Unique and Overlapping Proteins of Subjective Feelings of Mental and Physical Energy and Fatigue: An Exploratory Study Original Research
Main Article Content
Keywords
proteomics, biomarkers, mood states
Abstract
Introduction: Recent evidence suggests that subjective feelings of mental energy (ME), mental fatigue (MF), physical energy (PE), and physical fatigue (PF) are unique and overlapping biological correlates. This exploratory study aimed to identify unique and overlapping proteomic markers and their associated pathways for ME, MF, PE, and PF.
Methods: Participants (n=10) completed a 3-day protocol with saliva samples collected at multiple time points, including pre- and post-fatigue (Day 2). Trait and state levels of ME, MF, PE, and PF were assessed each day, and absolute and relative changes in mood and proteomic markers were calculated. Top 1% of proteomic markers were identified using a genetic algorithm with Random Forest Regressor, followed by Community Louvain network analysis and STRING-based protein–protein interaction analysis.
Results: Our analysis identified unique and overlapping proteomic markers for each of the 4 moods. The PTP analysis revealed that energy was associated with ATP generation (p<0.001), activation (p=0.003) and regulation of adaptive immunity (p<0.001), and markers of cardiac myopathy (p=0.028) while fatigue was associated with catabolism (p=0.008), oxidative stress, innate immunity (p<0.001), and necroptosis.
Conclusions: Consistent with prior research, the results highlight the distinct biological profiles of energy and fatigue, supporting their assessment as separate mental and physical state and trait moods.
References
1. Yoon JH, Park NH, Kang YE, Ahn YC, Lee EJ, Son CG. The demographic features of fatigue in the general population worldwide: a systematic review and meta-analysis. Front Public Health. 2023;11:1192121. doi:10.3389/fpubh.2023.1192121
2. Zhang G, Yau KKW, Zhang X, Li Y. Traffic accidents involving fatigue driving and their extent of casualties. Accid Anal Prev. 2016;87:34-42. doi:10.1016/j.aap.2015.10.033
3. Bakker RJ, van de Putte EM, Kuis W, Sinnema G. Risk factors for persistent fatigue with significant school absence in children and adolescents. Pediatrics. 2009;124(1):e89-e95.
4. Ricci JA, Chee E, Lorandeau AL, Berger J. Fatigue in the US workforce: prevalence and implications for lost productive work time. J Occup Environ Med. 2007;49(1):1-10.
5. Phillips RO. A review of definitions of fatigue – And a step towards a whole definition. Transp Res Part F Traffic Psychol Behav. 2015;29:48-56. doi:10.1016/j.trf.2015.01.003
6. Aaronson LS, Teel CS, Cassmeyer V, et al. Defining and Measuring Fatigue. Image J Nurs Sch. 1999;31(1):45-50. doi:10.1111/j.1547-5069.1999.tb00420.x
7. Boolani A, Hinkey JM, Merritt J, Ozga M, Alfred S, Baker L. Changes In Mental And Physical Energy And Fatigue Have Unique Biomarkers: An Exploratory Study: 2499. Med Sci Sports Exerc. 2024;56(10S):930. doi:10.1249/01.mss.0001060660.24860.c2
8. Boolani A, Bahr B, Milani I, et al. Physical activity is not associated with feelings of mental energy and fatigue after being sedentary for 8 hours or more. Ment Health Phys Act. 2021;21:100418.
9. Abd-Elfattah HM, Abdelazeim FH, Elshennawy S. Physical and cognitive consequences of fatigue: A review. J Adv Res. 2015;6(3):3. doi:10.1016/j.jare.2015.01.011
10. van der Weyden MS, Martin J, Rodriguez J, Boolani A. An Intense Bout of Acute Aerobic Exercise, but Not a Carbohydrate Supplement, Improves Cognitive Task Performance in a Sample of Black, Indigenous, and People of Color (BIPOC) Student Athletes. Sports. 2023;11(4):88.
11. Boolani A, O’Connor PJ, Reid J, Ma S, Mondal S. Predictors of feelings of energy differ from predictors of fatigue. Fatigue Biomed Health Behav. 2019;7(1):12-28. doi:10.1080/21641846.2018.1558733
12. Boolani A, Gallivan KM, Ondrak KS, et al. Trait Energy and Fatigue May Be Connected to Gut Bacteria among Young Physically Active Adults: An Exploratory Study. Nutrients. 2022;14(3). doi:10.3390/nu14030466
13. Kowalski KL, Boolani A, Christie AD. State and Trait Fatigue and Energy Predictors of Postural Control and Gait. Motor Control. 2021;1(aop):1-18.
14. Boolani A, Ryan J, Vo T, et al. Do changes in mental energy and fatigue impact functional assessments associated with fall risks? An exploratory study using machine learning. Phys Occup Ther Geriatr. 2020;38(3):283-301. doi:10.1080/02703181.2020.1748788
15. Manierre M, Jansen E, Boolani A. Sleep quality and sex modify the relationships between trait energy and fatigue on state energy and fatigue. PLOS ONE. 2020;15(1):e0227511. doi:10.1371/journal.pone.0227511
16. Frederick GM, O’Connor PJ, Schmidt MD, Evans EM. Relationships between components of the 24-hour activity cycle and feelings of energy and fatigue in college students: A systematic review. Ment Health Phys Act. 2021;21:100409. doi:10.1016/j.mhpa.2021.100409
17. Loy BD, Cameron MH, O’Connor PJ. Perceived fatigue and energy are independent unipolar states: Supporting evidence. Med Hypotheses. 2018;113:46-51.
18. Lott DC, Kim SJ, Cook Jr EH, de Wit H. Dopamine transporter gene associated with diminished subjective response to amphetamine. Neuropsychopharmacology. 2005;30(3):602.
19. Riby LM. The impact of age and task domain on cognitive performance: a meta-analytic review of the glucose facilitation effect. Brain Impair. 2004;5(2):145-165.
20. Dupree EJ, Goodwin A, Darie CC, Boolani A. A Pilot Exploratory Proteomics Investigation of Mental Fatigue and Mental Energy. Adv Exp Med Biol. 2019;1140:601-611. doi:10.1007/978-3-030-15950-4_36
21. Marcora SM, Staiano W, Manning V. Mental fatigue impairs physical performance in humans. J Appl Physiol. 2009;106(3):857-864.
22. Kikuchi H, Nakatani Y, Seki Y, et al. Decreased blood serotonin in the premenstrual phase enhances negative mood in healthy women. J Psychosom Obstet Gynecol. 2010;31(2):83-89.
23. Loy BD, O’Connor PJ. The effect of histamine on changes in mental energy and fatigue after a single bout of exercise. Physiol Behav. 2016;153:7-18.
24. Harrison NA, Brydon L, Walker C, et al. Neural Origins of Human Sickness in Interoceptive Responses to Inflammation. Biol Psychiatry. 2009;66(5):415-422. doi:10.1016/j.biopsych.2009.03.007
25. Stringer EA, Baker KS, Carroll IR, et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013;11(1):93.
26. Boolani A, Manierre M. An exploratory multivariate study examining correlates of trait mental and physical fatigue and energy. Fatigue Biomed Health Behav. 2019;7(1):29-40. doi:10.1080/21641846.2019.1573790
27. Chang ZS, Boolani A, Conroy DA, Dunietz T, Jansen EC. Skipping breakfast and mood: The role of sleep. Nutr Health. 0260106020984861.
28. Eshragh J, Dhruva A, Paul SM, et al. Associations between neurotransmitter genes and fatigue and energy levels in women after breast cancer surgery. J Pain Symptom Manage. 2017;53(1):67-84. e7.
29. Woods AL, Rice AJ, Garvican-Lewis LA, et al. The effects of intensified training on resting metabolic rate (RMR), body composition and performance in trained cyclists. PloS One. 2018;13(2):e0191644.
30. Boolani A, Hinkley J, Merritt JR, Ozga M, Alfred S, Baker LB. Changes in Mental and Physical Energy and Fatigue Have Unique Biomarkers: An Exploratory Study. In: 2024.
31. Lorenzo Calvo J, Fei X, Domínguez R, Pareja-Galeano H. Caffeine and Cognitive Functions in Sports: A Systematic Review and Meta-Analysis. Nutrients. 2021;13(3):3. doi:10.3390/nu13030868
32. Loy BD, O’Connor PJ, Dishman RK. The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis. Fatigue Biomed Health Behav. 2013;1(4):223-242.
33. Wender CLA, Manninen M, O’Connor PJ. The Effect of Chronic Exercise on Energy and Fatigue States: A Systematic Review and Meta-Analysis of Randomized Trials. Front Psychol. 2022;13. Accessed February 28, 2023. https://www.frontiersin.org/articles/10.3389/fpsyg.2022.907637
34. Fuller DT, Smith ML, Boolani A. Trait Energy and Fatigue Modify the Effects of Caffeine on Mood, Cognitive and Fine-Motor Task Performance: A Post-Hoc Study. Nutrients. 2021;13(2):412.
35. Gigliotti HM, Hodgson C, Riley M, et al. Trait Energy and Fatigue Influence Inter-Individual Mood and Neurocognitive Responses during Work Done While Sitting, Standing, and Intermittent Walking: A Randomized-Controlled Crossover Design. Appl Sci. 2023;13(7):4241.
36. Barrios N, Sames C, Allen A, Vieira ER, Boolani A. Intensity of Aquatic Physical Activity Is Best When Tailored to the Participants’ Mental and Physical Capabilities: An Exploratory Study. J Aquat Phys Ther. 2022;30(2):30-36.
37. Toczko M, Boolani A, Martin J. Applicability of Ratings of Perceived Exertion as a Measure of Subjective Fatigue in First Responders: An Exploratory Study. Res Directs Health Sci. 2024;4(1).
38. Narkhede P, Jaimala S, Amita M. Comparison of maximal oxygen consumption values estimated from six minute walk test and Queens College step test. Indian J Physiother Occup Ther. 2014;8(1):154.
39. Lindsey B, Bowden K, Shaul Y, et al. Improved Classification of Acute Physical Fatigue Using Salivary Proteomic Biomarkers: An Exploratory Study. bioRxiv. Preprint posted online March 2, 2026:2025.06.04.657971. doi:10.1101/2025.06.04.657971
40. O’Connor P. Mental and physical state and trait energy and fatigue scales. Published online 2006.
41. Pin E, Petricoin E, Cortes N, et al. IgA autoreactivity towards brain enriched and apoptosis regulating proteins in saliva of athletes after acute concussion and subconcussive impacts. J Neurotrauma. Published online 2021.
42. Pedregosa F, Varoquaux G, Gramfort A, et al. Scikit-learn: Machine learning in Python. Braun M, ed. J Mach Learn Res. 2011;12.
43. Roberts DR, Bahn V, Ciuti S, et al. Cross-validation strategies for data with temporal, spatial, hierarchical, or phylogenetic structure. Ecography. 2017;40(8):913-929. doi:10.1111/ecog.02881
44. Kursa MB, Rudnicki WR. Feature Selection with the Boruta Package. J Stat Softw. 2010;36:1-13. doi:10.18637/jss.v036.i11
45. Saeys Y, Inza I, Larrañaga P. A review of feature selection techniques in bioinformatics. Bioinformatics. 2007;23(19):2507-2517. doi:10.1093/bioinformatics/btm344
46. Díaz-Uriarte R, Alvarez de Andrés S. Gene selection and classification of microarray data using random forest. BMC Bioinformatics. 2006;7:3. doi:10.1186/1471-2105-7-3
47. Breiman L. Random Forests. Mach Learn. 2001;45(1):5-32. doi:10.1023/A:1010933404324
48. Blondel VD, Guillaume JL, Lambiotte R, Lefebvre E. Fast unfolding of communities in large networks. J Stat Mech Theory Exp. 2008;2008(10):P10008. doi:10.1088/1742-5468/2008/10/P10008
49. Clauset A, Newman MEJ, Moore C. Finding community structure in very large networks. Phys Rev E Stat Nonlin Soft Matter Phys. 2004;70(6 Pt 2):066111. doi:10.1103/PhysRevE.70.066111
50. Jeong H, Mason SP, Barabási AL, Oltvai ZN. Lethality and centrality in protein networks. Nature. 2001;411(6833):41-42. doi:10.1038/35075138
51. Wild B, Eichler M, Friederich HC, Hartmann M, Zipfel S, Herzog W. A graphical vector autoregressive modelling approach to the analysis of electronic diary data. BMC Med Res Methodol. 2010;10:28. doi:10.1186/1471-2288-10-28
52. Eaton NR, Bringmann LF, Elmer T, et al. A review of approaches and models in psychopathology conceptualization research. Nat Rev Psychol. 2023;2(10):622-636. doi:10.1038/s44159-023-00218-4
53. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550. doi:10.1073/pnas.0506580102
54. Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-D646. doi:10.1093/nar/gkac1000
55. Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM. Neuroendocrine and Immune Contributors to Fatigue. PM&R. 2010;2(5):338-346. doi:10.1016/j.pmrj.2010.04.008
56. Kop WJ, Hamulyak K, Pernot C, Appels A. Relationship of Blood Coagulation and Fibrinolysis to Vital Exhaustion. Biopsychosoc Sci Med. 1998;60(3):352.
57. Sheikh MH, Solito E. Annexin A1: Uncovering the Many Talents of an Old Protein. Int J Mol Sci. 2018;19(4):4. doi:10.3390/ijms19041045
58. Bikle DD. Vitamin D Regulation of Immune Function. Curr Osteoporos Rep. 2022;20(3):186-193. doi:10.1007/s11914-022-00732-z
59. Murata T, Chiba S, Kawaminami M. Changes in the expressions of annexin A1, annexin A5, inhibin/activin subunits, and vitamin D receptor mRNAs in pituitary glands of female rats during the estrous cycle: correlation analyses among these factors. J Vet Med Sci. 2022;84(8):1065-1073. doi:10.1292/jvms.22-0141
60. Richman LS, Kubzansky LD, Maselko J, Ackerson LK, Bauer M. The relationship between mental vitality and cardiovascular health. Psychol Health. 2009;24(8):919-932. doi:10.1080/08870440802108926
61. Christiansen JJ, Djurhuus CB, Gravholt CH, et al. Effects of Cortisol on Carbohydrate, Lipid, and Protein Metabolism: Studies of Acute Cortisol Withdrawal in Adrenocortical Failure. J Clin Endocrinol Metab. 2007;92(9):3553-3559. doi:10.1210/jc.2007-0445
62. Piche T, Huet PM, Gelsi E, et al. Fatigue in irritable bowel syndrome: characterization and putative role of leptin. Eur J Gastroenterol Hepatol. 2007;19(3):237-243.
63. Basnet S, Sharma S, Costea DE, Sapkota D. Expression profile and functional role of S100A14 in human cancer. Oncotarget. 2019;10(31):2996-3012. doi:10.18632/oncotarget.26861
64. Smith MR, Marcora SM, Coutts AJ. Mental fatigue impairs intermittent running performance. Med Sci Sports Exerc. 2015;47(8):1682-1690.
65. Boolani A, Fuller D, Mondal S, Gumpricht E. Trait Energy and Fatigue Modify Acute Ingestion of an Adaptogenic-Rich Beverage on Neurocognitive Performance. Appl Sci. 2022;12(9):4466.
66. Boolani A, Lindheimer JB, Loy BD, Crozier S, O’Connor PJ. Acute effects of brewed cocoa consumption on attention, motivation to perform cognitive work and feelings of anxiety, energy and fatigue: a randomized, placebo-controlled crossover experiment. BMC Nutr. 2017;3(1):8.
67. Piche T, Gelsi E, Schneider SM, et al. Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gut. 2002;51(3):434-439.
68. Sáinz N, Barrenetxe J, Moreno-Aliaga MJ, Martínez JA. Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 2015;64(1):35-46. doi:10.1016/j.metabol.2014.10.015
69. Davis JM, Alderson NL, Welsh RS. Serotonin and central nervous system fatigue: nutritional considerations12. Am J Clin Nutr. 2000;72(2):573S-578S. doi:10.1093/ajcn/72.2.573S
70. Thurmond RL, ed. Histamine in Inflammation. Springer US; 2010. doi:10.1007/978-1-4419-8056-4
71. Nuutinen S, Panula P. Histamine in Neurotransmission and Brain Diseases. In: Thurmond RL, ed. Histamine in Inflammation. Springer US; 2010:95-107. doi:10.1007/978-1-4419-8056-4_10
72. Cacquevel M, Lebeurrier N, Cheenne S, Vivien D. Cytokines in Neuroinflammation and Alzheimer’s Disease. Curr Drug Targets. 2004;5(6):529-534. doi:10.2174/1389450043345308
73. Levin SG, Godukhin OV. Modulating effect of cytokines on mechanisms of synaptic plasticity in the brain. Biochem Mosc. 2017;82(3):264-274. doi:10.1134/S000629791703004X
74. Monteleone I, Marafini I, Dinallo V, et al. Sodium chloride–enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice. J Crohns Colitis. 2017;11(2):237-245. doi:10.1093/ecco-jcc/jjw139
75. Brillon DJ, Zheng B, Campbell RG, Matthews DE. Effect of cortisol on energy expenditure and amino acid metabolism in humans. Am J Physiol-Endocrinol Metab. 1995;268(3):E501-E513. doi:10.1152/ajpendo.1995.268.3.E501
2. Zhang G, Yau KKW, Zhang X, Li Y. Traffic accidents involving fatigue driving and their extent of casualties. Accid Anal Prev. 2016;87:34-42. doi:10.1016/j.aap.2015.10.033
3. Bakker RJ, van de Putte EM, Kuis W, Sinnema G. Risk factors for persistent fatigue with significant school absence in children and adolescents. Pediatrics. 2009;124(1):e89-e95.
4. Ricci JA, Chee E, Lorandeau AL, Berger J. Fatigue in the US workforce: prevalence and implications for lost productive work time. J Occup Environ Med. 2007;49(1):1-10.
5. Phillips RO. A review of definitions of fatigue – And a step towards a whole definition. Transp Res Part F Traffic Psychol Behav. 2015;29:48-56. doi:10.1016/j.trf.2015.01.003
6. Aaronson LS, Teel CS, Cassmeyer V, et al. Defining and Measuring Fatigue. Image J Nurs Sch. 1999;31(1):45-50. doi:10.1111/j.1547-5069.1999.tb00420.x
7. Boolani A, Hinkey JM, Merritt J, Ozga M, Alfred S, Baker L. Changes In Mental And Physical Energy And Fatigue Have Unique Biomarkers: An Exploratory Study: 2499. Med Sci Sports Exerc. 2024;56(10S):930. doi:10.1249/01.mss.0001060660.24860.c2
8. Boolani A, Bahr B, Milani I, et al. Physical activity is not associated with feelings of mental energy and fatigue after being sedentary for 8 hours or more. Ment Health Phys Act. 2021;21:100418.
9. Abd-Elfattah HM, Abdelazeim FH, Elshennawy S. Physical and cognitive consequences of fatigue: A review. J Adv Res. 2015;6(3):3. doi:10.1016/j.jare.2015.01.011
10. van der Weyden MS, Martin J, Rodriguez J, Boolani A. An Intense Bout of Acute Aerobic Exercise, but Not a Carbohydrate Supplement, Improves Cognitive Task Performance in a Sample of Black, Indigenous, and People of Color (BIPOC) Student Athletes. Sports. 2023;11(4):88.
11. Boolani A, O’Connor PJ, Reid J, Ma S, Mondal S. Predictors of feelings of energy differ from predictors of fatigue. Fatigue Biomed Health Behav. 2019;7(1):12-28. doi:10.1080/21641846.2018.1558733
12. Boolani A, Gallivan KM, Ondrak KS, et al. Trait Energy and Fatigue May Be Connected to Gut Bacteria among Young Physically Active Adults: An Exploratory Study. Nutrients. 2022;14(3). doi:10.3390/nu14030466
13. Kowalski KL, Boolani A, Christie AD. State and Trait Fatigue and Energy Predictors of Postural Control and Gait. Motor Control. 2021;1(aop):1-18.
14. Boolani A, Ryan J, Vo T, et al. Do changes in mental energy and fatigue impact functional assessments associated with fall risks? An exploratory study using machine learning. Phys Occup Ther Geriatr. 2020;38(3):283-301. doi:10.1080/02703181.2020.1748788
15. Manierre M, Jansen E, Boolani A. Sleep quality and sex modify the relationships between trait energy and fatigue on state energy and fatigue. PLOS ONE. 2020;15(1):e0227511. doi:10.1371/journal.pone.0227511
16. Frederick GM, O’Connor PJ, Schmidt MD, Evans EM. Relationships between components of the 24-hour activity cycle and feelings of energy and fatigue in college students: A systematic review. Ment Health Phys Act. 2021;21:100409. doi:10.1016/j.mhpa.2021.100409
17. Loy BD, Cameron MH, O’Connor PJ. Perceived fatigue and energy are independent unipolar states: Supporting evidence. Med Hypotheses. 2018;113:46-51.
18. Lott DC, Kim SJ, Cook Jr EH, de Wit H. Dopamine transporter gene associated with diminished subjective response to amphetamine. Neuropsychopharmacology. 2005;30(3):602.
19. Riby LM. The impact of age and task domain on cognitive performance: a meta-analytic review of the glucose facilitation effect. Brain Impair. 2004;5(2):145-165.
20. Dupree EJ, Goodwin A, Darie CC, Boolani A. A Pilot Exploratory Proteomics Investigation of Mental Fatigue and Mental Energy. Adv Exp Med Biol. 2019;1140:601-611. doi:10.1007/978-3-030-15950-4_36
21. Marcora SM, Staiano W, Manning V. Mental fatigue impairs physical performance in humans. J Appl Physiol. 2009;106(3):857-864.
22. Kikuchi H, Nakatani Y, Seki Y, et al. Decreased blood serotonin in the premenstrual phase enhances negative mood in healthy women. J Psychosom Obstet Gynecol. 2010;31(2):83-89.
23. Loy BD, O’Connor PJ. The effect of histamine on changes in mental energy and fatigue after a single bout of exercise. Physiol Behav. 2016;153:7-18.
24. Harrison NA, Brydon L, Walker C, et al. Neural Origins of Human Sickness in Interoceptive Responses to Inflammation. Biol Psychiatry. 2009;66(5):415-422. doi:10.1016/j.biopsych.2009.03.007
25. Stringer EA, Baker KS, Carroll IR, et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013;11(1):93.
26. Boolani A, Manierre M. An exploratory multivariate study examining correlates of trait mental and physical fatigue and energy. Fatigue Biomed Health Behav. 2019;7(1):29-40. doi:10.1080/21641846.2019.1573790
27. Chang ZS, Boolani A, Conroy DA, Dunietz T, Jansen EC. Skipping breakfast and mood: The role of sleep. Nutr Health. 0260106020984861.
28. Eshragh J, Dhruva A, Paul SM, et al. Associations between neurotransmitter genes and fatigue and energy levels in women after breast cancer surgery. J Pain Symptom Manage. 2017;53(1):67-84. e7.
29. Woods AL, Rice AJ, Garvican-Lewis LA, et al. The effects of intensified training on resting metabolic rate (RMR), body composition and performance in trained cyclists. PloS One. 2018;13(2):e0191644.
30. Boolani A, Hinkley J, Merritt JR, Ozga M, Alfred S, Baker LB. Changes in Mental and Physical Energy and Fatigue Have Unique Biomarkers: An Exploratory Study. In: 2024.
31. Lorenzo Calvo J, Fei X, Domínguez R, Pareja-Galeano H. Caffeine and Cognitive Functions in Sports: A Systematic Review and Meta-Analysis. Nutrients. 2021;13(3):3. doi:10.3390/nu13030868
32. Loy BD, O’Connor PJ, Dishman RK. The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis. Fatigue Biomed Health Behav. 2013;1(4):223-242.
33. Wender CLA, Manninen M, O’Connor PJ. The Effect of Chronic Exercise on Energy and Fatigue States: A Systematic Review and Meta-Analysis of Randomized Trials. Front Psychol. 2022;13. Accessed February 28, 2023. https://www.frontiersin.org/articles/10.3389/fpsyg.2022.907637
34. Fuller DT, Smith ML, Boolani A. Trait Energy and Fatigue Modify the Effects of Caffeine on Mood, Cognitive and Fine-Motor Task Performance: A Post-Hoc Study. Nutrients. 2021;13(2):412.
35. Gigliotti HM, Hodgson C, Riley M, et al. Trait Energy and Fatigue Influence Inter-Individual Mood and Neurocognitive Responses during Work Done While Sitting, Standing, and Intermittent Walking: A Randomized-Controlled Crossover Design. Appl Sci. 2023;13(7):4241.
36. Barrios N, Sames C, Allen A, Vieira ER, Boolani A. Intensity of Aquatic Physical Activity Is Best When Tailored to the Participants’ Mental and Physical Capabilities: An Exploratory Study. J Aquat Phys Ther. 2022;30(2):30-36.
37. Toczko M, Boolani A, Martin J. Applicability of Ratings of Perceived Exertion as a Measure of Subjective Fatigue in First Responders: An Exploratory Study. Res Directs Health Sci. 2024;4(1).
38. Narkhede P, Jaimala S, Amita M. Comparison of maximal oxygen consumption values estimated from six minute walk test and Queens College step test. Indian J Physiother Occup Ther. 2014;8(1):154.
39. Lindsey B, Bowden K, Shaul Y, et al. Improved Classification of Acute Physical Fatigue Using Salivary Proteomic Biomarkers: An Exploratory Study. bioRxiv. Preprint posted online March 2, 2026:2025.06.04.657971. doi:10.1101/2025.06.04.657971
40. O’Connor P. Mental and physical state and trait energy and fatigue scales. Published online 2006.
41. Pin E, Petricoin E, Cortes N, et al. IgA autoreactivity towards brain enriched and apoptosis regulating proteins in saliva of athletes after acute concussion and subconcussive impacts. J Neurotrauma. Published online 2021.
42. Pedregosa F, Varoquaux G, Gramfort A, et al. Scikit-learn: Machine learning in Python. Braun M, ed. J Mach Learn Res. 2011;12.
43. Roberts DR, Bahn V, Ciuti S, et al. Cross-validation strategies for data with temporal, spatial, hierarchical, or phylogenetic structure. Ecography. 2017;40(8):913-929. doi:10.1111/ecog.02881
44. Kursa MB, Rudnicki WR. Feature Selection with the Boruta Package. J Stat Softw. 2010;36:1-13. doi:10.18637/jss.v036.i11
45. Saeys Y, Inza I, Larrañaga P. A review of feature selection techniques in bioinformatics. Bioinformatics. 2007;23(19):2507-2517. doi:10.1093/bioinformatics/btm344
46. Díaz-Uriarte R, Alvarez de Andrés S. Gene selection and classification of microarray data using random forest. BMC Bioinformatics. 2006;7:3. doi:10.1186/1471-2105-7-3
47. Breiman L. Random Forests. Mach Learn. 2001;45(1):5-32. doi:10.1023/A:1010933404324
48. Blondel VD, Guillaume JL, Lambiotte R, Lefebvre E. Fast unfolding of communities in large networks. J Stat Mech Theory Exp. 2008;2008(10):P10008. doi:10.1088/1742-5468/2008/10/P10008
49. Clauset A, Newman MEJ, Moore C. Finding community structure in very large networks. Phys Rev E Stat Nonlin Soft Matter Phys. 2004;70(6 Pt 2):066111. doi:10.1103/PhysRevE.70.066111
50. Jeong H, Mason SP, Barabási AL, Oltvai ZN. Lethality and centrality in protein networks. Nature. 2001;411(6833):41-42. doi:10.1038/35075138
51. Wild B, Eichler M, Friederich HC, Hartmann M, Zipfel S, Herzog W. A graphical vector autoregressive modelling approach to the analysis of electronic diary data. BMC Med Res Methodol. 2010;10:28. doi:10.1186/1471-2288-10-28
52. Eaton NR, Bringmann LF, Elmer T, et al. A review of approaches and models in psychopathology conceptualization research. Nat Rev Psychol. 2023;2(10):622-636. doi:10.1038/s44159-023-00218-4
53. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550. doi:10.1073/pnas.0506580102
54. Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-D646. doi:10.1093/nar/gkac1000
55. Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM. Neuroendocrine and Immune Contributors to Fatigue. PM&R. 2010;2(5):338-346. doi:10.1016/j.pmrj.2010.04.008
56. Kop WJ, Hamulyak K, Pernot C, Appels A. Relationship of Blood Coagulation and Fibrinolysis to Vital Exhaustion. Biopsychosoc Sci Med. 1998;60(3):352.
57. Sheikh MH, Solito E. Annexin A1: Uncovering the Many Talents of an Old Protein. Int J Mol Sci. 2018;19(4):4. doi:10.3390/ijms19041045
58. Bikle DD. Vitamin D Regulation of Immune Function. Curr Osteoporos Rep. 2022;20(3):186-193. doi:10.1007/s11914-022-00732-z
59. Murata T, Chiba S, Kawaminami M. Changes in the expressions of annexin A1, annexin A5, inhibin/activin subunits, and vitamin D receptor mRNAs in pituitary glands of female rats during the estrous cycle: correlation analyses among these factors. J Vet Med Sci. 2022;84(8):1065-1073. doi:10.1292/jvms.22-0141
60. Richman LS, Kubzansky LD, Maselko J, Ackerson LK, Bauer M. The relationship between mental vitality and cardiovascular health. Psychol Health. 2009;24(8):919-932. doi:10.1080/08870440802108926
61. Christiansen JJ, Djurhuus CB, Gravholt CH, et al. Effects of Cortisol on Carbohydrate, Lipid, and Protein Metabolism: Studies of Acute Cortisol Withdrawal in Adrenocortical Failure. J Clin Endocrinol Metab. 2007;92(9):3553-3559. doi:10.1210/jc.2007-0445
62. Piche T, Huet PM, Gelsi E, et al. Fatigue in irritable bowel syndrome: characterization and putative role of leptin. Eur J Gastroenterol Hepatol. 2007;19(3):237-243.
63. Basnet S, Sharma S, Costea DE, Sapkota D. Expression profile and functional role of S100A14 in human cancer. Oncotarget. 2019;10(31):2996-3012. doi:10.18632/oncotarget.26861
64. Smith MR, Marcora SM, Coutts AJ. Mental fatigue impairs intermittent running performance. Med Sci Sports Exerc. 2015;47(8):1682-1690.
65. Boolani A, Fuller D, Mondal S, Gumpricht E. Trait Energy and Fatigue Modify Acute Ingestion of an Adaptogenic-Rich Beverage on Neurocognitive Performance. Appl Sci. 2022;12(9):4466.
66. Boolani A, Lindheimer JB, Loy BD, Crozier S, O’Connor PJ. Acute effects of brewed cocoa consumption on attention, motivation to perform cognitive work and feelings of anxiety, energy and fatigue: a randomized, placebo-controlled crossover experiment. BMC Nutr. 2017;3(1):8.
67. Piche T, Gelsi E, Schneider SM, et al. Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gut. 2002;51(3):434-439.
68. Sáinz N, Barrenetxe J, Moreno-Aliaga MJ, Martínez JA. Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 2015;64(1):35-46. doi:10.1016/j.metabol.2014.10.015
69. Davis JM, Alderson NL, Welsh RS. Serotonin and central nervous system fatigue: nutritional considerations12. Am J Clin Nutr. 2000;72(2):573S-578S. doi:10.1093/ajcn/72.2.573S
70. Thurmond RL, ed. Histamine in Inflammation. Springer US; 2010. doi:10.1007/978-1-4419-8056-4
71. Nuutinen S, Panula P. Histamine in Neurotransmission and Brain Diseases. In: Thurmond RL, ed. Histamine in Inflammation. Springer US; 2010:95-107. doi:10.1007/978-1-4419-8056-4_10
72. Cacquevel M, Lebeurrier N, Cheenne S, Vivien D. Cytokines in Neuroinflammation and Alzheimer’s Disease. Curr Drug Targets. 2004;5(6):529-534. doi:10.2174/1389450043345308
73. Levin SG, Godukhin OV. Modulating effect of cytokines on mechanisms of synaptic plasticity in the brain. Biochem Mosc. 2017;82(3):264-274. doi:10.1134/S000629791703004X
74. Monteleone I, Marafini I, Dinallo V, et al. Sodium chloride–enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice. J Crohns Colitis. 2017;11(2):237-245. doi:10.1093/ecco-jcc/jjw139
75. Brillon DJ, Zheng B, Campbell RG, Matthews DE. Effect of cortisol on energy expenditure and amino acid metabolism in humans. Am J Physiol-Endocrinol Metab. 1995;268(3):E501-E513. doi:10.1152/ajpendo.1995.268.3.E501
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Mar 27, 2026
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Unique and Overlapping Proteins of Subjective Feelings of Mental and Physical Energy and Fatigue: An Exploratory Study: Original Research. (2026). Research in Health and Medicine, 6(1). https://doi.org/10.53520/rhm2026.104193
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