Biology subjects

Bai, S.

Publications and source records attributed to Bai, S..

At least 19 recordsLinked to original sources

bioRxiv2026

A native single-transcript TnpB architecture enables efficient virus-induced genome editing and visual screening of heritable progeny harboring phenotypically silent edits

TnpB are ultra-compact RNA-guided nucleases, yet most reported systems require separate expression of the nuclease and cognate reRNA, eroding their size advantage and restricting viral delivery in plants. Here we demonstrate that ISDra2 TnpB harnesses its native overlapping architecture in which the reRNA sequence resides within the 3' coding region of TnpB, processing its own mRNA to generate functional reRNA and enabling single-transcript genome editing in plants. Only a 7-bp conserved motif followed by a 16-20 bp spacer directly downstream of the coding sequence suffices for editing, requiring no exogenous ribozymes or independent guide promoters. This ultra-compact design enables simultaneous packaging of the editing system and an NbPDS silencing module into a single TRV vector, achieving robust editing in systemic Nicotiana benthamiana tissues and establishing a dual VIGE-VIGS strategy for direct visual selection of heritable, transgene-free edited progeny via distinct albino phenotypes, reducing laborious large-scale genotyping even for targets lacking inherent visible traits.

plant biology↗

bioRxiv2026

Single-dose Efficacy of a Next-Generation Mpox Vaccine Harnessing an Immunomodulatory Peptide

Rapidly deployable, single-dose vaccines that maintain durability under operational constraints remain an unmet need in outbreak preparedness. Live viral vectors such as Modified Vaccinia Ankara (MVA) offer strong safety profiles, yet their suboptimal immunogenicity often requires multidose regimens, reducing flexibility during emergency response. To address these limitations, we developed a modular vaccine platform that leverages immune checkpoint modulation to enhance immune cell priming without compromising the established safety profile of MVA. This platform, exemplified by the recombinant virus MVA-X, was engineered to express a peptide-based PD-1 antagonist (LD10) that provides localized, transient checkpoint blockade during early antigen presentation. The approach requires no external adjuvants, is compatible with lyophilization and stockpiling, and is readily adaptable to diverse antigens and pathogens. A single immunization with MVA-X produced durable protection that matched or exceeded that of a conventional two-dose MVA regimen against the prototypic orthopoxvirus vaccinia virus. Despite modest and contracting antibody titers, single-dose MVA-X vaccination conferred complete survival following both lethal and high-dose viral challenge at early (Day 55), intermediate (Day 90), and long-term (Day 150) time points. MVA-X also restricted viral replication at the primary site of infection, reduced systemic dissemination, and preserved lung architecture during peak disease. Importantly, MVA-X maintained efficacy in the highly susceptible CAST/EiJ mouse model following challenge with highly pathogenic Clade I monkeypox virus (MPXV). Together, these findings demonstrate that vaccine-intrinsic checkpoint modulation provides a modular strategy for enhancing the potency and durability of attenuated viral vectors while preserving their favorable safety profile, supporting broader application to emerging infectious diseases beyond Mpox.

immunology↗

bioRxiv2026

A gap-free telomere-to-telomere genome of the purple-pericarp rice landrace Mojiang ZN65 resolves transposon-driven structural variation at the pericarp-pigmentation loci

Background: Black and purple pericarp in rice requires activation of the basic helix-loop-helix (bHLH) regulator Kala4/OsB2, and the known black-rice allele is a complex promoter rearrangement. Such repeat-embedded alleles can be difficult to resolve in fragmented assemblies, and for many pigmented landraces it remains unclear whether they carry that allele or structurally different ones. We asked three questions about the purple-pericarp landrace Mojiang ZN65: what is the structure of its Kala4/OsB2 upstream region; how frequent is gain of its upstream block in a rice diversity panel, and do the accessions with that gain share its junction; and how is it distributed relative to a second regulatory variant, a duplicated repeat in the OsKala3 promoter. Results: We assembled a gap-free telomere-to-telomere genome of ZN65 (395.1 Mb; all 24 telomeres; consensus quality value 53.6; 99.6% complete Benchmarking Universal Single-Copy Orthologues; indica), in which the flavonoid pathway showed no pathway-wide copy-number expansion. Upstream of Kala4/OsB2, a ~5.87-kb segment (block A) is present in three non-tandem copies, spanned as single molecules by three ultra-long Nanopore reads (115,450 bp); each of 33 other assemblies yielded a single homologous hit (10 of them coverage- or divergence-limited). This arrangement differs from the canonical black-rice Kala4 allele. Among 533 accessions of the 3,000 Rice Genomes panel, read depth detected block A gain in four accessions (three at three or more copies, 0.56%; one at two). All four carry the ZN65 junction at the same base, and three carry a pigment term in their variety names from a lexicon fixed in advance (Fisher's exact test, P = 0.0023). All four also have OsKala3 promoter-repeat read depth consistent with the two-unit configuration reported for black-pericarp cultivars, a state found in 1.9% of the panel. Conclusions: ZN65 carries a rare Kala4/OsB2 structural variant whose junction is shared with other accessions named as pigmented rice and which, in this panel, occurs only in accessions whose OsKala3 promoter-repeat read depth indicates duplication. Its effect on pigmentation remains to be tested with measured pericarp phenotypes and functional assays.

plant biology↗

bioRxiv2026

A graph-based pangenome reveals the genetic basis of climate-resilient and horticultural traits in pear

Climate change poses an increasing threat to the cultivation of deciduous fruit trees, placing greater demands on modern pear breeding. Using pear germplasm adapted to diverse environments, we assembled 11 chromosome-level genomes. In combination with 13 publicly accessible pear genomes, we analyzed presence-absence variations (PAVs) and constructed a graph-based pangenome for pear. By performing a PAV-eQTL analysis of the fruit of 123 pear accessions, we identified PAVs significantly associated with expression levels of genes that may be involved in regulating agronomic traits. Population analysis of 268 pear accessions revealed two stop-gained variants in DAM1 of independent origin, which may function in advancing the blooming date and reducing the chilling requirement. We detected complex PAVs at the NOR1 locus, including two copy-number variations and one deletion. These PAVs contributed to the rapid diversification of the NOR1 locus and the fruit development period through regulating ARF5 and other ripening-related genes. We revealed the selection history of the NOR1 locus and developed novel pear individuals that accumulated alleles for low chilling requirement, early blooming date, and short fruit development period. The results provide valuable resources for pear genomics research and offer a guideline for breeding modern pears with climate resilience.

plant biology↗

bioRxiv2026

LagCI Enables Inference of Temporal Causal Relationships from Dense Multi-Omic Time Series

Inferring causal relationships from time-series data is critical for uncovering the dynamics of biological regulation. However, in multi-omics studies, this task is often hampered by sparse temporal sampling and the limitations of existing methods. To address this, we developed Lagged-Correlation Based Causal Inference (lagCI), a computational framework designed to identify time-lagged associations by combining comprehensive lag-correlation profiling with a robust statistical filtering scheme. Rather than relying on simple cross-correlation, lagCI analyzes the entire correlation profile and applies a quality-scoring system to filter out spurious associations that often plague high-dimensional datasets. We first tested lagCI on wearable physiological data, where it successfully captured the well-known causal link between physical activity and heart rate, even accounting for variations in lag times between individuals. Moving to high-frequency human multi-omics, we used lagCI to build a directed network of 1,624 molecules connected by over 157,000 predicted interactions. This network didnt just mirror established biology (such as cytokine-hormone crosstalk); it also pointed to specific molecular hubs that seem to orchestrate the timing of metabolic and immune responses. Overall, lagCI provides a data-driven way to extract temporal insights from dense longitudinal omics. Weve made the tool available as an R package with multiple interfaces to ensure its accessible for both bioinformaticians and clinicians.

bioinformatics↗

bioRxiv2025

A Retinoic Acid Autoregulatory Loop Governing Prefrontal-Motor Arealization

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behavior, and the motor cortex (MC), which executes movement. A hallmark of primate brain evolution is PFC expansion accompanied by a posterior displacement of the MC. Retinoic acid (RA) signaling has emerged as a key regulator of PFC specification and expansion. However, the mechanisms that spatially confine RA signaling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we defined an RA-associated gene regulatory network (RA-GRN) in the developing human PFC and identified MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder (ASD), as its key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories toward motor-like molecular and connectional features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signaling itself, is markedly reduced in the developing medial prefrontal cortex (mPFC). These findings revealed a conserved autoregulatory loop: RA [->] MEIS2 [->] ALDH1A3 [->] RA that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signaling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to psychiatric disorders.

neuroscience↗

bioRxiv2025

Swine wastewater drives dissemination of high-risk blaNDM-positive Escherichia coli clones

Swine wastewater can accelerate the spread of antibiotic-resistant bacteria among animals, the environment, and humans. Therefore, the molecular epidemiological characteristics of carbapenemase-producing E. coli isolates from swine wastewater was investigated. In this study, a total of 100 no-cloning carbapenemase-producing (blaNDM-1, blaNDM-5 and blaOXA-48-like) E. coli isolates were recovered from 316 swine wastewater samples collected from 29 swine farm in Shandong, China. Of which, two isolates that co-harbored blaOXA-48-like and mcr-1, as well as five isolates that co-harbored blaNDM-5 and tet(X4). All isolates were multidrug-resistant (MDR), with a majority exhibiting resistance to meropenem, ciprofloxacin, imipenem and gentamicin. Whole genome sequencing (WGS) analysis indicated that these isolates were belonged to 12 distinct sequence types (STs), with the most prevalent STs being ST10 and ST5299. Additionally, Phylogenomic analysis revealed that clonal spread of blaNDM-positive ST10 E. coli isolates at swine wastewater in multiple cities, including Binzhou, Dezhou, Heze and Weihai. Meanwhile, a notable divergence in SNPs was observed in isolates from this study and public database, which indicates that these blaNDM-positive E. coli isolates have high genetic diversity. In addition, WGS analysis further revealed that blaNDM co-existed with other antibiotic resistance genes, conferring resistance to twelve classes of antimicrobials. This study underscores the importance of surveillance for blaNDM-harboring microbes in swine wastewater, and continuous monitoring in swine wastewater is essential for ensure human and environmental health. IMPORTANCEThe study described the NDM-positive E. coli strains isolated from swine wastewater, where it was associated with antibiotic exposure. Notably, swine wastewater was increasingly considered to be related to CRE hosts. Pathogens originating from this source can be transmitted to humans via direct and indirect contact, as well as through the ingestion or inhalation of contaminated water or aerosols. In addition, under the selective pressure of antibiotics, the co-harbored of blaOXA-48-like and mcr-1, blaNDM-5 and tet(X4) genes within the same host bacterium signifies the emergence of an extremely MDR pathogen, posing a grave threat to public health. Consequently, the monitoring of blaNDM in swine wastewater is critical for containing the transmission and persistence of carbapenem-resistant pathogens.

microbiology↗

bioRxiv2025

What is next? Predictable visual sequences are encoded with anticipatory biases and reduced neural responses

Objects in motion follow predictable trajectories that the brain can easily anticipate. We investigated the underlying neural mechanisms, focusing on a form of representational momentum (RM), whereby the final state of a rotating object is misperceived along its future trajectory. Participants viewed two simultaneous streams of oriented gratings, one rotating predictably and the other random, and were instructed to attend to one of the two. Using EEG steady-state visual evoked potentials (SSVEPs) and decoding analysis, we found that attending to rotational sequences led to reduced neural response amplitude and systematic anticipatory shifts in the neural representation of orientation, relative to random sequences. These anticipatory biases emerged at early post-stimulus latencies and mirrored behavioral signatures of RM. Our findings suggest that the brain leverages internalized dynamics to form stable anticipatory representations with reduced neural activity strength.

neuroscience↗

bioRxiv2025

Lzp Ablation Ameliorates Dyslipidemia and Suppresses Atherosclerosis by Reducing Circulating Apolipoprotein B-Containing Lipoproteins

As the principal regulator of systemic lipid homeostasis, the liver uniquely orchestrates dietary lipid assimilation, de novo lipogenesis, very-low-density lipoprotein (VLDL) assembly and secretion, and clearance of atherogenic lipoprotein remnants. This central role positions liver-specific molecular targets as critical therapeutic nodes for mitigating hyperlipidemia and halting atherosclerosis progression. The liver-specific protein Lzp (also named as OIT3), previously shown to stabilize apolipoprotein B (ApoB), the core structural component of triglyceride-rich lipoproteins, has an undefined role in vascular disease pathogenesis. Here, utilizing ApoE-/-mice, a well-established model that closely mimics human atherosclerosis, we demonstrate that Lzp deletion reduces plasma cholesterol, triglycerides, and ApoB levels under both chow and Western diets, concomitant with a marked attenuation of aortic plaque burden. Additionally, Lzp deficiency reduces hepatic and circulating ApoB levels in hyperlipidemic ApoE-/- mice, without exacerbating hepatic steatosis or injury. Mechanistically, Lzp ablation is anticipated to impair hepatic VLDL-ApoB secretion based on our previous findings, resulting in reduced circulating VLDL, intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL) particles, attenuated lipid deposition, and suppressed macrophage-driven plaque inflammation. These results underscore the role of Lzp as a key regulator of systemic lipid metabolism and identify it as a potential candidate for further investigation toward therapeutic intervention of atherosclerotic cardiovascular disease. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/678175v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@118ead8org.highwire.dtl.DTLVardef@e215baorg.highwire.dtl.DTLVardef@1007212org.highwire.dtl.DTLVardef@412757_HPS_FORMAT_FIGEXP M_FIG C_FIG HightlightsO_LILzp deficiency attenuates atherosclerosis and improves plasma lipid profiles in ApoE-/- mice fed chow or Western diets. C_LIO_LILzp deficiency reduces hepatic and circulating apolipoprotein B levels in hyperlipidemic ApoE-/- mice without exacerbating hepatic steatosis or injury. C_LIO_LILzp represents a candidate therapeutic target, warranting further mechanistic and translational studies for atherosclerosis. C_LI

pathology↗

bioRxiv2025

Dual inhibition of sEH and COX-2 Improved Cognition in Alzheimer's Disease via Enhanced Myogenic Response and Cerebral Artery Distensibility

Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimers disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the Novel Object Recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 M) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Vehicle-treated AD rats displayed impaired functional hyperemia, whereas PTUPB (1 M) significantly restored this response. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats indicated that PTUPB influences genes related to contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD, likely by enhancing myogenic response and increasing cerebral artery distensibility. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.

neuroscience↗

bioRxiv2025

On-target toxicity limits the efficacy of CDK11 inhibition against cancers with 1p36 deletions

The cyclin-dependent kinase CDK11 is an understudied kinase that has been the subject of conflicting reports regarding its function in cancer. Here, we combine genetic and pharmacological approaches to demonstrate that CDK11 is a critical regulator of cancer cell survival that is required for RNA splicing and the expression of homologous recombination genes. Inhibition of CDK11 disrupts genome stability, promotes the retention of intronic sequences in mature mRNAs, and induces synthetic lethality with PARP inhibitors. Through integrative analysis of functional genomics datasets, we identify heterozygous deletions of chromosome 1p36 - which encompasses CDK11 and its activating cyclin CCNL2 - as a recurrent and predictive biomarker of sensitivity to CDK11 inhibition. To assess the therapeutic potential of CDK11, we develop MEL-495R, a selective and orally bioavailable CDK11 inhibitor. Additionally, we establish a genetically-engineered mouse model that allows us to differentiate between the on-target and off-target effects of CDK11 inhibitors in vivo. Using this platform, we demonstrate that MEL-495R induces widespread on-target toxicity, revealing a narrow therapeutic index. Together, these findings define CDK11 as a core cancer dependency, uncover a chromosomal deletion that sensitizes tumors to CDK11 inhibition, and provide a generalizable strategy for deconvolving drug efficacy and toxicity in vivo for novel oncology targets.

cancer biology↗

bioRxiv2025

Silencing Proline Dehydrogenases Improves Salt and Drought Tolerance in Gossypium hirsutum

Proline is a key compound that lowers cell water potential, scavenges reactive oxygen species, and stabilizes biomolecules and cell membranes, thus reducing stress-induced damage. Proline dehydrogenase (ProDH), the first rate-limiting enzyme in proline degradation, plays a crucial role in proline accumulation. We explored the role of the GhProDH gene family in regulating physiological responses to stress conditions through transcriptome, metabolome and functional analyses. Overexpression and gene silencing lines in Arabidopsis and cotton revealed that GhProDH2 plays a key role in regulating cottons tolerance to drought and salt stress. GhProDH2-4 improves cottons tolerance to drought and salt stress by engaging in carbon metabolism, glyoxylate cycle, and flavonoid metabolism pathways. These findings highlight the potential role of GhProDH2-4 to improve cotton stress resistance by genetically modifying pathways involved in proline biosynthesis and degradation.

molecular biology↗

bioRxiv2025

Canonical nuclear envelope protein emerin regulates structure and integrity of the erythrocyte plasma membrane

Red blood cells (RBC) are essential for the survival of aerobic organisms. Mutations in RBC plasma membrane proteins can give rise to a spectrum of diseases characterized by hemolysis, inefficient gas exchange, and anemia. We tested whether emerin (EMD), a nuclear envelope (NE) protein, is also expressed in anuclear cell types to regulate membrane structure and function. We find that emerin is localized to the RBC plasma membrane and regulates the localization of other membrane proteins involved in actin branching and cytoskeletal dynamics. Additionally, we find that loss of Emd in mice results in decreased RBC corpuscular volume and hemoglobin content in both sexes, as well as a male-specific increase in RBC number and hematocrit, consistent with other male-dominated EMD phenotypes. Along with decreased RBC size, we observed a reduction in the rate of osmotic lysis in Emd KO animals, particularly males. We found that human EMD mutations also have a statistically significant association with RBC phenotypes, namely MCV. Individuals with emerin-related Emery-Dreifuss muscular dystrophy (EDMD) also demonstrate a mild yet consistent RBC phenotype according to patient CBC data. Together, these data suggest that emerin can have cell-specific localization and functions independent of its canonical repertoire in nucleated cells.

cell biology↗

bioRxiv2025

A reference genome assembly of the alpine forage grass Elymus nutans

Elymus nutans Griseb. (Poaceae: Triticeae, 2n=6x=42) is a dominant perennial plant species in the Qinghai-Tibetan Plateau in China, which is an important forage resource in high-altitude and cold regions and is the most popular species used for high yield artificial grassland planting because of its rich nutritional value and good palatability for herbivorous ruminant animals. In this study, using advanced sequencing technology, we generated an allohexaploid reference genome for E. nutans, representing the three sets of chromosomes (subgenomes St, Y, and H). This is the first study to our knowledge to confirm the origin of the Y subgenome, which shares a close relationship with the V subgenome. We predict that E. nutans arose via two-step hybridization and that its speciation occurred [~]3.16 MYA. The whole genome in this study will update the Triticeae family genomics information and provide theoretical basis for the evolutionary of its related speicies.

plant biology↗

bioRxiv2025

A versatile cohesion manipulation system reveals CENP-A dysfunction accelerates female reproductive age-related egg aneuploidy.

Female reproductive aging is accompanied by a dramatic rise in the incidence of egg aneuploidy. Premature loss of chromosome cohesion proteins and untimely separation of chromosomes is thought to underly high rates egg aneuploidy during maternal aging. However, because chromosome cohesion loss occurs gradually over female reproductive lifespan and cytoskeletal defects alone can predispose eggs to chromosomal abnormalities, the root causes of exponential rise in egg aneuploidy at advanced reproductive ages remain a mystery. Here, we applied high-resolution live imaging to visualize for the first time cohesion protein dynamics underpinning meiotic chromosome segregation. To discover proteins whose dysfunction accelerates aneuploidies associated with female reproductive aging, we innovated the first experimental system in which chemically induced cohesion reduction rapidly triggers aging-like chromosomal abnormalities in young eggs. By integrating this direct cohesion manipulation system with quantitative high-resolution microscopy and targeted protein degradation tools, we identified the centromeric protein CENP-A as a new factor whose aging-like depletion causes a dramatic rise in premature separation of sister chromatids. Our work illuminates cohesion loss-independent origins of age-related egg aneuploidy and provides new avenues to discover therapeutic targets for extending the female reproductive lifespan.

cell biology↗

bioRxiv2024

TRAIT: A Comprehensive Database for T-cell Receptor-Antigen Interactions

Comprehensive and integrated resources on interactions between T-cell receptors and antigens are still lacking for adoptive T-cell-based immunotherapies, highlighting a significant gap that must be addressed to fully comprehend the mechanisms of antigen recognition by T-cells. In this study, we present TRAIT, a comprehensive database that profiles the interactions between T-cell receptors (TCRs) and antigens. TRAIT stands out due to its comprehensive description of TCR-antigen interactions by integrating sequences, structures and affinities. It provides nearly 8 million experimentally validated TCR-antigen pairs, resulting in an exhaustive landscape of antigen-specific TCRs. Notably, TRAIT emphasizes single-cell omics as a major reliable data source for TCR-antigen interactions and includes millions of reliable non-interactive TCRs. Additionally, it thoroughly demonstrates the interactions between mutations of TCRs and antigens, thereby benefiting affinity maturation of engineered TCRs as well as vaccine design. TCRs on clinical trials were innovatively provided. With the significant efforts made towards elucidating the complex interactions between TCRs and antigens, TRAIT is expected to ultimately contribute superior algorithms and substantial advancements in the field of T-cell-based immunotherapies. TRAIT is freely accessible at https://pgx.zju.edu.cn/traitdb.

immunology↗

bioRxiv2024

ENaC contributes to macrophage dysfunction in cystic fibrosis

BackgroundCystic fibrosis (CF) is a chronic systemic disease caused by dysfunctional or absent cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is expressed in human immune cells and plays a role in regulating innate immunity both directly and indirectly. Besides CFTR, research indicates that the epithelial sodium channel (ENaC) also contributes to dysfunction in CF airway epithelial cells. However, the impact of non-CFTR ion channel dysfunction on CF immune responses is not yet fully understood. A precise understanding of how CF immune function is regulated by ion channels may allow antibiotic-and mutation-agnostic treatment approaches to chronic bacterial infection and inflammation. Therefore, we hypothesized that ENaC is aberrantly expressed in CF macrophages and directly contributes to impaired phagocytic and inflammatory functions. MethodsENaC expression was characterized in human immune cells isolated from CF and non-CF blood donors. Monocyte-derived macrophage (MDM) function and bacterial killing was tested in the setting of ENaC modulation. ResultsBaseline expression of ENaC in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF controls and persisted after exposure to bacteria. Inhibition of CFTR in non-CF MDMs resulted in ENaC overexpression. CFTR modulator treatment reduced but did not eliminate ENaC overexpression in CF MDMs. Interestingly, ENaC inhibition with Amiloride increased CFTR expression. Amiloride-treated CF MDMs also showed normalized ROS production, improved autophagy, and decreased pro-inflammatory cytokine production. Finally, results from an ion channel microarray indicated that sodium channel expression in CF MDMs normalized after Amiloride treatment with minimal effect on other ion channels. DiscussionENaC is overexpressed in CF immune cells and is associated with abnormal macrophage function. ENaC modulation in immune cells is a novel potential therapeutic target for infection control in CF, either in combination with CFTR modulators, or as a sole agent for patients not currently eligible for CFTR modulators.

immunology↗

bioRxiv2024

Mechanical control of germ cell specification in Arabidopsis anthers

A central question in developmental biology is how the germline is established. We have studied the specification of the male germ cells (GCs) within the anther1-3. Hereby, we have focused on the potential role of mechanics, an aspect of anther development which has been very poorly characterized2,4. Using a combination of live imaging and mechanical measurements, we provide evidence that GCs originate in a special micro-mechanical niche, where inner tissues exert push on outer cell layers, placing them under compression. Mechanical perturbations significantly disrupted the GC specification and patterning. Moreover, we found that the master genetic regulator SPOROCYTELESS/NOZZLE (SPL/NZZ)5,6 is central in establishing this micro-mechanical environment by softening the cell wall. The mechanical cues, in turn, stabilize the transcription of SPL/NZZ. We propose here an intrinsic growth-derived mechano-chemical feedback loop that drives germ-cell fate acquisition.

developmental biology↗