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Gao, P.

Publications and source records attributed to Gao, P..

At least 55 records · Page 3Linked to original sources

Plant volatile-based fumigation improves mating competitiveness of males for population suppression of the global fruit pest Cydia pomonella

BACKGROUNDThe implementation of sterile insect technique (SIT) has proven effective in the area-wide suppression of several significant agricultural and sanitary pests by employing traditional cobalt-60 (60 Co-{gamma}) as a radiation source. Recently, X-ray has been validated as a feasible alternative to 60 Co-{gamma} radiation sources. Nonetheless, higher doses of X-ray irradiation lead to insect sterility but diminish mating competitiveness, thereby impacting the effectiveness of SIT applications. Thus, it is crucial to ascertain the optimal irradiation dose and develop strategies to enhance the mating competitiveness of sterile insects to enhance SIT efficacy. RESULTSIn this study, we determined the effect of various X-ray irradiation doses (ranging from 0 to 366 Gy) on the fecundity, fertility, and mating competitiveness of Cydia pomonella, a globally invasive fruit pest. Results demonstrated that the sterility rate of sterile males increased proportionally with irradiation dose up to 200 Gy, beyond which it plateaued. Notably, exposure to 200 Gy of irradiation notably decreased the mating competitiveness of male, as evidenced by a mating competitiveness index of 0.17 in laboratory and 0.096 in the orchard. This decline in mating competitiveness is likely linked to the down-regulation of genes associated with the recognition of sex pheromones, specifically CpomOR3a, CpomOR3b, and CpomOR5, following X-ray irradiation. Fumigation of the plant volatile, linalool at varying concentrations (70, 83, and 96 L/m 3) resulted in differential enhancements in male mating competitiveness, with the moderate concentration significantly improving the competitiveness of sterilized males, possibly by restoring their ability to recognize sex pheromones. Implementation of repeated releases of sterilized males on a pilot scale led to a notable reduction in the population of C. pomonella in the field. CONCLUSIONThese findings indicate that fumigation with plant volatiles has the potential to mitigate male sterility induced by X-ray irradiation, offering a promising approach to enhance the efficacy of SIT applications for the control of C. pomonella. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/604520v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@7ac9aeorg.highwire.dtl.DTLVardef@14ed866org.highwire.dtl.DTLVardef@1611e8borg.highwire.dtl.DTLVardef@11c6377_HPS_FORMAT_FIGEXP M_FIG C_FIG We determined the optimal X-ray irradiation dose and developed a linalool fumigation approach to improve the mating competitiveness of sterilized insects, thereby bolstering the efficacy of against Cydia pomonella.

zoology↗

Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality

Tumor heterogeneity poses a significant challenge in combating treatment resistance. Despite Polo-like kinase 1 (PLK1) being universally overexpressed in cancers and contributing to chromosomal instability (CIN), direct PLK1 inhibition hasnt yielded clinical progress. To address this, we utilized the synthetic dosage lethality (SDL) approach, targeting PLK1s genetic interactions for selective killing of overexpressed tumor cells while mitigating heterogeneity-associated challenges. Employing computational methods, we conducted a genome-wide shRNA screen, identifying 105 SDL candidates. Further in vivo CRISPR screening in a breast cancer xenograft model and in vitro CRISPR analysis validated these candidates. Employing Perturb-seq revealed IGF2BP2/IMP2 as a key SDL hit eliminating PLK1-overexpressing cells. Suppression of IGF2BP2, genetically or pharmacologically, downregulated PLK1 and limited tumor growth. Our findings strongly propose targeting PLK1s genetic interactions as a promising therapeutic approach, holding broad implications across multiple cancers where PLK1 is overexpressed.

cancer biology↗

PITPβ promotes COPI vesicle fission through lipid transfer and membrane contact formation

Intracellular transport among organellar compartments occurs in two general ways, by membrane-bound carriers or membrane contacts. Specific circumstances that involve the coordination of these two modes of transport remain to be defined. Studying Coat Protein I (COPI) transport, we find that phosphatidylcholine with short acyl chains (sPC) is delivered through membrane contact from the endoplasmic reticulum (ER) to sites of COPI vesicle formation at the Golgi to support the fission stage. Phosphatidylinositol transfer protein beta (PITP{beta}) plays a key role in this process, with the elucidation of this role advancing a new understanding of how PITP{beta} acts, providing a mechanistic understanding of a specific circumstance when vesicular transport requires membrane contact, and contributing to a basic understanding of how transport carriers in a model intracellular pathway are formed. SummarySpecific circumstances that membrane contact is needed for vesicular transport remain to be defined. We find that a critical lipid is delivered through membrane contact to support the fission stage of a model intracellular transport pathway.

cell biology↗

Multi-omics Reveals Immune Response and Metabolic Profiles during High-Altitude Mountaineering

The physiological perturbations induced by high-altitude exposure in mountain climbers, manifesting as metabolic and immunologic deviations, have been previously reported but are not fully understood. In this study, we obtained longitudinal multi-omic profiles of blood samples for healthy mountain climbers during two mountaineering stages (acclimatization and extreme altitude mountaineering). Our integrative assay included metabolomics and lipidomics profiling of plasma coupled with single-cell transcriptomic analysis of 375,722 immune cells. Longitudinal analysis revealed dynamic immune response profiles, during the acclimatization period, characterized by the downregulation of inflammatory responses in monocytes and classical dendritic cells (cDCs) and an increase in the proportion of cytotoxic CD8+ T cells with enhanced immune effector processes. In contrast, during extreme altitude mountaineering, the activation of inflammatory responses and impairment of T cell effector function were observed, concomitant with an increased cellular response to hypoxia and oxidative stress pathways. Furthermore, we found upregulated glycolysis and antioxidant gene expression during extreme altitude mountaineering, which was primarily orchestrated by HIF1A and NFE2L2, while decreased expression of these genes was observed in dysregulated plasmacytoid dendritic cells (pDCs). Finally, high-resolution plasma metabolic analysis revealed significant alterations in the metabolism of climbers, involving enhanced glutamine and fatty acid metabolism.

bioinformatics↗

Metabolic enzymes moonlight as selective autophagy receptors to protect plants against viral-induced cellular damage

AbstractRNA viruses co-opt the host endomembrane system and organelles to build replication complexes for infection. How the host responds to these membrane perturbations is poorly understood. Here, we explore the autophagic response of Arabidopsis thaliana to three viruses that hijack different cellular compartments. Autophagy is significantly induced within systemically infected tissues, its disruption rendering plants highly sensitive to infection. Contrary to being an antiviral defense mechanism as previously suggested, quantitative analyses of the viral loads established autophagy as a tolerance pathway. Further analysis of one of these viruses, the Turnip Crinkle Virus (TCV) that hijack mitochondria, showed that despite perturbing mitochondrial integrity, TCV does not trigger a typical mitophagy response. Instead, TCV and Turnip yellow mosaic virus (TYMV) infection activates a distinct selective autophagy mechanism, where oligomeric metabolic enzymes moonlight as selective autophagy receptors and degrade key executors of defense and cell death such as EDS1. Altogether, our study reveals an autophagy-regulated metabolic rheostat that gauges cellular integrity during viral infection and degrades cell death executors to avoid catastrophic amplification of immune signaling.

plant biology↗

ATG8ylation of vacuolar membrane protects plants against cell wall damage

Vacuoles are essential for cellular metabolism, growth, and the maintenance of internal turgor pressure. They sequester lytic enzymes, ions, and secondary metabolites that, if leaked into the cytosol, could lead to cell death. Despite their pivotal roles, quality control pathways that safeguard vacuolar integrity remained elusive in plants. Here, we discovered a conserved vacuolar quality control (VQC) pathway that is activated upon cell wall damage in a turgor pressure dependent manner. Cell wall perturbations induce a distinct modification - ATG8ylation - on the vacuolar membrane (tonoplast) that is regulated by the V-ATPase and ATG8 conjugation machinery. Genetic disruption of tonoplast ATG8ylation impairs vacuolar integrity, leading to cell death. Together, our findings reveal a homeostatic pathway that preserves vacuolar integrity upon cell wall damage.

plant biology↗

Phase Contrast Tomography (PCT)

Phase contrast microscopy has been employed for 2D imaging of thin samples since its invention. Herein, we propose and demonstrate phase contrast tomography (PCT) that incorporates the scanning of LED illumination with quantitative phase contrast microscopy (QPCM) to realize 3D phase imaging of a sample. The proposed PCT is demonstrated 3D imaging of 200-nm polystyrene microspheres (PMs) and sub-organelles inside COS7 cells. The results reveal that the proposed PCT has high spatial resolution and stability without speckle noise, and thence, it has a great potential to be applied to industrial testing and life science research.

biophysics↗

Metabolic shift to serine pathway induced by lipids confers oncogenic properties in non-transformed breast cells

A lipid metabolism gene signature is associated with the risk of estrogen negative breast cancer (ER-BC). In vitro, lipid exposure alters histone methylation affecting gene expression and increasing flux through various metabolic reactions; but little is known about the mechanism(s) linking lipids and epigenetic reprogramming with the genesis of ER-BC. Here we show that the metabolism of the medium-chain fatty acid Octanoic Acid (OA) in preference to glucose and glutamine results in a metabolic shift toward the serine pathway increasing the production of SAM, glutathione, and 2-HG, with implications for oncogenesis: SAM production results in epigenetic fostered plasticity leading to reprogramming/selecting cells that express Neural, EMT and BC related genes. 2-HG exposure results in appearance of DNA breaks, potentially consequent to the inhibition of essential demethylases for HR repair. ROS increases shortly after OA exposure and is mitigated by antioxidant defenses, which favors/enables the survival of specific cell subtypes.

cancer biology↗

Distinct dynamics and intrinsic properties in ventral tegmental area populations mediate reward association and motivation

Ventral tegmental area (VTA) dopamine neurons regulate reward-related associative learning and reward-driven motivated behaviors, but how these processes are coordinated by distinct VTA neuronal subpopulations remains unresolved. Here we examine the neural correlates of reward-related prediction-error, action, cue, and outcome encoding as well as effort exertion and reward anticipation during reward-seeking behaviors. We compare the contribution of two primarily dopaminergic and largely non-overlapping VTA subpopulations, all VTA dopamine neurons, and VTA GABAergic neurons of the mouse midbrain to these processes. The dopamine subpopulation that projects to the nucleus accumbens (NAc) core preferentially encodes prediction-error and reward-predictive cues. In contrast, the dopamine subpopulation that projects to the NAc shell preferentially encodes goal-directed actions and reflects relative reward anticipation. VTA GABA neuron activity strongly contrasts VTA dopamine population activity and preferentially encodes reward outcome and retrieval. Electrophysiology, targeted optogenetics, and whole-brain input mapping reveal heterogeneity among VTA dopamine subpopulations. Our results demonstrate that VTA subpopulations carry distinct reward-related learning and motivation signals and reveal a striking pattern of functional heterogeneity among projection-defined VTA dopamine neuron populations.

neuroscience↗

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease. Study HighlightsO_LIThe stability of the human microbiome varies among individuals and body sites. C_LIO_LIHighly individualized microbial genera are more stable over time. C_LIO_LIAt each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected. C_LIO_LIIndividuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions. C_LI

microbiology↗

HSV-1 ICP0 Dimer Domain Adopts a Novel β-barrel Fold

Infected cell protein 0 (ICP0) is an immediate-early regulatory protein of herpes simplex virus 1 (HSV-1) that possesses E3 ubiquitin ligase activity. ICP0 transactivates viral genes, in part, through its C-terminal dimer domain (residues 555-767). Deletion of this dimer domain results in reduced viral gene expression, lytic infection, and reactivation from latency. Since ICP0s dimer domain is associated with its transactivation activity and efficient viral replication, we wanted to determine the structure of this specific domain. The C-terminus of ICP0 was purified from bacteria and analyzed by X-ray crystallography to solve its structure. Each subunit or monomer in the ICP0 dimer is composed of nine {beta}-strands and two -helices. Interestingly, two adjacent {beta}-strands from one monomer "reach" into the adjacent subunit during dimer formation, generating two {beta}-barrel-like structures. Additionally, crystallographic analyses indicate a tetramer structure is formed from two {beta}-strands of each dimer, creating a "stacking" of the {beta}-barrels. The structural protein database searches indicate the fold or structure adopted by the ICP0 dimer is novel. The dimer is held together by an extensive network of hydrogen bonds. Computational analyses reveal that ICP0 can either form a dimer or bind to SUMO1 via its C-terminal SUMO-interacting motifs but not both. Understanding the structure of the dimer domain will provide insights into the activities of ICP0 and, ultimately, the HSV-1 life cycle.

microbiology↗

Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication. AUTHOR SUMMARYThe conserved CoV macrodomain (Mac1) counters the activity of host ADP-ribosyltransferases by removing ADP-ribose from target proteins and is critical for CoV replication and pathogenesis. Mac1 is a potential therapeutic target for CoV disease and several groups are actively developing Mac1 inhibitors. However, we lack a basic knowledge of how many of the key residues in the Mac1 ADP-ribose binding pocket contribute to its biochemical and virological functions. In this study, we engineered alanine mutations into two highly conserved residues in the ADP-ribose binding pocket of Mac1, both as recombinant proteins and recombinant viruses for both MERS-CoV and SARS-CoV-2 to determine their importance in both Mac1 biochemical functions and CoV infection. Interestingly, an isoleucine-to-alanine mutation in loop 2 of both MERS-CoV and SARS-CoV-2 Mac1 proteins enhanced ADP-ribose binding. But surprisingly, that proved to be detrimental to virus infection, indicating that this isoleucine functions to control Mac1 ADP-ribose binding and is beneficial for virus replication and pathogenesis. These results provide unique insight into how macrodomains control ADP-ribose binding to promote infection and will be critical for the development of novel inhibitors targeting Mac1 that could be used to treat CoV-induced disease.

microbiology↗

Adaptive IRE1 Signaling Elicits T Cell Metabolic Remodeling and Tumor Control

The efficacy of cancer immunotherapies is limited by the metabolic instability of the tumor microenvironment (TME) that disables T cell antitumor immunity. Metabolic imbalances within the TME are sensed and responded to by stress sensors of the endoplasmic reticulum (ER) unfolded protein response (UPR). The UPR comprises three integrated signaling pathways harboring both adaptive and deleterious phases based on the extent and duration of cell stress. Here, we elucidate the differential contributions of adaptive and deleterious signaling downstream of the UPR IRE1 pathway in T cell-regulated tumor control. T cells in murine and patient cancers experience persistent ER stress, leading to hyperactive IRE1 signaling that limits tumor control. However, amplifying the adaptive arm of the IRE1 UPR serves to eliminate mitochondrial toxicity and protect T cells from chronic ER stress, yielding robust tumor engraftment and long-term tumor immunity. Our findings establish the UPRs essential protective role in antitumor immunity.

immunology↗

Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization and Energy Synthesis in the Tumor Microenvironment

The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, enforcing lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC wholly rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell memory, engendering TILs with increased survival and polyfunctionality, with the ability to control solid cancer.

immunology↗

Molecular evaluation of Conogethes punctiferalis (Guenee, 1854): Species status and intraspecific divergence

Species are not only the fundamental units of taxonomy but also the basic units of pest management. Insects of Conogethes are important agricultural and forestry pests. However, species boundaries within Conogethes often appear obscure. In the present study, we re-evaluated the species status of Conogethes by applying three species delimitation approaches based on the mitochondrial DNA sequences, with particular emphasis on the yellow peach moth C. punctiferalis (Guenee, 1854). We first optimized species delimitation and inter-species genetic divergence threshold using a DNA barcoding dataset. Our results revealed that several nominal species of Conogethes species harbored deeply diverged mitochondrial lineages which were recognized as independent species by the species delimitation methods. The p-distance between the delimited putative species ranged from 0.0159 to 0.1321 with a mean of 0.0841. Then we refined the species status of C. punctiferalis using the smallest interspecific distance threshold based on a geographically comprehensive population-scale dataset. This procedure narrowed the species concept of C. punctiferalis to a genetically coherent unit. Further investigation of its intraspecific divergence in the geographic context revealed that the refined C. punctiferalis was still widely distributed with the same or highly similar mitochondrial haplotypes occurring across South and East Asia.

zoology↗

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↗

A resource for probing influences of perinatal factors on neurodevelopment in 3-10-years-old Chinese children

Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on childrens overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence childrens brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3-10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

neuroscience↗

Progressive community, biogeochemical and evolutionary remodeling of the soil microbiome underpins long-term desert ecosystem restoration

Ecological restoration of degraded lands is essential to human sustainability. Yet, an in-depth community, functional, and evolutionary microbial perspective of long-term restoration of damaged ecosystems is lacking. Herein, we comprehensively assessed the impact of long-term (up to 17 years) restoration of Tengger Desert, China, by multi-omic profiling of 1,910 topsoil samples. The soil biophysiochemical properties, especially soil hydraulics, microbiome stability, and functional diversity, significantly improved during restoration. The soil microbiome transitioned from an extreme oligotrophic and autotrophic community to a diverse copiotrophic ecosystem. The soil microbiota, including fungi, could mediate the soil physicochemical changes through metabolites. Importantly, the systematic rewiring of nutrient cycles featured the multi-domain preference of an efficient carbon fixation strategy in the extreme desert environment. Finally, the microbiome was evolving via positive selections of genes of biogeochemical cycles, resistance, and motility. In summary, we present a comprehensive community, functional, biogeochemical, and evolutionary landscape of the soil microbiome during the long-term restoration of desert environments. We highlight the crucial microbial role in restoration from soil hydraulic and biogeochemical perspectives, offering promising field applications. HighlightsO_LIThe desert soil microbiome transformed from simple oligotrophic to a diverse, stable, and nutrient-rich ecosystem with expanded functional diversity. C_LIO_LIRestoration led to systematically rewired biogeochemical cycles, which are highly efficient in carbon fixation in the desert environment. C_LIO_LIThe microbiome was evolving via positive selections of genes involved in biogeochemical cycles and environmental adaptations. C_LIO_LIMicrobes and metabolites could facilitate desert restoration from hydraulic and biogeochemical aspects, offering promising field applications. C_LI

microbiology↗