The individual and his immediate environment is mutually interactive as a deeply integrated system. With significant considerations in individual activities, health and education, clinical work covers concepts integrating biological, psychological, and social sciences and has applications when understanding social determinants of health.  Understanding "Person-in-Environment" considers that both the individual and environment share a reciprocal relationship [1]. Together with the "Ecological Systems Model" [2,3], "Bio psychosocial Approach" [4,5] and then "Bio psychosocial-Spiritual Approach" [6], the spectrum concepts of similarities illustrate the child´s own biology as the instigating machinery for development, but with different emphasis on the complex interaction of quality and context of the child´s surroundings on his primary microenvironment and illness development. Current views emphasize considerations on biological and psychological characteristics of the individual, formulation relating to his immediately surrounding networks and services, and regulating influence above these including economic, political and natural forces. Viewed in multiple levels, these approaches may be used to identify basic understanding of individuals or to evaluate contributory elements for health or disease and subsequent management.

Nevertheless, as the individual-environment system changes over time with untimely interactions altering behaviors, how actually developmental destiny can be shaped over the lifespan can be difficult. Other considerations utilizes theories of development through psychological theories, including psychoanalytic theory, as well as theories of development by Erikson [7], Piaget [8,9], and Kohlberg [10] as a progression through changing social environments, to understand an individual's overall development and any incomplete ungratified transition through the developmental stages. With disease and biomedical models additionally linked to pathophysiology, etiology, epidemiology, pathology, and other such concepts, they are useful to allow modern-day practice of healthcare. Well-appreciated, these still tends to be inadequate when precipitation and perpetuation of disease or health problems in an individual are looked into, as if other factors are neglected out.

Needless to say, human beings are adaptive. The body form, the body state, and the body disposition could comprehensively describe the whole person for how a person lives as being snug and fit in health or disease [11]. All these may develop, deviate or be deflected throughout the years. How well a person maintains himself to live as proper individual being in relatedness to his environment is a clear concern. Understanding life dynamics is useful. In due course, when holistic treatment calls for wholeness, it is not just recomposing the whole by treating all aspects of a person's health for the physical, psychological and societal components, since totality is difficult [12]. Befittingly, an integral person may still have wholistic gaps yet not filled but the person could remain positive as a whole [11]. This should be the better aim for long-term treatment of individuals in medicine, amongst management with lesion-based, multi-causality, holistic and integral medicine when compared [11]. The integral body relates with environment with organismic interactions. Preventive strategies have been emphasizing how to minimize behavioral concerns and problems. Developing individuals into proactivity is better than just prevention. More considerations should be done to build up individuals in robustness. It could start with understanding the body adaptive makeup shaped by environments.

Setup for the Body

Robusty has been used as a system concept. It is the ability of a system to keep stability and performance in an allowable or allowed range within its initial stable configuration even in conditions of disturbances-a functional reliability to handle variable influences and remain effective. Robustness is a ubiquitously observed property of biological systems as the complex systems are evolvable [13-16].

For individuals to benefit from robustness, organismic mechanisms are evolutionarily conserved. The embryogenetic and organogenetic mechanisms, being highly conserved evolutionarily among species [17-20] produce a tightly regulated organizational makeup, with functional tissues and operational organs matching the physiological needs of the organism for environments. To start with, many of the core genetic building sets are largely the same underlying the construction of extremely different animal body make-ups. Stereotyped, the endoderm layer evolved first [21], followed by the ectoderm layer and finally the mesoderm layer. Yet significant differences in mechanisms of pattern formation in early embryos among and within groups of animals, and these differences, are surprisingly having little correlation with phylogenetic relationships, but often correlated with ecological factors such as changes in life histories [22,23]. Epigenetic control can also shape the fundamental structure of the body [24]. Throughout pregnancy, particularly in later stages, the body is primed up from environmental cues for adjustments.

This setup to produce the body organizational makeup started predominantly with genes and with environmental contributions. Robustness of the biological systems often still continue to produce stable phenotypes in spite of perturbations. Starting at gene level, whether beneficial or disruptive, mutations provide the genetic variation that allows evolutionary change. Genetic perturbations may be compensated by the process of transcriptional adaptation of so-called adapting genes, a mechanism recently identified. Certain mutations can trigger this transcriptional modulation [25].

Composing the Body Makeup

Through regulation of gene expression in time-space and many cell-cell interactions, embryogenetic and organogenetic mechanisms at tissue, cellular, and molecular levels [26,27] develop the body makeup before birth. At cellular level, multiple processes include proliferation, differentiation, acquisition of polarity, and cell movement after conception. At tissue level, cell migration [28] and patterned cell differentiation collectively form the complex structures of adult organs. Final morphogenesis and self-organization is achieved through physical and chemical cues in the microenvironment [29-31]. Through these same processes, the mutually dynamic matrix of neural, perfusional, and the interconnective (NPI) elements spread out their contextual assembly over the body besides the basic hardcore organs [11].

The nervous system is ectodermal as it starts through an inductive signal from the mesoderm [32]. The initial mesodermal cells condense to form the notochord. Signals released from the notochord induce the ectoderm to thicken into neural ectoderm in the area immediately overlying it. Neural ectoderm thus committed to develop into neural tissue [33] gives rise to the neural tube and neural crest. Once the neural plate has been induced by the underlying mesoderm, it begins to differentiate into the primary rudiment of the developing central nervous system [34].

Location-specific chemical signals as well as physical signals in the microenvironment mediate information propagation [30,31] for a cascade of events regulating the timely gene expression in cells whereby differentiation of the various organ systems are effected. The contextual mesenchymal interconnective dimension contributes to instructive sculpting of the embryo topology [35] from inside out. The mesoderm is the youngest germ layer in evolutionary terms in vertebrates [36], and its appearance as additional germ layer facilitated the sophisticated mammalian cell movement and nutrient and gas exchange [37]. Connective tissues act as the main supportive tissue of many internal organs including the musculoskeletal and mantle frame [38].

Following similar differential cues from the micro-environment, neural elements and blood vessels develop in parallel in an entanglement relationship [11]. Perfusion and information go together. Even cardiac and cranial progenitors started together as the cardiovascular system during organogenesis [39] originates in close proximity to cranial progenitors. Simply, the hardcore organs as basic physiological firmaments as well as the embodying NPI make up the sophisticated formal order of body elements for dynamic snug-fit capacity for vitality in environments [11].

Intrinsic Variations and Pathological Variations

Born endowment of biological robustness through genetic setup over environmental forces is accompanied with variations. Variations are needed in the species for matching various environments as well as adapting to ever-evolving environmental changes to survive better. Biodiversity is variation at the genetic, species, and ecosystem levels. Genetic variations can alter gene activity or protein function and introduce different traits in an organism. Variability apart from being heritable, may be acquired when subjected to postnatal environmental effects. Epigenetics functionally affects the regulation of gene expression [40,41] and produce effects on cellular and physiological phenotypic traits. Epigenetic processes, particularly DNA methylation, contribute directly to DNA sequence evolution [42,43].

Genetic variations are related to single nucleotide polymorphisms (SNPs). Most gene mutations have no effect on health. Each human has on average 60 new mutations compared to their parents [44]. Genetic differences across human populations in traits may affect skin colour, bodily dimensions, lactose and starch digestion, high altitude adaptions, and predisposition to developing particular diseases [45]. With advances in sequence data generation, archiving and analysis, the 2015 report of the 1000 Genomes Project provide a comprehensive description of common human genetic variation in a diverse set of individuals from multiple populations [46].

Among genetic variants, both common and rare variants interplay in different degrees to influence complex traits, and contribute to common diseases and highly heritable diseases. Polygenic scores (the aggregation of estimated effects of genome-wide variants mostly focusing on common variants.) has been used to predict the contribution of a person’s genome to a phenotypic trait, defining population segments that differ markedly with respect to disease prevalence and incidence [47,48], and identifying high-risk individuals in some complex diseases [49]. Combined additive effects of common genetic variants can explain substantially the variations in a human phenotype. Height, as a model trait for the study of human polygenic traits, was studied recently by an embracive sample size. The results demonstrated a powerful genetic predictor of height explaining up to 40% of the inter-individual variation in height in independent European-ancestry samples using GWS SNPs alone, and more than 90% of h2SNP across diverse populations when incorporating all common SNPs within 35 kb of GWS SNPs [50].

Rare genetic variants may explain better for other common diseases. The heritability of blood pressure (BP) levels is estimated to be 30-50%, but multiple genetic variants in aggregate explained only 2-3% of the genetic variance of hypertension. Some new low-frequency and rare variants reportedly are consistently associated with BP traits, with size effects higher than 1.5 mmHg. When considering the joint impact of 107 mostly common variants, a 9.3 mmHg higher SBP was reported for subjects >50 years and carrying the highest genetic risk score [51]. Polygenic architecture of rare coding variation studied across common traits and diseases noted that rare coding variants explain 1.3% of phenotypic variance on average, much less than common variants, but most burden heritability is explained by ultra-rare loss-of-function variants [52].

When matured, the norms for individuals are assessed for each population concerned. However, as variations spread widely, without considering evolutionary-ecological variation-generation, “normal” can be difficult to define for many characteristics to cover meaningfully over the whole human species that inhabits such a broad geographic range [53]. Genetic influences may not be deterministic, when twin concordance and discordance for major diseases and mental disorders is reviewed [54]. Metabolic traits may illustrate the gene interplay. Inborn errors of metabolism (IEMs) are rare genetic disorders caused by mutations that impair the ability of different food-related enzymes.  Polygenic risk are reported to contribute to the variable penetrance of rare pathogenic mutations in genes such as LDLR, APOB, and PCSK9 for coronary artery disease [55]. Metabolic traits denoted by routine biochemical tests represent intermediate phenotypes widely-used in assessing disease risk. GWAS of nine metabolic traits (including glycemic, lipid, and liver enzyme levels) showed the need to consider the joint contribution of both common and rare variants on inherited risk of metabolic traits and related diseases [56]. For rare genetic variants studied in contribution to 414 plasma proteins, the frequency distribution of genetic variants is skewed towards the rare spectrum [57]. In metabolic traits and related diseases, though rare variants have limited contribution to overall trait variance, these lead in carriers substantial loss of predictive accuracy from polygenic predictions of disease risk from common variant alone [56]. Rare variants have larger effects on average, and could be of importance for precision medicine applications.

Pertinent Environmental Cues Received Early at Body Makeup Composing

The body setup to come out with robustness to survive would best obtain pertinent cues early from the surroundings to adjust itself for an adapted makeup. While genetic networks that shape the organs are evolutionarily conserved, cellular-physical mechanisms workup is generally a consequence of shared physical organization rather than due to evolutionary descent [58]. These shared physical organization and bioelectrical fields [59] can be early means to obtain surrounding physical cues. Subsequently, developmental windows open during pregnancy to obtain biological cues to allow the primal setup varying degrees of embryonic adaptations to its environment.

The epigenome mediates between the environment, genotype, and cellular response, especially with developmental windows open during pregnancy for environmental exposures. DNA methylation (DNAm) may play a critical role in bridging prenatal adverse events and cardiometabolic disorders including hypertension in later life. DNAm could be a metabolic memory bridging early and later life, and an indicator of more benefits from eating a low-fat weight-loss diet [60]. In the developmental origins of health and disease (DOHaD) perspective [61], maternal on embryo interactions would function to buffer against short-term, transient environmental stressors and to provide long term environmental information to facilitate shaping of appropriate developmental trajectories [61].

All these gene interplay, environmental cues, and adaptive variations establish an individual with a body to confront the surrounding with dynamic capabilities, with the body form, structure and related functions developed along evolutionary demands in meeting up with life. This body with biological robustness at birth [62] allows individuals to sustainably grow and develop in momentum. With biological robustness, doubly assured mechanisms are built in to make sure that the outcomes of biological processes are stereotypical and preserved even when environments vary or perturbations arise [63].

Robustness as an Endowed Preparedness for Adaptation

Endowed biological robustness is established as embryogenetic and organogenetic mechanisms, which produce a species with its characteristic strength, are tuned continually to environments. The constitution of phenotype is better understood as the effective primary means by which organisms acquire information from the environment in the continuous maintenance of essential organismal requirements. [64]. Biological robustness is maintained as temporal biological mechanisms are directed towards the destined preferential body state and core sustenance, thus promoting and incorporating epigenetic inheritance, rather than a simple manifestation of the concordance of intergenerational vertical genetic transmission exclusively based on selection. Functional robustness then refers to the system’s ability to maintain function when facing perturbations to the causal structures that support performance of that function [65].

What follows is growth and development. The same biological forces between body and environment interplay differing only in degrees to sustain the variations of individuals as well as allow adaptiveness.

Variations of Individuals: As many of the building sets of the body core are largely the same, stereotyped development follows the robust setup. By providing back-up opportunities, redundancy of regulatory elements such as transcriptional enhancers ensures insensitivity of gene expression programmes to environmental perturbations [66,67]. With connections of parts within a system, network topology including feedback or feed forward regulatory loops and signaling pathway cross-talk are important for being robust in development [68]. Along the concept of canalization, development for individuals may be depicted as a ball rolling down a slope in well-defined grooves, from which it is difficult to displace the developmental process [69] and produce different paths of organization. This is analogous to personality formation and temperaments.

Individual Adaptiveness: In spite of robust developmental setup, significant differences in mechanisms of pattern formation in early childhood among individuals, are often correlated with ecological factors. Under the robust momentum of growth and development, an individual is still adaptive. The degree of adaptivity varies.

Robustness and sensitivity represent the extremes of a continuum of possible responses to perturbations and the ease to interchange between developmental valleys and grooves. An adaptation is basically any attempt in variation that can increase one’s biological fitness or snug capacity in a specific environment through successful interaction. As adaptations may be biological or cultural in nature, the course will vary depending on the individual pursuit or environmental demand.

Snug-Fit along Developmental Valleys

An individual without overt hereditary and birth problems would be born as a snug integral person having biological robustness to fit for survival. The power of adaptation and plasticity is well appreciated. Snug is an important aspect that often goes unrecognized; fitness somehow becomes too often a handy concept to lumps everything that matters to the ability to fit, leading to confusing biological or social fitness theories [11]. Snug is a body functioning poised at the energy-efficient body state that autonomously maintains activities without stresses. A paper summarized the salient evidence and features [11]. To preserve its integral functionality, living as an organized unit in congruity with least incompatibility would be effective and more cost efficient. Energy efficiency is an important principle for optimizing physiological functions within organisms [70,71]. Conserving biological and physiological synchrony between the individual and environment in interactions produce snug (Figure 1).

In a fuller perspective, the body is striving to meet many objectives and would be more or less tuned to the environment with internal and external processes, which varies to a degree for how the individual acts fit to the environment and stays snug to the core itself. Over evolutionary fitness [72], much evidence from animal [73] and human studies [74,75] have shown that the individual behavior will be different depending on the core state of the body. With individual differences in core state variables, even personality could emerge as an adaptation [76-78]. The individual as such would coordinate operations interactively for efficacy consciously or subconsciously [11], being cantered on his core and remodeling matching capabilities [79].

Figure 1: An individual without overt hereditary and birth problems would be born as a snug integral person having biological robustness. The individual in development at the best would stay snug to the core itself acts fit to the environment.

For the snug integral person born, more stable and peaceful the environment, more body snug. Snug continues since infancy with healthy bonding when forming relational functioning, starting with an attachment system [80], not just comfort, but internal contextual strength. At this stage, young children develop well with comforting environment and tactile stimulation that help children grasp and feel safe as their world expands. Having dynamics conditioned with unstrained effectiveness at activities as a snug state would contribute to cognitive, social, and emotional growth [81,82].

Then during opportunities to explore their environment and relationships, testing their physical and mental abilities, children transpose snug feelings to fit within their cognitive stance to thrive in new environments (Figure 2). A thriving environment allows freedom within limits and children to act and explore freely and comfortably. In essence, the body has to have a stabilized core to support the individual over domains and terrains within capacity conserving energy for forward thrust and stability.

Figure 2: Functioning individual with well-patterned snug dynamics to balance with actuation and restitutions to snug-fit in environments.

The internal processes and external behavior of the brain and body in a self-organized system are set during development. As a whole, modified neuronal networks since early-life depend on the environment and energy/resources provision as well as individual potential and self-regulatory setup for remodeling for emotive or motive activities as these contribute to social engagement, cognitive, social, and emotional growth. Mechanisms to fit tend to strive for the best, physically and mentally, the way to handle everyday challenges. Layer upon layer, the rings on rings of adjustments embrace matching capabilities, starting early with visuomotor coordination, resource functioning, food selectivity, related striving or defensive behavior, reward-seeking behavior and stimulatory drives, evolving further with related social behavior and emotion-guided attention [83]. The body tends to maintain an adapting or positioned suspense with a forwarding stance. Self-relevant reward system affects the rewarding nature of social interaction and cognition. Cultural factors and success in future work and activities would influence the developmental path. Reactional patterns however often tend to stay as what has been initially founded as the parts during development aggregate into rings, and rings locked in with another ring [84].

Adaptive and Evolvable for Sustaining Robustness

Developmental adaptation refers to the ability of an organism to modify its phenotype in response to environmental exposures over the course of growth and development. Adaptations may be biological or cultural in nature. Environmental stress is referred to any condition that disturbs the normal functioning of the organism. Responses to external stress may directly confer survival fitness by means of complex regulatory networks and human beings may be still evolving [85].

Classically, acclimatization refers to longer term responses to environmental stressors in the natural world and functional adaptations are biological changes within an individual’s lifetime. Humans in extreme environments demonstrate the multiple levels of adaptation, from genetic to functional [86]. Understood as developmental acclimatization, some physiological adaptations can develop but only if the individual is exposed to the stress during growth. Humans with handicaps in early life demonstrate the ability of the non-affected body parts to compensate [87]. The human brain is rich in plasticity, even with the capacity to drastically change its somatotopic functional structure for sensorimotor representations in response to congenital or acquired limb deficiencies and dysfunction [88,89].

Cultural adaptations can also be “socially heritable” and transmitted across generations by teaching and learning. Over the diverse range of habitats, humans gradually accumulate information and skills across generations and develop well-adapted tools, beliefs, and practices with understanding. Learning of the worlds is one important strategy to obtain information and organize mental and physical constructs to function more effectively over domains and terrains.

Human lifecycle is particularly adapted with the period of immaturity more protracted than other primates [90,91]. Thus the stage of childhood up to juveniles is prolonged as a unique period to learn from predecessors wherefore the individual becomes more self-sufficient with the complex understanding before needing to confront the complicated sexual development and endeavoring in ambition and enjoyment of adulthood. For this matter, sexual development already proceeds during fetal and early post-natal life, but then suspended as the hypothalamic-pituitary-gonadal (HPG) axis is dominated by negative feedback for years in humans until re-initiation at about 9 years old of positive feedback promotes sexual maturation, followed by adolescence with adventurous desires with hormonal changes and behavioral reactions and intensification of exploratory interest and practice in adult social, economic, and sexual activities [92].

The childhood stage [93] is particularly developmentally plastic. The body and mind develop together, basically achieved through the body core and match processes to environment [94].  As well known, the brain and body develop at different rates. Neurobiology demonstrates the importance of temporal organization and multi-scalarity in making this robustness-with-plasticity possible [95]. In the body formation, the relatively stiff thoracic system is still mouldable [96,97] to allow, with the spine, alignment resets over the early ages of repeated physiological forces of axial loading, flexion and extension, lateral bending, and twisting during actuational dynamics. Endochondral ossification is not completed until around the age of 26. The sacrum as the large triangular bone at the base of the spine, with joints connecting the spine to the two wings of the pelvis and articulate with the hip bones for a crucial stabilizing mass, is not fused until the ages of 18-30 years to allow for body twists and turns to establish and settle. From physical growth with biological changes, and functional development and behavioral changes, the body endowed with biological robustness is further equipped for later expanding experience and roles in new environments.

Robustness Lost or Breakable in Time

There are specific architectural features of such robust yet evolvable systems and interpretable trade-offs between robustness, fragility, resource demands, and performance [14]. The biological robustness endowed from birth would lose its integrality-sustaining effect as the body grows older and develops in demanding surroundings as patterns tends to go off track over many different directions. A threshold-edging system could result in behavior with stochastic exaggerated responses as feedback regulation fluctuates wildly [98].

Newer threatening environments ushered by human interventions are now rapidly developing faster than the past from any natural progress [99,100]. Even though the human being keeps on renovating his mastery over surroundings for better health, protection and safety, the transformed advanced lifestyle often is also the advent of hardship. Where is the point the individual yield to environmental hardship that it can be prevented during development?

Marked deficiency and overload can of course break the robusty system. Poor nutrition can compromise. Even infantile iron deficiency anemia can affect normal brain growth and neurobehavioral development, even treatment of anemia [101]. On the other hand, as an example of insidious overload, the prevalence of dementia in humans could be the result of a functional adaptation as cell loss increased with mtDNA copy number. A high copy number in the brain would start as an advantage to delay the onset of cognitive decline until after reproductive age. An individual with a low copy number would have the onset of cognitive decline, while mild, starting early in life. Whereas, for high copy number, it would not start until middle age but progressed rapidly [102]. As well commented: “Information on the underlying genetic and physiological variation within human populations is critical for gaining insights about how the forces of social change and economic modernization affect variation in health outcomes.” [103].

Some significant adjustments to environmental stresses as changes in development may occurs in childhood and typically results in anatomical or physiological changes that are mostly irreversible in adulthood. DNA methylation may be viewed as an indicator as it fluctuates throughout different life stages in gene regulation while responding to environmental changes [104-108]. As it orchestrates the silencing of specific gene categories, fosters the differentiation process of embryonic stem cells, and upholds the stability of the parental genome [109], DNA methylation may be significant in the dynamics of growth and development. When overdone, they may result in transcriptional inactivation and aging in living organisms [109,110], or trigger hypermethylation or hypomethylation of genes and contributing to the onset and progression of diseases such as cancer [111-113].

No way that the system however robust and plastic would permit too large a difference. Adjustment from prolonged dietary insufficiency or accidents or critical confrontation with devastating environments can cause significant deviations. Many diseases can be viewed in the context of loss of robustness of physiological states, or, when robustness and pliability declines, subsequent well-coordinated mechanisms [114] fails to be installed.

What should one become? Issues and prevention of delays, maldevelopment and behavioral deviations have been widely elaborated [115-118]. Now, building up engaging adults and positive youths should be emphasized, even feasible when families are disadvantaged. Approaches have been discussed [119-121], but starting with energy-efficiency considerations for the individual, and with building up for well-coordinated mechanisms [114] in the body, a better appreciation of long term strategy could be offered (part II of this paper). Working only on the psychological part may not be good enough, as notably, autistic and hyperactive children can be treated better and more fully through the body itself [71,83,84]. Mind and body not separate.

Much variations are resulted from gene setup to the robust constitution of phenotype makeup at birth. Herein, information from the environment in the continuous maintenance of essential organismal requirements have effectively endowed individuals. Similarly with the person-environment mutuality, tuning continually to environments with good information is important for development of engaging adults. More than these, building up internal snug is essential to harvest self-vitality and characteristic strength for resourceful nurturing of positive individuals.

1. Weiss-Gal I. The person-in-environment approach: professional ideology and practice of social workers in Israel. Soc Work. 2008; 53: 65-75.
2. Bronfenbrenner U. Two worlds of childhood. London: Penguin. In Finnish: Bronfenbrenner U. 1974. Kaksi lapsuuden maailmaa. Helsinki: Tammi. 1965.
3. McHale SM, Dotterer A, Kim JY. An Ecological Perspective on the Media and Youth Development. Am Behav Sci. 2009; 52: 1186-1203.
4. Engel GL. The need for a new medical model: A challenge for biomedicine. Science. 1977; 196: 129-136.
5. Bolton D, Gillett G. The Biopsychosocial Model of Health and Disease: New Philosophical and Scientific Developments. Cham (CH): Palgrave Pivot. Chapter 1, The Biopsychosocial Model 40 Years On. 2019.
6. Sulmasy DP. A biopsychosocial-spiritual model for the care of patients at the end of life. Gerontologist. 2002; 42: 24-33.
7. Orenstein GA, Lewis L. Stat Pearls. StatPearls Publishing; Treasure Island (FL). Eriksons Stages of Psychosocial Development. 2022.
8. Malik F, Marwaha R. StatPearls. StatPearls Publishing; Treasure Island (FL). Cognitive Development. 2023.
9. Scott HK, Cogburn M. StatPearls. StatPearls Publishing; Treasure Island (FL). Piaget. 2023.
10. Ma HK. The moral development of the child: an integrated model. Front Public Health. 2013; 1: 57.
11. Yu ECL. From Core and Mantle to Primary Integrality - A Brief Introduction of the Fit and Snug States. J Altern Complement Integr Med. 2021; 7: 177.
12. Viegas SMF, Penna CMM. Integrality: life principle and right to health. Invest Educ Enferm. 2015; 33: 237-247.
13. Kitano H. Biological Robustness. Nature reviews. Genetics. 2004; 5: 826-37.
14. Kitano H. Biological robustness in complex host-pathogen systems. In: Boshoff HI, Barry CE. (Editors) Systems Biological Approaches in Infectious Diseases. Progress in Drug Research. Birkhauser Basel. 2007.
15. Wagner A. Robustness and evolvability in living systems. Princeton, NJ: Princeton University Press. 2007.
16. Masel J, Siegal ML. Robustness: mechanisms and consequences. Trends in Genetics. 2009; 25: 395-403.
17. Ross SE, Vazquez-Marin J, Gert KRB, Gonzalez-Rajal A, Dinger ME, Pauli A, et al. Evolutionary conservation of embryonic DNA methylome remodelling in distantly related teleost species. Nucleic Acids Res. 2023; 51: 9658-9671.
18. Uesaka M, Kuratani S, Irie N. The developmental hourglass model and recapitulation: An attempt to integrate the two models. J Exp Zool B Mol Dev Evol. 2022; 338: 76-86.
19. Liu J, Frochaux M, Gardeux V, Deplancke B, Robinson-Rechavi M. Inter-embryo gene expression variability recapitulates the hourglass pattern of evo-devo. BMC Biol. 2020; 18: 129.
20. Werneburg, Ingmar Spiekman, Stephan. Mammalian embryology and organogenesis. 2018.
21. Hashimshony T, Feder M, Levin M, Hall BK, Yanai I. Spatiotemporal transcriptomics reveals the evolutionary history of the endoderm germ layer. Nature. 2015; 519: 219-222.
22. Kalinka AT, Tomancak P. The evolution of early animal embryos: conservation or divergence?. Trends Ecol Evol. 2012; 27: 385-393.
23. Wray GA. The evolution of embryonic patterning mechanisms in animals. Semin Cell Dev Biol. 2000; 11: 385-393.
24. Bogdanovic O, Smits AH, de la Calle Mustienes E, Tena JJ, Ford E, Williams R, et al. Active DNA demethylation at enhancers during the vertebrate phylotypic period. Nat Genet. 2016; 48: 417-426.
25. Jakutis G, Stainier DYR. Genotype-Phenotype Relationships in the Context of Transcriptional Adaptation and Genetic Robustness. Annu Rev Genet. 2021; 55: 71-91.
26. Schoenwolf GC. Principles of developmental biology. J Musculoskelet Neuronal Interact. 2002; 2: 268-269.
27. Hashimoto M, Morita H, Ueno N. Molecular and cellular mechanisms of development underlying congenital diseases. Congenit Anom (Kyoto). 2014; 54: 1-7.
28. Satoshi K, Anna K. Cell biology of embryonic migration. Birth Defects Res Part C. Embryo Today Rev. 2008; 84: 102-122.
29. Shahbazi MN. Mechanisms of human embryo development: From cell fate to tissue shape and back Development. 2020; 147: 190629.
30. Genuth MA, Holley SA. Mechanics as a Means of Information Propagation in Development. Bioessays. 2020; 42.
31. Das D, Julich D, Schwendinger-Schreck J, Guillon E, Lawton AK, Dray N, et al. Organization of Embryonic Morphogenesis via Mechanical Information. Dev Cell. 2019; 49: 829-839.
32. De Vellis J, Carpenter E. General Development of the Nervous System. In: Siegel GJ, Agranoff BW, Albers RW, editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6^th Philadelphia: Lippincott-Raven. 1999.
33. Elshazzly M, Lopez MJ, Reddy V, Caban O. Embryology, Central Nervous System. In: StatPearls. Treasure Island (FL): StatPearls Publishing. 2023.
34. Cowan WM. The development of the brain. Sci Am. 1979; 241:11-133.
35. Dzamba BJ, DeSimone DW. Extracellular Matrix (ECM) and the Sculpting of Embryonic Tissues. Curr Top Dev Biol. 2018.
36. Technau U, Scholz CB. Origin and evolution of endoderm and mesoderm. Int J Dev Biol. 2003; 47: 531-539.
37. Ferretti E, Hadjantonakis AK. Mesoderm specification and diversification: from single cells to emergent tissues. Curr Opin Cell Biol. 2019; 61: 110-116.
38. Yu ECL. Body NPI Dimensions, the Neural, Perfusional, and Interconnective Matrix. ACAM. 2021; 9: 71-78.
39. Donovan MF, Cascella M. Embryology, Weeks 6-8. In: StatPearls. Treasure Island (FL): StatPearls Publishing. 2023.
40. Graff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev. 2011; 91: 603-649.
41. Moosavi A, Motevalizadeh Ardekani A. Role of Epigenetics in Biology and Human Diseases. Iran Biomed J. 2016; 20: 246-258.
42. Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Front Cell Dev Biol. 2014; 2: 49.
43. Alyson A, Vincent C, Benjamin O. How does epigenetics influence the course of evolution?. Philosophical Transactions of the Royal Society B: Biological Sciences. 2021; 376.
44. Conrad DF, Keebler JE, DePristo MA, Lindsay SJ, Zhang Y, Casals F, et al. Variation in genome-wide mutation rates within and between human families. Nature Genetics. 2011; 43: 712-714.
45. Reich D. Who we are and how we got here: ancient DNA and the new science of the human past (First Editor). Oxford, United Kingdom. 2018; 255.
46. The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015; 526: 68-74.
47. Torkamani A, Wineinger NE, Topol EJ. The personal and clinical utility of polygenic risk scores. Nat Rev Genet. 2018; 19: 581-590.
48. Mahajan A. Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018; 50: 1505-1513.
49. Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi S, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018; 50: 1219-1224.
50. Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, et al. A saturated map of common genetic variants associated with human height. Nature. 2022; 610: 704-712.
51. Warren HR, Evangelou E, Cabrera C.P, Gao H, Ren M, Mifsud B, et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017; 49: 403-415.
52. Weiner DJ, Nadig A, Jagadeesh KA, Dey KK, Neale BM, Robinson EB, et al. Polygenic architecture of rare coding variation across 394,783 exomes. Nature. 2023; 614: 492-499.
53. Graves JL Jr. Human biological variation and the "normal". Am J Hum Biol. 2021; 33: e23658.
54. Hagenbeek FA, Hirzinger JS, Breunig S, Bruins S, Kuznetsov DV, Schut K, et al. Maximizing the value of twin studies in health and behaviour. Nat Hum Behav. 2023; 7: 849-860.
55. Fahed AC, Wang M, Homburger JR, Patel AP, Bick AG, Neben CL, et al. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. Nat Commun. 2020; 11: 3635.
56. Kim YJ, Moon S, Hwang MY, Han S, Jang HM, Kong J, et al. The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians. Nat Commun. 2022; 13: 6642.
57. Kierczak M, Rafati N, Hoglund J, Gourle H, Lo Faro V, Schmitz D, et al. Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability. Nat Commun. 2022; 13: 2532.
58. Love AC. “Developmental mechanisms”, in The Routledge Handbook of the Philosophy of Mechanisms and Mechanical Philosophy, S. Glennan and P. Illari (Editorss.), New York: Routledge. 2017; 332-347.
59. Levin M. Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer. Cell. 2021; 184:1971-1989.
60. Kou M, Li X, Shao X, Grundberg E, Wang X, Ma H, et al. DNA Methylation of Birthweight–Blood Pressure Genes and Changes of Blood Pressure in Response to Weight-Loss Diets in the POUNDS Lost Trial. 2023; 80:1223-1230.
61. Lacagnina S. The Developmental Origins of Health and Disease (DOHaD). Am J Lifestyle Med. 2019; 14: 47-50.
62. Whitacre JM. Biological robustness: paradigms, mechanisms, and systems principles. Front Genet. 2012; 3: 67.
63. Sokac AM. Mechanical Networks Have Robustness Built into Their Topology, Too. Developmental cell. 2019; 50: 527-528.
64. Torday JS, Miller WB. Phenotype as Agent for Epigenetic Inheritance. Biology (Basel). 2016; 5: 30.
65. Boone, N Van Rooy, F De Brigard. Robustness and modularity. T Boone. J Cognitive Neuroscience. 2023; 35: 376-379.
66. Frankel N, Davis GK, Vargas D, Wang S, Payre F, Stern DL. Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature. 2010; 466: 490-493.
67. Levine M. Transcriptional enhancers in animal development and evolution. Curr Biol. 2010; 20: R754-763.
68. Posadas DM, Carthew RW. MicroRNAs and their roles in developmental canalization. Curr Opin Gen Dev. 2014; 27: 1-6.
69. Waddington CH. The strategy of the genes. Routledge Library Editions. 1957.
70. Fontana L, Atella V, Kammen DM. Energy efficiency as a unifying principle for human, environmental, and global health. F1000Research. 2013; 2: 101.
71. Yu ECL. From Self-Vitality System to Well-Coordinated Patterns - I. Neuro-Circulatory Perfusion. J Altern Complement Integr Med. 2023; 9: 375.
72. Dall SRX. Houston AI, McNamara JM. The behavioural ecology of personality: consistent individual differences from an adaptive perspective. Ecol Lett. 2004; 7: 734-739.
73. Sih A, Mathot KJ, Moiron M, Montiglio P, Wolf M, Dingemanse NJ. Animal personality and state–behaviour feedbacks: a review and guide for empiricists. Ecol Evol. 2015; 30: 50-60.
74. Schiralli K, Brazil K, Franklin P, Spadafora N, Al-Jbouri E. Encyclopedia of Evolutionary Psychological Science. Springer International Publishing. USA. 2019.
75. Me?edovic JM. Big Five traits as (mal) adaptive behavioural responses to harsh and unpredictable environment: Further evidence for the state dependent evolution of personality. Psiholoska istrazivanja XXIII. 2020; 23-41.
76. Wolf M, Weissing FJ. An explanatory framework for adaptive personality differences. Phil Trans R Soc. 2010; 365: 3959-3968.
77. Dingemanse NJ, Wolf M. Recent models for adaptive personality differences: a review. Phil Trans R Soc B. 2010; 365: 3947-3958.
78. Biro PA, Stamps JA. Are animal personality traits linked to life-history productivity?. Trends Ecol Evol. 2008; 23: 361-368.
79. Green J, Goldwyn R. Annotation: attachment disorganisation and psychopathology: new findings in attachment research and their potential implications for developmental psychopathology in childhood. J Child Psychol Psychiatry. 2002; 43: 835-846.
80. Bowlby J. Attachment and loss. Tavistock Institute of Human Relations, London, UK. 1969.
81. Feldman R. Mother–infant synchrony and the development of moral orientation in childhood and adolescence: Direct and indirect mechanisms of developmental continuity. Am J Orthopsychiat. 2007; 77:582-597.
82. Schonert-Reichl KA, Oberle E, Lawlor MS, Abbott D, Thomson K, Oberlander TF, et al. Enhancing Cognitive and Social–Emotional Development Through a Simple-to-Administer Mindfulness-Based School Program for Elementary School Children: A Randomized Controlled Trial. Dev Psychol. 2015; 51: 52-66.
83. Yu ECL. Developing Autism, The Parts Become The Whole. Scholars Press. 2020; 372.
84. Yu ECL. Impact from Early Rings on Rings of Maladjustment in Autism. SunText Rev Pediatr Care. 2021; 2: 113.
85. Humans Are Still Evolving, Scientific American. 2016.
86. Ilardo M, Nielsen R. Human adaptation to extreme environmental conditions. Curr Opin Genet Dev. 2018; 53: 77-82.
87. Morita T, Hirose S, Kimura N, Takemura H, Asada M, Naito E. Hyper-Adaptation in the Human Brain: Functional and Structural Changes in the Foot Section of the Primary Motor Cortex in a Top Wheelchair Racing Paralympian. Front Syst Neurosci. 2022; 16: 780652.
88. Hahamy A, Makin TR. Remapping in cerebral and cerebellar cortices is not restricted by somatotopy. J Neurosci. 2019; 39: 9328-9342.
89. Nakagawa K, Takemi M, Nakanishi T, Sasaki A, Nakazawa K. Cortical reorganization of lower-limb motor representations in an elite archery athlete with congenital amputation of both arms. Neuroimage Clin. 2020; 25: 102144.
90. Bogin B. Evolutionary hypotheses for human childhood. Yearbook of Physical Anthropology. 1997; 40: 63-89.
91. Bogin B. Evolution of Human Life History. Evolution of Nervous Systems. In J Kaas (Editor), Evolution of Nervous Systems. 2016; 37-50.
92. Bogin B. Puberty and adolescence: An evolutionary perspective. Encyclopedia of Adolescence. 2011; 1: 275-286.
93. Paquette D, Bigras M. Duration of Childhood. In: Shackelford T, Weekes-Shackelford V. (Editors) Encyclopedia of Evolutionary Psychological Science. Cham: Springer. 2018.
94. Yu ECL. CORE-vs-MATCH MODEL for Autism and Neuro-Developmental Disorders. J Paediatr Neonatol Med. 2020; 2: 112.
95. Marta Bertolaso, Silvia Caianiello, Emanuele Serrelli (Editors). Biological Robustness. Emerging Perspectives from within the Life Sciences Cham. Springer ISBN. 2018.
96. Yu ECL, Wong K. Mouldability of the Body Core in Adaptive Form. J Altern Complement Integr Med. 2022; 8: 222.
97. Masharawi Y, Rothschild B, Dar G, Peleg S, Robinson D, Been E, et al. Facet orientation in the thoracolumbar spine: Three-dimensional anatomic and biomechanical analysis. Spine. 2004; 29: 1755-163.
98. Mestek Boukhibar L, Barkoulas M. The developmental genetics of biological robustness. Ann Bot. 2016; 117: 699-707.
99. Baker RE, Mahmud AS, Miller IF, Rajeev M, Rasambainarivo F, Rice BL, et al. Infectious disease in an era of global change. Nat Rev Microbiol. 2022; 20:193-205.
100. Global Risks Report. World Economic Forum. ISBN. 2023; 13: 978-2-940631-36-0,
101. Vlasova RM, Wang Q, Willette A, Styner MA, Lubach GR, Kling PJ, et al. Infantile Iron Deficiency Affects Brain Development in Monkeys Even After Treatment of Anemia. Front Hum Neurosci. 2021; 15: 624107.
102. Holt AG, Davies AM. The prevalence of dementia in humans could be the result of a functional adaptation. Comput Biol Chem. 2023; 106:107939.
103. Leonard WR. Centennial perspective on human adaptability. Am J Phys Anthropol. 2018; 165: 813-833.
104. Greenberg MVC, Bourchis D. The diverse roles of DNA methylation in mammalian development and disease. Nature Reviews Molecular Cell Biology. 2019; 20: 590-607.
105. Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging cell. 2015; 14: 924-932.
106. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics. 2012; 13: 484-492.
107. Kader F, Ghai M. DNA methylation and application in forensic sciences. Forensic Science Int. 2015; 249: 255-265.
108. Raiber E-A, Hardisty R, Van Delft P, Balasubramanian S. Mapping and elucidating the function of modified bases in DNA. Nature Reviews Chemistry. 2017; 1: 0069.
109. Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013; 14: 204-220.
110. Bergman Y, Cedar H. DNA methylation dynamics in health and disease. Nat Struct Mol Biol. 2013; 20: 274-281.
111. Luo X, Zhang T, Zhai Y, Wang F, Zhang S, Wang G. Effects of DNA methylation on TFs in human embryonic stem cells. Front Genet. 2021; 12: 639461.
112. Yao B, Jin P. Cytosine modifications in neurodevelopment and diseases. Cell Mol Life Sci. 2014; 71: 405-418.
113. Zuo Y, Song M, Li H, Chen X, Cao P, Zheng L, et al. Analysis of the epigenetic signature of cell reprogramming by computational DNA methylation profiles. Curr Bioinforma. 2020; 15: 589-599.
114. Yu ECL. Neuro-vascular reserve in developing snug and fit buildup. J Integ Med. 2021; 10: 49-59.
115. Benesova O. Brain maldevelopment and delayed neuro-behavioural deviations, induced by perinatal insults, and possibilities of their prevention. J Hyg Epidemiol Microbiol Immunol. 1983; 27: 373-380.
116. Small S, Memmo M. Contemporary Models of Youth Development and Problem Prevention: Toward an Integration of Terms, Concepts, and Models. Family Relations. 2004; 53: 3-11.
117. Costello EJ. Early Detection and Prevention of Mental Health Problems: Developmental Epidemiology and Systems of Support. J Clinical Child and Adolescent Psychology. 2016; 45: 710-717.
118. Israelashvili M, Menesini E, Al-Yagon M. Introduction to the special issue on ‘Prevention and Social-Emotional Development in Childhood and Adolescence’. European J Developmental Psychology. 2020; 17: 787-807.
119. Guerra NG, Bradshaw CP. Linking the prevention of problem behaviors and positive youth development: core competencies for positive youth development and risk prevention. New Dir Child Adolesc Dev. 2008; 2008: 1-17.
120. Wang Q, Wu H. Associations between Maladaptive Perfectionism and Life Satisfaction among Chinese Undergraduate Medical Students: The Mediating Role of Academic Burnout and the Moderating Role of Self-Esteem. Front Psychol. 2022; 12: 774622.
121. Payton JW, Wardlaw DM, Graczyk PA, Bloodworth MR, Tompsett CJ, Weissberg RP. Social and emotional learning: a framework for promoting mental health and reducing risk behavior in children and youth. J Sch Health. 2000; 70: 179-185.