechanism that promotes the inherent asymmetric neural activity. We propose that the elevated glutamate in ubr-1 being the cause of the E/I shift, potentially contributes to the Johanson Blizzard Syndrome.

neuroscience↗

bioRxiv2023

In silico spatial transcriptomic editing at single-cell resolution

MotivationGenerative artificial intelligence (AI) has enabled fundamental breakthroughs in visual content creation by text-guided editing. However, the utility of such generative models remains largely understudied for processing increasingly complex bioimage data. ResultsWe propose to algorithmically edit gene expression data to drive cell-level morphological transitions using Generative Adversarial Networks (GAN) and GAN Inversion models. Leveraging cutting-edge spatial transcriptomic datasets with subcellular in-situ resolution and matched high-content imaging data, we propose an in-silico approach to quantify, model and imitate pathological processes in real-life clinical tissue samples. Availability and implementationThe code and video demo is accessible via https://github.com/CTPLab/In-silico-editing

bioinformatics↗