Exercise
Exercise refers to any bodily activity that enhances or maintains physical fitness and overall health and wellness. It encompasses a wide range of activities, from structured sports and athletic training to daily physical tasks. Historically, physical activity was integral to survival and daily living, but in modern societies, intentional exercise has become a crucial component for counteracting sedentary lifestyles and promoting well-being. The social importance of exercise is evident in widespread public health initiatives, community fitness programs, and the global sports industry, all advocating for regular physical activity to improve quality of life, foster social connections, and enhance overall societal health.
At a biological level, exercise induces a complex and dynamic cascade of physiological adaptations across multiple organ systems. These adaptations include significant improvements in cardiovascular function, such as increased cardiac efficiency, improved vascular health, and better blood pressure regulation; enhanced metabolic processes that impact glucose and lipid metabolism; stronger musculoskeletal systems; and positive effects on neurological and immunological functions. The body’s physiological responses to exercise, including metrics like heart rate and blood pressure during and after exertion, can vary considerably among individuals. This variability is partly attributed to genetic predispositions, which are increasingly being explored through research methods like genome-wide association studies. These studies investigate the genetic underpinnings of various “treadmill exercise responses,” such as “Stage 2 Exercise systolic blood pressure (SBP)”, “Stage 2 Exercise diastolic blood pressure (DBP)”, “Stage 2 Exercise heart rate”, “Post-exercise 3 minute recovery SBP”, “Post-exercise 3 minute recovery DBP”, and “Post-exercise 3 minute recovery heart rate”.[1]Understanding these genetic factors holds clinical relevance for developing personalized exercise prescriptions, predicting an individual’s susceptibility to exercise-related health conditions, and optimizing training regimens for both general health and athletic performance. Regular physical activity is a cornerstone of preventive medicine, playing a vital role in reducing the risk of chronic diseases such as heart disease, type 2 diabetes, certain cancers, and improving mental health outcomes.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Many genome-wide association studies (GWAS) face challenges related to insufficient statistical power, particularly for detecting genetic variants with small effect sizes. Research indicates limited power, sometimes less than 10% or even 1%, to detect a majority of associated single nucleotide polymorphisms (SNPs) at stringent genome-wide significance thresholds.[2] This low power can lead to false negatives, where genuine associations are missed, or, conversely, to an overestimation of effect sizes for the detected variants, a phenomenon known as the “winner’s curse”.[2] Such inflated effect sizes can potentially mislead interpretations regarding the true genetic contribution to a complex trait, underscoring the necessity for independent replication in larger, well-powered cohorts.
Distinguishing true genetic associations from random noise is a persistent challenge in GWAS due to the extensive multiple testing involved, where a significant number of findings may be false positives even with rigorous statistical control.[2] The lack of replication in independent samples, sometimes attributed to heterogeneity in study populations or insufficient power in replication cohorts, highlights the critical need for robust validation studies.[3] Furthermore, meticulous quality control procedures are paramount in large datasets to prevent subtle systematic differences or inaccurate genotype calls from generating spurious associations or obscuring genuine signals, thus influencing the reliability of findings.[4]
Phenotypic Heterogeneity and Challenges
Section titled “Phenotypic Heterogeneity and Challenges”The accurate and consistent of complex phenotypes, such as those related to exercise, is crucial for robust genetic association studies, yet it often presents significant challenges. Variations in how these traits are defined and ascertained across different cohorts can severely limit the ability to harmonize data and combine results effectively in meta-analyses.[3] For example, incomplete or inconsistent data collection methods can lead to misclassification of participants, potentially biasing results towards the null hypothesis and obscuring true genetic effects that might otherwise be detected.[3] Beyond direct , the interpretation of genetic associations can be complicated by external factors that influence phenotypic expression. Studies suggest that observed associations might reflect a genetically mediated susceptibility to practice effects or general placebo responses, rather than a direct genetic link to the core trait itself.[5] Such environmental or psychological confounders, including expectation bias, highlight the intricate interplay between genetic predispositions and non-genetic factors in shaping complex phenotypes, making it challenging to isolate purely genetic influences.
Generalizability and Population Structure
Section titled “Generalizability and Population Structure”The generalizability of genetic findings is often limited by the ancestral composition of the study populations. Findings derived from cohorts primarily composed of a single ethnic group, even if genetically homogenous and controlled for population structure, may not translate directly to other diverse populations.[6] Differences in allele frequencies and linkage disequilibrium patterns across ancestral groups can lead to a lack of replication in multi-ethnic cohorts or result in spurious associations if not adequately addressed through careful statistical adjustments for genetic ancestry.[3] This underscores the necessity for broad ancestral representation in GWAS to ensure the universal applicability of identified genetic variants and a comprehensive understanding of genetic architecture across human populations.
Variants
Section titled “Variants”Variants across several genes and genomic regions influence diverse biological pathways, from immune response and cellular metabolism to structural integrity, all of which can impact an individual’s physiological response to exercise. These genetic differences can lead to variations in biomarker levels, reflecting underlying health status and adaptive capacity to physical stressors.
Genes such as _IL1F10_ and _NPSR1_are central to immune regulation and neurological function, respectively, with variants potentially modulating the body’s reaction to physical activity. The variantrs544759166 , associated with _IL1F10_ and _RNU6-1180P_, is particularly significant as _IL1F10_ encodes a protein in the interleukin-1 family, which is crucial for orchestrating inflammatory responses.[7]Alterations in this gene’s activity can affect recovery from exercise, susceptibility to muscle damage, and overall inflammatory biomarker profiles. Similarly,rs10252228 , linked to _NPSR1_ and _DPY19L1_, is noteworthy because _NPSR1_encodes the neuropeptide S receptor, influencing arousal, anxiety, and stress perception. Variations here could impact an individual’s motivation, stress coping mechanisms during strenuous activity, and associated physiological biomarkers.[7]Other variants influence genes critical for maintaining structural integrity and metabolic health, which are fundamental for exercise performance and injury prevention. For instance,_ANK1_, with variant rs79097321 , is responsible for producing ankyrin-1, a protein essential for the stability and shape of red blood cells.[7] Optimal red blood cell function is vital for oxygen transport to working muscles, and variations in _ANK1_ could influence aerobic capacity and endurance. Furthermore, _PAPSS2_, associated with rs10887741 , plays a key role in sulfate metabolism, a process indispensable for the synthesis of connective tissues like cartilage. Genetic differences in _PAPSS2_may affect joint health, tissue repair following exercise, and the body’s ability to adapt to repetitive mechanical stress, impacting long-term physical activity engagement.[7] The _TRPS1_ gene, linked to rs147544219 , is a transcriptional repressor involved in skeletal development, and its variants might influence bone and joint characteristics relevant to exercise mechanics.
A substantial number of variants are located in or near pseudogenes and long non-coding RNAs (lncRNAs), which often exert subtle yet widespread regulatory control over gene expression and cellular functions. For example, rs117826014 is associated with _NMD3_ and the pseudogene _EEF1GP4_, while rs147544219 is also linked to _CARS1P2_ and _TRPS1_.[7] Pseudogenes, such as _RNU6-1180P_ (associated with rs544759166 ) and _RNU6-546P_ (associated with rs187522732 ), along with various lncRNAs like _LINC01876_ (with rs187522732 ), _LINC00470_, _AIDAP3_ (both with rs8097348 ), _LINC01068_, and _LINC01038_ (both with rs11350613 ), can modulate the activity of protein-coding genes. These regulatory variations can consequently influence critical biological pathways involved in muscle development, energy metabolism, and tissue repair, leading to individual differences in exercise adaptation and overall health biomarkers.[7] Variants in these non-coding and regulatory regions, along with those in _MAIP1_ and _SPATS2L_ (rs12612420 ), contribute to the complex genetic landscape that shapes an individual’s physiological response to physical activity.
Key Variants
Section titled “Key Variants”Biological Background of Exercise Responses
Section titled “Biological Background of Exercise Responses”Exercise encompasses a complex array of physiological adjustments that enable the body to meet increased metabolic demands and adapt to physical stress. These responses involve intricate molecular, cellular, and systemic changes that are influenced by both environmental factors and an individual’s genetic makeup. Understanding the biological underpinnings of exercise is crucial for appreciating its impact on health, disease prevention, and physical performance.
Cardiovascular Dynamics during Exercise
Section titled “Cardiovascular Dynamics during Exercise”Exercise elicits significant cardiovascular adjustments, including dynamic changes in heart rate, blood pressure, and blood flow distribution, which are essential for delivering oxygen and nutrients to working muscles and removing metabolic waste products. The heart’s structural adaptations, such as left ventricular mass, are closely linked to cardiovascular health and are influenced by genetic polymorphisms, specifically those found in theangiotensin-converting enzyme (ACE) gene.[8]These genetic influences highlight the intricate interplay between inherited factors and the heart’s physiological responses to physical activity.
Furthermore, endothelial function, particularly the ability of the brachial artery to vasodilate, plays a vital role in regulating blood flow and is a key component of overall cardiovascular health during exercise. Genetic variations at theendothelial nitric oxide synthase (eNOS) locus are associated with differences in this crucial vasodilator function.[9]After maximal exercise, the rate at which heart rate recovers serves as an indicator of autonomic nervous system activity and cardiovascular fitness, with polymorphisms in theacetylcholine receptor M2 (CHRM2) gene being linked to variations in this recovery process.[10]These integrated responses underscore the systemic nature of exercise physiology, where organ-specific effects, like cardiac remodeling and vascular adjustments, are coordinated to maintain physiological balance.
Genetic and Molecular Regulation of Exercise Capacity
Section titled “Genetic and Molecular Regulation of Exercise Capacity”Genetic mechanisms profoundly influence an individual’s capacity and physiological response to exercise, dictating variations in endurance, strength, and overall athletic performance. Gene polymorphisms, which are common variations in DNA sequences, can alter the function or expression of critical biomolecules involved in energy metabolism, cardiovascular regulation, and muscle performance. For instance, variations within thebeta1-adrenoceptorgene are associated with an individual’s aerobic power, particularly in the context of coronary artery disease.[11]This suggests that genetic differences can predispose individuals to varied levels of aerobic fitness and impact how their bodies efficiently utilize oxygen during physical activity.
At the molecular level, key biomolecules like the ACE enzyme contribute to complex regulatory networks that govern blood pressure and cardiac structure. The ACEenzyme is a central component of the renin-angiotensin-aldosterone system, and its gene polymorphisms can influence left ventricular mass, a critical determinant of cardiac function.[8] Similarly, the eNOS enzyme, encoded by its respective gene locus, is crucial for producing nitric oxide, a vital signaling molecule essential for vasodilation and blood flow regulation.[9]These genetic variations underscore how specific protein and enzyme functions, fundamental for cellular and tissue responses, are finely tuned by an individual’s genetic makeup, thereby affecting their overall exercise performance and long-term adaptation.
Systemic Integration and Homeostatic Control
Section titled “Systemic Integration and Homeostatic Control”Exercise represents a significant physiological challenge that demands a robust and integrated systemic response to maintain the body’s internal equilibrium, or homeostasis. Beyond immediate cardiovascular adjustments, the body orchestrates complex interactions across multiple organ systems to adapt to the increased demands. For example, the heart’s ability to recover after maximal exertion, influenced byCHRM2 gene polymorphisms, reflects the intricate interplay of the autonomic nervous system in modulating cardiac function.[10]This coordinated effort ensures that increased metabolic demands during exercise are met efficiently and that the body returns to a resting state effectively.
Disruptions in these homeostatic mechanisms, often influenced by genetic predispositions, can manifest as altered or suboptimal responses to exercise. The cumulative effect of these genetic variations on echocardiographic dimensions and endothelial function highlights their systemic consequences on overall cardiovascular health and the body’s capacity to adapt to physical stress.[1]Understanding these integrated biological processes, from molecular signaling pathways to organ-level function, is crucial for comprehending the diverse physiological responses to exercise and its long-term implications for health and disease.
Metabolic Reprogramming and Energy Homeostasis
Section titled “Metabolic Reprogramming and Energy Homeostasis”Exercise significantly alters cellular energy demands, triggering a dynamic shift in metabolic pathways to ensure adequate ATP supply.[12]This involves increased glucose uptake viaGLUT proteins and enhanced glycogenolysis, regulated by enzymes like glycogen synthase (GYS) and phosphofructokinase (PFK), which control glucose flux through glycolysis.[12]Concurrently, lipid metabolism is upregulated, with increased fatty acid oxidation facilitated by enzymes such as carnitine palmitoyltransferase (CPT), while lipogenesis (e.g., through fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase (GPAT)) and cholesterol synthesis (e.g., by HMGCR) are often suppressed, and triglyceride breakdown is promoted by hormone-sensitive lipase (HSL).[12]These processes are tightly regulated by signaling cascades, including the insulin pathway involving the insulin receptor (INSR), insulin receptor substrate (IRS), phosphoinositide kinase-3 (PI3K), phosphoinositide-dependent kinase-1 (PDK1), and mammalian target of rapamycin (mTOR), which modulate substrate utilization and energy storage in response to the body’s energetic state.[12]
Signal Transduction and Cellular Adaptation
Section titled “Signal Transduction and Cellular Adaptation”Exercise initiates a complex array of signal transduction events, beginning with the activation of various receptors, including G protein-coupled receptors (GPCR_s), which trigger intracellular cascades involving second messengers like cyclic guanosine monophosphate (cGMP) or diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) via its receptor (_IP3R).[12] These cascades converge on key kinases such as the mitogen-activated protein kinase (MAPK) and mTOR pathways, which are critical for coordinating cellular responses, including protein synthesis, cell growth, and adaptation to stress.[12] Post-translational modifications, such as phosphorylation orchestrated by kinases like PDK1 and mitogen-activated protein kinase 3 (MKK3), are crucial regulatory mechanisms that rapidly alter enzyme activity and protein function, allowing for dynamic adjustments to metabolic flux and gene expression.[12] The nitric oxide (NO) pathway, involving endothelial NOS and its regulators like NOSIP and NOSTRIN, is also activated, producing NO that signals through cGMP to mediate vasodilation, a critical physiological adaptation during exercise.[12]
Cardiovascular and Systemic Regulatory Networks
Section titled “Cardiovascular and Systemic Regulatory Networks”Exercise requires robust systems-level integration, particularly within the cardiovascular system, where multiple signaling pathways crosstalk to regulate heart rate, blood pressure, and vascular tone. Adrenergic stimulation, acting through beta1-adrenoceptors, increases heart rate and contractility, while cholinergic signaling via the acetylcholine receptor M2 (CHRM2) contributes to heart rate recovery post-exercise.[1] The endothelial nitric oxide synthase locus, producing nitric oxide (NO), is central to brachial artery vasodilation, improving blood flow to active tissues and regulating acute blood pressure responses.[1]These interconnected regulatory mechanisms ensure hierarchical control over physiological parameters, leading to emergent properties like enhanced aerobic power and improved cardiovascular efficiency.[1]
Genetic Modifiers and Disease Mechanisms
Section titled “Genetic Modifiers and Disease Mechanisms”Genetic variations play a significant role in individual responses to exercise and susceptibility to exercise-related health benefits or risks, influencing the regulation of gene expression and protein function. Polymorphisms in genes such as the beta1-adrenoceptor or the acetylcholine receptor M2 (CHRM2) can alter aerobic power and heart rate recovery, respectively.[1]Similarly, variations at the endothelial nitric oxide synthase locus are associated with differences in brachial artery vasodilator function, impacting blood pressure regulation during exercise.[1]Dysregulation within these pathways, such as altered angiotensin-converting enzyme activity, can contribute to conditions like hypertension and impact left ventricular mass, highlighting potential therapeutic targets for managing cardiovascular disease through exercise interventions.[1]The interplay of genes like estrogen receptor (ESR), dynamin 2 (DNM2), and eukaryotic initiation factor 4e binding protein (eF4EBP1), along with regulatory proteins like p300/CBP-associated factor (PCAF) and C-terminal Hsp70-interacting protein (CHIP), further underscores the complex genetic architecture underlying exercise physiology and its disease-modifying potential.[12]
Utility in Cardiovascular Risk Assessment
Section titled “Utility in Cardiovascular Risk Assessment”Treadmill exercise responses, encompassing changes in systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) during exertion and subsequent recovery, are fundamental metrics in cardiovascular risk assessment.[1]These physiological indicators offer critical insights into an individual’s cardiovascular system’s ability to adapt to stress, enabling clinicians to identify patients at an elevated risk for cardiovascular disease and events.[1]Abnormal patterns in these responses, even when accounting for demographic and clinical factors such as age, sex, body mass index (BMI), and baseline heart rate, can signify underlying cardiac or vascular dysfunction.[1]Consequently, the comprehensive evaluation of exercise responses serves as a vital diagnostic tool and a robust method for risk stratification in clinical practice.
Physiological Markers and Associated Comorbidities
Section titled “Physiological Markers and Associated Comorbidities”The detailed analysis of exercise responses, specifically the various treadmill exercise test (ETT) phenotypes like exercise SBP, DBP, HR, and their recovery kinetics, reveals significant associations with a spectrum of cardiometabolic comorbidities.[1]These responses are often considered in the context of and adjusted for established risk factors such as diabetes, current smoking status, and hypertension treatment, along with lipid profiles including total and high-density lipoprotein (HDL) cholesterol.[1]The inclusion of these factors as covariates in multivariable models underscores the complex interplay between exercise physiology and existing health conditions. This comprehensive assessment of exercise capacity thus contributes to a broader understanding of a patient’s overall health and their susceptibility to related systemic conditions.
Implications for Personalized Health Strategies
Section titled “Implications for Personalized Health Strategies”Understanding individual variations in treadmill exercise responses provides a valuable foundation for advancing personalized medicine approaches in cardiovascular health. By meticulously characterizing how an individual’s blood pressure and heart rate respond to and recover from exercise, clinicians can potentially refine risk prediction beyond conventional markers.[1]This enhanced understanding enables the development of tailored prevention strategies, allowing for targeted interventions for individuals exhibiting specific high-risk exercise response patterns. Furthermore, the longitudinal monitoring of these physiological responses can aid in evaluating the efficacy of lifestyle modifications or pharmacological therapies, guiding clinical adjustments to optimize patient care and improve long-term health outcomes.[1]
Frequently Asked Questions About Exercise
Section titled “Frequently Asked Questions About Exercise”These questions address the most important and specific aspects of exercise based on current genetic research.
1. Why do some workouts feel harder for me than my friend?
Section titled “1. Why do some workouts feel harder for me than my friend?”Your body’s physiological response to exercise, like heart rate and how quickly you fatigue, is partly shaped by your unique genetic predispositions. This means certain exercises might naturally feel more challenging or efficient for you compared to others, even with similar effort. Understanding these genetic factors can help tailor workouts that are most effective for your body.
2. Can I really change my body’s exercise response, or is it fixed?
Section titled “2. Can I really change my body’s exercise response, or is it fixed?”While your genetic makeup influences your baseline exercise responses, it’s not entirely fixed. Regular exercise definitely induces significant physiological adaptations that improve your cardiovascular function, metabolism, and strength over time. Your genes set a range, but your lifestyle and training play a huge role in optimizing your body’s potential within that range.
3. My heart rate spikes fast during exercise; is that normal for me?
Section titled “3. My heart rate spikes fast during exercise; is that normal for me?”Yes, individual heart rate responses during exercise can vary significantly, and genetics are a key factor. Your unique genetic predispositions influence how your cardiovascular system responds to exertion, including how quickly your heart rate rises and recovers. This variability is normal and is one of the “treadmill exercise responses” researchers study genetically.
4. Why do some people recover faster after a tough workout?
Section titled “4. Why do some people recover faster after a tough workout?”Recovery speed, like how quickly your heart rate or blood pressure returns to normal after exercise, is indeed influenced by genetics. Some individuals have genetic predispositions that enable faster physiological recovery. These post-exercise recovery metrics are actively studied to understand the genetic factors behind individual differences.
5. Does my family history affect how well I respond to exercise?
Section titled “5. Does my family history affect how well I respond to exercise?”Absolutely. Your family history reflects shared genetic predispositions that can influence various aspects of your health, including how your body adapts to and benefits from exercise. These genetic factors can affect things like your cardiovascular efficiency, metabolic processes, and musculoskeletal strength, impacting your overall exercise response.
6. Is a DNA test useful for figuring out my best workout plan?
Section titled “6. Is a DNA test useful for figuring out my best workout plan?”A DNA test couldoffer insights into your genetic predispositions related to exercise responses, potentially guiding personalized exercise prescriptions. Researchers are exploring how genetic factors can help optimize training regimens for both general health and athletic performance. However, current research still has limitations, and results need careful interpretation alongside other factors.
7. I’m from a diverse background; will general exercise advice work for me?
Section titled “7. I’m from a diverse background; will general exercise advice work for me?”General exercise advice provides a good foundation, but your ancestral background can influence how your body responds due to differences in genetic makeup across populations. Findings from studies primarily on one ethnic group may not directly apply to others. For a comprehensive understanding, research needs broader ancestral representation to ensure universal applicability.
8. Why does exercise lower blood pressure for some but not others?
Section titled “8. Why does exercise lower blood pressure for some but not others?”Exercise generally improves blood pressure regulation, but the extent of this benefit can vary due to individual genetic predispositions. Your unique genetic factors influence your body’s cardiovascular adaptations, affecting how significantly your blood pressure responds to and improves with regular physical activity. This is an area of ongoing genetic research.
9. Can my genes make me more prone to exercise-related issues?
Section titled “9. Can my genes make me more prone to exercise-related issues?”Yes, genetic factors can influence your susceptibility to certain exercise-related health conditions. Understanding these genetic predispositions can be clinically relevant for predicting individual risks and developing safer, more effective exercise plans. This is why personalized exercise prescriptions are being explored.
10. Do my genes impact how much my fitness improves with training?
Section titled “10. Do my genes impact how much my fitness improves with training?”Your genes definitely play a role in how your body responds to training and the extent of fitness improvement you experience. While consistent effort is crucial, your genetic makeup can influence the rate and magnitude of physiological adaptations, such as gains in cardiovascular efficiency or muscle strength. This variability helps explain why some people see faster or greater improvements.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, 2007.
[2] Liu, J. Z., et al. “Genome-wide association study of height and body mass index in Australian twin families.”Twin Research and Human Genetics, 2008.
[3] Pollack, S., et al. “Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.”Diabetes, 2018.
[4] Wellcome Trust Case Control Consortium. “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.” Nature, 2007.
[5] McClay, J. L., et al. “Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia.”Neuropsychopharmacology, 2010.
[6] Liu, Y. Z., et al. “Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males.”PLoS One, 2009.
[7] Benjamin EJ et al. Genome-wide association with select biomarker traits in the Framingham Heart Study. BMC Med Genet. 2007;8:65.
[8] Celentano, A., et al. “Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension.”Am J Cardiol, vol. 83, 1999, pp. 1196-1200.
[9] Kathiresan, S., et al. “Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function.” 2006.
[10] Hautala, A. J., et al. “Heart rate recovery after maximal exercise is associated with acetylcholine receptor M2 (CHRM2) gene polymorphism.”Am J Physiol Heart Circ Physiol, vol. 291, 2006, pp. H459-H466.
[11] Defoor, J., et al. “The CAREGENE study: polymorphisms of the beta1-adrenoceptor gene and aerobic power in coronary artery disease.”Eur Heart J, vol. 27, 2006, pp. 808-816.
[12] Gelernter, Joel. “Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.” Biol Psychiatry, vol. 77, no. 1, 1 Jan. 2015, pp. 164-175.