Biology subjects

Liu, R.

Publications and source records attributed to Liu, R..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Glo1 reduction in mice results in age- and sex-dependent metabolic dysfunction

ObjectivesAdvanced glycation end products (AGEs) have been implicated as an important mediator of metabolic disorders including obesity, insulin resistance, and coronary artery disease. Glyoxalase 1 (Glo1) is a critical enzyme in the clearance of toxic dicarbonyl such as methylglyoxal, precursors of AGEs. The role of AGE-independent mechanisms that underly Glo1-induced metabolic disorders have yet to be elucidated. MethodsWe performed a longitudinal study of female and male Glo1 heterozygous knockdown (Glo1+/-) mice with [~]50% gene expression and screened metabolic phenotypes such as body weight, adiposity, glycemic control and plasma lipids. We also evaluated atherosclerotic burden, AGE levels, and gene expression profiles across cardiometabolic tissues (liver, adipose, muscle, kidney and aorta) to identify pathway perturbations and potential regulatory genes of Glo1 actions. ResultsPartial loss of Glo1 resulted in obesity, hyperglycemia, dyslipidemia, and alterations in lipid metabolism in metabolic tissues in an age- and sex-dependent manner. Glo1+/- females displayed altered glycemic control and increased plasma triglycerides, which aligned with significant perturbations in genes involved in adipogenesis, PPARg, insulin signaling, and fatty acid metabolism pathways in liver and adipose tissues. Conversely, Glo1+/- males developed increased skeletal muscle mass and visceral adipose depots along with changes in lipid metabolism pathways. For both cohorts, most phenotypes manifested after 14 weeks of age. Evaluation of methylglyoxal-derived AGEs demonstrated changes in only male skeletal muscle but not in female tissues, which cannot explain the broad metabolic changes observed in Glo1+/-mice. Transcriptional profiles suggest that altered glucose and lipid metabolism may be partially explained by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Moreover, transcription factor (TF) analysis of the tissue-specific gene expression data identified TFs involved in cardiometabolic diseases such as Hnf4a (all tissues) and Arntl (aorta, liver, and kidney) which are female-biased regulators and whose targets are altered in response to Glo1+/-. ConclusionsOur results indicate that Glo1 reduction perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without significant changes in AGEs across metabolic tissues. Rather, tissue-specific gene expression analysis suggests that key transcription factors such as Hfn4a and Arntl as well as metabolite changes from alternative methylglyoxal detoxification such as pyruvate, likely contribute to metabolic dysregulation in Glo1+/- mice.

molecular biology↗

bioRxiv2025

Follicular mural granulosa cells stockpile glycogen to fuel corpus luteum pre-vascularization

The corpus luteum (CL) arises from the luteinization of follicular granulosa cells (GCs) and theca cells, marked by rapid progesterone elevation and angiogenesis. Intriguingly, angiogenesis lags behind progesterone elevation, creating an avascular phase during which luteal cells must fuel intensive steroidogenesis without perfusion. How the avascular CL meets this energetic demand remains a mystery. Here, we reveal a novel cellular adaptive mechanism-GC energy storage (GCES)-that resolves this enigma. We demonstrate that upon luteinization initiation, GCs enter a metabolically quiescent state yet enhance glucose uptake via SLC2A1, converting the glucose into glycogen through the hCG (LH)-MAPK-RUNX1-Insulin signaling axis. Catabolism of this glycogen reserve supplies the energy required for the avascular CL, ensuring normal luteogenesis. GCES is evolutionarily conserved across species. Genetic or pharmacological disruption of GCES or glycogenolysis induces luteal insufficiency, whereas timely glucose administration enhances GCES, improving luteal function and optimize reproductive outcome in both mouse and ovine models. In human study, orally intake of glucose post-hCG significantly augments GCES and enhances progesterone production in women. These results advance luteal physiology by uncovering a universal reproductive principle with direct clinical implications.

developmental biology↗

bioRxiv2025

Distinct cell types along thick ascending limb express pathways for monovalent and divalent cation transport

Kidney thick ascending limb cells reabsorb sodium, potassium, calcium, and magnesium and contribute to urinary concentration. These cells are typically viewed as of a single type that recycles potassium across the apical membrane and generates a lumen-positive transepithelial voltage driving calcium and magnesium reabsorption, although variability in potassium channel expression has been reported. Additionally, recent transcriptomic analyses suggest that different cell types exist along this segment, but classifications have varied and have not led to a new consensus model. We used immunolocalization, electrophysiology and enriched single nucleus RNA-Seq to identify thick ascending limb cell types in rat, mouse and human. We identified three major TAL cell types defined by expression of potassium channels and claudins. One has apical potassium channels, low basolateral potassium conductance, and is bordered by a sodium-permeable claudin. A second lacks apical potassium channels, has high basolateral potassium conductance and is bordered by calcium- and magnesium-permeable claudins. A third type also lacks apical potassium channels and has a high basolateral potassium conductance, but these cells are ringed by sodium-permeable claudins. The recognition of diverse cell types resolves longstanding questions about how solute transport can be modulated selectively and how disruption of these cells leads to human disease.

physiology↗

bioRxiv2025

Local nucleolar surveillance mechanisms maintain rDNA stability

The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. The highly repetitive and transcribed nature of the rRNA genes (rDNA) by RNA polymerase I (Pol I) poses a challenge for DNA repair and replication machineries. Here, we profile the nucleolar proteome and the chromatin landscape of stalled replication sites upon rDNA damage to characterize the early steps of nucleolar DNA damage response (nDDR). We observed early dynamics in nucleolar-nucleoplasmic proteome localization and identified nucleolar replication stress signatures involving chromatin remodeling networks, transcription-replication conflicts and DNA repair. Our findings define localized surveillance mechanisms that activate the nDDR. Further, we identified that upon rDNA damage, nucleolar RNA Polymerase (Pol) II binds to intergenic rDNA sequences and generates R-loops (DNA:RNA hybrid structures) that are essential for recruiting nDDR factors. Using a boutique CRISPR-Cas9 synthetic lethal screen of DNA repair factors with inhibitors of RNA Pol I transcription, we identified an unexpected protective role for the DNA translocase RAD54L in nDDR. Loss of Rad54L increases nucleolar R-loops and rDNA damage leading to defects in nucleolar structure and enhanced sensitivity to PARP and RNA Pol I inhibitors. Altogether, our study uncovers localized surveillance networks within the nucleolus that respond to rDNA damage. These insights expand our understanding of the molecular mechanisms governing nDDR and opens new avenues for developing nDDR-targeting therapies.

molecular biology↗

bioRxiv2025

Selective Targeting of Pathogenic Tau Seeds via a Novel VHH

In Alzheimers disease (AD) and related tauopathies, progressive pathology has been linked to prion mechanisms, whereby ordered tau assemblies, or "seeds," form in one cell and transit to neighboring or connected cells where they serve as templates for their own replication. Despite intensive efforts to develop early diagnosis and effective treatment, none has emerged. This is due partly to the structural heterogeneity of tau seeds and limitations in selectively targeting their pathogenic conformations. Here we report the discovery of a camelid variable heavy domain of heavy chain (VHH) that preferentially binds tau seeds of AD, corticobasal degeneration (CBD), and PS19 tauopathy mouse brains. From a published synthetic VHH yeast display library, we identified VHH clones that bound 2N4R tau monomer. After counter-screening for immunoprecipitation of seeding from human brain, we identified two seed-selective anti-tau VHH--VHH(510) and VHH(50)--that preferentially bound pathological tau. We enhanced the stability of these VHHs through framework mutations without affecting their seed-binding characteristics. We characterized VHH(510) in detail, determining that it binds the carboxy terminus of tau, maintains robust seed avidity even in the presence of competing monomer, and stains pathological tau inclusions in mouse and human AD tissues. These results highlight the power of seed-selective VHH to bind pathogenic tau, paving the way for future therapeutic and diagnostic applications across a wide range of neurodegenerative disorders.

neuroscience↗

bioRxiv2024

Methyl-CODEC enables simultaneous methylation and duplex sequencing

DNA mutations and methylation often contribute to disease development in a synergistic manner. While duplex sequencing is the most accurate method for detecting DNA mutations, it typically lacks the ability to simultaneously assess methylation or requires many reads. Here, we developed Methyl-CODEC to enable simultaneous methylation sequencing and duplex sequencing using single read pairs. To achieve this, Methyl-CODEC links an enzymatically deaminated sense strand to the reverse complement of the antisense strand, which is protected from conversion by using conversion-resistant dCTPs in the strand linking step of CODEC. Methyl-CODEC shows high concordance with standard enzymatic or bisulfite based whole genome methylation sequencing, while also uniquely preserving the original DNA sequence. This improves genetic sequencing accuracy, enables better alignment for next-generation sequencing (NGS), and distinguishes C>T mutations from unmethylated Cs. It also identifies rare mutations including those producing methylated Cs, which are enriched in CpG contexts. Methyl-CODEC opens new horizons for enhanced detection of biomarkers in cancer and molecular medicine.

genomics↗

bioRxiv2024

Non-continuous neuromodulation in awake, unrestrained felines increases bladder capacity

ObjectiveNeuromodulation is a standard therapy for bladder symptoms such as overactive bladder. Previous studies have demonstrated that non-continuous stimulation (NCS) can increase bladder capacity and that bladder pressure can be estimated from dorsal root ganglia (DRG) neural activity in anesthetized animal models. Our goal is to determine if NCS elicits similar bladder capacity effects as continuous stimulation (CS) and if bladder pressure can be estimated from DRG signals in an awake, unrestrained animal model. ApproachWe performed aseptic, chronic implant surgeries with seven adult, male felines. Three animals were used to establish procedures, three for experimental testing, and one did not yield data. Bipolar stimulating electrodes were placed on the pudendal nerve and sacral nerve on the same side. Microelectrode arrays were inserted in two ipsilateral sacral DRG. Two single-lumen catheters were implanted in the bladder dome for recording bladder pressure and infusing saline. Fixed-sequence, repeated bladder fills were performed in four awake felines to evaluate the bladder capacity during no-stimulation (NS), NCS, and CS at either the pudendal or sacral nerve. NCS was performed based on increases in bladder pressure estimated from DRG recordings or when 50% of the average NS bladder capacity was reached. Main resultsWe observed similar bladder capacity increases for NCS (122 {+/-} 31% of NS control) as for CS (121 {+/-} 33%) in the four animals. NCS paradigms reduced stimulation time by 46% on average. Median correlation coefficients of 0.46 and 0.64 (maximum 0.93) between the predicted and measured bladder pressure were obtained for awake trials with DRG bladder units in two animals. SignificanceThis study demonstrated the feasibility of using NCS to increase bladder capacity in awake, unrestrained felines and for decoding bladder pressure from DRG recordings. Further studies are needed to optimize NCS timing for clinical translation.

bioengineering↗

bioRxiv2024

Physiological activity within peripheral nerves influences neural output in response to electrical stimulation: an in vivo study

Neuromodulation therapies are often applied to peripheral nerves. These nerves can have physiological activity that interacts with the activity evoked by electrical stimulation, potentially influencing targeted neural output and clinical outcomes. Our goal was to quantify changes in sensory neural unit activity in response to variations in electrical stimulation frequency and amplitude. In a feline model, we applied cutaneous brushing to evoke pudendal nerve afferent activity with and without electrical stimulation via a pudendal nerve cuff electrode. We recorded neural output with microelectrode arrays implanted in ipsilateral sacral dorsal root ganglia (DRG). Combined inter-spike interval distributions for all DRG units showed ranges of flattening, increases, and shifts in response to electrical stimulation. These distributions and changes within them due to electrical stimulation were largely driven by a select few units. Mixed-effects models revealed that quicker firing units generally decreased in firing rate in response to electrical stimulation and, conversely, slower firing units increased in firing rate. A units underlying firing rate also drove the magnitude of change in mean output firing rate in response to stimulation. Further, the models reported a small, negative correlation between the output mean unit firing rate and the applied electrical stimulation frequency. These results demonstrate the potential impact of electrical stimulation on underlying neural firing activity and output. Peripheral neuromodulation may normalize abnormal firing patterns in nerves contributing to pathological disorders or alter unrelated physiological activity in off-target neurons. These factors should be considered when selecting neuromodulation settings in animal subjects and human patients.

neuroscience↗

bioRxiv2024

A high-resolution meiotic crossover map from single-nucleus ATAC-seq reveals insights into the recombination landscape in mammalian sperm

Meiotic crossovers promote correct chromosome segregation and the shuffling of genetic diversity. However, the measurement of crossovers remains challenging, impeding our ability to decipher the molecular mechanisms that are necessary for their formation and regulation. Here we demonstrate a novel repurposing of the single-nucleus Assay for Transposase Accessible Chromatin with sequencing (snATAC-seq) as a simple and high-throughput method to identify and characterise meiotic crossovers from sperm nuclei. We first validate the feasibility of obtaining genome-wide coverage from snATAC-seq by using ATAC-seq on bulk haploid mouse sperm, ensuring adequate variant detection for haplotyping. Subsequently, we adapt droplet-based snATAC-seq for crossover detection, revealing over 25,000 crossovers in F1 hybrid mice. Comparison between wildtype and a hyper-recombinogenic Fancm-deficient mutant mouse model confirmed an increase in crossover rates in this genotype, however a distribution which was unchanged. We also find that regions with the highest rate of crossover formation are enriched for DMC1 and PRDM9, with a subset that is further enriched for DMC1 in Fancm-deficient mice. Our findings demonstrate the utility of snATAC-seq as a robust and scalable tool for high-throughput crossover detection, offering insights into meiotic crossover dynamics and elucidating the underlying molecular mechanisms. It is possible that the research presented here with snATAC-seq of haploid sperm could be extended into fertility-related diagnostics.

genetics↗

bioRxiv2024

An AI-Cyborg System for Adaptive Intelligent Modulation of Organoid Maturation

Recent advancements in flexible bioelectronics have enabled continuous, long-term stable interrogation and intervention of biological systems. However, effectively utilizing the interrogated data to modulate biological systems to achieve specific biomedical and biological goals remains a challenge. In this study, we introduce an AI-driven bioelectronics system that integrates tissue-like, flexible bioelectronics with cyber learning algorithms to create a long-term, real-time bidirectional bioelectronic interface with optimized adaptive intelligent modulation (BIO-AIM). When integrated with biological systems as an AI-cyborg system, BIO-AIM continuously adapts and optimizes stimulation parameters based on stable cell state mapping, allowing for real-time, closed-loop feedback through tissue-embedded flexible electrode arrays. Applied to human pluripotent stem cell-derived cardiac organoids, BIO-AIM identifies optimized stimulation conditions that accelerate functional maturation. The effectiveness of this approach is validated through enhanced extracellular spike waveforms, increased conduction velocity, and improved sarcomere organization, outperforming both fixed and no stimulation conditions.

bioengineering↗

bioRxiv2024

Sub-cellular Imaging of the Entire Protein-Coding Human Transcriptome (18933-plex) on FFPE Tissue Using Spatial Molecular Imaging

Single-cell RNA-seq revolutionized single-cell biology, by providing a complete whole transcriptome view of individual cells. Regrettably, this was accomplished only for individual, tissue-dissociated cells. High-plex spatial biology has begun to recover the x, y, and z-coordinates of single-cells, but typically at the expense of far less than whole transcriptome coverage. To solve this problem, Bruker Spatial Biology has accomplished a commercial-grade panel (CosMx(R) Spatial Molecular Imager Whole Transcriptome Panel (WTx)), using 37,872 imaging barcodes, capable of sub-cellular imaging of the entire human protein-coding transcriptome. The imaging barcodes are encoded with 156 bits of information (4 on-cycles and 35 dark-cycles per code), at a Hamming Distance of 4 from each other to achieve a very low false-code detection. Key to achieving this high-plex capability was the ability to manufacture imaging barcodes that require no in-tissue amplification (every barcode is manufactured under GMP to contain exactly 30 fluorescent dyes) and uniform, size-exclusion purified, extremely small imaging barcodes ([~] 20 nm). A detailed study of six different human FFPE tissue types was performed (Colon, Pancreas, Hippocampus, Skin, Breast, Kidney), yielding over 5.4 billion transcripts from 2.7 million cells. We counted over 1,550 transcripts-per-cell on average and observed 900 unique genes per cell (measured as the median). Single fixed-cells containing well over 10,000 subcellularly imaged transcripts were accomplished. Advancing single-cell imaging to the whole transcriptome level opens a single unified approach to accomplish essentially all single-cell experiments, both imaging and non-imaging. Depending upon the sample type (e.g. fixed-cells, organoids, tissue sections, etc.), the transcripts per cell and genes per cell measured using the whole transcriptome panel often exceeds that obtained by the highest-resolution single-cell RNA-seq, can be performed on a single 5 {micro}m FFPE tissue section, with no dissociation bias (every cell is counted). Pathway analysis within the tumor bed of a colon adenocarcinoma sample found evidence of enrichment in pathways suggestive of an aggressive tumor type, and localized ligand-receptor analysis showed spatially restricted patterns related to adhesion, migration, and proliferation. The high-dimensional whole transcriptome data is streamed directly to a cloud-based Spatial Informatics Platform, allowing for the scalable processing of millions-of-single-cells and billions-of-transcripts per operation. The WTx data are combined with high-resolution antibody-based cell-morphology imaging and data-driven machine-learning cell segmentation algorithms, to generate the most complete view of single cell and sub-cellular spatial biology that has ever been obtained.

genomics↗

bioRxiv2024

Biomimetic porous silicon for rationally engineered combination therapy to induce immunogenic cell death

Combined chemo-photothermal therapy (CHT-PTT) is a promising treatment for metastatic cancers. It enables the synergistic induction of immunogenic cell death (ICD), while sensitising suppressive tumour microenvironment to immunotherapy. To induce ICD, the rational design of a combined CHT-PTT regimen remains unclear. In the present study, black porous silicon nanoparticles (BPSi NPs) were utilized as both drug carriers and photothermal conversion agents. To enhance their colloidal stability and homotypic targeting, BPSi NP surfaces were modified with polyethylene glycol and further coated with cancer cell membranes (CMs). Six chemotherapeutic drugs with different cell growth inhibition mechanisms were tested against metastatic MDA-MB-231 breast cancer cells to evaluate their ICD induction potentials. Finally, in the combined CHT-PTT, the effect of temperature was evaluated. Based on the analysis of ICD markers, high-mobility group box 1 and calreticulin proteins, we found that bromodomain-containing protein 4 inhibitor, (+)-JQ-1 (JQ1) was the optimal drug, and the mild-hyperthermia temperature of 45 {degrees}C was the best temperature setting in the combined CHT-PTT to induce ICD. Thus, our study provides rationally designed CHT-PTT regimen for efficient cancer treatment with high efficacy and low side effects.

bioengineering↗

bioRxiv2024

Chaperonin TRiC bridges radial spokes for folding proteins locally translated in mammalian sperm flagella

As animals evolved from external to internal fertilization, sperm flagella, which once transiently propelled sperm in water to reach nearby eggs, developed to beat for days or even longer within the female reproductive tract. How flagella were remodeled accordingly remains unclear. Unlike externally fertilizing zebrafish and sea urchin, mammalian sperm flagella feature a unique barrel-shaped bridge between axonemal radial spokes RS1 and RS2, though its components and function remain unknown. Here, using cryo-EM and cryo-ET combined with mass spectrometry and immunofluorescence staining, we reveal that this RS1-RS2 barrel (RRB) in mammalian sperm flagella is a group II chaperonin TRiC/CCT. We purified and resolved the unforeseen cryo-EM structure of TRiC from bovine sperm flagella, discovering that flagella TRiC contains the testis-specific CCT6B subunit. Additionally, we resolved the cryo-ET map of mouse sperm flagella RSs, containing the RRB, achieving unprecedented local resolution of 10-14 [A]. The in-situ RRB map displays two extra densities within its chambers in a polarized manner, suggesting the presence of folding substrates and a co-chaperone (likely phosducin-like 2). Notably, mammalian flagella also contain components of translation machineries and actively synthesize proteins. Our results suggest that the RRB TRiC folds locally translated proteins to sustain mammalian flagella, providing new insights into flagellar remodeling in internally fertilizing species. Our findings also shed lights on male fertility and potential treatments for infertility.

biophysics↗

bioRxiv2024

Functional Connectivity Alterations in Cocaine Use Disorder: Insights from the Triple Network Model and the Addictions Neuroclinical Assessment Framework

Cocaine use disorder (CUD) disrupts functional connectivity within key brain networks, specifically the default mode network (DMN), salience network (SN), and central executive network (CEN). While the triple network model has been proposed to explain various psychiatric disorders, its applicability to CUD requires further exploration. In the present study, we built machine learning classifiers based on different combinations of DMN/SN/CEN to distinguish cocaine-use disorder (CUD) subjects from healthy control (HC) subjects. Among them, the combination of the SN and the CEN results in a remarkably high accuracy of 73.4% (sensitivity/specificity: 69.6%/78.6%, AUC: 0.78), outperforming the model based on the full triple network. This supports the hypothesis that during the binge/intoxication stage of addiction, the SN and the CEN play a more critical role than the DMN, consistent with the Addictions Neuroclinical Assessment (ANA) framework. Functional connectivity analysis revealed decreased connectivity within the DMN and the SN and increased connectivity within the CEN in CUD patients, suggesting that alterations in these networks could serve as biomarkers for addiction severity.

neuroscience↗

bioRxiv2024

Manipulation of Host Cholesterol by SARS-CoV-2

Cholesterol homeostasis relies on lysosomes, which release free cholesterol from degraded lipids. We show that SARS-CoV-2 blocks lysosomal cholesterol export through its protein ORF3a. ORF3a binds the HOPS subunit VPS39, and disrupting this interaction restores cholesterol trafficking. Two mechanisms underlie this defect. First, ORF3a-VPS39 interaction traps the sorting receptor CI-MPR and the retrieval complex retromer in endosomes/lysosomes, impairing trafficking of the cholesterol transporter NPC2. Retromer deletion reproduced these defects. Second, ORF3a reduces bis(monoacylglycerol)phosphates (BMPs), lysosomal lipids required for cholesterol export. Lipidomics and proteomics revealed altered metabolism of BMP precursors, mitochondrial phosphatidylglycerols (PGs), and reduced mitochondrial proteins at lysosomes. ORF3a-VPS39 interaction decreased lysosome-mitochondrion membrane contact sites (MCS), excluding autophagy or mitochondrion-derived vesicles as routes for PG transfer. VPS39 deletion decreased the MCS and BMPs. These findings identify VPS39 as a regulator of NPC2 trafficking and BMP biosynthesis and reveal that ORF3a disrupts both pathways to block cholesterol egress.

cell biology↗

bioRxiv2024

KaMLs for Predicting Protein pKa Values andIonization States: Are Trees All You Need?

Despite its importance in understanding biology and computer-aided drug discovery, the accurate prediction of protein ionization states remains a formidable challenge. Physics-based approaches struggle to capture the small, competing contributions in the complex protein environment, while machine learning (ML) is hampered by scarcity of experimental data. Here we report the development of pKa ML (KaML) models based on decision trees and graph attention networks (GAT), exploiting physicochemical understanding and a new experiment pKa database (PKAD-3) enriched with highly shifted pKas. KaML-CBtree significantly outperforms the current state of the art in predicting pKa values and ionization states across all six titratable amino acids, notably achieving accurate predictions for deprotonated cysteines and lysines - a blind spot in previous models. The superior performance of KaMLs is achieved in part through several innovations, including separate treatment of acid and base, data augmentation using AlphaFold structures, and model pretraining on a theoretical pKa database. We also introduce the classification of protonation states as a metric for evaluating pKa prediction models. A meta-feature analysis suggests a possible reason for the lightweight tree model to outperform the more complex deep learning GAT. We release an end-to-end pKa predictor based on KaML-CBtree and the new PKAD-3 database, which facilitates a variety of applications and provides the foundation for further advances in protein electrostatics research. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/622800v3_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@15d2256org.highwire.dtl.DTLVardef@1795151org.highwire.dtl.DTLVardef@1c9ae02org.highwire.dtl.DTLVardef@1bf17a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

SARS-CoV-2 JN.1 reveals attenuated pathogenicity and airborne transmission

JN.1 is a subvariant of SARS-CoV-2 Omicron BA.2.86 lineage that was predominant worldwide in early 2024, of which the in vivo characteristics are largely unknown. Our results demonstrated that the replication of JN.1 was more efficient than that of the parental BA.2 in Vero cells, which demonstrated low dependence on TMPRSS2. Compared to Omicron variants BA.2 and XBB EG.5.1, JN.1 replicated less efficiently in hACE2 mouse lungs of which the intranasal infection was not lethal to hACE2 mice and led to weaker immune dysregulation. On a more sensitive, aged hACE2 hamster model, JN.1 led to a lower mortality rate and no weight loss, corresponding well with the low preference in lower airways. Lower amounts of viruses in nasal washes and exhaled aerosols were detected in JN.1 infected wildtype hamsters than EG.5.1, and consistently, JN.1 also exhibited largely reduced airborne transmission. Moreover, the poor transmission was also clearly demonstrated even by using hamsters expressing hACE2 receptors in the whole airway. Thus both pathogenicity and airborne transmission of JN.1 were demonstrated to be largely attenuated. ImportanceCurrently, SARS-CoV-2 JN.1 and its subvariants have fully replaced the previous dominant XBB lineage around the world. Although the strong immune evasion of JN.1 has been distinctly revealed, its in vivo pathogenicity and airborne transmission remained unclear. By using multiple Omicron-sensitive rodent models, our findings demonstrated that the pathogenicity of JN.1 was largely attenuated. The weak airborne transmission of JN.1 in wildtype and hACE2 hamsters was consistent with the reported relative lower transmissibility in human, and the using of airway-expressing hACE2 hamsters ulteriorly eliminates the potential bias in viral transmission studies induced by receptor divergence between animal models and human. These findings uncover the in vivo virological characteristics of SARS-CoV-2 novel lineage, providing insights for communicable disease control.

microbiology↗

bioRxiv2024

Principles of nutrition-dependent root-microbiome engineering for regulating crop yield via live microbial inoculants

As the second genome, host-associated microbiota can enhance the functions of host immune systems, improve host nutrient availability and acquisition capacity, and increase host resistance to abiotic stress. Constructing host-associated microbiomes by applying various bioinoculants has become an attractive tool for promoting human health and increasing food production. However, despite their promising properties, the efficacy of bioinoculants vary significantly in actual field and clinical practices. Understanding the global design principles that shape the outcomes of interactions between bioinoculants and target host-microbiome symbionts remains a considerable challenge. In this study, we used a wheat production system as a case study to quantitatively understand how soil nutrient status impacts the establishment of host-microbiome interaction networks and their subsequent interactions with external bioinoculants. We found that soil organic carbon, one of the most general soil properties for global crop productivity and resilience, could affect the outcome of bioinoculant applications in wheat production systems, which led to functional instability in bioinoculant application outcomes. The results of this study significantly improved our understanding of the global design principles of nutrition-dependent root-microbiome engineering for regulating crop yield via the application of live microbial inoculants and provide theoretical guidance for bioinoculant applications in agricultural practice.

microbiology↗