Biology subjects

Lu, Q.

Publications and source records attributed to Lu, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

Pan-cancer remodeling of reactive oxygen species homeostasis: distinct roles of the ROS-generation and antioxidant arms in immune context and outcome

Reactive oxygen species (ROS) are double-edged in cancer: tumor cells sustain high ROS generation while up-regulating antioxidant defense, so that the net balance between the two arms, rather than absolute ROS abundance, is the biologically meaningful quantity. Whether that balance defines a conserved tumor state across cancer types has been unclear. Here an experimentally measured ROS phenotype, obtained from a three-channel gold-nanocluster array, was generalized to public transcriptomes through a 107-gene ROS program scored in a large cell-line panel and in pan-cancer tumor and adjacent-normal tissue. The optical readout was reproducible and fully discriminative between cell lines, establishing the fingerprint as a quantitative starting point. In tumors, the generation and antioxidant arms were coordinately up-regulated relative to normal tissue, yet the two arms dissociated in their biology. The composite balance score tracked reduced immune infiltration consistently across cohorts, but arm-level decomposition showed that it was carried by low generation-arm activity in immune-cold tumors and followed arithmetically from how the balance score is defined; the association does not implicate antioxidant defense in immune infiltration. The clinical association pointed the other way: adverse outcome was attributable to the antioxidant arm, whereas generation was null. In cohort-held-out validation, tumors were separated from adjacent normal tissue, with redox programs outperforming generic phenotypic programs, indicating that the same program transfers across tumor types. Tumor remodeling of ROS homeostasis is therefore widespread, but its two arms carry distinct meanings: the balance score, driven by its generation term, reports immune context, whereas the antioxidant arm reports clinical risk.

cancer biology↗

bioRxiv2026

Shared and idiosyncratic coding regimes coexist in macaque IT

Population-level measurements portray object representations in primate inferotemporal cortex (IT) as smooth, low-dimensional, and predictable by deep neural networks (DNNs). However, it remains unclear whether this structured population-level picture is representative of the full diversity of its constituent neurons. Here, we used Neuropixels 2.0 probes to record large populations of well-isolated units from an fMRI-localized face patch in macaque anterior IT while monkeys viewed more than 3,000 natural images. Single-unit responses were substantially sparser and more heterogeneous than multi-unit activity (MUA). Sparse neurons collectively formed a higher-dimensional code, supported efficient image identification, and responded later than broadly tuned neurons. Partly independently of sparseness, some neurons exhibited reliable feature randomness: their stimulus preferences were reproducible across repeated presentations but discontinuous across DNN feature spaces, rather than reflecting trial-to-trial response variability or noise. These neurons were virtually uncorrelated with the surrounding population despite being located within the same face patch. By contrast, MUA responses were denser, more correlated, lower-dimensional, and better predicted by DNNs. Together, these findings suggest a dual coding architecture in anterior IT: shared low-dimensional structure supports category generalization, whereas sparse and reliably feature-random single-neuron responses expand the representational space and support efficient identification of individual visual inputs. Response sparseness and reliable feature randomness may therefore constitute fundamental computational resources for object recognition.

neuroscience↗

bioRxiv2026

Parasitic Vectors in Aquaculture: Neobenedenia girellae and Leeches as Potential Transmission Agents for Trypanosoma carassii spectrum and Pathogenic bacteria

Parasitic infections pose multifaceted threats to farmed fish, extending beyond direct pathogenicity to facilitate infections of bacteria, viruses, and microparasites. This synergistic interaction often leads to co-infections that significantly exacerbate disease outbreaks and mortality, presenting a severe challenge to aquaculture sustainability. Recently, a novel trypanosomiasis caused by the Trypanosoma carassii spectrum has emerged in cage-cultured Larimichthys crocea along the southeast coast of China, resulting in widespread prevalence and high mortality rates. Although this pathogen is hypothesized to originate from freshwater fish, its transmission route in marine environments has remained elusive. In this study, we investigated potential vectors and intermediate hosts of T. carassii spectrum, including leeches and monogenean in natural marine settings, and simulated transmission pathways using an established laboratory model involving T. carassii spectrum, Micropterus salmoides and the leech Poecilobdella manillensis. First, our field surveys in the coast of Ningde, Fujian Province, revealed a nearly 100% co-infection rate of T. carassii spectrum and the monogenean Neobenedenia girellae in diseased juvenile L. crocea. PCR analysis detected T. carassii spectrum traces in some N. girellae specimens, and subsequent experiments confirmed that N. girellae ingests the trypanosome while feeding on host blood. Furthermore, bacterial co-pathogens, such as Vibrio harveyi, were also detected within N. girellae. We also document two fatal leech infestations: Zeylanicobdella arugamensis in hybrid groupers (Epinephelus moara [female] X Epinephelus lanceolatus [male]) in Zhangpu, and Limnotrachelobdella okae in E. lanceolatus and E. fuscoguttatus in Raoping. These leeches tested negative for trypanosomes but carried pathogenic bacteria that co-infected the host fish; nonetheless, they are established vectors for trypanosome transmission. In a laboratory cohabitation model simulating T. carassii spectrum transmission, infected M. salmoides were housed with healthy conspecifics under three conditions: Group A (with the leech P. manillensis), Group B (no leeches), and Group C (no leeches, with physical separation between infected and healthy fish). After 14 days, blood smear microscopy and PCR analysis revealed infection rates in healthy fish of 58.33% in Group A, 40.00% in Group B, and 0% in Group C. Conclusively, T. carassii spectrum can be transmitted via leeches (with higher efficiency) and may also spread through direct contact under high-density aquaculture conditions, whereas N. girellae may act as an incidental vector, further research is warranted to clarify transmission dynamics in natural marine ecosystems. Additionally, our findings highlight the role of ectoparasites, including N. girellae and leeches, as potential reservoirs and vectors for bacterial pathogens of fish. In high-density intensive aquaculture, this vectorial capacity transforms parasites from primary pathogens into key drivers of polymicrobial disease outbreaks.

zoology↗

bioRxiv2026

Evaluating the cross-species transferability and scaling of sequence-to-function predictions in AlphaGenome

Deep learning models that predict molecular phenotypes directly from DNA sequence offer a powerful framework for interpreting genomic variation. Recently, AlphaGenome was introduced as a deep sequence-to-function architecture capable of predicting observations that historically required experiments. While the model has shown high accuracy, it was primarily evaluated on human variants scored against a reference genome. Here, we test performance on mouse data, the other species AlphaGenome was trained on although with fivefold fewer features than human (1,128 versus 5,930). We demonstrate that AlphaGenomes predictive performance varies considerably depending on the functional task. Specifically, predicted quantitative expression effects are directionally weak and compressed roughly 100-fold relative to empirical benchmarks across both reconstructed-haplotype and single-variant regimes. In contrast, canonical splice-site disruptions are recognized with near-identical accuracy in mouse and human (AUC 0.96 versus 0.98), displaying no cross-species divergence in predicted effect magnitude. We developed a scoring-approach for AI-agents to autonomously assess AlphaGenome prediction confidence and accurately differentiate between AlphaGenomes robust sequence-level recognition across species and its current limitations when interpreting un-fine-mapped regulatory variants. This demonstrates how GenAI innovations that are still under development can safely be harnessed by wrapping a responsible AI layer around the call to intercept flawed results, thereby adhering to international standards, such as the Australian Voluntary AI Safety Standard (VAISS).

bioinformatics↗

bioRxiv2026

Multimodal computational framework identifies B cell convergence in autoimmunity and ageing

Identification of the origin of pathogenic immune cells is crucial for therapeutic interventions and diagnosis but pseudotime methods struggle to trace immune cells accurately. Current trajectory inference methods for B cell development and response in health and disease either ignore or underutilize antigen receptor sequence information, limiting their ability to resolve developmental pathways, particularly for pathogenic populations. Widely used methods such as Monocle 3 reconstruct developmental paths from transcriptomic similarity alone, discarding the features from immune receptors. Dandelion has combined the immune receptor features with transcriptomics but it struggles to simulate the trajectory path of B cells. Here we present ClonoTrace, a computational framework that integrates BCR sequence features with transcriptomic trajectory inference through gated fusion of multimodal embeddings. In fetal B cell development and germinal centre development, ClonoTrace achieves higher trajectory inference accuracy than Monocle 3 and Dandelion. Applied to systemic lupus erythematosus, ClonoTrace identifies memory B cell extrafollicular maturation pathway in addition to naive B cell, accompanied by induction of ZEB2 with a concomitant decline of BACH2 along the trajectory, as the alternative origin of pathogenic double negative 2 B cells (DN2) in systemic lupus erythematosus (SLE) patients. In healthy ageing, ClonoTrace identified three pathways from naive, IgM+ memory B cells and switched-memory B cells mature through a DN2-associated transcriptional state that precedes age-associated B cells. ClonoTraces fate probability algorithm indicated that IgM+memory B cell to ABC transition emerged as the leading candidate age-associated transition, that is a process distinct from SLE DN2 maturation. ClonoTrace provides a generalizable framework for receptor-informed trajectory inference, revealing the developmental pathways of pathogenic B cell populations that are untraceable to single modality approaches in autoimmunity and aging.

bioinformatics↗

bioRxiv2026

Circadian clock gates retinal regeneration by orchestrating Cxcl12-dependent immune coordination

The circadian clock orchestrates tissue homeostasis and repair, yet its role in central nervous system (CNS) regeneration remains largely unexplored. Here, we identify the circadian clock as an essential regulator of adult zebrafish retinal regeneration, a CNS model. Retinal injuries induced at distinct circadian times elicit differential Muller glia (MG) reprogramming and progenitor proliferation, both of which exhibit robust diurnal fluctuations. Disrupting circadian rhythms--via constant darkness (DD) or day-night reversal (DL)--suppresses MG reprogramming, MG-derived progenitor cell (MGPC) formation and neuronal regeneration, concomitant with dampened retinal immune responses. Notably, intravitreal immune stimulation restores MGPC numbers in the retina under DD conditions, linking immune activation to circadian-regulated regeneration. Single-cell RNA-seq reveals that DD disrupts MG reprogramming trajectories while inducing unfolded protein response (UPR) and suppressing ATP/protein synthesis. Moreover, clock disruption alters microglia heterogeneity, and cell-cell communication analysis identifies the Cxcl12-Cxcr4 signaling as a key chemotactic axis between MG/endothelial cell and immune populations. Mechanistically, Bmal1b directly binds E-box motifs in the cxcl12a/12b promoters, driving their rhythmic transcription to orchestrate the immune response after injury. Importantly, exogenous Cxcl12a partially restores both immune and regenerative responses in clock-disrupted retinas, establishing the Cxcl12-Cxcr4 axis as a circadian-immune checkpoint for retinal repair. Collectively, our findings reveal a novel paradigm in which the circadian clock gates CNS regeneration through Cxcl12-mediated immune coordination, offering potential therapeutic insights for CNS repair in mammals.

neuroscience↗

bioRxiv2026

Oxidized protein states define metastatic fitness in lung cancer

AbstractReactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10*Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo. These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.

Cancer Biology↗

bioRxiv2026

Chromosome gigantism and auxin deconjugation underpin gall induction in a horned gall aphid

Insect galls are extended phenotypes built through sustained reprogramming of host development, yet the genomic innovations and effector mechanisms that enable this process remain poorly resolved. Here we generated chromosome-level genomes for the horned gall aphid Schlechtendalia chinensis and its host tree Rhus chinensis, and integrated these resources with morph-resolved salivary proteomics, metabolomics and functional assays. The aphid genome contains an anomalously expanded chromosome 1 spanning 93.61 Mb that carries 33.08% of anchored genes and concentrates 70.47% of genome-wide segmental duplications, together with elevated transposable-element load and multiple tandem gene clusters. We identified a salivary M20-family enzyme, ACY1, that consistent with an auxin-conjugate hydrolase. Loss- and gain-of-function assays show that ACY1 hydrolyzes stored, inactive auxin-amino acid conjugates in host tissue, increasing local active auxin levels. This hormone manipulation reprograms plant cell development to form galls. Our findings demonstrate how concentrated genomic duplication can drive the evolution of an effector that controls host physiology, suggesting a potential principle in the evolution of parasitic traits.

molecular biology↗

bioRxiv2026

Nucleoporin1 maintains male germ unit organization and transport in Arabidopsis pollen tubes, likely through shaping nuclear morphology

The male germ unit (MGU) in Arabidopsis pollen is comprised of one vegetative nucleus (VN) and two sperm nuclei (SN). It is evolutionarily specialized to deliver immotile sperm nuclei to an ovule for fertilization. Despite some progress in research on MGU, its organization and transport remain only partially understood. Here, we identified Nucleoporin1/136 as a new player in the structural organization and positioning of MGU in pollen tubes. We and others have previously reported the reduced fertility of nup1-1 plants; however, the mechanism remains unknown. In this work, we further examined the role of NUP1 in fertility using two mutant alleles, nup1-1 and nup1-2-/+. The reciprocal crosses between the nup1 mutants and the Col-0 wild type indicate that the nup1 mutant pollen is defective. To study the effect of a complete NUP1 knockout on pollen, we generated a transgenic line that produces pollen with and without NUP1 expression. This work led to the surprising discovery that the NUP1 protein is inherited from the pollen mother cell to the daughter cell during microgametophyte development. Subsequent in vitro experiments showed that NUP1 is required for pollen germination and pollen tube elongation. Further microscopic studies demonstrated that NUP1 is highly expressed in VN and essential for maintaining nuclear shape and size. We also demonstrated that NUP1 is required for proper MGU organization and transport, likely through maintaining VN morphology. Notably, our finding of nuclear morphology-mediated regulation of MGU may also explain the mechanistic details underlying the defective MGU movement in previously reported mutants such as kaku4, wit, and wip, which have abnormal nuclear morphology.

plant biology↗

bioRxiv2026

CN-RNN: a Deep Learning Framework for Copy Number Variation Detection with Exome Sequencing Data

Copy number variations (CNVs) are major structural genomic variants that contribute to a wide range of human diseases. Accurate detection of CNVs from whole-exome sequencing (WES) data has been a long-sought goal for clinical and population genetic studies. Despite recent progress, existing WES-based CNV callers still suffer from high false-positive rates and reduced recall for short-length variants, and current deep learning methods have not fully used complementary information in region-level genomic features. Here we present CN-RNN, a deep learning-based CNV caller for WES data. The model combines a bidirectional long short-term memory (BiLSTM) branch that captures local depth changes and contextual dependencies across neighboring exons with a parallel multi-layer perceptron (MLP) branch that encodes region-level metadata such as GC content, mappability, and exon length. CN-RNN was trained on the Autism Sequencing Consortium (ASC) parent-child trio cohort using the Mendelian rule of inheritance to ensure high-quality training sets. It was evaluated across three independent datasets, in which we showed that CN-RNN outperformed existing WES-based CNV callers and deep learning methods. CN-RNN offers a scalable, accurate tool for CNV profiling in WES-based studies and supports broader application of CNV analysis in population and clinical research. CN-RNN is available at https://github.com/FeifeiXiao-lab/CN-RNN.

genetics↗

bioRxiv2026

Metabolic dehalogenation of halomethanes by mercury methylators

Mercury (Hg) methylators play key roles in the global Hg cycle. Nonetheless, the Hg methylators are widely present in Hg-absent environments and the Hg methylation is a cometabolic process without cell growth, which leave the origin and evolution of the Hg methylation as a mystery. Here, we reported the CCl4/trihalomethane-to-dihalomethane dehalogenation by model Hg methylators in a metabolic way. Heterologously-expressed HgcAB catalyzed both the CCl4 dechlorination and Hg methylation. Halomethanes were shown to sustain the Hg-methylation community without adding external carbon source, electron donor and acceptor. Metadata analyses suggested the halomethane dehalogenation potential of Hg methylators at the global scale. These results, together with much higher global flux and kinetic Vmax of the metabolic halomethanes dehalogenation relative to the co-metabolic Hg methylation, suggested halomethanes as the potential HgcAB substrates for the evolution of Hg methylation.

microbiology↗

bioRxiv2026

A neural mechanism for online discovery of latent contexts

Experience unfolds as a stream shaped by hidden causes that change over time. Adaptive behavior requires inferring the underlying states and adjusting when they change. Yet, how neural circuits discover and track latent states remains unclear. Here we introduce NeuraGEM, a neural architecture that combines fast transient activity with slow synaptic plasticity to implement an online analogue of Expectation-Maximization. By separating timescales, NeuraGEM clusters sequential experiences, detects context changes, and stabilizes task-specific computations. The model generalizes beyond conventional recurrent networks and reproduces key features of human contextual learning, including curriculum-dependent effects. It also gives rise to population dynamics resembling those observed in brain circuits, including line-attractor structure and transient error responses at change points. Together, these findings provide a mechanistic account of how neural circuits organize experience into latent states that support rapid inference and adaptive behavior.

neuroscience↗

bioRxiv2026

Telomere-to-telomere assembly and haplotype analysis of tetraploid Dendrobium officinale illuminate Orchidaceae polyploid evolution and mycorrhizal symbiosis genes

Dendrobium officinale is a typical epiphytic orchid. We report the telomere-to-telomere (T2T) genome assembly for D. officinale, representing the first T2T reference genome within the Orchidaceae family. The assembly is anchored to 19 chromosomes and contains 38 complete telomeres and 15 characterized centromeres. We further generated haplotype-resolved assemblies of the autotetraploid genome, identifying 12,761 sets of tetra-allelic genes. Based on synonymous substitution analysis, we inferred that the autotetraploidization event occurred approximately 0.86 million years ago. A systematic analysis of the SWEET gene family across the genus Dendrobium revealed that the gene family size is shaped primarily by epiphytic types and environmental factors. In D. officinale from Langshan, eight SWEET genes were specifically expressed in roots, suggesting they may play specialized roles in the root mycorrhizal system, potentially contributing to the D. officinales ability to recruit and maintain fungal partners. Together, these resources provide valuable foundations for studies of orchid evolution, functional genomics, and molecular breeding.

bioinformatics↗

bioRxiv2026

Smooth muscle cell estrogen receptor alpha promotes arterial stiffness in the absence of estradiol

BackgroundClinical evidence supports a greater impact of arterial stiffening in cardiovascular mortality in women versus men. Arterial stiffness increases across the menopausal transition, implicating a role of the loss of estrogens in arterial stiffening, but mediating mechanisms remain unclear. MethodsThe role of estradiol and smooth muscle cell (SMC) estrogen receptor alpha (ER) in arterial stiffening, by aortic pulse wave velocity (PWV), was assessed in 3 models: (1) the loss of estradiol in young, female mice comparing sham surgery or bilateral ovariectomy (OVEX) {+/-} estradiol, (2) the impact of sham versus OVEX surgery in young, female SMC-ER-intact and SMC-ER-knockout (KO) littermates, and (3) arterial stiffening during natural aging by comparing young and aged, female and male SMC-ER-intact and SMC-ER-KO littermates. Mechanistic pathways were assessed using histological assessment of aortic fibrosis and elastin degradation, aortic MMP expression, and atomic force microscopy. ResultsOVEX increased PWV and aortic medial fibrosis, with no impact on elastin integrity, in young female mice. Arterial stiffening and fibrosis were prevented in OVEX mice that were supplemented with estradiol. OVEX-induced arterial stiffening in SMC-ER-intact female mice was prevented in SMC-ER-KO littermates. In this model, OVEX was also associated with increased aortic medial fibrosis without changes in elastin integrity. Aging from 3 to 18 months significantly increased PWV in female and male SMC-ER-intact mice. Aging-induced stiffening was fully prevented in female and partially prevented in male SMC-ER-KO mice. SMC-ER contributes to aging-associated arterial stiffening by sex-specific mechanisms, including elastin degradation in females and phenotypic changes in SMC stiffness and probability to form cellular adhesions in males. Circulating estradiol was significantly decreased in serum from aged compared with young female mice. ConclusionsThese findings support that SMC-ER contributes to arterial stiffening in female and male mice in situations where the vasculature is exposed to low levels of estradiol.

physiology↗

bioRxiv2026

Disentangling blade and vasculature shape in grapevine leaves

The leaf blade and vasculature develop together within a shared morphological space. Despite shared molecular patterning pathways, it is unknown if developmental and evolutionary variation affect these tissues separately or together in a coordinated way. Grapevine leaves have a morphometric history and abundant data measuring the shape of the blade and vasculature together. Using a combination of topological data analysis and deep learning, we perform reciprocal semantic segmentation of leaf blade and vasculature. Each tissue contains sufficient information to predict the other. We hypothesize that this is due to a one-to-one relationship between blade and vein. Using thin plate splines to swap and warp different combinations of blade and vein shapes, we show that a set of leaves with a many-to-one relationship of blade and vein are distinguishable from true leaves. We also swap blade and vein across the developmental series and between species and show that only reversing the developmental series disrupts the relationship between blade and vasculature. We end by discussing the evolutionary and developmental implications that there is a unique, one-to-one mapping between blade and vein that allows each to be predicted from the other. Author summaryLeaves are made of two closely connected parts: the flat blade that captures light and the network of veins that transports water, nutrients, and developmental signals. Although these tissues grow together and share common molecular patterning pathways, it has remained unclear whether a particular blade shape is uniquely linked to a specific vein pattern. In this study, we use grapevine leaves as a model system and combine mathematical shape analysis with deep learning to examine this relationship. We show that the shape of the blade alone can accurately predict the vein network, and that the vein network can likewise predict the blade. This finding suggests a near one-to-one relationship between these two tissues. To test this idea, we created artificial leaves in which blade and vein shapes were deliberately mismatched. Although these synthetic leaves appeared realistic at a global level, a neural network was able to distinguish them from real leaves based on subtle differences. We further show that this tight coupling is maintained by the developmental sequence of leaf growth rather than by species identity, revealing a conserved constraint linking leaf form and internal structure.

plant biology↗

bioRxiv2026

Negative regulation of TH17-mediated inflammation by the nuclear receptor REV-ERBβ

TH17 cells play a central role in several human autoimmune diseases. We and others reported the nuclear receptor, REV-ERB, as a cell-intrinsic repressor of TH17-mediated pathogenicity. REV-ERB{beta}, REV-ERBs closely related family member, is thought to be functionally redundant to REV-ERB, which we sought to explore in TH17-mediated immunity. Our data indicate that deletion of REV-ERB{beta} enhances TH17-mediated pro-inflammatory cytokine expression and exacerbated disease in mouse models of multiple sclerosis and colitis. RNA-sequencing indicates REV-ERB{beta} and REV-ERB do not have similar transcriptional profiles. REV-ERB{beta} does not appear to regulate gene expression through interaction with the classic co-repressor NCoR1, which is in contrast to REV-ERB in TH17 cells, nor does it utilize heme, its known endogenous ligand for its repressive functions. Our results establish that while REV-ERB{beta} also acts as a negative regulator of TH17-cell function and pathogenicity, it does so in a manner that is non-redundant, independent, and unique to REV-ERB.

immunology↗

bioRxiv2026

Small molecule modulators targeting the interactions of small GTPase ARF1 with C9orf72:SMCR8:WDR41 complexes implicated in ALS/FTD

The hexanucleotide repeat expansion in C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). The C9orf72 protein forms a complex with SMCR8 and WDR41 (CSW), which functions as a GTPase-activating protein (GAP) regulating ARF1 and RAB small GTPases. While these findings implicated ARF1-GAP dysregulation in ALS/FTD and supported ARF1 suppression as potential intervention, small molecules that modulate ARF1-CSW interactions are lacking. In this study, we demonstrated upregulation of tyrosine-phosphorylated (Tyr-782) ASAP1 (also known as AMAP1, DDEF1, or Centaurin {beta}4), an ARF-GAP, in human motor cortex of both sporadic ALS and ALS with C9orf72 mutations. Ectopic C9orf72 expression partially mimicked the effects of a known ARF1 inhibitor brefeldin A to disperse Golgi apparatus. Computer-aided rational drug design with high-throughput in-silico screening identified MCULE-5095997944 (Named as SCC944) as a ARF1-CSW modulator. SCC944 binds directly to ARF1 and reduced GTP-bound ARF1 levels upon ARF1 activation. SCC944 demonstrated brefeldin A-like ARF1-dependent alteration of organelle organization including Golgi, microtubules, and mitochondria, but also a protein trafficking pattern that is distinct from brefeldin A mechanism. These studies identified the first small molecule targeting ARF1-CSW interaction and further support ARF1 modulation as a potential therapeutic approach for ALS/FTD.

pharmacology and toxicology↗

bioRxiv2026

Elucidating Odorant Masking Effects in Food Matrices Through Olfactory Receptor-Based Profiling

Dynamic interactions among aroma compounds, especially odorant masking, constitute a key determinant of the intricate flavor profiles of thermally processed foods. However, the molecular and receptor-level mechanisms governing mutual odor suppression remain largely unclear. This study investigated the reciprocal sensory masking between 2,3,5-trimethylpyrazine and L-menthol via systematic sensory evaluation. Olfactory receptor screening identified OR5K1 as the responsive receptor for 2,3,5-trimethylpyrazine (EC50 = 27.67 {+/-} 2.02 mol/L) and OR2W1 as the functional receptor for L-menthol (EC50 = 22.69 {+/-} 3.85 mol/L). Consistently, quantitative cellular response assays further validated that 2,3,5-trimethylpyrazine and L-menthol exert mutual inhibitory effects on their respective receptors, as evidenced by the significant inhibition of receptor signaling. Moreover, molecular modeling predicted that 2,3,5-trimethylpyrazine and L-menthol competitively occupy the same orthosteric pocket via analogous binding conformations. These results provide novel receptor-level insights into odorant inhibitory effects, connecting sensory perception to molecular recognition, and deepen mechanistic understanding of flavor perception.

cell biology↗