Biology subjects

Park, S.

Publications and source records attributed to Park, S..

At least 19 recordsLinked to original sources

bioRxiv2026

KRAS-driven metabolic reprogramming of enhanced MFSD2A-mediated lysophosphatidylcholine scavenging promotes survival and progression of pancreatic ductal adenocarcinoma

Oncogenic KRAS drives lipid reprogramming in pancreatic ductal adenocarcinoma (PDAC) to promote disease progression, and these changes are manifest in circulation. Using mass spectrometry, we performed lipidomic analyses on plasmas from a cohort of 93 newly-diagnosed resectable PDAC cases, 43 patients with chronic pancreatitis, and 93 age- and sex-matched healthy controls, the results of which revealed pronounced reductions in circulating lysophosphatidylcholines (LysoPC) as a prominent feature associated with PDAC. Using stable-isotope resolved lipidomics, we further found that PDAC cells exhibit a lipid scavenging phenotype characterized by preferential uptake of extracellular unsaturated LysoPCs to sustain pro-growth signals. Restricting bioavailability of extracellular unsaturated LysoPCs shifted the metabolic phenotype of PDAC cells towards enhanced de novo lipogenesis and autophagy, which was accompanied by suppression of AKT signaling activities and increased susceptibility to apoptosis. Using bulk, single-cell, and spatial transcriptomic datasets together with functional experiments, we identified oncogenic KRAS-mediated upregulation of major facilitator superfamily domain-containing protein 2a (MFSD2A) as a key mediator that facilitates extracellular uptake of LysoPCs in PDAC cells. Loss of MFSD2A expression mimicked LysoPC restriction and resulted in inhibition of AKT signaling and increased propensity of PDAC cells to undergo apoptosis in vitro and suppressed tumor growth in vivo. Therapeutic targeting of the KRAS-MFSD2A-LysoPC axis via repurposing of the synthetic alkyl-lysophospholipid edelfosine promoted potent anti-cancer effects in vitro that were mechanistically attributed to reduced extracellular uptake of LysoPCs, and attenuation of AKT signaling. Collectively, our findings describe a previously unrecognized onco-metabolic program of enhanced LysoPC scavenging mediated by MFSD2A that promotes PDAC progression and that is therapeutically targetable via repurposing edelfosine.

cancer biology↗

bioRxiv2026

Angiotensin (1-7)-based Proteomimetic Polymers as Topicals for the Remediation and Repair of the Cornea following Injury

The cornea is the outermost layer of the eye, most vulnerable to injury including from chemical exposure, either environmental, industrial or chemical weapons. For example, exposure of the eye to sulfur mustard (SM) can cause mustard gas keratopathy, resulting in devastating consequences for vision. Available treatments for corneal mustard keratopathy are either ineffective, or if used for a prolonged time, have deleterious side effects. Here, we aimed to harness the anti-inflammatory and anti-angiogenic peptide angiotensin-(1-7), known as Ang-(1-7), that is derived from the renin-angiotensin system (RAS). We designed and developed a protein-like polymer (PLP) displaying a brush of norleucine modified Ang (1-7) peptides (NLE Ang (1-7) PLP), which is a more potent derivative of Ang-(1-7), for administration as an eye drop. In a mouse model of nitrogen mustard (NM)-induced corneal injury, topical treatment and intraperitoneal (i.p.) injection of NLE Ang (1-7) PLP persistently minimized: (i) corneal haze; (ii) edema; (iii), expression of pro-inflammatory and pro-angiogenic genes; and (iv) neovascularization and conjunctivalization as evidenced after a prolonged treatment and recovery period. Collectively, our observations have demonstrated the efficacy of this novel polymer proteomimetic based eye drop treatment in reducing chemical agent-induced corneal injury as well as indicating its potential application in other ocular surface diseases associated with inflammation and angiogenesis.

bioengineering↗

bioRxiv2026

Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx

The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.

bioengineering↗

bioRxiv2026

Inertial coupling between swing and stance legs shapes ankle torque profile during running

The spring-loaded inverted pendulum (SLIP) model has effectively explained center of mass (CoM) and ground reaction force (GRF) dynamics during human gait despite its simplicity, describing both walking and running within the same mechanical principles. A recent study extended the explanatory capability of the SLIP model to joint dynamics by reproducing ankle joint dynamics during walking. However, during running, the model did not capture the empirical ankle torque profile, suggesting that such mechanical unification may not hold at the joint level. Because the previous model represented the body as a single point mass, it neglected leg inertia, which may become important during running as rapid motion generates substantial angular momentum. To address this limitation, we propose an extended two-mass model that separates the whole-body mass into the swing-leg and the remaining body mass, thereby explicitly incorporating swing-leg inertia into stance-leg joint dynamics. The swing leg is modeled using a linear spring and a torsional spring at the hip joint for its radial and rotational motion. Through inertial coupling, swing-leg dynamics influence the stance-leg ankle torque. Consequently, the proposed model reproduces the symmetric, single-peaked ankle torque profile observed experimentally while preserving the CoM and GRF of the previous model. These findings suggest that the discrepancy of the previous model during running may be explained by the omission of swing-leg inertia. By accounting for the gait-mode-dependent contribution of swing-leg inertia, the proposed model provides a unified mechanical framework for extending simple gait models from CoM-level behavior to joint dynamics.

bioengineering↗

bioRxiv2026

Predator type shapes call-type composition and post-threat vocal dynamics in Japanese quail (Coturnix japonica): a pilot case-series

Japanese quail (Coturnix japonica) rely on an extensive vocal repertoire to coordinate social behaviour and respond to predation risk, yet how individual call types are modulated by predator identity remains poorly characterized. In this pilot case-series, two sexually mature Japanese quail (each contributing more than 2,000 classified vocalizations across repeated predator-exposure trials) were exposed to simulated aerial (hawk) and terrestrial (cat) predator stimuli across four social contexts, before, during, and after stimulus presentation. Vocalizations were classified, via blind dual-observer review, into 18 spectrographically distinct call types (an exploratory repertoire estimate, not independently statistically validated), of which 10 were acoustically characterized. Chi-square analyses of the full call-type composition revealed highly significant differences between hawk and cat exposure in both individuals (both p < 0.0001); call types 5 and 10 were significantly cat-biased and call type 2 was significantly hawk-biased in both individuals. An exploratory correlation suggested that call types with a higher maximum frequency tended to be relatively hawk-biased (Spearman rho = -0.67, p = 0.033, uncorrected for multiple comparisons). Independently, call-type composition shifted significantly between the pre- and post-exposure phases in all four individual-by-predator combinations (all p < 0.0001), driven substantially by a consistent post-exposure increase in call type 9 across both individuals and both predator classes. Additional exploratory analyses of social-context (mirror and concealed-conspecific) effects on call-type composition are presented in the supporting information. Given the small sample size (n = 2), these findings are presented as case-based, hypothesis-generating observations intended to justify and inform a fully powered follow-up study, rather than as population-level conclusions.

animal behavior and cognition↗

bioRxiv2026

Blockade of Kv3.1 by MK-801, a PCP-Derivative NMDA Receptor Inhibitor: Implications for Models of Schizophrenia

MK-801, a phencyclidine (PCP) derivative also known as dizocilpine, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). The NMDAr plays a critical role in mediating excitatory synaptic transmission in the central nervous system (CNS) and is important in regulating synaptic plasticity, learning, and memory. MK-801 is known to induce schizophrenia-like phenotypes in animal models by blocking the NMDAr. Several studies have reported that the cognitive impairment associated with schizophrenia is linked to functional defects of ion channels in parvalbumin-positive GABAergic interneurons. Kv3.1 is a voltage-gated K+ (Kv) channel involved in the rapid repolarization of the action potential in neurons; it is richly expressed in parvalbumin-positive GABAergic interneurons and is associated with fast, repetitive spike generation. A decrease of Kv3.1 in the CNS has been reported to be associated with schizophrenia. In the present study, the effect of MK-801 on Kv3.1 was investigated using the whole-cell patch-clamp technique in Chinese hamster ovary (CHO) cells stably expressing Kv3.1. MK-801 caused a concentration-dependent inhibition of Kv3.1, with an IC50 of 10.81 M and a Hill coefficient of 0.89. The blocking potency was stronger at depolarized potentials, indicating a voltage-dependent block. MK-801 also produced a use-dependent block, inducing progressive inhibition with repeated stimulation at increased frequencies (1 Hz and 2 Hz), consistent with a delay in recovery from inactivation of Kv3.1 in the presence of MK-801. In addition, MK-801 induced a hyperpolarizing shift in the voltage dependence of the steady-state inactivation curve of Kv3.1. Taken together, these results indicate that MK-801 blocks Kv3.1 expressed in CHO cells in a concentration-, voltage-, and state-dependent manner. Given the importance of Kv3.1 in parvalbumin-positive, fast-spiking GABAergic interneurons, these findings suggest that MK-801 may alter the firing patterns of these inhibitory neurons, contributing to the onset and symptoms of schizophrenia.

pharmacology and toxicology↗

bioRxiv2026

Complement component C4 regulates amyloid pathology and glial reactivity in mouse model of Alzheimer's Disease

The complement system, a proteolytic cascade crucial for innate immune system function, is dysregulated in brain aging and neurodegenerative diseases, including Alzheimer Disease (AD). In models of AD, complement proteins, including C1q and C3, are upregulated and mediate microglial clearance of amyloid plaques and pruning of synapses. Among complement genes, C4b, which in mice encodes complement protein C4, is the most highly upregulated in astrocytes in the setting of aging and amyloid pathology. While C4 plays a key role in the complement cascade, there have been no investigations of the direct role of C4 in regulating AD pathology. To probe the function of C4 in amyloid plaque-related pathology, we crossed a germ line C4b knockout mouse (C4 KO) to the 5XFAD mouse model of AD-related amyloidosis. To our surprise, we observed striking reductions in amyloid plaque pathology across multiple brain regions in 5XFAD-C4 KO mice relative to standard 5XFAD controls. This reduction in plaque burden stands in sharp contrast to previous reports of C3 deletion in AD models, which increases plaques. Additionally, we observed a reduction in neuroinflammation and peri-plaque glial clustering in 5XFAD-C4 KO mice, suggestive of a role for C4 in regulating overall neuroinflammatory tone in AD. Finally, we observed a phenotypic shift of the peri-plaque microglia to a more reactive disease-associated microglia (DAM) phenotype, indicating that C4 could be an important factor in regulating microglial reactivity in AD. Altogether, our results demonstrate that C4 may have functions beyond the classical complement cascade and may serve as a key facilitator of AD-related glial function and pathology and a possible target for therapeutic modification.

neuroscience↗

bioRxiv2026

Human iPSCs and iPSC-Derived Endothelial Cells from PAD Patients and Healthy Donors Exhibit Comparable Characteristics and Potency: Implications for Autologous Cell Therapy in Peripheral Artery Disease

BACKGROUND: Peripheral artery disease (PAD) can lead to amputation in advanced cases, making cell therapy using human induced pluripotent stem cells (hiPSCs) a promising therapeutic option. hiPSC-derived endothelial cells (hiPSC-ECs) have shown favorable effects in treating experimental ischemic cardiovascular disease. An autologous approach for PAD patients is preferable to avoid immunological reactions. However, it is yet unknown whether hiPSCs and hiPSC-ECs derived from PAD patients have similar characteristics and potency compared to those derived from non-PAD donors. Therefore, we explored whether there are significant differences in the characteristics and potency of hiPSCs and hiPSC-ECs between non-PAD donors and PAD patients. METHODS: We generated hiPSCs from the blood of non-PAD donors and patients with PAD. We determined the pluripotency of hiPSCs using qRT-PCR, flow cytometry, immunostaining, RNA-seq, and teratoma formation assay. The genetic stability of hiPSCs was confirmed by G-banding karyotyping. We then differentiated hiPSCs into endothelial cells (ECs) in a clinically compatible manner. We compared the characteristics and therapeutic potency of hiPSC-ECs derived from non-PAD and PAD groups using qRT-PCR, flow cytometry, immunostaining, and RNA-seq. In vitro endothelial functions were determined by nitric oxide (NO) production and capillary network formation. Therapeutic potency and incorporation of engrafted hiPSC-ECs were evaluated in a hindlimb ischemia model. RESULTS: We successfully generated hiPSCs from the blood of seven non-PAD donors and eight PAD patients. Both non-PAD and PAD-derived hiPSCs exhibited similar expression levels of pluripotency markers. All hiPSCs, regardless of the group, formed teratomas and showed normal karyotypes. RNA-seq analyses revealed similar gene expression profiles between the groups. hiPSC-ECs derived from both non-PAD and PAD donors exhibited similar expression levels of EC markers at both the gene and protein levels. RNA-seq analyses showed no significant overall differences in gene expression profiles between the groups. Functional analyses demonstrated similar endothelial characteristics and function in hiPSC-ECs from both groups. Both groups showed similar perfusion recovery, limb salvage, and vessel-forming capacity. Engrafted hiPSC-ECs from both groups also exhibited similar angiogenic and vessel-forming capabilities. CONCLUSIONS: Our study demonstrated no significant differences in hiPSCs and hiPSC-ECs derived from non-PAD donors and PAD patients in terms of molecular and cell biological characteristics, therapeutic effects, and vessel-forming capability. Our study indicates that hiPSCs and hiPSC-ECs derived from PAD patients can serve as a novel platform for autologous cell therapy.

cell biology↗

bioRxiv2026

Forecasting viral evolution from phylogenetic trees

Viral mutation forecasting plays a key role in pandemic preparedness by enabling researchers to anticipate novel variants and design proactive interventions. Evolutionary histories, represented as phylogenetic trees, offer key insights into the emergence of past and present strains, yet their role in predicting future sequence changes remains largely unexplored. We introduce antiGen, a machine learning model that forecasts the evolutionary future of viruses by learning from their evolutionary past. antiGen achieves state-of-the-art performance for predicting mutations to the SARS-CoV-2 spike protein, anticipating never-before-seen mutations and mutations that emerge years after the model's training window. antiGen-forecasted spike mutations also retain pseudoviral infectivity in vitro. Moreover, antiGen demonstrates leading predictive performance on surface proteins of influenza virus, respiratory syncytial virus, and dengue virus despite far less available sequencing data. Viral evolution models that explicitly learn from phylogenetic structure offer a valuable resource for applications ranging from epidemiological modeling to therapeutic development.

evolutionary biology↗

bioRxiv2026

OsPATROL1 overexpression accelerates stomatal opening to enhance photosynthetic induction and growth under fluctuating light in rice

Slow stomatal opening after increases in irradiance constrains carbon gain under fluctuating light, yet stomatal kinetics remain an underexplored target for crop improvement. Here, we investigated Oryza sativa PROTON ATPASE TRANSLOCATION CONTROL 1 (OsPATROL1), which encodes a Munc13-like protein implicated in stomatal regulation in Arabidopsis thaliana. OsPATROL1 overexpression had modest, condition-dependent effects on steady-state gas exchange and did not alter stomatal morphology or biochemical traits. In contrast, it consistently accelerated stomatal opening and photosynthetic induction, reducing the stomatal conductance time constant during induction by 41-43%. During 12 h of simulated natural fluctuating light, OsPATROL1-overexpressing plants maintained higher stomatal conductance and net CO2 assimilation rate, increasing cumulative assimilation by 8-12% while maintaining their intrinsic water-use efficiency (iWUE). Under artificial fluctuating light, overexpression alleviated growth reductions relative to steady light. Under glasshouse conditions, total biomass increased by 34-44%, accompanied by greater tiller number, root biomass, bleeding sap rate, and leaf nitrogen content. Taken together, these results indicate that OsPATROL1 overexpression accelerates stomatal opening, enhances photosynthetic induction and daytime carbon gain without compromising iWUE, and is associated with greater growth.

plant biology↗

bioRxiv2026

Thal-Kak: unifying biomolecular structure predictors reveals a sampling-selection gap

Complementary all-atom structure predictors sample different solutions, but how to allocate a fixed sampling budget across them and select the best output remains unclear. Thal-Kak unifies five released predictors under shared upstream inputs and a common schema. Across FoldBench and CASP16, model mixing improves oracle sampling over single-model runs, but selection remains a bottleneck because confidence scores do not transfer across models and existing quality-assessment methods cannot resolve this gap.

bioinformatics↗

bioRxiv2026

Optogenetic activation of parabrachial tachykinin1 neurons drives nonphotic circadian entrainment

Mammalian circadian rhythms are primarily entrained by light, but nonphotic cues can also reorganize behavioral timing through mechanisms that remain poorly understood. Nocturnal foot shocks delivered to rodents while they forage away from the safety of their nesting area have been shown to entrain circadian behavioral rhythms and shift foraging and feeding to the daytime. To identify the neural circuits underlying this nonphotic fear entrainment, we optogenetically stimulated tachykinin 1-expressing neurons in the parabrachial nucleus (Tac1PBN) during the subjective night while the animals foraged outside of their nest, which recapitulated the total activity-rest phase switch in circadian behaviors induced by foot shocks. Furthermore, selective stimulation of Tac1PBN projections to the central amygdala (CeA) produced a significant but reduced phase shift compared to direct stimulation of Tac1PBN cell bodies. When Bmal1, a core clock gene, was conditionally deleted from the CeA, mice failed to fear-entrain, implicating the CeA molecular clock as a necessary component for fear entrainment. Together, these experiments demonstrate that activation of a defined neuronal population outside of the suprachiasmatic nucleus (SCN) can reorganize circadian behavior by engaging a non-SCN circadian oscillator network that requires an intact CeA molecular clock.

neuroscience↗

bioRxiv2026

Temporal single-cell profiling of the parabrachial Calca neurons reveals molecular dynamics driving nociplastic pain

Parabrachial Calca neurons are necessary for chronic pain and sufficient to drive nociplastic pain in mice, but how they sustain a pain state that outlasts its trigger is unknown. We performed temporal single-cell mRNA sequencing of the parabrachial nucleus (PBN) across the onset, chronic, and recovery phases of Calca neuron-driven tactile allodynia, using fixed-tissue profiling and reference-atlas registration to track molecularly defined populations over time. Activation broadly induced immediate-early genes, after which Calca neurons displayed changes in expression of genes that affect signaling and synaptic plasticity, with bidirectional changes that mirrored the onset and resolution of allodynia. The gene encoding brain-derived neurotrophic factor (Bdnf) remained persistently elevated in the chronic phase. BDNF infusion in the PBN prolonged allodynia, whereas blockade of its receptor (TrkB) attenuated it, and inactivating the Bdnf gene in Calca neurons abolished their hyperexcitability, attenuated allodynia, and relieved pain in a migraine model. These observations pinpoint BDNF as a driver of persistent nociplastic pain.

neuroscience↗

bioRxiv2026

Structural proteomics reveals a coagulation-complement accessibility signature of macrovascular invasion in hepatocellular carcinoma

Macrovascular invasion (MVI) and extrahepatic spread (EHS) define the most aggressive, treatment-refractory hepatocellular carcinoma (HCC), yet blood-based markers that report the underlying protein-network biology are lacking. Conventional proteomics measures protein abundance but not the conformational and protein-protein-interaction (PPI) states that govern function. We applied covalent proteome painting (CPP)--a dimethylation-based accessibility assay that reads out binding-site openness--to matched tumor and serum, reasoning that intravascular tumor dissemination remodels plasma protein complexes in a manner detectable as changes in accessibility. Eight treatment-native HCC patients were profiled by CPP using matched FFPE tumor and top-14- depleted serum on a Q Exactive Orbitrap HF. The 85 tumor-serum common proteins defined an 81-protein targeted panel, validated by multiple-reaction-monitoring (MRM) mass spectrometry with heavy stable-isotope-standard peptides (296 peptides; 3,717 light/heavy transition pairs) in 22 FFPE tumors and 22 matched sera. Accessibility was the light/heavy ratio (high, open; low, closed). We assessed differential accessibility, serum-tissue translatability, pathway enrichment, and biomarker/survival performance. Aggressive disease showed broadly decreased protein accessibility. MVI-associated changes were directionally concordant between tumor and serum (Spearman {rho}=0.21; 59% concordant), driven by coagulation and complement proteins (FGG, CTSD, LBP, C4BPA); the EHS axis did not translate. Decreased-accessibility proteins were enriched for complement-coagulation cascades and IGF/IGFBP transport. A six-protein serum accessibility signature discriminated MVI (leave-one-out cross-validated AUC 0.80; best single markers ceruloplasmin 0.83 and haemoglobin- 0.77), and MVI status trended with shorter overall survival (log-rank p=0.06). Accessibility-based serum proteomics captures MVI-associated protein-complex remodeling that abundance assays miss, nominating a coagulation/complement-anchored serum signature for vascular-invasive HCC that warrants prospective validation.

systems biology↗

bioRxiv2026

Fast remote nucleotide sequence alignment with Riboseek

Structure prediction has reached RNA, where generating deep alignments is now the bottleneck. We developed Riboseek, a search and alignment tool for RNA and DNA that represents sequences as overlapping di-mers. Riboseek is more sensitive for homology detection than BLASTN and nhmmer, and generates alignments 250- and 376-fold faster than nhmmer and rMSA. With structure-aware realignment, it approaches rMSAs base-pair recovery, while remaining 29-fold faster. We provide a web server and 1.7 million precomputed alignments for putatively structured RNAs. Riboseek is freely available at https://github.com/steineggerlab/riboseek.

bioinformatics↗

bioRxiv2026

Photosynthetic assimilate determines branch size and biomass more than branch number in Arabidopsis

Shoot branching is a primary determinant of plant form and crop yield, yet whether auxin or carbon supply is the proximal regulator of branching remains contested. In Arabidopsis, an earlier report that exogenous auxin fails to restore apical dominance after decapitation has been taken to weaken the case for auxin, and several studies have proposed that sugars are the primary regulator. Resolving this has been difficult because most perturbations of sugar status also disturb auxin. Here, we revisit the control of Arabidopsis branching using well-controlled, largely unperturbed plants and approaches designed to isolate each pathway. Contrary to the earlier report, apically applied auxin restored the suppression of rosette branching after decapitation, placing Arabidopsis in line with other species. In a dataset of 718 plants, cauline and rosette branching were weakly but significantly negatively correlated, consistent with a polar-auxin-transport-based model and contrary to a previous conclusion of no relationship. Removing all rosette leaves at bolting slowed bud growth but did not alter the final number of branches. Varying photosynthetic photon flux density across six natural accessions, analyzed by piecewise structural equation modeling, showed that photoassimilate acted far more strongly on the mass deposited into branches than on whether a bud initiates a branch. We conclude that auxin remains a major regulator of apical dominance in Arabidopsis, and that photosynthetic assimilate, while required as a substrate for branch growth, contributes little to determining branch number but more to branch size and biomass.

plant biology↗

bioRxiv2026

A targeted plasma-proteomic axis separates autoimmune thyroid disease from growth-hormone deficiency

Targeted mass spectrometry (multiple-reaction monitoring, MRM) enables reproducible, multiplexed quantification of plasma proteins, but whether a fixed targeted panel can resolve endocrine disorders with overlapping systemic features is unknown. We analyzed a 256-protein targeted panel (1,894 peptides; 3,790 transitions) quantified in 57 participants spanning autoimmune thyroid disease (Hashimotos thyroiditis, n=7; Graves disease, n=5) and growth-hormone deficiency (GHD; partial, n=26; complete, n=19). Protein abundances were obtained by transition summation, log2 transformation, and per-sample median normalization. We applied unsupervised analysis (PCA, PERMANOVA), differential expression (limma), an ordered severity-trend test, and leave-one-out cross-validated classification with feature selection performed strictly inside each fold. All 256 proteins were quantified in every sample (median inter-sample r=0.875). PC1 (36% variance) separated autoimmune thyroid disease from GHD (p=0.016), whereas the global four-group structure was not significant (PERMANOVA p=0.17). No protein reached FDR<0.05, but the autoimmune-versus-GHD contrast was strongly enriched for low p-values (26 proteins at p<0.05; binomial p=5.4x10-4). The signal was biologically coherent: immunoglobulin/B-cell-receptor proteins, including CD79A, were lower, whereas proteasome subunits (PSMC5, PSMC3) and the NF-{kappa}B subunit RELA were higher in autoimmune disease. A cross-validated classifier separated the two classes (AUC 0.72; permutation p=0.05; eight proteins selected in all folds), whereas GHD severity was not predictable (AUC 0.31). A fixed 256-protein targeted panel reproducibly captures an immunoglobulin/B-cell-receptor and proteasome/NF-{kappa}B axis that distinguishes autoimmune thyroid disease from GHD but cannot resolve within-class severity.

systems biology↗

bioRxiv2026

Sex and race shape serum protein biomarkers and bias diagnostic reference intervals

Clinical protein biomarkers--whether measured by FDA-cleared in-vitro diagnostic (IVD) assays or deployed as laboratory-developed tests (LDTs)--are routinely interpreted against fixed, population-agnostic reference intervals. Whether the baseline serum concentrations of these proteins differ systematically by sex and by self-reported race in healthy individuals has not been tested across a broad clinical panel on a single standardized platform. Using scheduled multiple reaction monitoring - mass spectrometry (MRM-MS) with stable-isotope-labelled internal standards, we quantified 87 proteins (39 FDA-cleared analytes; 48 LDT/research markers) in 60 healthy, age-matched donors balanced across three races (White, Hispanic, Black) and both sexes. Sex was a pervasive axis of variation: donors separated by sex in unsupervised multivariate space (PERMANOVA p = 0.020) but not by race (p = 0.14). Three FDA-target proteins differed by sex at FDR q < 0.05--sex hormone-binding globulin, haemoglobin- and albumin--with directions preserved within every race. Race differences were real but protein-specific, exemplified by ancestry-associated CD14. Critically, applying a single pooled 95% reference interval mis-flagged as many as [~]25% of a demographic subgroup as abnormal, versus the 5% expected. Demographic context should therefore be incorporated into reference intervals and decision thresholds for protein-based diagnostics.

molecular biology↗