Biology subjects

Shen, Y.

Publications and source records attributed to Shen, Y..

At least 127 records · Page 7Linked to original sources

bioRxiv2025

CODAvision: best practices and a user-friendly interface for rapid, customizable segmentation of medical images

Image-based machine learning tools have emerged as powerful resources for analyzing medical images, with deep learning-based semantic segmentation commonly utilized to enable spatial quantification of structures in images. However, customization and training of segmentation algorithms requires advanced programming skills and intricate workflows, limiting their accessibility to many investigators. Here, we present a protocol and software for automatic segmentation of medical images guided by a graphical user interface (GUI) using the CODAvision algorithm. This workflow simplifies the process of semantic segmentation of microanatomical structures by enabling users to train highly customizable deep learning models without extensive coding expertise. The protocol outlines best practices for creating robust training datasets, configuring model parameters, and optimizing performance across diverse biomedical image modalities. CODAvision enhances the usability of the CODA algorithm (Nature Methods, 2022) by streamlining parameter configuration, model training, and performance evaluation, automatically generating quantitative results and comprehensive reports. We expand beyond the original implementation of CODA to serial histology by demonstrating robust performance across numerous medical image modalities and diverse biological questions. We provide sample results in data types including histology, magnetic resonance imaging (MRI), and computed tomography (CT). We demonstrate the diverse use of this tool in applications including quantification of metastatic burden in in vivo models and deconvolution of spot-based spatial transcriptomics datasets. This protocol is designed for researchers with interest in rapid design of highly customizable semantic segmentation algorithms and a basic understanding of programming and anatomy.

bioinformatics↗

bioRxiv2025

Non-invasive skin topical delivery of hyaluronan

Hyaluronic acid (HA), a key glycosaminoglycan in the skin extracellular matrix, diminishes with aging, leading to dryness, wrinkles, and loss of elasticity. While subcutaneous HA injection remains the standard treatment, it is invasive and associated with complications. Here, we developed a zwitterionic polymer-based nanogel system (HA/OP) for noninvasive transdermal HA delivery. The nanogels, formed by complexing HA with poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OP), exhibited pH-responsive behavior, remaining stable at weakly acidic skin surface pH ([~]5) but dissociating in neutral dermal environments. HA/OP nanogels efficiently permeated the stratum corneum via sebum-assisted enrichment and para-corneocyte transport, followed by transcytosis and enhanced paracellular penetration mediated by myosin light-chain kinase (MLCK) upregulation. This enabled deep HA deposition in the dermis and subcutaneous tissue, significantly improving skin hydration and reducing wrinkles in hairless mice without irritation. Our findings present a safe, needle-free strategy for topical HA delivery, addressing a major unmet need in cosmetic and dermatological applications.

bioengineering↗

bioRxiv2025

Integration of nuclear morphology and 3D imaging to profile cellular neighborhoods

Nuclear morphology is an indicator of cellular function and disease states, as changes in nuclear size, shape, and texture often reflect underlying disease-related genetic, epigenetic, and microenvironmental alterations. For disease diagnosis, nuclear segmentation performed in 2D hematoxylin and eosin (H&E)-stained tissue sections has long represented the gold standard. However, recent advances in three-dimensional (3D) histology, which provide a more biologically accurate representation of the spatial heterogeneity of human microanatomy, has led to improved understandings of disease pathology. Yet challenges remain in the development of scalable and computationally efficient pipelines for extracting and interpreting nuclear features in 3D space. 2D histology neglects crucial spatial information, such as 3D connectivity, morphology, and rare events missed by sparser sampling. Here, through extension of the CODA platform, we integrate 3D imaging with nuclear segmentation to analyze nuclear morphological features in human tissue. Analysis of 3D tissue microenvironments uncovered critical changes in 3D morphometric heterogeneity. Additionally, it enables the spatial characterization of immune cell distribution in relation to tissue structures, such as variations in leukocyte density near pancreatic ducts and blood vessels of different sizes. This approach provides a more comprehensive understanding of tissue and nuclear structures, revealing spatial patterns and interactions that are critical for disease progression.

bioinformatics↗

bioRxiv2025

Microtubule acetylation is a biomarker of cytoplasmic health during cellular senescence

Cellular senescence is marked by cytoskeletal dysfunction, yet the role of microtubule post-translational modifications (PTMs) remains unclear. We demonstrate that microtubule acetylation increases during drug-induced senescence in human cells and during natural aging in Drosophila. Elevating acetylation via HDAC6 inhibition or TAT1 overexpression in BEAS-2B cells disrupts anterograde Rab6A vesicle transport, but spares retrograde transport of Rab5 endosomes. Hyperacetylation results in slowed microtubule polymerization and decreased cytoplasmic fluidity, impeding diffusion of micron-sized condensates. These effects are distinct from enhanced detyrosination, and correlate with altered viscoelasticity and resistance to osmotic stress. Modulating cytoplasmic viscosity reciprocally perturbs microtubule dynamics, revealing bidirectional mechanical regulation. Senescent cells phenocopy hyperacetylated cells, exhibiting analogous effects on transport and microtubule polymerization. Our findings establish acetylation as a biomarker for cytoplasmic health and a potential driver of age-related cytoplasmic densification and organelle transport decline, linking microtubule PTMs to biomechanical feedback loops that exacerbate senescence. This work highlights the role of acetylation in bridging cytoskeletal changes to broader aging hallmarks.

cell biology↗

bioRxiv2025

A new class of OLD family ATPases functions in cell cycle progression in thermoacidophilic archaea

Overcoming lysogenization defect (OLD) proteins are diverse ATPases-nucleases functioning in antiphage defense in bacteria. However, the role of these proteins in archaea is currently unknown. Here, we describe a new class of archaeal OLD family ATPases and show that they do not appear to be involved in antiviral defense but play an essential role in cell cycle progression. The gene in Saccharolobus islandicus REY15A, named as Cran1 (Cell cycle related ATPase and nickase 1), cannot be deleted and exhibits cyclic expression patterns, with a peak expression during the transition from M-G1 to S cell cycle phase. Cran1 overexpression leads to significant growth retardation, cell size enlargement, and increased cellular DNA content. Cran1 displays potent nickase and ATPase activities in vitro, with the nickase activity being dependent on the presence of the ATPase domain. Notably, Cran1 copurifies with chromatin-associated proteins, such as Cren7 and a histone deacetylase homolog, suggesting its involvement in chromatin-related activities. Collectively our results suggest that Cran1 plays an important role in cell cycle progression, revealing a novel function of OLD family proteins.

microbiology↗

bioRxiv2025

Roles and transcriptional regulation of the endogenous cellulases in association with substrate and cellular processes in a thermoacidophilic archaeon

Microbes of the order Sulfolobales are potentially next generation platforms for cellulose degradation and utilization. However, the mechanisms of cellulose degradation and utilization remain unclear. In this study, we analyzed the enzymatic activity, localization, transcriptional regulation, and interplay of three endogenous cellulases Cel1, Cel2A, and LacS, and the association of transcription with cellular processes in the model thermophilic archaeon Saccharolobus islandicus REY15A. Overexpression strains based on a vector developed in this study as well as single and double deletion mutants of the three cellulase genes were constructed and analyzed. We reveal that Cel1 and Cel2A are membrane-associated, and a higher proportion of Cel2A is secreted into the medium than Cel1. The expression of all the three cellulases is induced by carboxymethylcellulose sodium (CMC). Furthermore, we found that the transcriptional levels of cel1, cel2A, and lacS are interdependent and cel1 and cel2A levels apparently increased with lacS deletion and overexpression of an ABC transporter, suggesting of an intracellular oligosaccharide-dependent regulatory mechanism. We showed that a cell cycle transcription factor aCcr1 binds to the promoter of cel1 in vitro. Additionally, we accidentally found that the cellulase genes expression increases in the presence of uracil synthesis pathway and deletion of the cellulase genes facilitates cell growth in CMC-containing medium. This study reveals an ingenious and intricated mechanism for cellulose utilization to adapt to extreme environment in archaea and provide insights for engineering Sulfolobales archaea as biomass-degrading and utilization platforms.

microbiology↗

bioRxiv2025

Restoration of tumor suppressor protein with enhanced activity using engineered tRNAs to induce tumor regression

Cancer develops through a gradual accumulation of mutations including nonsense mutations in tumor suppressor genes (TSGs), which drive tumor proliferation and progression due to the impairment or complete loss of tumor suppressor protein function. The ability to restore functional tumor suppressor protein from mutant driver TSGs is a longstanding aspiration in cancer therapy, however, current strategies face formidable challenges in recovering proteins harboring heterogeneous mutations and circumventing dominant-negative effects exerted by endogenous mutant proteins. Therefore, the development of therapeutic interventions that are effective and generalizable across diverse nonsense mutations in cancer, to rescue endogenous mutant tumor suppressor proteins remains an urgent yet unmet need. Here we find that engineered suppressor transfer RNA (sup-tRNA) could overcome nonsense mutations in key driver tumor suppressor genes, such as TP53, thereby avoiding the dominant-negative effects through the restoration of endogenous mutant p53 with its original functions. Optimized sup-tRNA that we named super tRNA, enabling high-fidelity incorporation of desired amino acids, can further enhanced the transcriptional activity of p53 to suppress tumor cell proliferation. Moreover, we also establish a computational model to guide super tRNAs design, and demonstrate that super tRNA could effectively inhibit tumor growth by targeted readthrough of nonsense mutations in different tumor suppressor genes. In two xenograft models harboring nonsense mutant TP53, we observed up to a 70% reduction in tumor volume after lipid nanoparticle (LNP)-based sup-tRNA treatment, along with robust recovery of p53 expression and function, and no hematological or histological abnormalities detected. Our findings demonstrate the potential of sup-tRNA as a feasible and effective strategy to rescue and enhance tumor suppressor protein function, thereby preventing cancer development. As a novel therapeutic RNA, sup-tRNA provides a flexible strategy for targeting driver mutations in cancer, thereby expanding the potential of tRNA-based therapy in precision oncology.

bioengineering↗

bioRxiv2025

High-Quality Cell Capture Reveals Transcriptomic Changes After Single-Axon Injury of Mauthner Cells

In vivo single-cell capture methods based on micropipettes are essential for correlating morphological characteristics with transcriptomic profiling under physiological conditions. However, they often suffer from significant contamination of off-target cells. Consequently, we developed Hip-seq, which significantly reduces heavily contaminated cells, decreases contamination levels, improves cell reproducibility, and enhances data analysis accuracy compared to patch-seq. Using Hip-seq, we found that axon regeneration failure could be due to abnormal activation of translation and the circadian clock. Axon-regenerable central neurons reactivated axon development-related genes during regeneration. And one-to-one associated analysis helped identify pro-regenerative genes.

neuroscience↗

bioRxiv2025

Two sites in the C-terminal β-chain tail mediate interactions of the chaperone clusterin with amyloid beta and other misfolded client proteins

Clusterin (CLU) is a constitutively secreted mammalian chaperone that binds in extracellular body fluids to misfolded client proteins to neutralise their toxicity and mediate their safe disposal by cell uptake and intracellular degradation. However, the regions of CLU critical for its interactions with misfolded proteins remain still largely unknown. To identify binding sites, we expressed a panel of CLU deletion and alanine-stretch mutants in a recently developed mammalian expression system. Mutant CLU molecules lacking detectable structural aberrations were subjected to functional analyses to compare their abilities with that of wild type CLU to bind to misfolded proteins and to inhibit protein aggregation. These analyses implicated two regions in the flexible {beta}-chain C-terminal tail of CLU as being important in the interactions of the chaperone with misfolded proteins, including aggregating the Alzheimers amyloid {beta}-peptide (A{beta}). We then designed in silico sequence-specific single-domain camelid nanobodies to confirm the function of the two putative client protein binding sites. Based on our experimental results and in silico binding site predictions, we suggest that the potent ability of CLU to promiscuously interact with many different misfolded proteins, regardless of their size or structure, arises from the location of multiple client protein binding sites in its flexible tail region.

biochemistry↗

bioRxiv2025

Correlative In Situ Cryo-ET Reveals Cellular and Viral Remodeling Associated with Selective HIV-1 Core Nuclear Import

Lentiviruses like HIV-1 infect non-dividing cells by traversing the nuclear pore, but studying this process has been challenging due to its scarcity and dynamic nature in infected cells. Here, we developed a robust cell-permeabilization system that recapitulates HIV-1 nuclear import and established an integrated cryo-correlative workflow combining cryo-CLEM, cryo-FIB, and cryo-ET for targeted imaging of this process. These advancements enabled the successful capture of 1,899 HIV-1 cores at various stages of nuclear import. Statistical and structural analyses of native wild-type and mutant cores revealed that HIV-1 nuclear import depends on both capsid elasticity and nuclear pore adaptability, as well as nuclear factors such as CPSF6. Brittle cores fail to enter the nuclear pore complex (NPC), while CPSF6-binding-deficient cores stall inside the NPC, resulting in impaired nuclear import. Intriguingly, nuclear pores function as selective filters favoring the import of smaller, tube-shaped cores. Our study opens new avenues for dissecting the biochemistry and structural biology of HIV-1 nuclear import as well as downstream events including core uncoating and potentially integration, with unprecedented detail.

microbiology↗

bioRxiv2025

Distinct Clinical Phenotypes in KIF1A-Associated Neurological Disorders Result from Different Amino Acid Substitutions at the Same Residue in KIF1A

KIF1A is a neuron-specific kinesin motor responsible for intracellular transport along axons. Pathogenic KIF1A mutations cause KIF1A-associated neurological disorders (KAND), a spectrum of severe neurodevelopmental and neurodegenerative conditions. While individual KIF1A mutations have been studied, how different substitutions at the same residue affect motor function and disease progression remains unclear. Here, we systematically examine the molecular and clinical consequences of mutations at three key motor domain residues--R216, R254, and R307--using single-molecule motility assays and genotype-phenotype associations. Our findings reveal that mutations at R216 and R254 produce residue-specific effects, with some substitutions partially retaining function, whereas R307 mutations universally abolish motility, likely due to its critical role in microtubule binding. Mutant motor properties correlate with developmental outcomes, with R307 mutations linked to the most sever impairments. These results demonstrate that even single-residue substitutions can lead to distinct molecular and clinical phenotypes, highlighting the finely tuned mechanochemical properties of KIF1A. By establishing residue-specific genotype-phenotype relationships, this work provides fundamental insights into KAND pathogenesis and informs targeted therapeutic strategies.

biophysics↗

bioRxiv2025

comBO: A combined human bone and lympho-myeloid bone marrow organoid for pre-clinical modelling of haematopoietic disorders

The bone marrow supports lifelong blood and immune cell production. Current human bone marrow organoid models do not include both lymphoid and myeloid elements and lack the complexity of stromal cell types present in native haematopoietic tissues, precluding the accurate ex vivo modelling of human pathologies. Here we introduce "comBOs" (combined bone and lympho-myeloid bone marrow organoids) that include osteolineage, vascular, lymphoid and myeloid cells. comBOs are generated by the differentiation of induced pluripotent stem cells guided by physiologically-relevant oxygen and cytokine exposures within an innovative granular microgel scaffold to increase scalability and reproducibility. We demonstrate that comBOs can be used to generate "chimeroids" - incorporating healthy or aberrant cells from adult donors - and recapitulate features of diseased microenvironments. ComBOs are one of the most physiologically-relevant human organoid systems to date, and this study showcases the potential of 3D in vitro disease models for discovery science and translational studies.

cancer biology↗

bioRxiv2025

MYRF is Essential in Mesothelial Cells to Promote Lung Development and Maturation

The mesothelium is a squamous monolayer that ensheathes internal organs, lines the body cavity, and the diaphragm. It serves as a protective barrier, coated in glycocalyx, and secretes lubricants to facilitate tissue movement. How the mesothelium forms is poorly understood. Here, we investigate Myrf, a transcription factor gene expressed in the mesothelium, because it carries variants in patients with Congenital Diaphragmatic Hernia (CDH), a disorder that affects the diaphragm, lung, and other organs. In mice, inactivation of Myrf early in organogenesis resulted in CDH and defective mesothelial specification, compromising its function as a signaling center for lung growth. Inactivation of Myrf later led to enhanced mesothelium differentiation into mesenchymal cell types through partial epithelial-to-mesenchymal transition (EMT), resulting in a unique accumulation of smooth muscle encasing the lung. In this role, MYRF functions in parallel with YAP/TAZ. Together, these findings establish MYRF as a critical regulator of mesothelium development, and when mutated, causes CDH.

developmental biology↗

bioRxiv2025

Structural basis for HIV-1 capsid adaption to rescue IP6-packaging deficiency

Inositol hexakisphosphate (IP6) promotes HIV-1 assembly via its interaction with the immature Gag lattice, effectively enriching IP6 within virions. During particle maturation, the HIV-1 protease cleaves the Gag polyproteins comprising the immature Gag lattice, releasing IP6 from its original binding site and liberating the capsid (CA) domain of Gag. IP6 then promotes the assembly of mature CA protein into the capsid shell of the viral core, which is required for infection of new target cells. Recently, we reported HIV-1 Gag mutants that assemble virions independently of IP6. However, these mutants are non-infectious and unable to assemble stable capsids. Here, we identified a mutation in the C-terminus of CA - G225R - that restores capsid formation and infectivity to these IP6-packaging-deficient mutants. Furthermore, we show that G225R facilitates the in vitro assembly of purified CA into capsid-like particles (CLPs) at IP6 concentrations well below those required for WT CLP assembly. Using single-particle cryoEM, we solved structures of CA hexamer and hexameric lattice of mature CLPs harbouring the G225R mutation assembled in low-IP6 conditions. The high-resolution (2.7 [A]) cryoEM structure combined with molecular dynamics simulations of the G225R capsid revealed that the otherwise flexible and disordered C-terminus of CA becomes structured, extending to the pseudo two-fold hexamer-hexamer interface, thereby stabilizing the mature capsid. This work uncovers a structural mechanism by which HIV-1 adapts to a deficiency in IP6 packaging. Furthermore, the ability of G225R to promote mature capsid assembly in low-IP6 conditions provides a valuable tool for capsid-related studies and may indicate a heretofore unknown role for the unstructured C-terminus in HIV-1 capsid assembly.

microbiology↗

bioRxiv2025

CryoEM-enabled visual proteomics reveals de novo structures of oligomeric protein complexes from Azotobacter vinelandii

Single particle cryoelectron microscopy (cryoEM) and cryoelectron tomography (cryoET) are powerful methods for unveiling unique and functionally relevant structural states. Aided by mass spectrometry and machine learning, they promise to facilitate the visual exploration of proteomes. Leveraging visual proteomics, we interrogate structures isolated from a complex cellular milieu by cryoEM to identify and classify molecular structures and complexes de novo. That approach determines the identity of six distinct oligomeric protein complexes from partially purified extracts of Azotobacter vinelandii using both anaerobic and aerobic cryoEM. Identification of the first unknown species, phosphoglucoisomerase (Pgi1), is achieved by comparing three automated model building programs: CryoID, DeepTracer, and ModelAngelo with or without a priori proteomics data. All three programs identify the Pgi1 protein, revealed to be in a new decameric state, as well as additional globular structures identified as glutamine synthetase (GlnA) and bacterioferritin (Bfr). Large filamentous assemblies are observed in tomograms reconstructed from cryoFIB milled lamellae of nitrogen-fixing A. vinelandii. Enrichment of these species from the cells by centrifugation allows for structure determination of three distinct filament types by helical reconstruction methods: the Type 6 Secretion System non-contractile sheath tube (TssC), a novel filamentous form of the soluble pyridine transhydrogenase (SthA), and the flagellar filament (FliC). The multimeric states of Pgi1 and SthA stand out in contrast to known crystallographic structures and offer a new structural framework from which to evaluate their activities. Overall, by allowing the study of near-native oligomeric protein states, cryoEM-enabled visual proteomics reveals novel structures that correspond to relevant species observed in situ. O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/636493v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@59bd1eorg.highwire.dtl.DTLVardef@18f0f36org.highwire.dtl.DTLVardef@12fe3a7org.highwire.dtl.DTLVardef@10aeda7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Avoidance of fratricide and improved efficacy of CD33-MSLN CAR-iNK cells in treating acute myeloid leukemia

Acute myeloid leukemia (AML) patients are often older, which brings challenges of endurance and persistent efficacy of autologous CAR-T cell therapies. Allogenic CAR-NK cell therapies may offer reduced toxicities and enhanced anti-leukemic potential against AML. In this study, we designed a novel CD33-mesothelin loop CAR (Loop CAR) and evaluated its anti-tumor efficacy in human umbilical cord blood-derived NK (UCB-NK) cells and human pluripotent stem cell-derived NK (hPSC-iNK) cells. The Loop CAR exhibited superior cytotoxicity against dual-antigen-positive tumor cell lines and primary AML cells. To further avoid fratricide caused by endogenous CD33 expression in NK cells, we established a hPSC-derived cell line via knockout of CD33 gene (CD33KO) and engineered Loop CAR. Rather than enforced expression of exogenous CD16, we generated abundant mature CD33KO-Loop CAR-iNK cells highly expressing endogenous CD16 via an organoid induction approach. This innovative strategy effectively mitigated NK cell fratricide and significantly enhanced CD33 and mesothelin-mediated specific cytotoxicity. Moreover, the CD33KO-Loop CAR-iNK cells demonstrated superior tumor-killing activity in AML xenograft mice and significantly prolonged survival. hPSC-derived CD33KO-Loop CAR-iNK cells possess unique advantages and translational potential for treating AML.

cancer biology↗

bioRxiv2025

Engineered CRO-CD7 CAR-NK cells derived from pluripotent stem cells avoid fratricide and efficiently suppress human T-cell malignancies

BackgroundT cell malignancies are highly aggressive hematological tumors with limited effective treatment options. CAR-NK cell therapy targeting CD7 has emerged as a promising approach for treating T-cell malignancies. However, conventional CAR-NK cell therapy faces the challenges of cell fratricide due to CD7 expression on both malignant cells and normal NK cells. Additionally, engineering CARs into human tissue-derived NK cells demonstrates heterogeneity, low transduction efficiency, and high manufacturing costs. MethodsThe human pluripotent stem cells (hPSCs) were genetically modified by knocking out the CD7 gene and introducing the CD7 CAR expression cassette to generate CD7 KO-CD7 CAR-hPSCs. These modified hPSCs were subsequently differentiated into CD7 KO-CD7 CAR-iNK cells using an efficient organoid induction method. The cytotoxicity of CD7 KO-CD7 CAR-iNK cells against CD7+ tumor cells was evaluated. Furthermore, we overexpressed the CXCR4 gene in CD7 KO-CD7 CAR-hPSCs and derived CXCR4-expressing CD7 KO-CD7 CAR-iNK (CRO-CD7 CAR-iNK) cells. The dynamics of CRO-CD7 CAR-iNK cells in vivo were tracked, and their therapeutic efficacy was assessed using human T-cell acute lymphoblastic leukemia (T-ALL) xenograft models. ResultsThe CD7 KO-CD7 CAR-iNK cells derived from CD7 KO-CD7 CAR-hPSCs effectively avoided fratricide, demonstrated normal expansion, and exhibited potent and specific anti-tumor activity against CD7+ T-cell tumor cell lines and primary T-ALL cells. CXCR4 overexpression in CRO-CD7 CAR-iNK cells improved their homing capacity and extended their persistence in vivo. The CRO-CD7 CAR iNK cells significantly suppressed tumor growth and prolonged the survival of T-ALL tumor-bearing mice. ConclusionsOur study provides a reliable strategy for the large-scale generation of fratricide-resistant CD7 CAR-iNK cells with robust anti-tumor effects from hPSCs, offering a promising cell product to treat T-cell malignancy.

cancer biology↗

bioRxiv2025

An evolutionarily conserved mechanism for reformatting odor concentration in early olfactory circuits

Understanding how stimuli from the sensory periphery are progressively reformatted to yield useful representations is a fundamental challenge in neuroscience. In olfaction, assessing odor concentration is key for many behaviors, such as tracking and navigation. Initially, as odor concentration increases, the average response of first-order sensory neurons also increases. However, the average response of second-order neurons remains flat with increasing concentration - a transformation that is believed to help with concentration-invariant odor identification, but that seemingly discards concentration information before it could be sent to higher brain regions. By combining neural data analyses from diverse species with computational modeling, we propose strategies by which second-order neurons preserve concentration information, despite flat mean responses at the population level. We find that individual second-order neurons have diverse concentration response curves that are unique to each odorant -- some neurons respond more with higher concentration and others respond less -- and together this diversity generates distinct combinatorial representations for different concentrations. We show that this encoding scheme can be recapitulated using a circuit computation, called divisive normalization, and we derive sufficient conditions for this diversity to emerge. We then discuss two mechanisms (spike rate vs. timing based) by which higher order brain regions may decode odor concentration from the reformatted representations. Since vertebrate and invertebrate olfactory systems likely evolved independently, our findings suggest that evolution converged on similar algorithmic solutions despite stark differences in neural circuit architectures. Finally, in land vertebrates a parallel olfactory pathway has evolved whose second-order neurons do not exhibit such diverse response curves; rather neurons in this pathway represent concentration information in a more monotonic fashion on average, potentially allowing for easier odor localization and identification at the expense of increased energy use.

neuroscience↗