Biology subjects

Jia, R.

Publications and source records attributed to Jia, R..

At least 19 recordsLinked to original sources

bioRxiv2026

SILCS-Guided Feature Encoding Expands Ligand Recognition at an HBV Core Protein Interface

Hepatitis B virus (HBV) infection depends on coordinated capsid assembly and virion production. A hydrophobic pocket at the intradimer interface of the HBV core protein has been linked to secretion phenotypes and shown to bind small molecules, but its interaction landscape remains poorly defined. Here, we combine atomistic molecular dynamics (MD) simulations, fragment mapping, pharmacophore modeling, and biophysical binding assays to characterize this pocket and identify ligands with binding modes that extend beyond the known pocket. This workflow narrowed an initial library of approximately 4.7 million compounds to eight candidates for experimental evaluation by saturation transfer difference (STD) NMR and surface plasmon resonance (SPR). Of these eight, compound B3 showed detectable STD NMR signals, concentration-dependent SPR binding, and an MD-supported binding mode that retained hydrophobic-pocket anchoring while also extending toward the spike-proximal loop. Together, these results illustrate how dynamic fragment mapping can identify ligand candidates that engage broader interaction landscapes at protein-interface pockets.

biophysics↗

bioRxiv2026

Autoluminescence characteristics of 25 Phalaenopsis orchids following transient transformation with eFBP2

Engineering autoluminescent plants, especially horticultural crops, has recently emerged as a promising research area, with one current approach involving the transgenic introduction of fungal bioluminescence pathway genes. Although autoluminescent plants such as tobacco and petunia have been created, it remains unclear whether all horticultural plants have the potential to be autoluminescent after genetic modification, especially those having flowers with dark colors and thick cuticles. To understand whether, and what if any, floral traits affect autoluminescence potential, we assess the autoluminescence characteristics of 25 representative Phalaenopsis cultivars after transient transformation of fungal bioluminescence pathway genes, alongside several key morphological and biochemical traits. Our results demonstrate that autoluminescence characteristics are correlated with floral color lightness, organ textures and epidermal cell types. In contrast, the content of the substrates of luciferin--caffeic acid and tyrosine, and the infiltration ease of inoculation solution into floral organs after injection, have limited effects on autoluminescence characteristics. Autoluminescence intensity can be reasonably predicted using five floral traits investigated, as 80.4% of variation can be explained by these traits. Our study not only identifies specific Phalaenopsis cultivars with high potential for developing autoluminescent lines but also provides a selection framework applicable to other horticultural crops.

plant biology↗

bioRxiv2026

Structure-aware geometric graph learning for modeling protease-substrate specificity at scale

Protease-substrate specificity is central to cellular regulation and disease pathogenesis, and accurately modeling its structural determinants remains challenging. Substrate recognition is governed by spatial constraints and higher-order relationships that extend beyond local sequence motifs. Most computational approaches rely predominantly on motif-centric or sequence-based representations, limiting their ability to capture the geometric and relational structure underlying enzymatic specificity. Here, we introduce OmniCleave, a structure-aware geometric graph learning framework for modeling protease-substrate specificity at scale. OmniCleave is trained on 57,278 structure-informed protease-substrate pairs derived from 9,651 substrates spanning over 100 proteases across six distinct families. The framework integrates multi-scale structural graphs with higher-order protease relational topology, explicitly encoding spatial context and inter-protease dependencies within a unified geometric representation. This formulation moves beyond local pattern recognition and enables transferable modelling across six protease families. Across large-scale benchmarks, the framework consistently outperforms existing approaches and reveals interpretable geometric determinants underlying substrate recognition. Experimental validation confirms three novel caspase-3 substrates and 21 cleavage sites predicted by OmniCleave, supporting the biological relevance of the learned representations. Together, OmniCleave provides a scalable geometric framework for modeling protease-substrate specificity, with practical utility for systematic analysis of protease biology.

bioinformatics↗

bioRxiv2025

Mutation or deletion of the Avr6 avirulence effector gene of Fulvia fulva leads to breakdown of the Cf-6 leaf mold resistance locus in tomato

Genetic resistance mediated by Cf cell-surface receptors is a cornerstone of tomato breeding against leaf mold disease caused by the fungal pathogen Fulvia fulva. After widespread deployment of the Cf-9 resistance locus, breeders increasingly relied on Cf-6, yet Cf-6-mediated resistance has already been overcome in multiple regions. The molecular basis of this breakdown, and the identity of the matching avirulence (Avr) effector, have remained unresolved. Here, we use comparative genomics and functional genetics to identify the F. fulva effector Avr6 as the previously described apoplastic protein Ecp5. Sequencing of Cf-6-breaking strains revealed either deletion of the Ecp5 locus or non-synonymous mutations in its coding sequence. Using transient expression, targeted gene knockout, and complementation assays, we show that Ecp5 is both necessary and sufficient for Cf-6-mediated recognition and defence activation. We then use Avr6-triggered cell death as a phenotypic marker in a bulked segregant analysis combined with Comparative Subsequence Sets analysis (CoSSa) to map Cf-6 to a [~]2 Mb interval on the short arm of chromosome 12 that overlaps the previously described Cf-Ecp5.12 locus. Sequencing of Avr6 in a broad strain collection reveals a predominantly conserved allele under apparent purifying selection, with recent independent loss-of-function variants in Europe and South America that confer virulence on Cf-6 plants. Together, these findings establish the Avr6-Cf-6 gene-for-gene pair, explain the erosion of Cf-6-mediated resistance, and illustrate how effector loss or mutation provides a rapid route for F. fulva adaptation, with important implications for designing more durable resistance strategies against tomato leaf mold.

microbiology↗

bioRxiv2025

A large global soil carbon sink informed by repeated soil samplings

Partitioning the terrestrial carbon sink between vegetation and soil is crucial for predicting future climate change, but the role of soils remains poorly quantified. Here, we compiled 3,099 soil organic carbon time series spanning five decades. We found a global soil organic carbon sink of 1.83 {+/-} 0.9 (mean {+/-} SE) petagrams per year from 1992 to 2020, driven by extratropical young forests, boreal old forests, and grasslands, while trends in tropical ecosystems remain uncertain. Our findings suggest the net land sink resides almost exclusively belowground as soil carbon, emphasizing the global opportunity of soil conservation and restoration for climate mitigation.

ecology↗

bioRxiv2024

Structural Basis of GPCR-G Protein Pre-coupling and Activation: Insights from CCR1-Gi Complex

GPCR-mediated G protein activation cycle contains obligated step of the receptor-G protein assembly before G protein activation (pre-coupling state). However, transient nature of this pre-coupling state has prevented structural and mechanistic understanding of this essential step of G protein activation cycle. In this study, we discover that CCR1 has high level of pre-coupling state, which allows its rapid response to chemokines. Taking advantage of this observation, we uncover molecular mechanism of the pre-coupling state by solving the cryo-electron microscopy structure of the chemokine receptor CCR1 in complex with its cognate G protein (Gi) in a pre-coupled, inactivated state. This structure reveals that CCR1 adopts a conformation distinct from both its fully active and inactive states, with the G proteins 5 helix partially inserted into the receptors intracellular cavity. Notably, the C-terminal four residues of the G subunit are disordered in this pre-coupled state, contrasting with their well-defined -helical structure in the fully active complex. Functional assays demonstrate that while deletion of these four C-terminal G residues does not affect pre-coupling, it abolishes G protein activation upon agonist binding. This finding highlights the critical role of these residues in GPCR-mediated G protein activation, but not in initial recruitment. Furthermore, our studies indicate that the ability to form pre-coupled complexes is conserved among chemokine receptors, suggesting a common mechanism for rapid signal transduction in this GPCR subfamily. These results provide the first structural evidence for GPCR-G protein pre-coupling and offer molecular insights into the transition from inactive to active states. Our findings fill the long-missing gap in understanding GPCR-mediated G protein activated cycle.

biophysics↗

bioRxiv2024

Modeling Decision-Making Under Uncertainty with Qualitative Outcomes

Modeling decision-making under uncertainty typically relies on quantitative outcomes. Many decisions, however, are qualitative in nature, posing problems for traditional models. Here, we aimed to model uncertainty attitudes in decisions with qualitative outcomes. Participants made choices between certain outcomes and the chance for more favorable outcomes in quantitative (monetary) and qualitative (medical) modalities. Using computational modeling, we estimated the values participants assigned to qualitative outcomes and compared uncertainty attitudes across domains. Our model provided a good fit for the data, including quantitative estimates for qualitative outcomes. The model outperformed a utility function in quantitative decisions. Additionally, we found an association between ambiguity attitudes across domains. Results were replicated in an independent sample. We demonstrate the ability to extract quantitative measures from qualitative outcomes, leading to better estimation of subjective values. This allows for the characterization of individual behavior traits under a wide range of conditions. Author SummaryIn the current study, we explored how people make decisions when the outcomes arent easily measured in numbers, such as in medical choices. Traditional mathematical models, which rely on numerical data, often fall short in these situations, leading to a gap in understanding how people evaluate these qualitative outcomes. Using hierarchical Bayesian modeling, we developed a model that bridges this gap by translating qualitative outcomes into individualized quantitative values, enabling us to better understand the underlying decision-making processes. Our model not only provides a better fit to real-world data than existing models with qualitative or quantitative outcomes but also allows for meaningful comparisons of how people handle uncertainty across different decision-making scenarios. This approach opens new doors for studying decision-making in areas where traditional methods struggle, offering a more nuanced view of human behavior in complex situations.

neuroscience↗

bioRxiv2024

Different Roles of D1/D2 Medium Spiny Neurons in the Nucleus Accumbens in Pair Bond Formation of Male Mandarin Voles

The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, involvements of DA release, real time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.

neuroscience↗

bioRxiv2024

RUNX2 Isoform II Protects Cancer Cells from Ferroptosis by Promoting PRDX2 Expression in Oral Squamous Cell Carcinoma

Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis. RUNX2 has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis and apoptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferation in vitro and tumorigenesis in vivo in oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis and apoptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can up-regulate RUNX2 isoform II to inhibit ferroptosis and apoptosis, and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway. Research organismHuman, Mouse, Oral Squamous Cell Carcinoma

cancer biology↗

bioRxiv2024

Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health

The nuclear receptor Liver X Receptor- (LXR) activates lipogenic gene expression in hepatocytes. Its inhibition has therefore been proposed as a strategy to treat metabolic-dysfunction-associated steatotic liver disease (MASLD). In order to understand the impact of reducing LXR activity on human health we first examined the association between the carriage of rare loss of function mutations in NR1H3 (encoding LXR) and metabolic and hepatic phenotypes. We identified 63 rare predicted damaging variants in the ligand binding domain of LXR in 454,787 participants in UK Biobank. On functional characterisation, 42 of these were found to be severely impaired. Consistent with loss of the lipogenic actions of LXR, carriers of damaging mutations in LXR had reduced serum triglycerides ({beta}=-0.13 s.d. {+/-}0.03, P=2.7x10-5, N(carriers)=971). Surprisingly, these carriers also had elevated concentrations of serum liver enzymes (e.g. ALT: {beta}=0.17s.d. {+/-}0.03, P=1.1x10-8, N(carriers)=972) with a 35% increased risk of clinically significant elevations in ALT (OR=1.32, 95%CI:1.15-1.53, P=1.2x10-4, N(carriers)=972), suggestive of hepatotoxicity. We generated a knock-in mouse carrying one of the most severely damaging mutations (Nr1h3 p.W441R) which we demonstrated to have dominant negative properties. Homozygous knock-in mice rapidly developed severe hepatitis and fibrotic liver injury following exposure to western diet despite markedly reduced steatosis, liver triglycerides and lipogenic gene expression. This phenotype was completely rescued by viral over-expression of wildtype LXR specifically in hepatocytes, indicating a cell-autonomous effect of the mutant on hepatocyte health. While homozygous LXR knockout mice showed some evidence of hepatocyte injury under similar dietary conditions, the phenotype of the LXRW441R/W441R mouse was much more severe, suggesting that dominant negative mutations that actively co-repress target genes can result in pathological impacts significantly more severe than those seen with simple absence of the receptor. In summary, our results show that loss of function mutations in LXR occur in at least 1/450 people and are associated with evidence of liver dysfunction. These findings implicate LXR in the maintenance of human liver health, identify a new murine model of rapidly progressive fibrotic liver disease and caution against LXR antagonism as a therapeutic strategy for MASLD.

genetics↗

bioRxiv2024

Mechanism Study on the Effect of Kidney Tonifying and Liver Soothing Methods on Mouse Oocyte Quality by Regulating OSFs and Smads Pathways

Objective: To observe the effects of kidney tonifying and liver soothing methods on the secretion of factor BMP-6, related receptors ALK-2/6, and downstream Smads pathway Smad1/5/844 in oocytes, and to explore the targeted mechanisms of their effects on mouse oocyte quality; Method: Healthy female mice aged 6-7 weeks were randomly divided into 6 groups, namely high and low dose kidney tonifying groups; High - and low-dose liver soothing groups; Control group and normal group. The high-dose and low-dose groups of tonifying the kidney were given oral solution of tonifying the kidney and regulating the meridian at 5.4g/ml and 2.7g/ml, respectively. The high-dose and low-dose groups of soothing the liver were given suspension of Xiaoyao Pill at 0.6g/ml and 0.3g/ml, respectively. The control group and normal group were given distilled water by gavage. Immunohistochemistry and Western blot were used to detect the expression of BMP-6, ALK-2/6, and Smad1/5/8/4 proteins in oocytes, while PCR was used to detect the mRNA expression of these indicators in oocytes; Result: Both methods can increase the expression of BMP-6 in oocytes of mice in the treatment group, activate ALK-2/6, and phosphorylate Smad1/5/8 to bind with Smad4, initiating signal transduction; The high-dose group of kidney tonifying is superior to other groups in regulating BMP-6, ALK-2/6, and Smad1/5/4. Conclusion: Kidney tonifying and liver soothing methods can regulate BMP-6 and its Smads pathway through different mechanisms to improve mouse oocyte quality.

synthetic biology↗

bioRxiv2023

Direct Pacbio sequencing methods and applications for different types of DNA sequences

The development of Sanger sequencing and next-generation sequencing methods within the past few years have assisted investigators profile the diversity and relative abundances of heterogenous species in vector preparations. Especially Recombinant adeno-associated viruses (rAAVs), genome editing, and mRNA related research are currently the most prominently investigated platform in different area and essentially use for synthetic biology, gene and cell therapy, food industrial and medicinal pharmer etc. area. However, these types of research related constructs always contain high GC sequences, poly structure, long-length DNA sequences and ITR repeats sequences. Unfortunately, Sanger sequencing and NGS platforms may be inaccessible to investigators with limited resources, require large amounts of input material, or may require long wait times for sequencing and analyses. Recent advances with PacBio sequencing have helped to bridge the gap for quick and relatively inexpensive long-read sequencing needs. Specifically, long-read sequencing methods, like single molecule real-time (SMRT) sequencing, have been used to uncover truncations, chimeric genomes, and inverted terminal repeat (ITR) mutations in vectors. Recombinant adeno-associated virus (raav) is the most prominent platform in the field of current research, and its sequence is characterized by high GC, multi-structure, long sequence, genome, and repeat sequence. Sanger sequencing has certain defects in the detection of recombinant adeno-associated viruses. Meanwhile, Sanger needs to design sequencing primers based on known sequences to determine whether the sequences are correct. When sequence information is incomplete, it can only randomly design primers, obtain a sequence by luck, and then conduct the next round of sequencing. However, PacBios limitations and sample biases are not well-defined for sequencing. And sometimes the accuracy for base calling was low, resulting in a high degree of miscalled bases and false indels. These false indels led to read-length compression; thus, assessing heterogeneity based on read length is not advisable with current PacBio technologies. In this study, we explored the capacity for PacBio sequencing to directly interrogate content to obtain full-length resolution of encapsulated genomes. We found that the PacBio platform can cover the entirety of different type sequences like poly structure, long-length DNA fragment, high GC sequences and repeat sequences, especially the rAAV sequences from ITR to ITR without the need for pre-fragmentation. At the same time, the sequencing process was optimized to complete the sequencing of long difficult plasmids with the fewest plasmids and the fastest time. In summary, the optimization PacBio sequencing and novel bioinformation (BI) analysis method are able to correctly identify truncation hotspots in single-strand and self-complementary vectors using by SMRT sequencing and can serve as a rapid and low-cost alternative for proofing different type of sequences.

molecular biology↗

bioRxiv2023

MetalPrognosis: a Biological Language Model-based Approach for Disease-Associated Mutations in Metal-Binding Site prediction

Protein-metal ion interactions play a central role in the onset of numerous diseases. When amino acid changes lead to missense mutations in metal-binding sites, the disrupted interaction with metal ions can compromise protein function, potentially causing severe human ailments. Identifying these disease-associated mutation sites within metal-binding regions is paramount for understanding protein function and fostering innovative drug development. While some computational methods aim to tackle this challenge, they often fall short in accuracy, commonly due to manual feature extraction and the absence of structural data. We introduce MetalPrognosis, an innovative, alignment-free solution that predicts disease-associated mutations within metal-binding sites of metalloproteins with heightened precision. Rather than relying on manual feature extraction, MetalPrognosis employs sliding window sequences as input, extracting deep semantic insights from pre-trained protein language models. These insights are then incorporated into a convolutional neural network, facilitating the derivation of intricate features. Comparative evaluations show MetalPrognosis outperforms leading methodologies like MCCNN and PolyPhen-2 across various metalloprotein test sets. Furthermore, an ablation study reiterates the effectiveness of our model architecture. To facilitate public use, we have made the datasets, source codes, and trained models for MetalPrognosis online available at http://metalprognosis.unimelb-biotools.cloud.edu.au/.

bioinformatics↗

bioRxiv2023

Sequential breakdown of the complex Cf-9 leaf mould resistance locus in tomato by Fulvia fulva

O_LILeaf mould, caused by Fulvia fulva, is a devastating disease of tomato plants. In many commercial tomato cultivars, resistance to this disease is governed by the Cf-9 locus, which comprises five paralogous genes (Cf-9A-9E) that encode receptor-like proteins. Two of these proteins contribute to resistance: Cf-9C recognizes the previously identified F. fulva effector Avr9 and provides resistance during all plant growth stages, while Cf-9B recognises the yet-unidentified F. fulva effector Avr9B and provides mature plant resistance only. In recent years, F. fulva strains have emerged that have overcome the Cf-9 locus, with Cf-9C circumvented through Avr9 deletion. To understand how Cf-9B is circumvented, we set out to identify Avr9B. C_LIO_LIComparative genomics, in planta transient expression assays and gene complementation experiments were used to identify Avr9B, while gene sequencing was used to assess Avr9B allelic variation across a worldwide strain collection. C_LIO_LIA strict correlation between Avr9 deletion and resistance-breaking mutations in Avr9B was observed in strains recently collected from Cf-9 cultivars, whereas Avr9 deletion but no mutations in Avr9B were observed in older strains. C_LIO_LIThis research showcases how F. fulva has evolved to sequentially break down the two functional resistance genes of the complex Cf-9 locus and highlights that this locus now has limited value for controlling leaf mould disease in worldwide commercial tomato production. C_LI

microbiology↗

bioRxiv2022

Individual Decision-Making Underlying the Tragedy of the Commons

Group decision-making is common in everyday life, whether a family is sharing a meal or a corporation is dividing profits. Research in economics on group decision-making has coalesced into a theory known as the tragedy of the commons, which states that resources are inevitably overused when shared by a group. However, even while multiple approaches to mitigating overuse of common resources have been put forward, notable counterexamples to the tragedy of the commons exist such that groups are ultimately able to avoid resource overuse. Development of a computerized paradigm amenable to behavioral modeling and simulation analyses could allow for exploration of whether resources will be overused in a given group of individuals and allow for the rapid testing of behavioral interventions designed to reduce instances of resource overuse. Using a newly developed group decision-making task, we studied how participants made decisions to utilize shared resources for the potential to receive a larger amount of money or conserve resources for a smaller amount of money. Using behavioral modeling, we found that valuation of resource overuse is most impacted only when an exceptionally small amount of resources are remaining. Using computational analyses, we were able to differentiate individual participants by both group earnings and self-reported social attitudes in ways that correlated with their willingness to utilize resources. These results signify the importance of individual differences in group composition regarding the tragedy of the commons, emphasizing the impact of the attitudes and behaviors of individual group members in predicting shared resource use.

animal behavior and cognition↗

bioRxiv2022

Allele-specific gene editing approach for vision loss restoration in RHO-associated Retinitis Pigmentosa

Mutant RHO is the most frequent genetic cause of autosomal dominant retinitis pigmentosa. Here, we developed an allele-specific gene editing therapeutic drug to selectively target the human T17M RHO mutant allele while leaving the wild-type RHO allele intact for the first time. We identified a Staphylococcus aureus Cas9 (SaCas9) guide RNA that was highly active and specific to the human T17M RHO allele. In vitro experiments using HEK293T cells and patient-specific induced pluripotent stem cells (iPSCs) demonstrated active nuclease activity and high specificity. Subretinal delivery of a single adeno-associated virus serotype 2/8 packaging SaCas9 and sgRNA to the retinas of the RHO humanized mice showed that this therapeutic drug targeted the mutant allele selectively, thereby downregulating the mutant RHO mRNA expression. Administration of this therapeutic drug resulted in a long-term (up to 11 months after treatment) improvement of retinal function and preservation of photoreceptors in the mutant humanized heterozygous mice. Our study demonstrated a dose-dependent therapeutic effect in vivo. Unwanted off-target effects were not observed at the whole-genome sequencing level. Our study provides strong support for the further development of this effective therapeutic drug to treat RHO-T17M associated autosomal dominant retinitis pigmentosa (adRP), also offers a generalizable framework for developing gene editing medicine. Furthermore, our success in retoring the vision loss in the suffering RHO humanized mice verifies the feasibility of allele-specific CRISPR/Cas9-based medicines for other autosomal dominant inherited retinal dystrophies.

genetics↗

bioRxiv2022

Brevicidine, a bacterial non-ribosomally produced cyclic antimicrobial lipopeptide with a unique modus operandi

Due to the accelerated appearance of antibiotic-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately-needed. Brevicidine, a bacterial non-ribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMR Enterobacteriaceae pathogens, with a MIC value ranging between 0.5M (0.8mg/L) and 2M (3.0mg/L). In addition, brevicidine showed potent anti-biofilm activity against the Enterobacteriaceae pathogens, with same 100% inhibition and 100% eradication concentration of 4M (6.1mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity via interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including inhibition of adenosine triphosphate synthesis, inhibits the dehydrogenation of nicotinamide adenine dinucleotides, accumulation of reactive oxygen species in bacteria, and inhibition of protein synthesis. Lastly, brevicidine showed a good therapeutic effect in a mouse peritonitis-sepsis model. Our findings pave the way for further research on clinical applications of brevicidine, to combat the prevalent infections caused by AMR Gram-negative pathogens worldwide.

microbiology↗

bioRxiv2022

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants following an order of BA.1>BA.2>BA.4/5. In naive animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccines targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection across all VOCs. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine- primed populations.

molecular biology↗