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Cao, A.

Publications and source records attributed to Cao, A..

At least 19 recordsLinked to original sources
bioRxiv2026

A learned oral signal drives long-lasting thirst satiation

Drinking quenches thirst long before the ingested water has been absorbed. Here we investigate the mechanism by combining sham drinking, which uncouples water ingestion from rehydration, with recordings of thirst-promoting neurons in the brain. We show that sham drinking suppresses thirst and rapidly inhibits thirst-promoting neurons despite no water absorption. Remarkably, this suppression of thirst neurons in the absence of rehydration is proportional to the amount of water consumed and persists for tens of minutes after drinking has stopped. This sustained inhibition is triggered by passage of water through the oral cavity, but not licking or swallowing alone, and undergoes extinction with repeated sham drinking, indicating it is learned. Complementary experiments using hypertonic saline demonstrate this learning is bidirectional. These findings reveal that the experience of rapid thirst quenching is not a hard-wired response to the consumption of water, but rather a learned prediction of future bodily state.

neuroscience↗
bioRxiv2025

An efficient artificial esterase with a dynamic conformation via conformational engineering

The catalytic turnover number (kcat) of current enzyme mimics and de novo designed enzymes is still orders of magnitude lower than that of natural enzymes, because mimicking the fast-dynamic feature of enzyme active centers remains a great challenge. Herein, we created a gold nanoparticle-based artificial esterase, Goldenzyme, by conformational engineering to reconstruct dynamic active centers resembling that of -chymotrypsin. NMR characterization shows that Goldenzyme possesses a fast-dynamic feature, about 6-fold faster than typical -helix. Therefore, Goldenzyme efficiently hydrolyzes p-nitrophenyl acetate with a net kcat of 6.37 s-1 per active center, more than 5-fold of that of -chymotrypsin (1.19 s-1), and Goldenzyme can even hydrolyze some non-activated esters that -chymotrypsin cannot. Our conformational engineering approach demonstrates the possibility of creating artificial enzymes that surpass natural ones.

biochemistry↗
bioRxiv2024

A stimulus-computable rational model of habituation in infants and adults

How do we decide what to look at and when to stop looking? Even very young infants engage in active visual selection, looking less and less as stimuli are repeated (habituation) and regaining interest when novel stimuli are subsequently introduced (dishabituation). The mechanisms underlying these looking time changes remain uncertain, however, due to limits on both the scope of existing formal models and the empirical precision of measurements of infant behavior. To address this, we developed the Rational Action, Noisy Choice for Habituation (RANCH) model, which operates over raw images and makes quantitative predictions of participants looking behaviors in a classic visual habituation paradigm. In a series of pre-registered experiments, we exposed infants and adults to stimuli for varying durations and measured looking time to familiar and novel stimuli. We found that these data were well captured by RANCH. Using RANCHs stimulus-computability, we also tested its out-of-sample predictions about the magnitude of dishabituation in a new experiment in which we manipulated the similarity between the familiar and novel stimulus. By framing looking behaviors as rational decision-making, this work identified how the dynamics of learning and exploration guide our visual attention from infancy through adulthood.

animal behavior and cognition↗
bioRxiv2024

High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

Pathological high shear stress (HSS, 100 dyn/cm2) is generated in distal pulmonary arteries (PA) (100-500 m) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm2). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Kruppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.

cell biology↗
bioRxiv2023

Shape-changing electrode array for minimally invasive large-scale intracranial brain activity mapping

Large-scale brain activity mapping is important for understanding the neural basis of behaviour. Electrocorticograms (ECoGs) have high spatiotemporal resolution, bandwidth, and signal quality. However, the invasiveness and surgical risks of electrode array implantation limit its application scope. We developed an ultrathin, flexible shape-changing electrode array (SCEA) for large-scale ECoG mapping with minimal invasiveness. SCEAs were inserted into cortical surfaces in compressed states through small openings in the skull or dura and fully expanded to cover large cortical areas. MRI and histological studies on rats proved the minimal invasiveness of the implantation process and the high chronic biocompatibility of the SCEAs. High-quality micro-ECoG activities mapped with SCEAs from rodent brains during seizures and canine brains during the emergence period revealed the spatiotemporal organization of different brain states with resolution and bandwidth that cannot be achieved using existing noninvasive techniques. The biocompatibility and ability to map large-scale physiological and pathological cortical activities with high spatiotemporal resolution, bandwidth, and signal quality in a minimally invasive manner offer SCEAs as a superior tool for applications ranging from fundamental brain research to brain-machine interfaces.

neuroscience↗
bioRxiv2022

Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy

RationaleElucidating the immune landscape within and surrounding pulmonary arteries (PAs) is critical in understanding immune-driven vascular pathology in pulmonary arterial hypertension (PAH). Although more severe vascular pathology is often observed in hereditary (H)PAH patients with BMPR2 mutations, the involvement of specific immune cell subsets remains unclear. MethodsWe used cutting-edge multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to compare PAs and adjacent tissue in PAH lungs (idiopathic (I)PAH and HPAH) with unused donor lungs. MeasurementsWe quantified immune cells proximity and abundance, focusing on those linked to vascular pathology, and evaluated their impact on pulmonary arterial smooth muscle cells (SMCs) and endothelial cells (ECs). ResultsDistinct immune infiltration patterns emerged between PAH subtypes, with intramural involvement independently linked to PA occlusive changes. Notably, we identified monocyte-derived dendritic cells (mo-DCs) within PA subendothelial and adventitial regions, influencing vascular remodeling by promoting SMC proliferation and suppressing endothelial gene expression across PAH subtypes. In HPAH patients, pronounced immune dysregulation encircled PA walls, characterized by heightened perivascular inflammation involving TIM-3+ T cells. This correlated with an expanded DC subset expressing IDO-1, TIM-3, and SAMHD1, alongside increased neutrophils, SMCs, and -SMA+ECs, reinforcing the severity of pulmonary vascular lesions. ConclusionsThis study presents the first architectural map of PAH lungs, connecting immune subsets not only with specific PA lesions but also with heightened severity in HPAH compared to IPAH. Our findings emphasize the therapeutic potential of targeting mo-DCs, neutrophils, cellular interactions, and immune responses to alleviate severe vascular pathology in IPAH and HPAH.

immunology↗
bioRxiv2022

High sensitivity intrinsic optical signal imaging through flexible, low-cost adaptations of an upright microscope

Intrinsic optical signal imaging (IOSI) is a staple technique in modern neuroscience. Pioneered over thirty years ago, IOSI allows macroscopic mapping of neuronal activity throughout the cortex. The technique has been used to study sensory processing and experience-dependent plasticity, and is often used as an adjunctive procedure to localize cortical areas for subsequent targeting by other imaging or physiology techniques. Despite the ubiquity of IOSI in neuroscience there are few commercially available IOSI systems. As a result, investigators have typically resorted to building their own imaging systems. Over the years, simplified systems built on existing microscope platforms have been proposed. Still, these often require additional, sometimes costly, custom-built hardware, which presents challenges for investigators without significant experience in optics or microscopy design. Here we present a straightforward set of adaptations that can be applied to any standard upright microscope, using readily available, inexpensive, commercial parts for illumination, optics, and signal detection, that enables high sensitivity IOSI. Using these adaptations, we are able to readily map sensory-evoked signals across the somatosensory and visual cortex, including single-whisker barrel cortical activity maps in mice. We show that these IOSI maps are highly reproducible across animals and can be used to study plasticity mechanisms in the somatosensory cortex. We also provide open-source applications to control illumination and analyze raw data to generate activity maps. We anticipate these resources will be particularly useful for neuroscience investigators from broad technical backgrounds looking to add IOSI capabilities to an existing microscope on a budget.

neuroscience↗
bioRxiv2022

Alterations of pulmonary surfactant function by e-cigarette vapour

E-cigarette (EC) and vaping use continue to remain popular amongst teenage and young adult populations, despite several reports of vaping associated lung injury. This popularity is due in part to the vast variety of appealing flavours and nicotine concentrations easily accessible on the market. One of the first compounds that EC aerosols comes into contact within the lungs during a deep inhalation is pulmonary surfactant. This lipid protein mixture lines the alveoli, reducing surface tension and preventing alveolar collapse. Impairment of surfactants critical surface tension reducing activity can contribute to lung dysfunction. Currently, information on how EC aerosols impacts pulmonary surfactant remains limited. We hypothesized that exposure to EC aerosol impairs the surface tension reducing ability of surfactant. Bovine Lipid Extract Surfactant (BLES) was used as a model surfactant in a direct exposure syringe system. BLES (2ml) was placed in a syringe (30ml) attached to an EC. The generated aerosol was drawn into the syringe and then expelled, repeated 30 times. Biophysical analysis after exposure was completed using a constrained drop surfactometer (CDS). Minimum surface tensions increased after exposure to the EC aerosol. Variation in device used, addition of nicotine, or temperature of the aerosol had no additional effect. Two e-liquid flavours, menthol and red wedding, had further detrimental effects, resulting in higher surface tension than the vehicle exposed BLES. Alteration of surfactant properties through interaction with the produced aerosol was observed with a basic e-liquid vehicle, however additional compounds produced by added flavourings appeared to be able to increase inhibition. In conclusion, EC aerosols alter surfactant function through increases in minimum surface tension. This impairment may contribute to lung dysfunction and susceptibility to further injury.

biophysics↗
bioRxiv2022

The evolution of two transmissible leukaemias colonizing the coasts of Europe

Transmissible cancers are malignant cell clones that spread among individuals through transfer of living cancer cells. Several such cancers, collectively known as bivalve transmissible neoplasia (BTN), are known to infect and cause leukaemia in marine bivalve molluscs. This is the case of BTN clones affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and north-west Africa. To investigate the origin and evolution of contagious cancers in common cockles, we collected 6,854 C. edule specimens and diagnosed 390 cases of BTN. We then generated a reference genome for the species and assessed genomic variation in the genomes of 61 BTN tumours. Analysis of tumour-specific variants confirmed the existence of two cockle BTN lineages with independent clonal origins, and gene expression patterns supported their status as haemocyte-derived marine leukaemias. Examination of mitochondrial DNA sequences revealed several mitochondrial capture events in BTN, as well as co-infection of cockles by different tumour lineages. Mutational analyses identified two lineage-specific mutational signatures, one of which resembles a signature associated with DNA alkylation. Karyotypic and copy number analyses uncovered genomes marked by pervasive instability and polyploidy. Whole-genome duplication, amplification of oncogenes CCND3 and MDM2, and deletion of the DNA alkylation repair gene MGMT, are likely drivers of BTN evolution. Characterization of satellite DNA identified elements with vast expansions in the cockle germ line, yet absent from BTN tumours, suggesting ancient clonal origins. Our study illuminates the evolution of contagious cancers under the sea, and reveals long-term tolerance of extreme instability in neoplastic genomes.

evolutionary biology↗
bioRxiv2022

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

BackgroundMultiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate, highlighting a critical need for new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. MethodsMyeloma cells treated with FABP inhibitors (BMS3094013 and SBFI-26) were examined in vivo and in vitro for cell cycle, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation. Myeloma cell responses to BMS309403 and/or SBFI-26 were assessed with RNA-sequencing and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using DepMap. Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. ResultsMyeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation in vitro. FABPi had potent anti- tumor effects both in vitro and in vivo in two pre-clinical MM mouse models where increased mouse survival was observed. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5. ConclusionsThis study establishes the FABP family as a therapeutically actionable dependency in multiple myeloma with a multitude of actions and cellular roles that result in the support of myeloma progression. Statement of translational relevanceMultiple myeloma (MM) is an incurable disease of the plasma cell and MM patients require better treatments as soon as possible. The fatty acid binding protein (FABP) family plays a number of roles in cells, including supporting fatty acid oxidation, lipid shuttling and signal transduction. Here, we demonstrate with CoMMpass and other clinical data that FABPs represent a biomarker for aggressive disease in MM, and are a novel, targetable protein family expressed by myeloma cells. Pharmacologically inhibiting FABPs kills tumor cells and induces cell cycle arrest in vitro and in pre-clinical models. Mechanisms of action are multitudinous, as we discovered with RNA-sequencing, proteomic analysis, and phenotyping assays. Cell metabolism, cell signaling, cell stress, and epigenetic signatures were altered in MM cells when FABPs were inhibited. In summary, targeting FABP5 holds great therapeutic potential for killing diseased cells, with few negative off-target effects on healthy cells.

cancer biology↗
bioRxiv2021

Biosynthetic gene cluster profiling predicts the positive association between antagonism and phylogeny in Bacillus

Understanding the driving forces and intrinsic mechanisms of microbial competition is a fundamental question in microbial ecology. Despite the well-established negative correlation between exploitation competition and phylogenetic distance, the process of interference competition that is exemplified by antagonism remains controversial. Here, we studied the genus Bacillus, a commonly recognized producer of multifarious antibiotics, to explore the role of phylogenetic patterns of biosynthetic gene clusters (BGCs) in mediating the relationship between antagonism and phylogeny. Comparative genomic analysis revealed a positive association between BGC distance and phylogenetic distance. Antagonistic tests demonstrated that the inhibition phenotype positively correlated with both phylogenetic and predicted BGC distance, especially for antagonistic strains possessing abundant BGCs. Mutant-based verification showed that the antagonism was dependent on the BGCs that specifically harbored by the antagonistic strain. These findings highlight that BGC-phylogeny coherence regulates the positive correlation between congeneric antagonism and phylogenetic distance, which deepens our understanding of the driving force and intrinsic mechanism of microbial interactions.

ecology↗
bioRxiv2021

Paired feed-forward excitation with delayed inhibition allows high frequency computations across brain regions

The transmission of high-frequency temporal information across brain regions is critical to perception, but the mechanisms underlying such transmission remain unclear. Long-range projection patterns across brain areas are often comprised of paired feedforward excitation followed closely by delayed inhibition, including the thalamic triad synapse, thalamic projections to cortex, and projections within hippocampus. Previous studies have shown that these joint projections produce a shortened period of depolarization, sharpening the timing window over which the postsynaptic neuron can fire. Here we show that these projections can facilitate the transmission of high-frequency computations even at frequencies that are highly filtered by neuronal membranes. This temporal facilitation occurred over a range of synaptic parameter values, including variations in synaptic strength, synaptic time constants, short-term synaptic depression, and the delay between excitation and inhibition. Further, these projections can coordinate computations across multiple network levels, even amid ongoing local activity. We suggest that paired feedforward excitation and inhibition provides a hybrid signal - carrying both a value and a clock-like trigger - to allow circuits to be responsive to input whenever it arrives.

neuroscience↗
bioRxiv2021

Endogenous Retroviral Elements Generate Pathologic Neutrophils and Elastase Rich Exosomes in Pulmonary Arterial Hypertension

Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus, elevated HERVs explain pathological neutrophils linked to PAH induction and progression.

immunology↗
bioRxiv2020

Evolution-inspired dissection of caspase activities enables the redesign of caspase-4 into an LPS sensing interleukin-1 converting enzyme

Innate immune signaling pathways comprise multiple proteins that promote inflammation. This multistep means of information transfer suggests that complexity is a prerequisite for pathway design. Herein, we examined this possibility by studying caspases that regulate inflammasome-dependent inflammation. Several caspases differ in their ability to recognize bacterial LPS and cleave interleukin-1{beta} (IL-1{beta}). No caspase is known to contain both activities, yet distinct caspases with complementary activities bookend an LPS-induced pathway to IL-1{beta} cleavage. Using unique caspases present in carnivorans as a guide, we identified molecular determinants of IL-1{beta} cleavage specificity within caspase-1. This knowledge enabled the redesign of human caspase-4 to operate as a one-protein signaling pathway, which intrinsically links LPS detection to IL-1{beta} cleavage and release, independent of inflammasomes. Strikingly, cat caspase-4 displays the activities of redesigned human caspase-4. These findings illustrate natural signaling pathway diversity and highlight how multistep innate immune pathways can be condensed into a single protein.

immunology↗
bioRxiv2020

A novel high-accuracy genome assembly method utilizing a high-throughput workflow

Across domains of biological research using genome sequence data, high-quality reference genome sequences are essential for characterizing genetic variation and understanding the genetic basis of phenotypes. However, the construction of genome assemblies for various species is often hampered by complexities of genome organization, especially repetitive and complex sequences, leading to mis-assembly and missing regions. Here, we describe a high-throughput gold standard genome assembly workflow using a large-scale bacterial artificial chromosome (BAC) library with a refined two-step pooling strategy and the Lamp assembler algorithm. This strategy minimizes the laborious processes of physical map construction and clone-by-clone sequencing, enabling inexpensive sequencing of several thousand BAC clones. By applying this strategy with a minimum tiling path BAC clone library for the short arm of chromosome 2D (2DS) of bread wheat, 98% of BAC sequences, covering 92.7% of the 2DS chromosome, were assembled correctly for this species with a highly complex and repetitive genome. We also identified 48 large mis-assemblies in the reference wheat genome assembly (IWGSC RefSeq v1.0) and corrected these large mis-assemblies in addition to filling 92.2% of the gaps in RefSeq v1.0. Our 2DS assembly represents a new benchmark for the assembly of complex genomes with both high accuracy and efficiency.

genomics↗
bioRxiv2020

Oleic acid triggers hippocampal neurogenesis by binding to TLX/NR2E1

Adult hippocampal neurogenesis underpins learning, memory, and mood, but diminishes with age and illness. The orphan nuclear receptor TLX/NR2E1 is known to regulate neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is unknown. We found that neural stem and progenitor cells require monounsaturated fatty acids to survive and proliferate. Specifically, oleic acid (18:1{omega}9) binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell cycle and neurogenesis genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation. These findings pave the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.

neuroscience↗
bioRxiv2019

Controlling Strawberry Mites: Comparison of New Bio-Pesticides and Conventional Chemical Pesticides

BACKGROUNDTetranychus cinnabarinus is one of the pest insects most severely influencing strawberry production. It has a high attack rate and causes severe economic losses. Laboratory toxicity tests and greenhouse experiments were carried out using 13 acaricides to determine their efficacy and potential mechanisms of action.\n\nRESULTSAbamectin showed the highest efficacy against T. cinnabarinus female mites; its LC50 value was 0.18mg L-1. Pyridaben, cyhalothrin, veratrine, and carbosulfan showed reasonably high efficacy; their LC50 values were 2.69 mg L-1, 3.94 mg L-1, 5.98 mg L-1, and 6.75 mg L-1, respectively. Less effective were hexythiazox and bifenthrin, their LC50 values were 9.82 mg L-1 and 19.09 mg L-1, respectively. Other acaricides such as spirodiclofen, chlorantraniliprole, chlorfenapyr, spinosad, and bifenazate did not show good efficacy. The status of female mites treated with avermectin, pyridaben, kanghebio and cyhalothrin changed significantly under a fluorescence microscope. There were no significant differences among female mites treated with spirotetramat, chlorantraniliprole, spinosad and bifenazate. Enzyme activity tests showed that Kanghebio and cyhalothrin obviously inhibited Ca2+-adenosine triphosphatase (Ca2+-ATPase), while veratrine and kanghebi obviously inhibited acetylcholinesterase (TChE) and monoamine oxidase (MAO). Cyhalothrinexerted an auxo-action on MAO. Greenhouse experiment indicated that abamectin showed the best efficacy, as well as the longest duration of efficacy, pyridaben, cyhalothrin, veratrine, and kanghebio followed, while carbosulfan, hexythiazox, and bifenthrin performed the worst.\n\nCONCLUSIONSOur study provided a scientific basis for chemical pesticides to be replaced by these and potentially other new bio-pesticides.

biochemistry↗