Candidate Biological Markers for Social Anxiety Disorder: A Systematic Review
Abstract
:1. Introduction
2. Methods
3. Results and Discussion
3.1. Genetics
BIOMARKER TYPE | REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|---|
Genetics | [33] | SLC6A4 | SNPs genotyping (SAD vs. HC) | 1125 | Two SNPs with nominal significance: - rs818702 (p = 0.032) - rs140701 (p = 0.048) After Bonferroni’s correction: SAD = HC (p > 0.05) | Moderate | / |
[34] 2 | 5HTT (SLC6A4), 5HT2AR | Linkage analysis (first-degree family members of probands affected by SAD) | 17 families (122 members) | No linkage to SAD (p > 0.05) | Moderate | / | |
[35] 2 | DRD2, DRD3, DRD4, DAT1 | Linkage analysis (families of probands affected by SAD) | 17 families (122 members) | No linkage to SAD (p > 0.05) | Moderate | / | |
[36] | Genome | Genome-wide linkage scan (families of probands affected by Panic Disorder) | 17 families (163 members) | Linkage to SAD for chromosome 16 (p = 0.0003) | Moderate | d = 0.165 | |
[37] | MANEA | Multi-stage association study (SAD vs. HC) | 131 | C allele of the MANEA (rs1133503*C) (p = 0.004) | Moderate | d = 0.422 | |
Epigenetics | [22] | OTXR methylation | Multilevel epigenetic study (SAD vs. HC) | 220 | ↓ OXTR methylation at CpG3 (Chr3: 8 809 437) (p < 0.001) | Strong | d = 0.535 |
[45] | Genome methylation | Epigenome-wide association study (SAD vs. HC) | 143 | DMRs within SLC43A2 (p < 5 × 10−4) and TNXB (p < 3 × 10−26) | Weak | NA |
3.2. Epigenetics
3.3. Endocrine Biomarkers
3.3.1. Cortisol
HORMONAL SYSTEM | REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|---|
Cortisol and sAA | [53] | Salivary cortisol, plasma cortisol, sAA, prolactin | Cross-sectional (SAD vs. HC) Secretion after TSST | 166 | SAD = HC: - Salivary cortisol stress response (p > 0.131) - Plasma cortisol stress response (p = 0.084) - sAA stress response (p > 0.343) - Prolactin stress response (F < 1) - Basal hair cortisol levels (p = 0.918) | Moderate | / |
[54] | sAA, salivary cortisol | Cross sectional (SAD vs. HC) Response to electrical stimulation | 112 | sAA: SAD > HC at all-time points (p < 0.01) Salivary cortisol: SAD = HC at all-time points (p > 0.05) | Moderate | sAA: d = 0.576 | |
[55] | UFC, post-dexamethasone plasma cortisol | Cross-sectional (SAD vs. HC) | 54 patients (UFC); 64 patients (plasma cortisol) | SAD = HC - UFC (p = 0.15) - Post-dexamethasone (p = 0.37) | Weak | / | |
[56] | sAA, salivary cortisol Measured in non-stressed conditions: - after awakening - during the day (including late evening) - after a low dose (0.5 mg) of dexamethasone | Cross-sectional (SAD vs. HC) | 86 | SAD = HC - Awakening sAA (p = 0.114) - Salivary cortisol (awakening, diurnal, late evening) (p = 0.201) - Post-dexamethasone salivary cortisol (p = 0.256) SAD > HC: - Diurnal sAA (p = 0.044) - Post-dexamethasone sAA (p = 0.040) | Moderate | Diurnal sAA: d = 0.508 Post-dexamethasone sAA: d = 0.518 | |
[57] | Salivary cortisol - 1-h cortisol awakening response - evening cortisol - cortisol response after 0.5 mg of dexamethasone ingestion | Cross sectional (ADs vs. HC) | Current: 140 SAD patients Remitted: 487 SAD patients | SAD = HC (p > 0.05) | Moderate | / | |
[59] | Plasma ACTH, plasma cortisol, salivary cortisol | Cross-sectional (SAD vs. HC) Secretion after TSST | 70 | Baseline ACTH, plasma and salivary cortisol: SAD = HC (p > 0.05) ACTH secretion pattern and AUCg: SAD = HC (p > 0.05) Plasma cortisol: SAD < HC - secretion pattern (p = 0.011) - AUCg (p = 0.007) Salivary cortisol: - secretion pattern SAD = HC (p > 0.05); - AUCg, SAD < HC (p = 0.007) | Strong | Plasma cortisol: d = 0.165 (secretion pattern); d = 0.229 (AUCg) Salivary cortisol: d = 0.229 (AUCg) | |
[60] | Plasma cortisol, plasma ACTH | Cross-sectional (SAD vs. HC) Secretion after stressors: - mental arithmetic - short-term memory test in front of an audience | 30 | Baseline ACTH and cortisol: SAD = HC (p > 0.05) Delta max 2 cortisol response: SAD > HC (p < 0.04) Delta max 2 ACTH response: SAD = HC (p > 0.05) | Strong | Delta max 2 cortisol response: d = 0.767 | |
[61] | Plasma cortisol and EA relationship | Cross-sectional (SAD vs. HC) Secretion after TSST | 24 | SAD ≠ HC (p = 0.015) - SAD: ↓ total cortisol secretion (AUCg) with ↑ EA score (r2 = −0.177) - HC: ↑ total cortisol secretion (AUCg) with ↑ EA score (r2 = 0.49) | Weak | d = 2.606 | |
[62] | Cortisol plasma level and 5-HT1A receptor distribution | Cross-sectional (SAD vs. HC) | 30 | Plasma cortisol: SAD < HC (p = 0.016) | Moderate | d = 0.897 | |
[63] | sAA | RCT sAA levels after TSST | 39 | SAD = HC (p > 0.05) | Strong | / | |
Sexual steroids and cortisol | [58] | Platelet DHEA, DHEA-S, pregnenolone and cortisol | Cross-sectional (SAD vs. HC) | 47 | SAD = HC - DHEA: p = 0.75 - DHEA-S: p = 0.490 - Pregnenolone: p = 0.500 - Cortisol: p = 0.1285 - Cortisol/DHEA: p = 0.18 - Cortisol/DHEA-S: p = 0.72 | Moderate | / |
Sexual steroids | [64] | Salivary testosterone | Cross-sectional (ADs vs. HC) | SAD patients: 135 males and 252 females | SAD females < HC (p < 0.001) SAD males = HC (p = 0.76) | Moderate | Females: d = 0.299 |
[65] | PREG-S, ALLO and DHEA-S | Cross-sectional (SAD vs. HC) | 24 males | PREG-S: SAD < HC (p = 0.008) ALLO: SAD = HC (p = 0.96) DHEA-S: SAD = HC (p = 0.165) | Moderate | PREG-S: d = 1.184 | |
Thyroid hormones | [66] | T3, T4, fT4, TSH, anti-thyroid Ab | Cross-sectional (SAD vs. HC) | 43 patients | SAD = HC - T3: p = 0.59 - T4: p = 0.95 - fT4: p = 0.81 - TSH: p = 0.81 - TSH TRH response pattern: p = 0.71 - Antityhroid Ab: p > 0.05 | Moderate | / |
3.3.2. Salivary Alpha Amylase
3.3.3. Sexual Steroids
3.3.4. Thyroid Hormones
3.4. Immunological Markers
REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|
[78] | IL-6, TNF-α, hsCRP | Prospective (ADs vs. HC) | 384 SAD patients: current = 255, remitted = 129 | SAD = HC Current: - IL-6 p = 0.963 - TNF-α p = 0.314 - hsCRP p = 0.129 Remitted: - IL-6 p = 0.241 - TNF-α p = 0.925 - hsCRP p = 0.365 | Moderate | / |
[79] | CRP | Cross-sectional (ADs vs. HC) | 508 SAD patients | SAD = HC (p = 0.124) | Moderate | / |
[80] | CRP, IL-6, TNF-α | Cross-sectional (ADs vs. HC; comparison among ADs) | 651 SAD patients | ADs = HC (p > 0.05) CRP: SAD < ADs (p = 0.04) IL-6: SAD < ADs (p = 0.05); female SAD patients p = 0.007; male SAD patients p = 0.61 TNF-α: SAD = ADs (p = 0.64) | Moderate | CRP: d = 0.207 IL6: d = 0.205 (female SAD patients d = 0.281) |
[81] | LPS-stimulated TNF-α, IL-6, IL-8 | Cross-sectional (SAD vs. HC; OCD vs. HC; SAD vs. OCD) | 26 SAD patients | SAD = HC TNF-α: p = 0.69 IL-6: p = 0.82 IL-8: p = 0.62 SAD = OCD TNF-α: p = 0.971 IL-6: p = 0.076 IL-8: p = 0.103 | Weak | / |
[82] | Basal and LPS-stimulated IFN-γ, IL-10, IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α | Cross-sectional (SAD vs. HC) | 68 | Stimulated IFN-γ, IL-10, IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α: SAD = HC (p > 0.05) Unstimulated IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α: SAD = HC (p > 0.05) Unstimulated IL-10: - SAD < HC (p = 0.04) - SAD males < HC (p = 0.016) - SAD females = HC (p = 0.30) | Moderate | Unstimulated IL-10: d = 0.517 (males: d = 0.872) |
[83] | IL-2, soluble IL-2R | Cross-sectional (SAD vs. HC) | 30 | SAD = HC (p > 0.05) | Weak | / |
[84] | Circulating lymphocyte phenotypic surface markers | Cross-sectional (SAD vs. HC; PD vs. HC) | 65 | ↑ CD16 (p < 0.05) | Moderate | d = 0.442 |
3.5. Antioxidant Markers
REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|
[82] | KYN, TRYP, KYNA, KYN/TRYP, KYNA/KYN | Cross-sectional (SAD vs. HC) | 68 | SAD > HC - KYNA (p = 0.0005) - KYNA/KYN (p = 0.0005) KYN: p = 0.78 TRYP: p = 0.58 KYN/TRYP: p = 0.70 | Moderate | KYNA: d = 0.941 KYNA/KYN: d = 1.037 |
[94] | SOD, CAT, GSHPx, MDA | Clinical Trial (SAD vs. HC; pre- and post- citalopram treatment) | 78 | Baseline: SAD > HC - SOD (p < 0.05) - CAT (p < 0.01) - GSH-Px (p < 0.01) - MDA (p < 0.01) All ↓ after citalopram treatment (p < 0.05) | Weak | Baseline SOD: d = 1.297 Baseline CAT: d = 1.352 Baseline GSH-Px: d = 1.5827 Baseline MDA: d = 2.0111 |
[95] | SOD, GSH-Px, CAT, MDA | Cross-sectional (SAD vs. HC) | 36 | SAD > HC - SOD (p < 0.01) - CAT (p < 0.01) - GSHPx (p < 0.001) - MDA (p < 0.001) | Weak | SOD: d = 1.319 CAT: d = 0.891 GSHPx: d = 1.816 MDA: d = 4.859 |
[96] | AGEs | Cross-sectional case-control (affective disorders and ADs vs. HC) | 691 SAD patients | SAD = HC (p > 0.05) | Moderate | / |
3.6. Neurotrophic Factors
REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|
[108] | Serum BDNF | Cross-sectional (ADs vs. HC) | 105 SAD patients | SAD = HC (p > 0.05) | Strong | / |
[109] | Serum BDNF | Cross-sectional (ADs vs. HC) | 20 SAD patients | SAD = HC (p = 0.913) | Moderate | / |
[110] | Serum GDNF | Cross-sectional (ADs vs. HC) | 70 SAD patients | SAD > HC (p = 0.004) | Moderate | NA |
3.7. Neuroimaging
IMAGING TECHNIQUE | REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|---|
fMRI | [113] | RSFC | Cross-sectional (SAD vs. HC) | 28 | Increased LSAS score = ↑ RSFC in: - left ↔ right amygdala (p = 0.01) - left amygdala ↔ right TVA (p = 0.04) - left ↔ right TVA (p = 0.03) | Moderate | / |
[114] | RSFC | Cross-sectional (SAD vs. HC) | 36 | ↓ positive connections within the frontal lobe: right median PFC ↔ right inferior frontal cortex (p < 0.05) ↓ negative connections frontal ↔ occipital lobes: right median PFC ↔ left calcarine fissure, left superior occipital cortex, left cuneus (p < 0.05) | Moderate | NA | |
[115] | RSFC, network topology | Cross-sectional (SAD vs. HC) | 84 | - ↓ 49 positive connections (p < 0.05) in the frontal, occipital, parietal–(pre) motor, and temporal regions - ↓ default mode network connectivity (p < 0.01) - ↑ Lp (p < 0.01); ↓ Cp (p < 0.01) | Moderate | NA | |
[116] | Amygdala response to angry schematic faces | Cross sectional (SAD vs. HC) | 22 | Angry vs. neutral faces: ↑ responses (all p < 0.001) in: -- right dorsal amygdala; -- left supramarginal gyrus; -- left supplementary eye field; ↓ right dACC response | Moderate | - Amygdala: d = 1.782 - Left supramarginal gyrus: d = 2.029 - Left supplementary eye field: d = 1.949 - Right dACC: d = 1.914 | |
[117] | Amygdala activation to facial expressions | Cross-sectional (SAD vs. HC) Harsh (angry, fearful, and contemp- tous) vs. accepting (happy) facial emotional expressions | 30 | ↑ left allocortex activation (amygdala, uncus, parahippocampampal gyrus activation): - to contemptuous vs. happy faces (p = 0.004) - to angry vs. happy faces (p = 0.02) | Moderate | d = 1.14 d = 1.00 | |
[118] | Amygdala reactivity to emotional faces with low, moderate, and high intensity | Cross sectional (SAD vs. HC) | 22 | ↑ left amygdala activation to high intensity emotional faces (p < 0.05) | Moderate | d = 0.899 | |
[119] | Amygdala reactivity to threatening faces of low, moderate, and high intensity | Cross-sectional (SAD vs. HC) | 24 | - ↑ left amygdala reactivity to threatening faces at moderate (p < 0.03) and high intensity (p < 0.003) - ↑ right amygdala reactivity for high intensity (p < 0.04) SAD = HC: - left amygdala low intensity (p = 0.10) - right amygdala for moderate (p = 0.18) or low (p = 0.34) intensity | Moderate | - Left amygdala, moderate intensity: d = 0.947 - Left amygdala, high intensity: d = 1.361 - Right amygdala, high intensity: d = 0.891 | |
[120] | Amygdala connectivity to PFC at rest and during threat processing | Cross-sectional (SAD vs. HC) (EFMT; a resting state Task) | 37 | At rest: ↓ connectivity - right amygdala ↔ rostral ACC (p < 0.05) During threat: ↓ connectivity - right amygdala ↔ rostral ACC (p < 0.05) - left amygdala ↔ rostral ACC (p < 0.05) - right amygdala ↔ DLPFC (p < 0.05) - left amygdala ↔ DLPFC (p < 0.05) | Moderate | At rest: d= 0.557–1.649 During threat: - d = 0.557 - d = NA - d = NA - d = 0.557 | |
[121] | DLPFC activation during perception of laughter | Cross- sectional (SAD vs. HC) | 26 | ↑ activation during reappraisal in the left DLPFC (p = 0.007) | Moderate | / | |
[122] | Insula Reactivity and Connectivity to ACC when processing threat | Cross-sectional (SAD vs. HC) (EFMT fear, angry, happy expressions) | 55 | ↑ activation to fear (>happy) faces in the left aINS (p < 0.003) and right aINS (p < 0.005) ↓ connectivity right aINS ↔ dACC during fearful face processing (p < 0.05) | Moderate | - Left aINS: d = 1.2365 - Right aINS: d = 0.823 - Right aINS ↔ dACC: d = 1.4741 | |
[123] | Brain activation during exposure to emotional faces | Cross-sectional (SAD vs. HC) | 46 | Higher LSAS scores = ↑ activation - left anterior insula (p < 0.05) - right lateral PFC (p < 0.05) | Moderate | - Left aINS: d = 1.435 - Right lateral PFC: d = 1.666 | |
[124] | FC during face processing | Cross sectional (SAD vs. HC; SAD vs. PD) | Primary sample: 16 SAD patients Replication sample: 14 SAD patients | ↓ FC left temporal pole ↔ left hippocampus (p = 0.042), particularly with angry faces (p = 0.027) | Strong | - All faces: d = 0.190 - Angry faces: d = 0.245 | |
[125] | Fearful face processing brain signal (whole brain, fear network parietal lobe); regional gray matter volume | Cross-sectional (SAD vs. HC) (fMRI/sMRI + SVM) | 26 males | Fearful face processing: - Whole brain activation: SAD ≠ HC (p = 0.034) - Fear network activation: SAD ≠ HC (p = 0.017) - Parietal lobe activation: SAD = HC (p = 0.548) Gray matter volume: - Whole brain: SAD ≠ HC (p = 0.001) - Regional in fear network: SAD = HC (p = 0.397) - Regional in parietal lobe: SAD = HC (p = 0.232) | Moderate | - Whole brain activation: d = 0.742 - Fear network activation: d = 0.954 - Whole brain gray matter volume: d = 1.896 | |
[126] | CT and CSA | Cross sectional (SAD vs. HC) | 64 | ↓ CT in 3 clusters in the bilateral SFG with large portions extending into the rMFG and rostral ACC (p < 0.05) ↑ CSA clusters (p < 0.05): - left SFG/rostral ACC - left rMFG - left STG/parts of MTG - right SFG/ACC - right lOFC/rMFG | Moderate | NA | |
PET | [62] | Relationship between cortisol plasma levels and 5-HT1A receptor BP | Cross-sectional (SAD vs. HC) | 30 males | ↑ cortisol plasma levels: ↓ 5-HT1A BP in: - amygdala (p = 0.0067) - hippocampus (p = 0.04) | Moderate | - Amygdala: d = 0.863 - Hippocampus: d = 0.8072 |
[127] | 5-HT1A receptor BP | Cross-sectional (SAD vs. HC) | 30 males | ↓ 5-HT1A BP: - amygdala (p = 0.024) - insula (p = 0.024) - ACC (p = 0.032) | Moderate | - Amygdala: d = 0.7892 - Insula: d = 1.292 - ACC: d = 1.131 |
3.8. Neuropsychogical Markers
REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|
[121] | Laughter perception and interpretation | Cross-sectional (SAD vs. HC) | 26 | ↑ negative perception of laughter (p = 0.005) | Moderate | d = 1.219 |
[129] | Eye movement parameters (visual scanpath) | Cross-sectional (SAD vs. HC) | 30 | “Hyperscanning” strategy for SAD: ↓ n. of fixation to neutral and sad faces (p < 0.01) ↓ total fixation duration (p < 0.01) ↓ scanpath length for neutral faces (p < 0.01) ↑ raw scanpath length for neutral and sad faces (p < 0.05) | Moderate | - Total n. of fixations: d = 1.102 - Total fixation duration: d = 1.231 - Scanpath length, neutral faces: d = 0.978 - Scanpath length, sad faces: d = 0.846 |
[130] | Gaze avoidance | Cross-sectional (SAD vs. HC) | 50 | ↑ gaze avoidance: ↓ fixations (p = 0.04) ↓ dwell time (p = 0.03) | Strong | - Fixations: d = 3.559 - Dwell time: d = 3.561 |
[131] | Gaze avoidance | Cross-sectional (SAD vs. NSAC) | 39 | ↑ gaze avoidance: ↓ Total time holding eye contact (p = 0.04) ↓ Number of fixation on eyes (p = 0.02) ↓ Fixation durations upon eyes (p = 0.047) | Moderate | - Total time holding eye contact: d = 0.283 - Number of fixations on eyes: d = 0.473 - Fixation durations upon eyes: d = 0.345 |
[132] | FNE, SADS, TCI, platelet 5HT2 receptor density | Cross-sectional (SAD vs. HC) | 20 SAD males | ↑ FNE (p < 0.0001) ↑ SADS (p < 0.0001) ↑ harm avoidance (TCI) (p < 0.0001) ↓ novelty seeking (TCI) (p < 0.0001) ↓ cooperativeness (TCI) (p < 0.0001) ↓ self-directedness (p < 0.0001) Platelet 5HT2, receptor density: SAD = HC (p > 0.05) | Weak | - FNE: d = 4.427 - SADs: d = 4.2596 - Harm avoidance: d = 4.203 - Novelty seeking: d = 2.191 - Cooperativeness: d = 1.692 - Self-directedness: d = 4.054 |
[133] | Negative interpretative bias (sorting cards with emotional expressions at baseline and under threat) | Cross-sectional (SAD vs. HC) | 52 | ↑ probability of misclassifying neutral cards as angry under threat (p < 0.005) | Strong | d = 1.835 |
3.9. Others (Neuropeptides and Electrocardiographic Parameters)
BIOMARKERS TYPE | REFERENCE | BIOMARKER UNDER STUDY | STUDY DESIGN | SAMPLE SIZE | FINDINGS | QUALITY SCORE 1 | COHEN’S d |
---|---|---|---|---|---|---|---|
Neuropeptides | [137] | Plasma NPY, plasma NE | Cross-sectional (SAD vs. HC vs. PD) Resting conditions and after cold stress | 11 SAD patients | SAD = HC (p > 0.05) | Weak | / |
[138] | Plasma oxytocin | Cross-sectional (SAD vs. HC) | 46 | SAD = HC (p = 0.8) | Moderate | / | |
[139] | Plasma oxytocin | Cross-sectional (SAD vs. HC) Levels at baseline and after Trust Game | 67 | - Baseline: SAD = HC (p = 0.059) - Mean endpoint: SAD < HC (p = 0.025) - Change score (magnitude of change in oxytocin from baseline to endpoint): SAD = HC (p = 1.0) - AUC: SAD < HC (p = 0.011) | Moderate | Mean endpoint: d = 1.0361 AUC: NA | |
Electro-cardiographic parameters | [140] | QT dispersion (QTd) | Cross-sectional (SAD vs. HC) | 31 | SAD > HC (p < 0.0001) | Strong | d = 1.616 |
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Caldiroli, A.; Capuzzi, E.; Affaticati, L.M.; Surace, T.; Di Forti, C.L.; Dakanalis, A.; Clerici, M.; Buoli, M. Candidate Biological Markers for Social Anxiety Disorder: A Systematic Review. Int. J. Mol. Sci. 2023, 24, 835. https://doi.org/10.3390/ijms24010835
Caldiroli A, Capuzzi E, Affaticati LM, Surace T, Di Forti CL, Dakanalis A, Clerici M, Buoli M. Candidate Biological Markers for Social Anxiety Disorder: A Systematic Review. International Journal of Molecular Sciences. 2023; 24(1):835. https://doi.org/10.3390/ijms24010835
Chicago/Turabian StyleCaldiroli, Alice, Enrico Capuzzi, Letizia M. Affaticati, Teresa Surace, Carla L. Di Forti, Antonios Dakanalis, Massimo Clerici, and Massimiliano Buoli. 2023. "Candidate Biological Markers for Social Anxiety Disorder: A Systematic Review" International Journal of Molecular Sciences 24, no. 1: 835. https://doi.org/10.3390/ijms24010835