Biology subjects

Tanaka, H.

Publications and source records attributed to Tanaka, H..

At least 19 recordsLinked to original sources

bioRxiv2026

HPV-Associated Tonsillar Intraepithelial Neoplasia and Oral High-Risk HPV mRNA as a Candidate Biomarker

Early detection of human papillomavirus (HPV)-associated oropharyngeal cancer is an unmet need, as its premalignant lesions remain unestablished. We hypothesized that such lesions exist in individuals with oral high-risk HPV (HR-HPV) mRNA. We preoperatively screened 1,180 individuals undergoing tonsillectomy due to benign conditions and detected five with oral HR-HPV mRNA. Serial sectioning of the entire excised tonsils identified HPV-associated intraepithelial lesions in three of these five individuals. A similar lesion was identified in an additional individual with oral HPV16 infection with unknown oral HR-HPV mRNA status. Intraepithelial lesions in two individuals were HPV16-associated and showed moderate-to-severe atypia, whereas those in the other two individuals were associated with other HR-HPV and showed minimal-to-mild atypia. Based on HPV life cycle, the former were classified as transforming lesions and the latter as productive-to-intermediate lesions. Spatial transcriptomic analysis revealed molecular profiles intermediate between those of normal epithelium and HPV-associated oropharyngeal cancer. These findings establish the first evidence for HPV-associated tonsillar premalignant lesions and suggest oral HR-HPV mRNA as a candidate biomarker.

cancer biology↗

bioRxiv2026

NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM

Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.

molecular biology↗

bioRxiv2026

Microvascular pathology of proteotoxic endothelial signature characterizes Progressive Supranuclear Palsy

Cerebrovascular pathology is increasingly implicated in neurodegenerative diseases, yet its pathomechanistic contribution remains poorly defined. Building on prior evidence of dysregulated iron and oxygen homeostasis in early-affected brain regions of progressive supranuclear palsy (PSP), we hypothesized that brain microvascular alterations may play an etiological role in select neurodegenerative proteinopathies. First, we conducted a systematic neuropathological evaluation of 178 brains from the University Health Network Neurodegenerative Brain Collection, including Alzheimers disease-related neuropathologic change (ADNC; n=30), Lewy body disease with high or intermediate ADNC (n=38) and low ADNC (n=16), multiple system atrophy (MSA; n=14), PSP (n=39), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP; n=10), and controls (n=31). Arteriolosclerosis, microinfarction, and calcification were assessed in the basal ganglia and frontal cortex. Iron burden was correlated by quantification of Perls staining in MSA and PSP, where vessel pathology was most severe. Single-nucleus RNA-sequencing (snRNA-seq) of frontal cortex tissue from control (n=5) and PSP (n=8) cases with varying arteriolosclerosis severity was performed to characterize the vascular transcriptome, with validation against an independent snRNA-seq evaluation of PSP (n= 11), Picks disease (n=9), AD (n=10), and control (n=10) brains. Histological analysis revealed disease-specific involvement of microvascular pathology in neurodegenerative diseases, identifying PSP to demonstrate most prominent and widespread vessel wall thickening across regions examined. Regression analysis using demographic, APOE and MAPT genetic risk status, and neuropathological features of cases corroborated the distinct association with PSP pathology. Elevated iron load in early affected regions of MSA and PSP brains correlated with greater vessel wall thickening, suggesting a possible pathomechanistic relationship between the two disease physiologies. snRNA-seq analysis of vascular transcriptome identified robust upregulation of heat shock proteins and hypoxia-related genes in PSP endothelial cells and pericytes across both datasets. Importantly, we found the proteotoxic signature to be strongly associated with higher vessel scores in PSP cases, linking microvascular morphology to endothelial dysfunction. Our comprehensive neuropathological evaluation coupled with correlative snRNA-seq analysis establish PSP-specific arteriolar thickening associated with endothelial proteotoxic state as a candidate pathogenic mechanism. The cerebral arteriolar unit represents a compelling therapeutic target for disease modification in PSP.

pathology↗

bioRxiv2026

A geometric and dynamical theory of latent computations in biological neural networks

Many neural recordings have revealed low-dimensional sets of behaviorally relevant variables encoded within large-scale neural activity patterns. However, dimensionality reduction analyses alone cannot yield causal explanations for how networks stably implement computations that are resilient to the substantial variability of single neuron dynamics. Further, existing methods for dimensionality reduction often rely on simplifying assumptions about network structure that limit their applicability and explanatory power. To provide a theoretical framework describing the dynamics of low-dimensional computation in high-dimensional neural networks, here we introduce the concept of latent processing units (LPUs), which are architecture-agnostic computational elements operating within biological neural circuitry. Six theorems governing coding and computation by LPUs collectively provide explanations for a range of common biological findings: low-dimensional sets of coding variables can generate high-dimensional neural dynamics; many neurons have activity patterns that represent behaviorally relevant variables but exert little influence on downstream circuits; linear readouts of neural population activity commonly permit near-optimal decoding; the drift of neural representations is often substantial even while network computations remain intact. Overall, our treatment of LPUs, as enacted in network dynamics, unifies the geometric and dynamical views of neural computation under a joint framework and provides systems neuroscience with a causal account of how the brain executes reliable computations.

neuroscience↗

bioRxiv2026

Estimation of the curved body length of tuna larvae from microscope images using a zero-shot model and image processing techniques

Fixed larval specimens often shrink and curve, making length measurement labor-intensive. Although recent studies have demonstrated efficient fish-length estimation from images using deep learning, methods for estimating curved length remain limited. Furthermore, although deep learning is a powerful method for object detection in images, an essential step for length measurement, it requires preparing large amounts of training data, which can hinder practical implementation. In this study, we used a zero-shot model that requires no training to detect fish in an image. The curved length was then estimated using an image-processing approach that combines image thinning with Bezier curve approximation, and its accuracy was evaluated. We analyzed 1,040 larvae from five tuna species captured in stereomicroscope images. Manual measurements (notochord length or standard length; 1.5-8.5 mm) were conducted by two measurers and served as reference values. Fish regions were detected using GroundedSAM, and curved body centerlines were extracted through image thinning and approximated with Bezier curves. The curve length was used as the estimated body length. Estimation accuracy was assessed using bias and standard deviation between estimated and manual measurements. GroundedSAM detected all 1,040 fish, although there were 49 overdetections. Overdetection was caused by the double-detection of a single fish or by the misidentification of debris and light reflections as fish. Although the standard deviation of the differences between manual measurements and the image analysis-based (IAB) method was larger than the inter-measurer differences, the bias for [≤]5 mm was comparable to or smaller than the inter-measurer bias. According to the strength-of-agreement criteria for the concordance correlation coefficient, the IAB method demonstrated substantial agreement in the [≤]5.0-mm range. The IAB method accurately measured most curved tuna larvae without prior training, particularly in the [≤]5.0-mm range. Combining the IAB method with manual remeasuring can improve the efficiency of curved-length measurement tasks.

ecology↗

bioRxiv2026

Deep learning cell type classification using nuclear DNA patterns

Multicellular organisms comprise various types of cells, which are characterized by gene expression through interactions between chromosomal DNA and nuclear proteins. Many cutting-edge methods have been developed to reveal the three-dimensional organization of chromosomes. The detailed analyses of whole chromosomes have begun to uncover structural features specific to several cell types. Here, we show that cell types are instantly and highly accurately classified using conventional DNA staining and a convolutional neural network (CNN). A high-resolution single slice image of the nucleus is sufficient for the accurate classification of both live and fixed cells, including neurons and non-neural cells. These findings suggest that there may be cell-type-specific features decipherable by deep learning in a thin two-dimensional slice of the nucleus.

cell biology↗

bioRxiv2026

Thiol methyltransferase METTL7B coordinates lipid metabolism and promotes tumor progression in pancreatic cancer

Dysregulated lipid metabolism drives cancer progression, yet the molecular mechanisms linking lipid accumulation to pancreatic cancer remain poorly understood. Here, we identify methyltransferase-like 7B (METTL7B) as a key regulator of lipid metabolism and tumor progression in pancreatic cancer. Integrated analysis of large-scale transcriptomic datasets revealed that METTL7B is upregulated in pancreatic cancer compared with normal tissues, and elevated METTL7B expression is associated with poor patient prognosis. Functional experiments demonstrated that METTL7B is required for pancreatic cancer cell proliferation, migration, and metastasis. We identified hepatocyte nuclear factor 4 (HNF4A) and hepatocyte nuclear factor 4{gamma} (HNF4G), well-established regulators of lipid homeostasis, as transcription factors that directly upregulate METTL7B expression in pancreatic cancer cells. Moreover, we showed that METTL7B localizes around lipid droplets and promotes their accumulation in pancreatic cancer cells. Lipidomic analyses revealed that METTL7B depletion selectively reduces long-chain triacylglycerols and increases shorter-chain ceramides, while also modulating other lipid droplet-related lipid classes in a chain-length-dependent manner. Collectively, these findings suggest that METTL7B regulates lipid metabolism and malignant behavior in pancreatic cancer and may represent a potential therapeutic target.

molecular biology↗

bioRxiv2026

An evolutionary landscape of sesame: chromosomal variation, allopolyploid speciation and metabolic specialization.

Sesame (Sesamum indicum) is one of the earliest domesticated oilseed crops and is valued for antioxidant lignans that stabilize oil quality. However, the genomic and evolutionary history of the genus Sesamum, including the origin of its allotetraploid relative S. radiatum and the diversification of lignan metabolism, remains poorly understood owing to limited chromosome-scale genomic resources. Here we present chromosome-level genome assemblies for three wild Sesamum species, two Ceratotheca species and a Japanese sesame cultivar to reconstruct genome and karyotype evolution across the Sesamum-Ceratotheca complex. Comparative analyses show that the derived x=16 lineage originated from an ancestral x=13 karyotype through chromosome fission, fusion and translocation, whereas another x=13 lineage underwent extensive restructuring associated with retrotransposon expansion. Phylogenomics places Ceratotheca within the x=16 Sesamum clade and reveals that S. radiatum originated through hybridization involving a C. sesamoides-like ancestor. The antioxidative lignan gene CYP92B14 was reintroduced via the BB progenitor, linking hybridization with restoration of oil-stabilizing metabolism during sesame evolution.

genomics↗

bioRxiv2026

HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging

Age-associated functional decline is partly driven by progressive chromatin degeneration. Maintenance of chromatin integrity preserves cell identity and promotes healthy aging, but through different mechanisms in proliferating and non-proliferating cells. However, specific mechanisms of chromatin maintenance and their compensatory capacity in proliferating and non-proliferating cells are undefined. The histone chaperone HIRA deposits the histone variant H3.3 in a DNA replication-independent manner, leading to its accumulation in aging, non-proliferating cells. Here, we show that hepatocyte-specific loss of HIRA causes loss of cell identity, metabolic dysfunction, and accelerated fibrotic pathology with age. Transcriptomic and epigenomic analyses indicate that HIRA-H3.3 preserves chromatin integrity and sustains transcription of highly expressed genes, including cell identity genes. Partial hepatectomy, associated with induced proliferation, restores identity of HIRA knockout livers with compensatory deposition of canonical histones H3.1/2. Together, these results demonstrate that HIRA-mediated H3.3 deposition is essential for safeguarding cell identity and tissue function during aging of non-proliferating cells, but this function can be rescued by tissue regeneration and associated cell proliferation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/710643v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@a2a26aorg.highwire.dtl.DTLVardef@154e5aeorg.highwire.dtl.DTLVardef@b315a7org.highwire.dtl.DTLVardef@152bca4_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2026

Histone variant H2A.Z mutant suppresses the senescence-associated secretory phenotype

Cellular senescence features a durable cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP) driven in part by chromatin remodeling. The histone variant H2A.Z plays an essential role in regulating gene expression through modulating nucleosome dynamics and is known to regulate the expression of cell cycle genes during the early stages of cellular senescence. However, how the intrinsic stability of H2A.Z-containing nucleosomes plays a role in the establishment of the senescent phenotype remains unexplored. To investigate this, we employed H2A.Z R80C, a H2A.Z mutant that destabilizes nucleosomes by disrupting histone-DNA interactions. We observed that expression of H2A.Z R80C causes suppression of SASP in senescent primary human fibroblasts, without affecting expression of cell cycle genes. H2A.Z knockdown did not suppress the SASP, demonstrating that SASP suppression is likely due to altered stability of H2A.Z-containing nucleosomes rather than loss of H2A.Z function. Mechanistically, SASP suppression is linked to decreased H3K27ac at SASP gene loci. These findings offer a novel avenue for understanding and manipulating the SASP during aging and other senescence-related pathologies.

molecular biology↗

bioRxiv2026

Structural basis of lenacapavir-induced HIV-1 capsid disruption during virion maturation

Long-acting lenacapavir (LEN) has emerged as a highly effective, potentially game-changing therapy for HIV treatment and prevention1-5. Although its mechanism of action in the early phase of HIV-1 replication, when the capsid directs key post-entry steps such as reverse transcription, nuclear import, and integration, has been well characterized1,2,6-8, its effects during the late phase of replication, when the capsid assembles and matures within budding virions, remain poorly understood. Here, we determine the cryo-electron microscopy structure of the mature HIV-1 capsid lattice assembled within virus-like particles in the presence of LEN. Our structural analyses revealed that LEN alters interhexamer interactions, perturbs capsid lattice curvature, and thereby prevents the formation of a functional cone-shaped capsid. Biochemical analyses further demonstrated that LEN-containing cores lose reverse transcriptase due to a compromised capsid integrity, whereas integrase and viral RNA remain associated. Functionally, viruses produced in the presence of LEN exhibited markedly reduced infectivity, low reverse transcription activity, and poor integration. Together, these findings provide mechanistic insight into the late-phase action of LEN and provide key directions for the design of future inhibitors.

microbiology↗

bioRxiv2026

Wetting-mediated extracellular phase separation drives long-range cell adhesion

Cells must efficiently locate and engage for tissue formation and immune coordination, yet classical receptor-ligand binding is limited to nanometre distances and is inherently slow [1-3]. Here, we uncover a previously unrecognised physical principle, liquid-like adhesion by phase separation (LAPS). This process creates dynamic wetting layers on cell surfaces [4, 5], functioning as "liquid bridges" that enable robust, long-range cell capture across tens of micrometres. Remarkably, this wetting-mediated attraction remains effective at nanomolar concentrations--conditions where bulk phase separation would not be expected--and facilitates high-fidelity cell sorting through competitive wetting. By integrating aqueous two-phase systems, endogenous proteins (Galectin-3, CCL5), and fluid-particle-dynamics simulations [6], we demonstrate that extracellular liquid-liquid phase separation not only mediates long-range cell capture but also acts as a physical catalyst for contact-dependent signaling. These findings establish extracellular phase separation as a key physical principle complementing molecular recognition in multicellular systems, offering new opportunities for understanding immune response, tissue morphogenesis, and therapeutic strategies targeting the extracellular environment [7, 8].

biophysics↗

bioRxiv2025

Structural basis of asymmetric transcription through a composite nucleosome formed by a hexasome and an octasome

The overlapping dinucleosome (OLDN), a composite chromatin particle consisting of a hexasome and a canonical octasome, forms immediately downstream of transcription start sites, likely through chromatin remodeling activity, and has been proposed to act as a transient regulatory intermediate during transcription. However, how RNA polymerase II (RNAPII) engages with and transcribes through this unusual structure remains unclear. Here, we reconstituted OLDNs in vitro and performed transcription assays with RNAPII. We found that transcription efficiency was markedly higher when RNAPII initiated from the hexasome side than from the octasome side. Cryo-electron microscopy further revealed that transcription from the hexasome side induced pronounced conformational rearrangements, in which RNAPII progression dramatically opened the hexasome-octasome interface. These results uncover the mechanism by which RNAPII senses the intrinsic transcriptional polarity of OLDNs and suggest that OLDNs function as dynamic, directionally sensitive regulators of transcription elongation.

molecular biology↗

bioRxiv2025

Phase-targeting rapid cryofixation of the beating heart and histological analysis unveil contractile state-dependent sarcomere dynamics

The heart is a functional syncytium consisting of numerous cardiomyocytes that repetitively exhibit coordinated contractions/relaxations. However, the extent to which myocyte sarcomere arrangements in the heart differ across beats is unknown. To examine this, we conducted cardiac phase-targeting rapid cryofixation of Langendorff-perfused rat hearts. We adjusted the timepoint of cryogen exposure to the electrically paced heart and observed phase-dependent differences in the sarcomere length (SL) of subepicardial myocytes by -actinin immunohistochemistry, namely a significantly shorter SL during systole than during diastole. We detected spatially inhomogeneous SL distributions by generating a heatmap of the myocardium. For peak systole the SL heatmap exhibited nearly uniform SL shortening within and among the individual myocytes with some myocardia exhibiting nonuniform SLs. During diastole, the heart showed predominant SL elongation, which was also accompanied by patchy distributions of locally short-SL regions, reflecting inhomogeneous SLs. This SL inhomogeneity was attenuated by pharmacological relaxation by 2,3-butanedione monoxime. The heatmap of the rapidly-frozen heart during ventricular fibrillation also revealed inhomogeneous SLs within and among individual myocytes. Overall, cardiac phase-targeting cryofixation unveiled in-depth behaviors on SL in the heart. Our cryofixation strategy will open a new horizon to clarify precise spatiotemporal changes in sarcomere structures and understand cardiac functions.

biophysics↗

bioRxiv2025

Parallel Evolution of Bacteroidota as Long-Term Endosymbionts of Insects

Symbiotic relationships transform diverse aspects of both symbiont and host biology. The most visible changes include a massive reduction of the endosymbiont genome and the development of novel host organs, cells, and compartments specialized for harboring the symbionts. However, many insect symbiosis studies have previously focused either on Proteo-bacteria or only on a particular symbiosis stage, limiting our broad understanding of how and why symbiont diversity arises from specific microbial clades, how the symbiont genomes erode over evolutionary time, and what the consequences of symbiosis are for diverse host-symbiont pairs. Thanks to the repeated gains and losses of nutritional symbionts, scale insects provide an ideal evolutionary playground for tracking the parallel transitions of insect symbionts that originated as independent evolutionary replicates from the same bacterial phylum. Using extensive genome sampling across the scale insect phylogeny, we recapitulated the path of Bacteroidota transitioning from recently established host-associated bacteria to highly specialized insect endosymbionts with minimal gene sets. Their genomes exhibit strikingly parallel patterns of gene loss and pseudogenization across all gene categories, with some stochastic differences in essential genes for genetic processing and amino acid biosynthesis. In addition to the genetic transition, we show with imaging methods that the symbiotic cells and organs exhibit a trend from more dispersed bacteriocytes to highly compact (and likely more specialized) bacteriomes, which are closely localized to the hosts digestive system. Our results outline at both genomic and cellular levels a recurrent path by which insect symbioses independently arise, are temporarily maintained for up to several hundred million years, and then are replaced by new symbionts that repeat the process. The gradual nature of the process implies that the outcomes of symbiosis initially depend on how professional vs. naive the host and symbiont are. Over evolutionary time, compatible host-symbiont lineages emerge from these interactions and become preferred.

evolutionary biology↗

bioRxiv2025

Structural basis for MurJ inhibition by phage lysis protein SglPP7 suggesting convergence

Some bacteriophages encode lysis proteins that inhibit essential bacterial processes, the elucidation of which is valuable for developing antibacterial strategies against drug-resistant pathogens. We determined the cryo-EM structure of the complex between the essential E. coli lipid II flippase MurJ and a phage lysis protein, SglPP7. MurJ was locked in an outward-facing conformation by SglPP7, similar to the MurJ/LysM complex; however, distinct interactions suggest convergent evolution among phage lysis proteins.

molecular biology↗

bioRxiv2025

Nucleosome stability safeguards cell identity, stress resilience and healthy aging

Nucleosomes are the minimal repeating units of chromatin. Their dynamic assembly and disassembly underpins chromatin organization and genome regulation. However, it remains unclear how intrinsic nucleosome stability contributes to higher-level yet fundamental cellular and organismal properties--such as preservation of cell identity, lineage specification, stress resilience and ultimately healthy aging. To address this, we tested the impact of decreased intrinsic nucleosome stability across multiple cell, tissue and organismal models by introducing histone mutants that weaken histone-histone interactions. While nucleosome instability did not broadly alter global chromatin accessibility, DNA damage, cell proliferation or viability, it impaired lineage-specific gene expression programs, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated the onset of age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-- including environmental, epigenetic and mitotic stress--in human cells and Saccharomyces cerevisiae. These cross-species findings identify nucleosome stability as an evolutionarily conserved epigenetic safeguard that preserves cell identity and stress resilience and supports organismal function and healthy aging.

genomics↗

bioRxiv2025

GLP1 receptor agonists attenuate systemic inflammation through microbiota mediated enrichment of Faecalibacterium prausnitzii and Roseburia spp

This study investigated the comparative anti-inflammatory effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and nonsteroidal anti-inflammatory drugs (NSAIDs), with a particular focus on microbiota-mediated mechanisms. A total of 120 participants were enrolled, including a GLP-1 RA group (n = 60) and an NSAID control group (n = 60). After 12 weeks of treatment, the GLP-1 RA group showed significant reductions in systemic inflammatory markers, with C-reactive protein (CRP) decreasing from 4.3 {+/-} 0.6 to 2.1 {+/-} 0.4 mg/L (p < 0.01), interleukin-6 (IL-6) decreasing from 3.6 {+/-} 0.5 to 1.8 {+/-} 0.3 pg/mL (p < 0.01), and tumor necrosis factor- (TNF-) decreasing from 18.2 {+/-} 1.5 to 12.5 {+/-} 1.2 pg/mL (p < 0.05). In contrast, the NSAID group exhibited only modest reductions in these markers without achieving normalization. Microbiome analysis revealed a significant post-treatment enrichment of Faecalibacterium prausnitzii (r = -0.46 with CRP, p < 0.001) and Roseburia spp. (r = -0.39 with CRP, p < 0.01) in the GLP-1 RA group, whereas NSAIDs showed no comparable effect. These findings establish a novel mechanistic link between incretin-based therapies and host immune homeostasis, highlighting the potential of GLP-1 RAs as systemic anti-inflammatory agents beyond their metabolic benefits.

immunology↗