ARTICLE | doi:10.20944/preprints202208.0355.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: developmental delay; de novo mutation; protein-protein interaction; PPI interface; protein in-teractome; PsymuKB
Online: 19 August 2022 (04:50:42 CEST)
Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DMNs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPI harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We then observed that PsychiPPIs preferentially affected hub proteins in the human protein interactome network. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as FGFR3 and ALOX5, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity.
ARTICLE | doi:10.20944/preprints201804.0216.v1
Subject: Behavioral Sciences, Developmental Psychology Keywords: autism, ASD, psychological evaluations, ATEC, Autism Treatment Evaluation Checklist, MSEC, language delay, developmental disorder, language therapy
Online: 16 April 2018 (16:27:16 CEST)
Background: Mental synthesis is the conscious purposeful process of synthesizing a novel mental image from objects stored in memory. In our everyday use of language, we rely on mental synthesis to communicate an infinite number of images with a finite number of words. In typical children, the timeline of mental synthesis acquisition is highly correlated with an increasing vocabulary. Children with ASD, on the other hand, may learn hundreds of words but never acquire mental synthesis. In these individuals, tests assessing vocabulary comprehension may fail to demonstrate the profound deficit in mental synthesis and the resulting inability to understand flexible syntax and spatial prepositions. Objective: We developed a 20-question parent-reported evaluation tool designed to quantitatively assess mental synthesis ability and to serve as a complimentary scale for Autism Treatment Evaluation Checklist (ATEC). Results: Internal reliability was good (Cronbach’s alpha > .9), and the MSEC exhibited adequate test-retest reliability after a three- and nine-months follow up period. The MSEC results positively correlated with the ATEC communication subscale, providing support for construct validity. Moreover, MSEC scores were significantly different for children of different ASD severity levels confirming the known groups validity. Conclusions: This study represents the first step toward the development of an instrument to measure mental synthesis in children with ASD. Although the current empirical evaluation demonstrated strong evidence of excellent psychometric properties, such as validity and reliability, additional studies should be performed to replicate these findings.
ARTICLE | doi:10.20944/preprints202208.0385.v1
Subject: Biology, Anatomy & Morphology Keywords: Developmental Field; Gompertz Equation; Information Theory; Developmental Biology
Online: 22 August 2022 (15:42:19 CEST)
A model for cell proliferation in developmental fields is derived from information theory using a few biological postulates. The model provides an explanation for the success of the Gompertz equation in describing the growth of embryonic, neoplastic, and regenerative systems. Although this equation has been applied to many growth phenomena, its use has been entirely empirical. A theoretical justification for the use of the Gompertz equation in characterizing developmental processes is presented. The model also accounts for a reported relationship among the parameters of the Gompertz equation. A method for quantification and comparison of the determination of developmental fields at different levels of organization is suggested.
ARTICLE | doi:10.20944/preprints202205.0280.v1
Subject: Life Sciences, Genetics Keywords: purine-rich element binding protein A gene; PURA; MIM: 600473; transcriptional activator protein Pur-alpha; cognitive developmental delay; mental retardation; Mutation c.697_699del p.Phe233del
Online: 20 May 2022 (16:58:04 CEST)
A whole-exome capture and next-generation sequencing applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, severe cognitive deficit, without any identifiable Syndromic pattern, and to her parents, disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated to Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated one, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURA WT and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural confor-mation in the ~5Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein-DNA Docking corroborated these results in silico Analysis that showed a loss of the contact of the PURA-Phe233del III repeat domain model with the DNA. Together, i) the energetic and stereochemical, ii) the hydropathic indices and polarity surfaces, and iii) the hybrid Quantum Mechanics-Molecular Mechanics (QM-MM) analyses of the PURA molecular models demarcate at the atomic resolution the specific surrounding region affected by these mutations and paves the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.
REVIEW | doi:10.20944/preprints202207.0132.v1
Subject: Behavioral Sciences, Behavioral Neuroscience Keywords: developmental stuttering; attention; auditory feedback
Online: 8 July 2022 (05:24:28 CEST)
It has been known for a long time that many people who stutter are immediately fluent in certain conditions, for instance, when they speak in unison with others, in sync with the clicking of a metronome, or when they hear themselves speak in an altered manner. To understand why stuttering is reduced or even eliminated in such conditions is desirable because it may help understand why stuttering occurs in normal speaking conditions. However, empirical findings in this area appear conflicting and confusing, especially with regard to the role of auditory feedback. The article gives an overview of the variety and diversity of fluency-enhancing conditions and of theories proposed to explain their effect. These theories are evaluated in the light of recent empirical findings. A new hypothesis is proposed, based on findings showing that speech processing is limited without attention to the auditory channel. It is assumed that fluency-enhancing conditions draw the speaker’s attention to the auditory channel and, thereby, improve the processing of auditory feedback and its use in speech control. Implications of this account for a causal theory of stuttering and for the treatment of the disorder are discussed.
ARTICLE | doi:10.20944/preprints202009.0408.v1
Subject: Behavioral Sciences, Developmental Psychology Keywords: developmental theory; hierarchical complexity; modeling; measurement
Online: 17 September 2020 (12:29:16 CEST)
Imagination is more important than knowledge, but if intellect does not provide the needed logical structures, capacities for envisioning new possibilities are overly constrained. The sustainability problems we face today cannot be solved with the same kind of thinking that created them, but clarity on what counts as a new kind of thinking is sorely lacking. This article proposes methodical, model-based ways of heeding Bateson's warning about the negative consequences for the ecology of mind that follow from ignoring the contexts of relationships. Informed by S. L. Star's sense of boundary objects, a sequence of increasingly complex logical types distinguishes and interconnects qualitatively different kinds of thinking in ways that liberate imaginative new possibilities for life. The economy of thought instantiated at each level of complexity is only as meaningful, useful, beautiful, ethical, and efficient as the standards informing local adaptive improvisations. Standards mediating the general and specific, global and local, universally transcendent and embodied particulars enable meaningful negotiations, agreements, and communications. Attending to the differences between levels of discourse sets up new possibilities for creative and imaginative entrepreneurial approaches to viable, feasible, and desirable goals for measuring and managing sustainable development.
COMMUNICATION | doi:10.20944/preprints201904.0259.v1
Subject: Biology, Plant Sciences Keywords: developmental transition; proteomics; Gossypium hirsutum; Gossypium arbadense
Online: 23 April 2019 (13:08:15 CEST)
Cotton fiber development transition from elongation to secondary cell wall biosynthesis is a critical growth shifting phase that affects cotton ﬁber final length, strength and other properties. Morphological dynamic analysis indicates that an asynchronous fiber developmental pattern between two cotton species. The critical time point for Gh and Gb fiber elongation termination is, respectively, 23 and 27 days post-anthesis (dpa). The temporal changes of protein expression at three representative development periods (15–19, 19–23, 23–27 dpa) were examined in both species with iTRAQ technics. Strikingly, a large proportion of differentially expressed proteins (DEPs) was identified at 19–23 dpa in Gh or at 23–27 dpa in Gb, corresponding to their fiber developmental transition timing from elongation to secondary cell wall biosynthesis. To better understand fibers transitional development, we comparatively analyzed those DEPs in 19–23 dpa of Gh vs. in 23–27 dpa of Gb, and noted that these cotton species indeed share fundamentally similar fiber development features under the biological processes. It also showed that there have limited overlaps in both specific upregulated and downregulated proteins between the two species, suggesting specie-specific protein regulations in development. Proteomic profiling revealed dynamic changes of several key proteins and biological processes that potentially correlate with fiber development transition. During the transition, upregulated proteins mainly involved in carbohydrate/energy metabolism, oxidation-reduction, cytoskeleton, protein turnover, Ca2+ signaling etc, whereas important downregulated proteins mostly concentrated in phenylpropanoid and flavonoid secondary metabolism pathways. Several changed proteins in this key stage were also validated by qRT-PCR. Overall, the present study provides accurate pictures of the regulatory networks of functional proteins during the fiber developmental transition.
ARTICLE | doi:10.20944/preprints202203.0364.v1
Subject: Behavioral Sciences, Developmental Psychology Keywords: Working memory training; intervention; developmental language disorder; children
Online: 28 March 2022 (13:43:53 CEST)
Recent research has suggested that working memory training interventions may benefit children with Developmental Language Disorder (DLD). The current study investigated a short and engaging adaptive working memory intervention that targeted executive skills and aimed to improve both language comprehension and working memory abilities in children with DLD. Forty-seven 6- to 10-year-old children with DLD were randomly allocated to an executive working memory training intervention (n=24) or an active control group (n=23). A pre-test/intervention/post-test/9-month-follow-up design was used. Outcome measures included assessments of language (to evaluate far transfer of the training) and working memory (to evaluate near transfer of the training). Hierarchical multiple regression analyses controlling for pre-intervention performance and age found group to be a significant predictor of sentence comprehension and of performance on six untrained working memory measures at post-intervention and 9-month follow-up. Children in the intervention group showed significantly higher language comprehension and working memory scores at both time points than children in the active control group. The intervention programme showed potential to improve working memory and language comprehension in children with DLD and demonstrated several advantages: it involved short sessions over a short period; caused little disruption in the school day; and was enjoyed by children.
REVIEW | doi:10.20944/preprints202104.0241.v2
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: educational method; parent; developmental care and premature infant
Online: 23 April 2021 (09:49:08 CEST)
Babies born prematurely are at risk of experiencing visual disturbances, hearing loss, disabilities, the risk of infection and even death. Care for premature babies requires serious attention for both health workers and parents. The role of parents is very important both during hospitalization and at home. Therefore, in order to improve the abilities of parents, it is necessary to make educational efforts with the right method.ObjectivesThis literature review aims to provide an overview of educational methods that nurses can use to improve the ability of parents to care for or care for the development of premature babies. The method used is to search for literature that fits the established theme using 5 data based, namely Scopus, ProQuest, Science Direct, Elsevier Clinicaly for Nursing and Web of Science. The strategy used in finding literature that fits the theme and is used in this literature review uses the PICOS framework. Then conducted a review with the PRISMA method. The literature selection results obtained 572 publications, after going through the selection obtained 11 literatures that match the theme, with 11 educational methods. These methods can be grouped into ideas, namely increasing parental involvement during treatment, using technology, stress management and continuous monitoring. The ability of parents to care for premature babies is needed in order to minimize complications in infants, reduce morbidity, avoid disabilities, increase growth and development of premature babies optimally and reduce parental stress levels, increase parental confidence and good parents' self-efficacy. Choosing the right educational method can improve the ability of parents to properly care for and provide developmental care for premature babies.
REVIEW | doi:10.20944/preprints202104.0372.v1
Subject: Biology, Anatomy & Morphology Keywords: pannexin; connexin; oocyte; developmental competence; oogenesis; maturation; fertilization
Online: 14 April 2021 (12:25:21 CEST)
The oocyte is the major determinant of embryo developmental competence in all mammalian species. Although fundamental advances have been generated in the field of reproductive medicine and assisted reproductive technologies in the past three decades, researchers and clinicians are still trying to elucidate molecular factors and pathways which could be pivotal for the oocyte’s developmental competence. The cell-to-cell and cell-to-matrix communications are crucial not only for oocytes but also for multicellular organisms in general. This latter mentioned communication is among others possible due to the Connexin and Pannexin families of large-pore forming channels. Pannexins belong to a protein group of ATP-release channels, therefore of high importance for the oocyte due to its requirements of high energy supply. An increasing body of studies on Pannexins provided evidence that these channels not only play a role during physiological processes of an oocyte but also during pathological circumstances which could lead to the development of diseases or infertility. Connexins are proteins that form membrane channels and gap-junctions, and more precisely, these proteins enable the exchange of some ions and molecules, and therefore playing a fundamental role in the communication between the oocyte and accompanying cells. Herein, the role of Pannexins and Connexins for the processes of oogenesis, folliculogenesis, oocyte maturation and fertilization will be discussed, and at the end of this review, Pannexin and Connexin related pathologies and their impact on the developmental competence of oocytes will be provided.
REVIEW | doi:10.20944/preprints202009.0672.v1
Subject: Biology, Anatomy & Morphology Keywords: iPSC; hematopoiesis; developmental biology; anemia; thrombosis; immunodeficiency; cancer
Online: 27 September 2020 (08:39:30 CEST)
Human induced pluripotent stem cell (iPSC)-based model systems can be used to produce blood cells for the study of both hematologic and non-hematologic disorders. This commentary discusses recent advances that have utilized iPSC-derived red blood cells, megakaryocytes, myeloid cells, and lymphoid cells to model hematopoietic disorders. In addition, we review recent studies that have defined how microglial cells differentiated from iPSC-derived monocytes impact neurodegenerative disease. Related translational insights highlight the utility of iPSC models for studying pathologic anemia, bleeding, thrombosis, autoimmunity, immunodeficiency, blood cancers, and neurodegenerative disease such as Alzheimer’s.
REVIEW | doi:10.20944/preprints202002.0068.v1
Subject: Life Sciences, Genetics Keywords: cis-regulatory element; developmental modularity; evolutionary modularity; Heliconius
Online: 5 February 2020 (14:02:51 CET)
Developmental modularity has long been viewed as a hierarchical organization that facilitates evolution over macro-evolutionary time through modification or co-option of preexisting modules. More recently, developmental modularity has been proposed as a micro-evolutionary mechanism capable of driving rapid evolution of novel color pattern phenotypes between closely related taxa. In this scenario, swapping allelic variants of modular cis-regulatory elements (CREs) via recombination generates novel phenotypes by shuffling preexisting color pattern modules into new arrangements. Recent evidence from Drosophila and butterflies, however, provides a series of examples in which pleiotropic CREs function in multiple developmental contexts. The potential prevalence of pleiotropy in CRE function is a major barrier to the proposed evolutionary role of CRE modules and encourages us to reconsider the relative importance of modularity for microevolutionary change. Here we first review the case for the apparent frequent exchange of modular color pattern phenotypes as a mechanism facilitating diversification. We then contrast this with recent evidence of CRE pleiotropy and argue that exchange of CRE modules should not be the default assumption, even when phenotypes look modular. Finally, we review experimental data on Heliconius butterfly wing patterns—which appear modular—and introduce the concept of evolutionary modularity as an alternative to developmental modularity. Evolutionary modularity reconciles the appearance of modularity in comparative genomic studies of Heliconius color patterns with experimental data supporting a non-modular architecture. We propose that evolutionary modularity provides a potentially important pathway for exchange of phenotypic elements between hybridizing taxa independent of the underlying developmental architecture.
ARTICLE | doi:10.20944/preprints201907.0186.v1
Subject: Behavioral Sciences, Developmental Psychology Keywords: preschool; leukaemia; adaptive behaviour; developmental skills; healthy peers
Online: 16 July 2019 (06:04:09 CEST)
Early childhood is considered to be a period of rapid development, with the acquisition of abilities predicting future positive school competences. Motor, cognitive and social difficulties related to cancer therapies heavily impact the development of children with cancer. This study focused on two main aims: to assess the developmental pathways of preschool children with acute lymphoblastic leukaemia one year post-treatment and to compare these abilities both with those of a control group of healthy peers and with Italian norms. Forty-four children and their families, recruited through the Haematology-Oncologic Clinic of the Department of Child and Woman Health (University of Padua), agreed to participate to this study. The children’s mean age was 4.52 years (SD = 0.94, range = 2.5-6 years), equally distributed by gender, all diagnosed with Acute Lymphoblastic Leukaemia. Matched healthy peers were recruited through paediatricians’ ambulatories. Each family was interviewed adopting the Vineland Adaptive Behaviour Scales. Paired sample Wilcoxon tests revealed that children were reported to have significantly more developmental difficulties than their healthy peers. When compared with Italian norms they scored particularly low in verbal competence, social and coping skills. No significant association were found between treatment variables and developmental abilities. These findings suggest that the creation of specialized interventions both for parents and children may fill the possible delays in children’s development probably due to stress, lack of adequate stimulation or difficult adaptation.
ARTICLE | doi:10.20944/preprints201905.0086.v1
Subject: Behavioral Sciences, Developmental Psychology Keywords: preschool; leukaemia; adaptive behaviour; developmental skills; healthy peers
Online: 8 May 2019 (09:39:26 CEST)
Early childhood is considered to be a period of rapid development, with the acquisition of abilities predicting future positive school competences. Motor, cognitive and social difficulties related to cancer therapies heavily impact the development of children with cancer. This study focused on two main aims: to assess the developmental pathways in preschool children with leukaemia one year post-treatment; and to compare these abilities with those of a control group of healthy peers. Forty-eight children and their families, recruited through the Haematology-Oncologic Clinic of the Department of Child and Woman Health (University of Padua), agreed to participate in this study. The children’s mean age was 4.36 years (SD = 1.07, range = 1.91–6 years), equally distributed by gender, most of whom were diagnosed with Acute Lymphoblastic Leukaemia (N = 44). Matched healthy peers were recruited through paediatricians’ ambulatories. Each family was interviewed adopting the Vineland Adaptive Behaviour Scales. Paired sample t-tests revealed that children, especially aged 42–72 months, were reported to have significantly more developmental difficulties than their healthy peers, particularly in verbal competence, social and coping skills and gross motor abilities. These findings suggest that the creation of specialized interventions for both parents and children may fill the possible delays in children’s development due to toxic therapies and their associated hospitalisation.
ARTICLE | doi:10.20944/preprints202110.0337.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: Developmental coordination disorder (DCD); MABC-2; Motor skills training
Online: 25 October 2021 (10:23:34 CEST)
The present study aimed to investigate the effect of a motor skills training program in children with DCD considering their gender. The Movement Assessment Battery for Children (MABC-2) classified the children and assessed skill changes over time. The study was implemented at four kindergartens in the Khorezm region of Uzbekistan. In the study, all children had DCD (5.17 ± 0.70 years; 10 girls), and all indicators on MABC-2 were less than 16 percent. Participants were divided into an experimental group (n=17) receiving ten weeks of motor skills training program for 45 min twice per week, the control group (n=7) proceeded with exercises of everyday living. All children in the experimental group had a significant increase in total percentile rank of MABC-2 and concerning each domain (manual dexterity; throwing and catching; balance). In the control group, a significant decrease in the total percentile rank of MABC-2 and each domain of MABC-2 was observed. The effectiveness of the intervention program was similar across both genders. The study supports that a period of 10 weeks of a motor skills training program can increase the quality of children's motor coordination and represent a valuable procedure for physical education specialists to enhance motor skills for children with DCD.
CONCEPT PAPER | doi:10.20944/preprints202106.0578.v1
Subject: Biology, Animal Sciences & Zoology Keywords: homology; developmental mechanism; evidential integration; eumetazoan body plan; phylogenetics
Online: 23 June 2021 (11:45:06 CEST)
Reconstructing ancestral species is a challenging endeavour: fossils are often scarce or enigmatic, and inferring ancestral characters based on novel molecular approaches (e.g. comparative genomics or developmental genetics) has long been controversial. A key philosophical challenge pertinent at present is the lack of a theoretical framework capable of evaluating inferences of homology made through integration of multiple kinds of evidence (e.g. molecular, developmental, or morphological). Here, I present just such a framework. I start with a brief history and critical assessment of attempts at inferring morphological homology through developmental genetics. I then bring attention to a recent model of homology, namely Character Identity Mechanisms (DiFrisco, Love, & Wagner, 2020), intended partly to elucidate the relationships between morphological characters, developmental genetics, and homology. I utilise and build on this model to construct the evaluative framework mentioned above, which judges the epistemic value of evidence of each kind in each particular case based on three proposed criteria: effectiveness, admissibility, and informativity, as well as providing a generalised guideline on how it can be scientifically operationalised. I then point out the evolution of the eumetazoan body plan as a case in point where the application of this framework can yield satisfactory results, both empirically and conceptually. I will conclude with a discussion on some potential implications for more general philosophy of biology and philosophy of science, especially surrounding evidential integration, models and explanation, and reductionism.
ARTICLE | doi:10.20944/preprints201608.0108.v1
Subject: Biology, Anatomy & Morphology Keywords: developmental biology; computational biology; lineage trees; embryogenesis; biological complexity
Online: 10 August 2016 (11:36:39 CEST)
Embryonic development proceeds through a series of differentiation events. The mosaic version of this process (binary cell divisions) can be analyzed by comparing early development of Ciona intestinalis and Caenorhabditis elegans. To do this, we reorganize lineage trees into differentiation trees using the graph theory ordering of relative cell volume. Lineage and differentiation trees provide us with means to classify each cell using binary codes. Extracting data characterizing lineage tree position, cell volume, and nucleus position for each cell during early embryogenesis, we conduct several statistical analyses, both within and between taxa. We compare both cell volume distributions and cell volume across developmental time within and between single species and assess differences between lineage tree and differentiation tree orderings. This enhances our understanding of the differentiation events in a model of pure mosaic embryogenesis and its relationship to evolutionary conservation. We also contribute several new techniques for assessing both differences between lineage trees and differentiation trees, and differences between differentiation trees of different species. The results suggest that at the level of differentiation trees, there are broad similarities between distantly related mosaic embryos that might be essential to understanding evolutionary change and phylogeny reconstruction. Differentiation trees may therefore provide a basis for an Evo-Devo Postmodern Synthesis.
ARTICLE | doi:10.20944/preprints202009.0290.v1
Subject: Biology, Ecology Keywords: hormesis; developmental toxicity; endocrine disruptor; herbicide; ecological risk assessment (ERA)
Online: 13 September 2020 (15:33:58 CEST)
Some herbicides exert hormetic or biphasic non-monotonic dose-response (NMDR), which is one of the major challenges for ecological risk assessment (ERA) of pesticides pollution. In this study, fish embryo toxicity test (FET) with Javanese medaka (Oryzias javanicus) to sublethal concentration of diuron was determined. Inverted U-shape heart rate was observed at 3 days post-exposure (dpe) and 7 dpe. However, at 13 dpe the heart rate (104 ± 2.90 heartbeat/min.) decreased in 10.00 mg.L-1 exposed-embryos. At 20 dpe, hatchability and survival rate were reduced in 5.00 mg.L-1 and 10.00 mg.L-1 exposed groups. Hormetic developmental deformities were observed in embryo-larvae of Javanese medaka. The results revealed a biphasic effect of low concentrations of diuron on some morphological and physiological features of Javanese medaka embryo-larvae, which might be attributed to endocrine disruption of this herbicide. Further studies to support these effects were recommended.
REVIEW | doi:10.20944/preprints201811.0055.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: Arabidopsis; developmental pathways; environmental responses; HD-Zip transcription factors; hormones
Online: 2 November 2018 (12:33:38 CET)
HD-Zip proteins are unique to plants, and contain a homeodomain closely linked to a leucine zipper motif, which are involved in dimerization and DNA binding. Based on homology in the HD-Zip domain, gene structure and the presence of additional motifs, HD-Zips are divided into four families, HD-Zip I–IV. Phylogenetic and bioinformatics analysis of HD-Zip genes using transcriptomic and genomic datasets from a wide range of plant species indicate that the HD-Zip protein class was already present in green algae. Later, HD-Zips experienced multiple duplication events that promoted neo- and sub-functionalizations. HD-Zip proteins are known to control key developmental and environmental responses, and a growing body of evidence indicates a strict link between members of the HD-Zip II and III families and the auxin machineries. Interactions of HD-Zip proteins with other hormones such as brassinolide and cytokinin have also been described. However, it is striking that among the genes regulated by REV, a HD-Zip III protein playing a key role in apical development, are genes that mediate ABA signaling. Furthermore, HAT1 and HAT3, two HD-Zip II proteins involved in key developmental processes, repress ABA biosynthesis and signaling, indicating an essential role of these factors in adjusting development to changing environment.
ARTICLE | doi:10.20944/preprints201804.0328.v1
Subject: Biology, Plant Sciences Keywords: epigenomics, hordeum vulgare, leaf, root, tissue-specific methylation, developmental epigenomics
Online: 25 April 2018 (16:53:56 CEST)
The barley (Hordeum vulgare) genome comprises over 32,000 genes, with differentiated cells expressing only a subset of genes; the remainder being silent. Mechanisms by which tissue-specific genes are regulated are not entirely understood, although DNA methylation is likely to be involved. DNA methylation patterns are not static during plant development, but it is still unclear whether different organs possess distinct methylation profiles. Methylation-sensitive GBS was used to generate DNA methylation profiles for roots, leaf-blades and leaf-sheaths from five barley varieties, using seedlings at the three-leaf stage. Differentially Methylated Markers (DMMs) were characterised by pairwise comparisons of roots, leaf-blades and leaf-sheaths of three different ages. While very many DMMs were found between roots and leaf parts, only a few existed between leaf-blades and leaf-sheaths, with differences decreasing with leaf rank. Organ-specific DMMs appeared to target mainly repeat regions, implying that organ differentiation partially relies on the spreading of DNA methylation from repeats to promoters of adjacent genes. Furthermore, the biological functions of differentially methylated genes in the different organs correlated with functional specialisation. Our results indicate that different organs do possess diagnostic methylation profiles and suggest that DNA methylation is important for both tissue development and differentiation and organ function.
REVIEW | doi:10.20944/preprints202207.0436.v1
Subject: Biology, Physiology Keywords: SUMO; MSC; osteoblast; chondrocyte; osteoclast; signaling pathway; arthritis; osteosarcoma; developmental disorders
Online: 28 July 2022 (09:04:33 CEST)
The modification of proteins by small ubiquitin-related modifier (SUMO) molecules, SUMOylation, is a key post-translational modification involved in a variety of biological processes such as chromosomes organization, DNA replication and repair, transcription, nuclear transport, and cell signaling transduction. In recent years, emerging evidence has shown that SUMOylation regulates the development and homeostasis of the skeletal system, with its dysregulation causing skeletal diseases, suggesting that SUMOylation pathways may serve as a promising therapeutic target. In this review, we summarize the current understanding of the molecular mechanisms by which SUMOylation pathways regulate skeletal cells in the physiological and disease contexts.
CASE REPORT | doi:10.20944/preprints202008.0502.v1
Subject: Medicine & Pharmacology, Other Keywords: KARS gene; aminoacylation; leucodistrophy; epilepsy; hearing loss developmental delay; whole exome sequencing
Online: 24 August 2020 (03:10:45 CEST)
The KARS gene encodes the aminoacyl-tRNA synthetase (aaRS) which activates and joins the lysin with its corresponding transfer RNA (tRNA), through the ATP-dependent aminoacylation of the amino acid. The KARS gene mutations have been linked to diverse neurologic phenotypes such as: neurosensorial hearing loss, leukodistrophy, microcephaly, developmental delay or regression, peripheral neuropathy, cardiomyopathy, impairment of the mitochondrial respiratory chain, hyperlactatemia, among others. This article presents the case of a Colombian pediatric patient with two pathological missense variants in a compound heterozygous state in the KARS gene.
ARTICLE | doi:10.20944/preprints202111.0013.v1
Subject: Life Sciences, Molecular Biology Keywords: Nonsense-mediated mRNA Decay; UPF3B-knockout; RNA-Sequencing; Intellectual disability; Neuro-developmental disorders
Online: 1 November 2021 (12:17:15 CET)
UPF3B is a constituent of the classical nonsense-mediated mRNA decay (NMD) pathway that degrades both the aberrant transcripts and a set of physiological transcripts. In higher eukaryotes, UPF3B have significant biochemical functions in diverse cellular processes including NMD and translation. UPF3B plays a crucial role in neuronal development and differentiation. Next-generation sequencing technologies identified several loss-of-function mutations in the UPF3B gene that results in neuro-developmental disorders in humans. To uncover the mechanistic role of UPF3B in neuronal functions, we have generated the UPF3B-knockout mammalian cell line model system using CRISPR-Cas9 gene editing method. RNA-Sequencing Analysis of cellular transcriptome from UPF3B-KO cells identified specific genes involved in cell growth and neuronal functions. Altered expression of genes related to the axon guidance pathway delineated the UPF3B function to regulate the neuron-specific genes. Functional enrichment analysis identified the genes involved in the disorders related to mental health and intellectual disability. Our study has the potential to identify the direct players of intellectual disability and will have broader implications.
ARTICLE | doi:10.20944/preprints202011.0737.v1
Subject: Behavioral Sciences, Applied Psychology Keywords: sensorhub; reading in children; developmental differences; background colours; overlay colours; eeg; ecg; eda; eyetracking
Online: 2 December 2020 (15:34:36 CET)
The study investigated the influence of white vs 12 background and overlay colours on the reading process in school age children. Previous research reported that colours could affect reading skills as an important factor of the emotional and physiological state of the body. The aim of the study was to assess developmental differences between second and third grade students of elementary school and to evaluate differences in electroencephalography (EEG), ocular, electrodermal activities (EDA) and heart rate variability (HRV). Our findings showed a decreasing trend with age regarding EEG power bands (Alpha, Beta, Delta, Theta) and lower scores of reading duration and eye-tracking measures in younger children compared to older children. As shown in the results, HRV parameters showed higher scores in 12 background and overlay colours among second than third grade students which is linearly correlated to the level of stress and readable from EDA measures as well. The existing study showed the calming effect on second graders in turquoise and blue background colours. Considering other colours separately for each parameter, we assumed that there are no systematic differences in Reading duration, EEG power band, Eye-tracking and EDA measures.
BRIEF REPORT | doi:10.20944/preprints201806.0014.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: development; milestones; screening; poverty; stunting; lead exposure; developmental risk; child health; global health; pediatrics
Online: 1 June 2018 (11:11:19 CEST)
There is a need for developmental screening that is easily administered in resource-poor settings. 1) We hypothesized that known risk factors would predict failed developmental screening on an adapted screening tool in East African children living in poverty. 2) The sample included 100 healthy Ugandan children aged 6-59 months. We adapted a parent-reported developmental screener based on the Child Development Review chart. The primary outcome was failure to meet age-appropriate milestones for any developmental domain. Venous blood was analyzed for lead, and caregivers completed a demographics questionnaire. We used multivariate logistic regression models to determine if elevated blood lead and stunting predicted failure on the screener, controlling for maternal education level, age in months past the lower bound of the child’s developmental age group, and absence of home electricity. 3) In the sample, 14% (n=14) of children failed one or more milestones on the screener. Lead levels or stunting did not predict failing the screener after controlling for covariates. 4) Though this tool was feasibly administered, it did not demonstrate preliminary construct validity and is not yet recommended for screening in high-risk populations. Future research should include a larger sample size and cognitive interviews to ensure it is contextually relevant.
ARTICLE | doi:10.20944/preprints202202.0017.v1
Subject: Biology, Other Keywords: protein-protein interactions; interactome; congenital heart disease; developmental disorder; hypoplastic left heart syndrome; web application
Online: 1 February 2022 (16:00:59 CET)
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5,000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein-protein interactions (PPIs) using our High-precision Protein-Protein Interaction Prediction (HiPPIP) model. The interactome is available on a webserver with advanced search capabilities (http://severus.dbmi.pitt.edu/wiki-HLHS). 364 genes including 73 novel interactors were differentially regulated in tissues/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. 60.5% of the interactome consisted of housekeeping genes that may harbor large-effect mutations and drive HLHS etiology but show limited transmission. Network proximity of diabetes, Alzheimer’s disease, and liver carcinoma-associated genes to HLHS genes suggested a mechanistic basis for their comorbidity with HLHS. Interactome genes showed tissue-specificity for sites of extracardiac anomalies (placenta, liver and brain). The HLHS interactome shared significant overlaps with the interactomes of ciliopathy and microcephaly-associated genes, with the shared genes respectively enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly respectively.
CONCEPT PAPER | doi:10.20944/preprints202008.0451.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: Metazoa; body plan; developmental pathways; limb development; Shh; centriole; cell division; cilia; centriole gene expression
Online: 20 August 2020 (09:49:27 CEST)
Metazoans have an elaborate and functionally segmented body. It evolves from a single cell by systematic divisions. Metazoans attain structural complexity with exquisite precision, which is a molecular mystery. The indispensable role of centrioles in cell division and ciliogenesis can shed insight into this riddle. Cell division helps in growth of the body and is a highly regulated and integrated process. Its errors cause malignancies. The cell mass is organized during organogenesis. Prior to it, the centrioles are retrieved from the cell cycle to initiate ciliogenesis. The cilia-modulated developmental signaling pathways elaborate the body plan. The secluded compartment of the cilium reduces noise during signaling and is essential for a precise body plan development. The dysfunctional centrioles and cilia can distort body plan. Thus, centriole has a dual role in growth and cellular organization. This concept review analyses the comprehensive interactome and the key domain features (like C2 domain) of molecules which connect and disarm the centriole from the cell cycle and ciliogenesis by switching on or off the essential regulators of the pathways. The concentration of these signaling pathways at the centriole reinforces the hypothesis that centriole is the molecular workstation to carve out structural design and complexity in metazoans.
ARTICLE | doi:10.20944/preprints201806.0280.v2
Subject: Behavioral Sciences, Cognitive & Experimental Psychology Keywords: phonagnosia, acquired, developmental, apperceptive, associative, voice-identity processing, speaker recognition, core-voice system, extended system
Online: 4 December 2018 (16:31:48 CET)
The voice contains elementary social communication cues, conveying speech, as well as paralinguistic information pertaining to the emotional state and the identity of the speaker. In contrast to vocal-speech and vocal-emotion processing, voice-identity processing has been less explored. This seems surprising, given the day-to-day significance of person recognition by voice. A valuable approach to unravel how voice-identity processing is accomplished is to investigate people who have a selective deficit in recognising voices. Such a deficit has been termed phonagnosia. In the present chapter, we provide a systematic overview of studies on phonagnosia and how they relate to current neurocognitive models of person recognition. We review studies that have characterised people who suffer from phonagnosia following brain damage (i.e. acquired phonagnosia) and also studies, which have examined phonagnosia cases without apparent brain lesion (i.e. developmental phonagnosia). Based on the reviewed literature, we emphasise the need for a careful behavioural characterisation of phonagnosia cases by taking into consideration the multistage nature of voice-identity processing and the resulting behavioural phonagnosia subtypes.
ARTICLE | doi:10.20944/preprints202208.0135.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: physiologically based pharmacokinetic modelling; propofol; low cardiac output; pharmacokinetics; neonate; developmental pharmacology; asphyxia; hypothermia; pediatrics; pharmacokinetics
Online: 8 August 2022 (06:12:36 CEST)
Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.
REVIEW | doi:10.20944/preprints202110.0233.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: microbiome; public health; chronic diseases; microimmunosome; eating disorders; subtance use disorder; commensals; pathobionts; sensory receptors; developmental programming
Online: 15 October 2021 (16:57:40 CEST)
The is a sequential article to an initial review suggesting that Microbiome First medical approaches to human health and wellness could both aid the fight against noncommunicable diseases and conditions (NCDs) and help to usher in sustainable healthcare. This current review article specifically focuses on public health programs and initiatives and what has been termed by medical journals as a catastrophic record of recent failures. Included in the review is a discussion of the four priority behavioral modifications (food choices, cessation of two drugs of abuse, and exercise) advocated by the World Health Organization as the way to stop the ongoing NCD epidemic. The lack of public health focus on the majority of cells and genes in the human superorganism, the microbiome, is highlighted as is the “regulatory gap” failure to protect humans, particularly the young, from a series of mass population toxic exposures (e.g., asbestos, trichloroethylene, dioxin, polychlorinated biphenyls, triclosan, bisphenol A and other plasticizers, polyfluorinated compounds, herbicides, food emulsifiers, high fructose corn syrup, certain nanoparticles, endocrine disruptors, obesogens). The combination of early life toxicity for the microbiome and connected human physiological systems (e.g., immune, neurological), plus a lack of attention to the importance of microbial rebiosis has facilitated rather than suppressed, the NCD epidemic. This review article concludes with a call to place the microbiome first and foremost in public health initiatives as a way to both rescue public health effectiveness and reduce the human suffering connected to co-morbid NCDs.
REVIEW | doi:10.20944/preprints201609.0022.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: Pervasive developmental disorder; Autism spectrum disorder (ASD); brain network; Theory of Mind (ToM); Music Therapy (MT); therapeutic effect
Online: 6 September 2016 (11:53:58 CEST)
Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. Evidence based studies have reported the extensive therapeutic application of music on various part of the brain in a nonverbal child with autism through hearing or making music.Hence we hypothesized that MT intervention can improve the communication capacity in people with ASD, than customary neurorestoration therapy alone.
REVIEW | doi:10.20944/preprints202103.0245.v1
Subject: Life Sciences, Biochemistry Keywords: early life adversity; stress; psychosocial stress; hypothalamus-pituitary-adrenal axis; ageing; immuno-senescence; inflammageing; Developmental origins of health and disease
Online: 9 March 2021 (09:26:00 CET)
There are many ‘faces’ of early life adversity (ELA), such as childhood trauma, institutionalization, abuse or exposure to environmental toxins. These have been implicated in the onset and severity of a wide range of chronic non-communicable diseases later in life. The later-life disease risk has a well-established immunological component. This raises the question as to whether accelerated immune-ageing mechanistically links early-life adversity to the lifelong health trajectory resulting in either ‘poor’ or ‘healthy’ ageing. Here we examine observational and mechanistic studies of ELA and inflammageing, highlighting common and distinct features in these two life stages. Many biological processes appear in common including reduction in telomere length, increased immuno-senescence, metabolic distortions and chronic (viral) infections. We propose that ELA shapes the developing immune, endocrine and nervous system in a non-reversible way, creating a distinct phenotype with accelerated immuno-senescence and systemic inflammation. We believe that ELA acts as an accelerator for inflammageing and age-related diseases. Furthermore, we now have the tools and cohorts to be able to dissect the interaction between early life adversity and later life phenotype. This should, in the near future, allow us to identify the ecological and mechanistic processes that are involved in ‘healthy’ or accelerated immune-ageing.
REVIEW | doi:10.20944/preprints202011.0683.v1
Subject: Medicine & Pharmacology, Allergology Keywords: gut microbiota; early-life gut microbiota; gut dysbiosis; long-term health and disease; Developmental Origins of Health and Disease (DOHaD)
Online: 27 November 2020 (11:22:07 CET)
Abstract: Early life gut microbiota have been increasingly recognized as major contributors to short and/or long-term human health and diseases. Numerous studies have demonstrated that human gut microbial colonization begins at birth but continues to develop a succession of taxonomic abundances for two to three years until the gut microbiota reaches adult-like diversity and proportions. Several factors, including gestational age (GA), delivery mode, birth weight, feeding types, antibiotic exposure, maternal microbiome and diet influence the diversity, abundance and function of the early life gut microbiota. Gut microbial life is essential for assisting with the digestion of food substances to release nutrients, exerting control over pathogens, stimulating or modulating the immune system and influencing many systems such as the liver, brain, and endocrine system. Microbial metabolites play multiple roles in these interactions. Furthermore, studies provide evidence supporting that imbalances of the gut microbiota in early life, referred to as dysbiosis, are associated with specific childhood or adult disease outcomes, such as asthma, atopic dermatitis, diabetes, allergic diseases, obesity, cardiovascular diseases (CVD) and neurological disorders. These findings support that the human gut microbiota may play a fundamental role in the risk of acquiring diseases that may be programmed during the early life stage. In fact, it is critical to explore the role of the human gut microbiota in early life. In this review, we summarize the general understanding of the colonization and development of the gut microbiota in early life, highlighting the recent findings regarding the relationship between the gut microbiota composition and their metabolites, and immune functions, which could significantly influence long-term health and disease. We then review known pathophysiological interactions of the early gut microbiome with a number of well characterized diseases and pose potential etiological mechanisms.
Subject: Behavioral Sciences, Applied Psychology Keywords: spiritual intelligence; biology of knowledge; developmental psychology; logical analysis; neurology; neuroscience; transpersonal psychology; Howard Gardner; theory of multiple intelligences; cognitive sciences
Online: 22 October 2021 (08:16:01 CEST)
The concept of spiritual intelligence is currently at the focus of scientific debate. One of the most important problems is if it is a valid intelligence that meets the criteria developed by scholars. In this paper, I look at this idea in the context of Howard Gardner's theory of multiple intelligences and show some evidence from biology, neurology, and other scientific disciplines
REVIEW | doi:10.20944/preprints202005.0472.v1
Subject: Biology, Plant Sciences Keywords: stele; stelar architecture; plant development; plant anatomy; procambium; endodermis; boundary layer; developmental domain; protostele; siphonostele; eustele; vascular tissue; xylem, phloem; pith; evo-devo; evolution; fossil
Online: 31 May 2020 (15:28:34 CEST)
The stele concept is one of the oldest enduring concepts in plant biology. This paper reviews the concept and its foundations, and builds an argument for an updated view of steles and their evolution. The history of studies of stelar organization has generated a widely ranging array of definitions of the stele that determine the way we classify steles and construct scenarios about the evolution of stelar architecture. Because at the level of the organism biological evolution proceeds by, and is reflected in, changes in development, concepts of structure need to be grounded in development in order to be relevant in an evolutionary perspective. For the stele, most of the traditional definitions that incorporate development have viewed it as the totality of tissues that either originate from procambium – currently the prevailing view – or are bordered by a boundary layer (e.g., endodermis). A definition of the stele that would bring consensus between these perspectives recasts the stele as a structural entity of dual nature. Here, I review briefly the history of the stele concept, basic terminology related to stelar organization, and traditional classifications of the steles. I then revisit boundary layers from the perspective of histogenesis as a dynamic mosaic of developmental domains. I use classic and recent anatomical and molecular data to reaffirm and explore the importance of boundary layers for stelar organization. Drawing on data from comparative anatomy, developmental regulation, and the fossil record, I offer a model for a stele concept that integrates both the boundary layer and the procambial perspective, consistent with a dual nature of the stele. The dual stele model posits that stelar architecture is determined in the apical meristem by two major cell fate specification events: a first one that specifies a provascular domain and its boundaries, and a second event that specifies a procambial domain (which will mature into conducting tissues) from cell subpopulations of the provascular domain. If the position and extent of the developmental domains defined by the two events are determined by different concentrations of the same morphogen (most likely auxin), then the distribution of this organizer factor in the shoot apical meristem, as modulated by changes in axis size and the effect of lateral organs, can explain the different stelar configurations documented among tracheophytes. This model provides a set of working hypotheses that incorporate assumptions and generate implications that can be tested empirically. The model also offers criteria for an updated classification of steles that is in line with current understanding of plant development. In this classification, steles fall into two major categories determined by the configuration of boundary layers – boundary protosteles and boundary siphonosteles, each with subtypes defined by the architecture of the vascular tissues. Validation the dual stele model and, more generally, in-depth understanding of the regulation of stelar architecture, will necessitate targeted efforts in two areas: (i) the regulation of procambium, vascular tissue, and boundary layer specification in all extant vascular plants, considering that most of the diversity in stelar architecture is hosted by seed-free plants, which are the least explored in terms of developmental regulation; (ii) the configuration of vascular tissues and, especially, boundary layers, in as many extinct species and lineages as possible.
Subject: Life Sciences, Biochemistry Keywords: glucose; glycogen; gluconeogenesis; early life adversity; acute stress; chronic stress; psychosocial stress; hypothalamus-pituitary-adrenal axis; ageing; immuno-senescence; inflamm-ageing; Developmental origins of health and disease
Online: 23 March 2021 (09:04:41 CET)
The physiological response to a psychological stressor broadly impacts energy metabolism. In-versely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA) and sympathetic nervous system activation. Glu-cocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of ener-gy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physi-ological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunc-tion, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothe-sise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.