Biology subjects

Wang, Q.

Publications and source records attributed to Wang, Q..

At least 343 records · Page 19Linked to original sources

bioRxiv2024

The Rhizobial effector NopT targets Nod factor receptors to regulate symbiosis in Lotus japonicus

It is well-documented that type-III effectors are required by Gram-negative pathogens to directly target different host cellular pathways to promote bacterial infection. However, in the context of legume-rhizobium symbiosis, the role of rhizobial effectors in regulating plant symbiotic pathways remains largely unexplored. Here, we show that NopT, a YopT-type cysteine protease of Sinorhizobium fredii NGR234 directly targets the plants symbiotic signaling pathway by associating with two Nod factor receptors (NFR1 and NFR5 of Lotus japonicus). NopT inhibits cell death triggered by co-expression of NFR1/NFR5 in Nicotiana benthamiana. Full-length NopT physically interacts with NFR1 and NFR5. NopT proteolytically cleaves NFR5 both in vitro and in vivo, but can be inactivated by NFR1 as a result of phosphorylation. NopT plays an essential role in mediating rhizobial infection in L. japonicus. Autocleaved NopT retains the ability to cleave NFR5 but no longer interacts with NFR1. Interestingly, genomes of certain Sinorhizobium species only harbor nopT genes encoding truncated proteins without the autocleavage site. These results reveal an intricate interplay between rhizobia and legumes, in which a rhizobial effector protease targets NFR5 to suppress symbiotic signaling. NFR1 appears to counteract this process by phosphorylating the effector. This discovery highlights the role of a bacterial effector in regulating a signaling pathway in plants and opens up the perspective of developing kinase-interacting proteases to fine-tune cellular signaling processes in general. One-sentence summaryThe rhizobial effector NopT and two Nod factor receptors of Lotus japonicus, NFR1 and NFR5, mutually interact to precisely regulate rhizobial symbiosis.

plant biology↗

bioRxiv2024

SARS-CoV-2 Omicron BA.2.87.1 Exhibits Higher Susceptibility to Serum Neutralization Than EG.5.1 and JN.1

As SARS-CoV-2 continues to spread and mutate, tracking the viral evolutionary trajectory and understanding the functional consequences of its mutations remain crucial. Here, we characterized the antibody evasion, ACE2 receptor engagement, and viral infectivity of the highly mutated SARS-CoV-2 Omicron subvariant BA.2.87.1. Compared with other Omicron subvariants, including EG.5.1 and the current predominant JN.1, BA.2.87.1 exhibits less immune evasion, reduced viral receptor engagement, and comparable infectivity in Calu-3 lung cells. Intriguingly, two large deletions ({Delta}15-26 and {Delta}136-146) in the N-terminal domain (NTD) of the spike protein facilitate subtly increased antibody evasion but significantly diminish viral infectivity. Collectively, our data support the announcement by the USA CDC that the public health risk posed by BA.2.87.1 appears to be low.

microbiology↗

bioRxiv2024

Brain-wide neuronal circuit connectome of human glioblastoma

Glioblastoma (GBM), a universally fatal brain cancer, infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression1-6. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic7-9. The extent of integration of GBM cells into brain-wide neuronal circuitry is not well understood. Here we applied a rabies virus-mediated retrograde monosynaptic tracing approach10-12 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrated into brain-wide neuronal circuits and exhibited diverse local and long-range connectivity. Beyond glutamatergic inputs, we identified a variety of neuromodulatory inputs across the brain, including cholinergic inputs from the basal forebrain. Acute acetylcholine stimulation induced sustained calcium oscillations and long-lasting transcriptional reprogramming of GBM cells into a more invasive state via the metabotropic CHRM3 receptor. CHRM3 downregulation suppressed GBM cell invasion, proliferation, and survival in vitro and in vivo. Together, these results reveal the capacity of human GBM cells to rapidly and robustly integrate into anatomically and molecularly diverse neuronal circuitry in the adult brain and support a model wherein rapid synapse formation onto GBM cells and transient activation of upstream neurons may lead to a long-lasting increase in fitness to promote tumor infiltration and progression.

cancer biology↗

bioRxiv2024

Compartment-Specific Antibody Correlates of Protection to SARS-CoV-2 Omicron in Macaques

Antibodies represent a primary mediator of protection against respiratory viruses such as SARS-CoV-2. Serum neutralizing antibodies (NAbs) are often considered a primary correlate of protection. However, detailed antibody profiles including characterization of antibody functions in different anatomic compartments are not well understood. Here we show that antibody correlates of protection against SARS-CoV-2 challenge are different in systemic versus mucosal compartments in rhesus macaques. In serum, neutralizing antibodies were the strongest correlate of protection and were linked to Spike-specific binding antibodies and other extra-neutralizing antibody functions that create a larger protective network. In contrast, in bronchiolar lavage (BAL), antibody-dependent cellular phagocytosis (ADCP) proved the strongest correlate of protection rather than NAbs. Within BAL, ADCP was linked to mucosal Spike-specific IgG, IgA/secretory IgA, and Fc{gamma}-receptor binding antibodies. Our results support a model in which antibodies with different functions mediate protection at different anatomic sites. The correlation of ADCP and other Fc functional antibody responses with protection in BAL suggests that these antibody responses may be critical for protection against SARS-CoV-2 Omicron challenge in mucosa.

immunology↗

bioRxiv2024

Molecular regulation of Bna1205ams1 required for male fertility and development of a recessive genic male-sterility system in Brassica napus

Through the comprehensive use of two pollination control systems of cytoplasmic male sterility (CMS) and genic male sterility (GMS), the rapeseed yield was increased by more than 20%. However, more hybrid production systems and detailed mechanisms underlying male sterility are required. Here, we reported a novel two-line hybrid production system of 1205A for GMS and also investigated the underlying mechanism for male sterility. Five co-segregated kompetitive allele specific PCR (KASP) markers were developed and validated, which could be used for transferring the male sterility trait into external B. napus breeding lines and developing further two-line hybrid production systems of GMS. Inheritance studies detected one gene locus of Bna1205ams1 for regulating the male sterility of 1205A. As a potential candidate gene of Bna1205ams1, BnaC03g27700D was fine mapped and narrowed down to a 181.47 kb region on chrC03 and validated by functional analysis. The mutation of BnaC03g27700D in 1205A resulted in large metabolic fluctuations, most of which were involved in aborted tapetal PCD, which could lead to reduced pollen fertility with abnormal pollen exine. The developed new GMS line of 1205AB provided us with the opportunity to identify a new male sterility gene of BnaC03g27700D in B. napus. The study of BnaC03g27700D aims to renew the annotation of the gene and provide new resources for basic research on the genetic control of male sterility.

molecular biology↗

bioRxiv2024

Unconventional IFNω-like genes dominate the type I IFN locus and the constitutive antiviral responses in bats

Bats are the natural reservoir hosts of some viruses, some of which may spillover to humans and cause global-scale pandemics. Different to humans, bats may coexist with high pathogenic viruses without showing symptoms of diseases. As one of the most important first defenses, bat type I interferon (IFN-Is) were thought to play a role during this virus coexistence and thus were studied in recent years. However, there are arguments that whether bats have a contracted genome locus or constitutive expressed IFNs, mainly due to species-specific findings. We hypothesized that because of the lacking of pan-bat analysis, the common characters for bat IFN-Is have not been revealed yet. Here, we characterized the IFN-I locus for 9 Yangochiroptera bats and 3 Yinpterochiroptera based on the their high quality bat genomes. We also compared the basal expression for 6 bats and compared the antiviral, anti-proliferative activity and thermo-stability of a representative Rhinolophus bat IFNs. We found a dominance of unconventional IFN{omega}-like responses in the IFN-I system, which is unique to bats. In contrast to IFNa-dominated IFN-I loci in the majority of other mammals, bats generally have shorter IFN-I loci with more unconventional IFN{omega}-like genes (IFN{omega} or related IFNa{omega}), but with less or even no IFNa genes. In addition, bats generally have constitutively expressed IFNs, the highest expressed of which is more likely an IFN{omega}-like gene. Likewise, the highly expressed IFN{omega}-like protein also demonstrated the best antiviral activity, anti-proliferative activity or thermo-stability, as shown in a representative Rhinolophus bat species. Overall, we revealed pan-bat unique characteristics in IFN-I system, which provide insights into our understanding of the innate immunity that contribute to a special coexistence between bats and viruses.

immunology↗

bioRxiv2024

Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer

Triple-negative breast cancer (TNBC) relies on glutamine uptake by the transporter ASCT2 to sustain their unique glutamine metabolism and growth. Despite previous data showing cell growth inhibition after ASCT2 knockdown, ASCT2 CRISPR knockout was well-tolerated by breast cancer cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady state levels were higher in ASCT2 knockout compared to control TNBC cells. Proteomics data revealed upregulation of macropinocytosis, reduction in glutamine efflux and glutamine synthesis in ASCT2 knockout cells. Loss of ASCT2 in TNBC cell line HCC1806 induced a 5-10-fold increase in macropinocytosis across 5 separate ASCT2 knockout clones, compared to a modest 2-fold increase in the shRNA ASCT2 knockdown. By comparison, ASCT2 knockout impaired cell proliferation in a non-macropinocytic breast cancer cell line, HCC1569. These data suggest that macropinocytosis provides a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, which suggests therapeutic targeting may need to focus on downstream glutamine metabolism pathways.

cancer biology↗

bioRxiv2024

Unveiling neoadjuvant chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing

BackgroundChemotherapy is widely used to treat lung adenocarcinoma (LUAD) patients comprehensively. Considering the limitations of chemotherapy due to drug resistance and other issues, it is crucial to explore the impact of chemotherapy and immunotherapy on these aspects. Methods and MaterialsTumor samples from nine LUAD patients, of which four only received surgery and five received neoadjuvant chemotherapy, were subjected to scRNA-seq analysis. In vitro and in vivo assays, including flow cytometry, immunofluorescence, Seahorse assay, and tumor xenograft models, were carried out to validate our findings. ResultsA total of 83,622 cells were enrolled for subsequent analyses. The composition of cell types exhibited high heterogeneity across different groups. Functional enrichment analysis revealed that chemotherapy drove significant metabolic reprogramming in tumor cells and macrophages. We identified two subtypes of macrophages: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG+) and sorted them by flow cytometry. The proportion of Pro-mac cells in lung adenocarcinoma tissues increased significantly after neoadjuvant chemotherapy. Pro-mac cells promote tumor growth and angiogenesis and also suppress tumor immunity. Moreover, through analyzing the remodeling of T and B cells induced by neoadjuvant therapy, we noted that chemotherapy ignited a relatively more robust immune cytotoxic response towards tumor cells. ConclusionOur study demonstrates that chemotherapy induces metabolic reprogramming within the TME of LUAD, particularly affecting the function and composition of immune cells such as macrophages and T cells. We believe our findings will offer insight into the mechanisms of drug resistance and provide novel therapeutic targets for LUAD in the future.

cancer biology↗

bioRxiv2024

Robust SARS-CoV-2 Neutralizing Antibodies Sustained through Three Months Post XBB.1.5 mRNA Vaccine Booster

SARS-CoV-2-neutralizing antibodies were substantially expanded one month after a shot of XBB.1.5 monovalent mRNA vaccine (XBB.1.5 MV) booster, but the durability of this response remained unknown. Here, we addressed this question by performing neutralization assays on four viral variants (D614G, BA.5, XBB.1.5, and JN.1) using sera from 39 adult participants obtained at [~]1 month and [~]3 months post an XBB.1.5 MV booster. Our findings indicate that the resultant neutralizing antibody titers were robust and generally maintained at stable levels for the study period, similar to those following XBB infection. Importantly, this durability of neutralizing antibody titers contrasts with the decline observed after a booster of the original monovalent or BA.5 bivalent mRNA vaccine. Our results are in line with the recent national data from the Centers for Disease Control and Prevention, showing the efficacy against symptomatic SARS-CoV-2 infection is sustained for up to 4 months after an XBB.1.5 MV booster.

immunology↗

bioRxiv2024

Division of labour underlies efficient colony defence in a clonal ant

The ecological success of social insects is often credited to the division of labour (DOL), yet empirical evidence directly linking DOL to colony efficiency is rare, in part because variation in DOL between colonies is often confounded by variation in colony traits (e.g., group size, genetic diversity) that can independently affect group efficiency. Here, we measure the link between DOL and efficiency in a crucial task, colony defence, in a social insect that affords precise experimental control over relevant individual and colony traits, the clonal raider ant (Ooceraea biroi). We find that DOL in defence behaviour emerges within colonies of near-identical workers, and is consistently associated with enhanced defence efficiency. This positive relationship is robust to variation in the social environment (group size and the presence and type of brood), indicating that the extent of behavioural variation between members of a social group can serve as a key indicator of group efficiency.

animal behavior and cognition↗

bioRxiv2024

Upregulation of the Proto-Oncogene Src Kinase in Alzheimer's Disease: From Molecular Interactions to Therapeutic Potential

Alzheimers disease (AD) is a progressive neurodegenerative disease, resulting in an irreversible deterioration of multiple brain regions associated with cognitive dysfunction. Phosphorylation of the microtubule-associated protein, Tau, is known to occur decades before symptomatic AD. The Src family of tyrosine kinases are known to phosphorylate select tyrosine sites on Tau and promote microtubule disassembly and subsequent neurofibrillary tangle (NFT) formation. Our data show that the proto-oncogene, non-receptor tyrosine kinase Src colocalizes with a range of late (PHF1) to early (MC1) AD-associated phosphorylated Tau epitopes. The strongest co-occurrence is seen with MC1 (probability of MC1 given Src =100%), an early AD-specific conformational dependent epitope. Single-cell RNA sequencing data of 101 subjects show that Src is upregulated in both AD inhibitory and excitatory neurons. The most significantly affected, by orders of magnitude, were excitatory neurons which are the most prone to pathological Tau accumulation. We measured Src phosphorylation by mass spectrometry across a cohort of 48 patient neocortical tissues and found that Src has increased phosphorylation on Ser75, Tyr187, and Tyr440 in AD, showing that Src kinase undergoes distinct phosphorylation alterations in AD. Through Brownian dynamics simulations of Src and Tau, we show that as Tau undergoes the transition into disease-associated paired helical filaments, there is a notable seven-fold increase in Src contact with Tau. These results collectively emphasize Src kinases central role in Tau phosphorylation and its close association with Tau epitopes, presenting a promising target for potential therapeutic intervention.

neuroscience↗

bioRxiv2024

ChineseEEG: A Chinese Linguistic Corpora EEG Dataset for Semantic Alignment and Neural Decoding

An Electroencephalography (EEG) dataset utilizing rich text stimuli can advance the understanding of how the brain encodes semantic information and contribute to semantic decoding in brain-computer interface (BCI). Addressing the scarcity of EEG datasets featuring Chinese linguistic stimuli, we present the ChineseEEG dataset, a high-density EEG dataset complemented by simultaneous eye-tracking recordings. This dataset was compiled while 10 participants silently read approximately 11 hours of Chinese text from two well-known novels. This dataset provides long-duration EEG recordings, along with pre-processed EEG sensor-level data and semantic embeddings of reading materials extracted by a pre-trained natural language processing (NLP) model. As a pilot EEG dataset derived from natural Chinese linguistic stimuli, ChineseEEG can significantly support research across neuroscience, NLP, and linguistics. It establishes a benchmark dataset for Chinese semantic decoding, aids in the development of BCIs, and facilitates the exploration of alignment between large language models and human cognitive processes. It can also aid research into the brains mechanisms of language processing within the context of the Chinese natural language.

neuroscience↗

bioRxiv2024

The nanoscale organization of the Nipah virus fusion protein informs new membrane fusion mechanisms.

Paramyxovirus membrane fusion requires an attachment protein for receptor binding and a fusion protein for membrane fusion triggering. Nipah virus (NiV) attachment protein (G) binds to ephrinB2 or -B3 receptors, and fusion protein (F) mediates membrane fusion. NiV-F is a class I fusion protein and is activated by endosomal cleavage. The crystal structure of a soluble GCN4-decorated NiV-F shows a hexamer-of-trimer assembly. Here, we used single-molecule localization microscopy to quantify the NiV-F distribution and organization on cell and virus-like-particle membranes at a nanometer precision. We found that NiV-F on biological membranes forms distinctive clusters that are independent of endosomal cleavage or expression levels. The sequestration of NiV-F into dense clusters favors membrane fusion triggering. The nano-distribution and organization of NiV-F are susceptible to mutations at the hexamer-of-trimer interface, and the putative oligomerization motif on the transmembrane domain. We also show that NiV-F nanoclusters are maintained by NiV-F-AP-2 interactions and the clathrin coat assembly. We propose that the organization of NiV-F into nanoclusters facilitates membrane fusion triggering by a mixed population of NiV-F molecules with varied degrees of cleavage and opportunities for interacting with the NiV-G/receptor complex. These observations provide insights into the in-situ organization and activation mechanisms of the NiV fusion machinery.

microbiology↗

bioRxiv2024

Optogenetic Locus Coeruleus Stimulation Improves Pupil Size Tracking of Cortical State

Brain state heavily influences our perception, cognition, and behavior. Multiple neuromodulatory systems, including the locus coeruleus - norepinephrine (LC-NE) system, contribute to the regulation of brain state. This research harnesses machine learning and optogenetics technologies to probe the impact of the LC on cortical state and pupillary responses in awake mice. Our integrative approach combines EEG recordings with pupillometry to capture the LCs optogenetic activation, evoking notable EEG spectral power shifts synchronized with pupil dilation. These changes provide a noninvasive glimpse into the cortical states, modulated by the LCs activity. Central to our methodology is the application of Support Vector Regression (SVR) modeling, which robustly correlates LC-induced pupillary changes with EEG power fluctuations. These insights help reinforce the LCs crucial role in modulating prefrontal activity and its regulatory influence over arousal states. Beyond advancing our comprehension of the LCs function, our work also highlights the potential for developing closed-loop stimulation systems. These systems, integrated with machine-learning techniques and multi-modal data, could offer precise therapeutic interventions for neurological disorders characterized by abnormal arousal states.

neuroscience↗

bioRxiv2024

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, causing sensory loss and debilitating neuropathic pain1,2. Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia3, the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and the diabetic metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is detectable. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages4 and express neurodegeneration-associated microglia marker genes5 although there is no axon loss or demyelination. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings reveal a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.

neuroscience↗

bioRxiv2024

Ligand supplementation restores the cancer therapy efficacy of an antirheumatic drug auranofin from serum inactivation

Auranofin, an FDA-approved antirheumatic gold drug, has gained ongoing interest in clinical studies for treating advanced or recurrent tumors. However, gold ions dynamic thiol exchange nature strongly attenuates its bioactivity due to the fast formation of covalent albumin-gold adducts. Here we report that newly-added thiols can modulate the dynamic albumin-gold binding and recover the therapeutic efficacy. Initially, we found that auranofin supplemented with its own thiol ligand, TGTA (1-thio-{beta}-D-glucose tetraacetate), significantly restored the anticancer activities in cells and patient-derived xenograft models. Then, screening a collection of ligand fragments followed by machine learning evaluation unveiled diverse synergizing thiols, including pantethine that effectuates auranofin at a low dosage used for rheumatoid arthritis. Interestingly, the thiol exchange inside cells accounts for a cuproptosis-like phenotype induced by auranofin. Together, we believe the ligand-enabled dynamic modulation strategy is of value to researchers and clinicians contemplating metallodrugs and ligand-like molecules in cancer therapy.

cancer biology↗

bioRxiv2024

PHOSPHATE-INDUCED 1 and its paralogs positively regulate cellulose biosynthesis in Arabidopsis.

Cellulose is not only the most abundant biopolymer on Earth but also an essential multi-purpose resource, primarily synthesized by cellulose synthase complexes (CSCs) located on plasma membrane in vascular plants. Although insights into the functions of CSCs have been provided by the identification of cellulose synthase catalytic subunits, our understanding of the regulation of CSC activity remains limited. In this study, combining molecular and genetic methods, we demonstrated that both PHI-1 and its paralogs residing in the plasma membrane are involved in the cellulose biosynthesis regulation as a positive regulatory component of CSCs by feeding developmental and environmental cues into their activities in Arabidopsis (Arabidopsis thaliana). Our finding reveals a mechanism for how plants regulate cellulose synthesis in response to developmental and environmental signals, and thus improves the likelihood that cellulose biosynthesis could be feasibly adapted for sustainable purposes.

plant biology↗

bioRxiv2024

Biologically Driven In Vivo Occlusion Design Provides a Reliable Experimental Glaucoma Model

Fluid transport through the trabecular meshwork is a major regulator of intraocular pressure in healthy and glaucomatous eyes. Existing microbead occlusion models enable in vivo study of pressure-related glaucomatous pathology, but their long-term reliability is limited by inadequate bead-tissue interface design. Inspired by the graded porous architecture and fluid-transport function of the trabecular meshwork, we develop an injectable Viscobeads platform for sustained modulation of aqueous humor outflow. These composite microbeads integrate a non-degradable polystyrene core for structural support with a biodegradable poly(lactic-co-glycolic acid) viscoelastic shell that improves mechanical adaptation to heterogeneous trabecular meshwork fenestrations. This biologically informed design enhances outflow obstruction and enables stable IOP elevation for at least 8 weeks after a single injection. In mice, Viscobeads induce sustained ocular hypertension (average 21.4 mm Hg) and lead to a 34% loss of retinal ganglion cells by day 56. Pattern electroretinogram and flash visual evoked potential measurements further reveal early retinal ganglion cell dysfunction followed by later visual pathway impairment. Beyond disease induction, this platform supports in vivo gene screening for retinal ganglion cell survival and identifies altered sleep behavior during glaucoma progression. This work establishes a materials-driven strategy for chronic ocular hypertension modeling and therapeutic evaluation.

biophysics↗