ARTICLE | doi:10.20944/preprints202208.0385.v1
Subject: Biology And Life Sciences, Anatomy And Physiology 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.
COMMUNICATION | doi:10.20944/preprints202307.1454.v1
Subject: Medicine And Pharmacology, Other Keywords: decamethylcyclopentasiloxane; developmental toxicity; reproductive toxicity
Online: 7 August 2023 (03:00:17 CEST)
A paper in this journal on decamethylcyclopentasiloxane (D5) used unreliable methods to reach unreliable conclusions. The authors concluded that D5 exposure should be viewed as causing human reproductive disorders and should be considered a developmental toxicant, that is, toxic to the developing embryo. The inadequate methods could not have answered the authors' research questions, and the paper should be withdrawn.
REVIEW | doi:10.20944/preprints202207.0132.v1
Subject: Social Sciences, Behavior Sciences 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.
REVIEW | doi:10.20944/preprints202311.1132.v1
Subject: Medicine And Pharmacology, Other Keywords: handwriting; developmental dysgraphia; product; process; diagnosis
Online: 17 November 2023 (05:25:56 CET)
Handwriting is a complex perceptual-motor task that requires years of training and practice before complete mastering. Its acquisition is crucial since handwriting is the basis, together with reading, for the acquisition of higher-level skills such as spelling, grammar, syntax, and text composition. Despite correct learning and practice of handwriting, some children never master this skill to a sufficient level. These handwriting deficits, referred to as developmental dysgraphia, can seriously impact the acquisition of other skills and thus the academic success of the child if they are not diagnosed and handled early. In this review, we present a non-exhaustive listing of the tools which are the most reported in the literature for the analysis of handwriting and the diagnosis of dysgraphia. Tools focusing on both the final handwriting product and the handwriting process will be considered. We will then discuss the pros and cons of the existing tools, and the perspectives for the development of future tools.
ARTICLE | doi:10.20944/preprints202009.0408.v1
Subject: Social Sciences, 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.
ARTICLE | doi:10.20944/preprints202310.1632.v1
Subject: Biology And Life Sciences, Aquatic Science Keywords: Culaea inconstans; fitness; condition; developmental asymmetry; reproduction
Online: 26 October 2023 (03:34:07 CEST)
Multiple indicators have been used to assess the degree of exposure of fish to anthropogenic chemicals in their stream habitats. We hypothesized that brook stickleback (Culaea inconstans) in a headwater stream receiving urban and agricultural runoff (South Fork Whitewater River, SFWR) would exhibit poorer condition, reduced reproductive fitness, and greater left side-to-right side morphological asymmetry (i.e., fluctuating asymmetry or FA) than would fish from a nearby headwater stream with a forested drainage basin (Garvin Brook). Male and female fish were collected from both streams just prior to spawning in 2013-2015. In 2013 and 2014, fish were assessed for overall condition (Fulton’s K) and internal measures of condition (hepatosomatic index, HSI) and reproductive fitness (gonadosomatic index [GSI], total egg count, egg weight). In 2015, measurements of head length, jaw length, eye diameter, pectoral fin length, and pelvic fin length were made on both sides of each fish for use in assessing degree of FA. We observed declining condition with fish size, increased liver size, and reduced egg counts and egg size in female brook stickleback in SFWR relative to those from Garvin Brook. SFWR females had significantly higher FA than Garvin females for all structures assessed except pelvic fin length. FA also was slightly higher for all structures in SFWR males compared to Garvin males, but differences were not significant. A composite FA index combining all measurements from an individual fish into a single value displayed highly significant differences for female fish (SFWR FA >> Garvin FA), but not for male fish (SFWR FA = Garvin FA). Exposure of brook stickleback to reduced water quality in SFWR during early development appears to increase morphological asymmetry in female (but not male) fish, and continuing exposure to compromised water quality throughout life impacts both general condition and reproductive fitness of stickleback, especially older female fish, in SFWR.
COMMUNICATION | doi:10.20944/preprints201904.0259.v1
Subject: Biology And Life Sciences, 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/preprints202303.0157.v2
Subject: Public Health And Healthcare, Physical Therapy, Sports Therapy And Rehabilitation Keywords: Intellectual and Developmental Disabilities; Gait; Exercise Program; Kinematics
Online: 22 September 2023 (12:53:06 CEST)
This study examines the effects and durability of postural exercise on gait kinematics in people with intellectual and developmental disabilities (IDD). Thirty-four men with mild IDD were assigned to either the training group (n = 19) or the control group (n = 15). The TG performed the intervention over 8 weeks, 3 days/week, 1 h/day. The results indicated that the intervention program had a significant effect on some variables of gait. Also, in the TG between post-test and follow-up, there was no significant difference, which indicated that gait variables were maintained by the TG one month after the end of the program. This study provides evidence that postural exercises can be used as an effective intervention for improving gait in individuals with IDD.
ARTICLE | doi:10.20944/preprints202303.0498.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: Developmental milestones; artificial intelligence; classification algorithms; infant growth
Online: 29 March 2023 (03:06:52 CEST)
Psychomotor developmental delay in infants includes failure to acquire abilities such as sitting, walking, grasping objects and communication at the ages when most infants have acquired these abilities. Known risk factors include a large number of aspects of family environment, socioeconomic position, problems in pregnancy and birth, and maternal health. It is clinically useful to be able to screen for developmental delay so that healthcare interventions can be considered. The present research used machine learning (random forest) to create an algorithm predicting psychomotor delay in 9-month-old infants using information ascertainable at birth and in early infancy. The dataset was the UK longitudinal Millennium Cohort study. Fifty-two predictors measuring socioeconomic indicators, paternal, family and social support for the mother, beliefs about good parenting, maternal health, pregnancy and birth were included in the initial algorithm. Feature reduction showed that of the 52 variables, birthweight, family income and parents’ ages had the highest feature importance scores and could alone correctly predict developmental delay with over 99% sensitivity and 100% specificity. The relationships between delay and some of the predictors, particularly income, were nonlinear and complex. The results suggest that the risk of psychomotor developmental delay can be identified in early infancy using machine learning, and that the best predictors are factors present prior to birth. Surprisingly, the most important factors included in the present study did not include illnesses during pregnancy such as eclampsia and infections.
ARTICLE | doi:10.20944/preprints202301.0097.v1
Subject: Biology And Life Sciences, Plant Sciences Keywords: mitochondria; iron transporters; MIT; developmental defects; RNA-seq
Online: 5 January 2023 (03:42:32 CET)
Iron is the most abundant micronutrient in plant mitochondria and it has a crucial role in biochemical reactions involving electron transfer. It has been described in Oryza sativa that Mitochondrial Iron Transporter (MIT) is an essential gene and that knockdown mutant rice plants have a decreased amount of iron in mitochondria, strongly suggesting that OsMIT is involved in mitochondrial iron uptake. In Arabidopsis thaliana, two genes encode MIT homologues. In this study, we analyzed different AtMIT1 and AtMIT2 mutant alleles, confirming that individually AtMIT1 nor AtMIT2 genes are essential. When we generated crosses between Atmit1 and Atmit2 alleles we were able to isolate homozygous double mutant plants. Interestingly, homozygous double mutant plants were obtained only when mutant alleles of Atmit2 with the T-DNA insertion in the intron region were used for crossings, and in these cases a correctly spliced AtMIT2 mRNA was generated, although at a low level. Atmit1 Atmit2 double homozygous mutant plants, which were knockout for AtMIT1 and knockdown for AtMIT2, were grown and chacterised in iron sufficient conditions. Pleiotropic developmental defects were observed including abnormal seeds, increased number of cotyledons, slow growth rate, pinoid stems, defects in flower structures and reduced seed set. We observed a possible phenomenon of T-DNA suppression in the next generation of Atmit1 Atmit2 double homozygous mutant plants, correlating with an increased splicing of the AtMIT2 intron containing the T-DNA. Molecular analysis of gene expression markers for mitochondrial and oxidative stress showed that Atmit1 Atmit2 double homozygous mutant plants express a degree of mitochondrial perturbation. A RNA-Seq study was performed and we could identify more than 760 genes differentially expressed in Atmit1 Atmit2, including genes involved in iron transport, coumarin metabolism, and hormones metabolism, transport and signaling. Our data suggest that some of the phenotypes observed in Atmit1 Atmit2 double homozygous mutant plants are mediated by defects in auxin homeostasis.
HYPOTHESIS | doi:10.20944/preprints202211.0211.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cancer morphospace; microenvironmental complexity; genome instability; developmental abnormalities
Online: 11 November 2022 (03:18:06 CET)
Human cancers comprise an heterogeneous array of diseases with different progression patterns and responses to therapy. However, they all develop within a host context that constraints their natural history. As it occurs with the diversity of organisms, one can conjecture that there is order in the cancer multiverse. Is there a way to capture the broad range of tumor types within a space of the possible? Here we define the oncospace, a coordinate system that integrates the ecological, evolutionary and developmental components of cancer complexity. The spatial position of a tumor results from its departure from the healthy tissue along these three axes, and progression trajectories inform about the components driving malignancy across cancer subtypes. We postulate that the oncospace topology encodes new information regarding tumorigenic pathways, subtype prognosis and therapeutic opportunities: treatment design could benefit from considering how to nudge tumors towards empty evolutionary deserts in the oncospace.
ARTICLE | doi:10.20944/preprints202203.0364.v1
Subject: Social Sciences, 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: Public Health And Healthcare, Nursing 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 And Life Sciences, Anatomy And Physiology 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 And Life Sciences, Anatomy And Physiology 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: Biology And Life Sciences, Biochemistry And Molecular Biology 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: Social Sciences, 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: Social Sciences, 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/preprints202312.0538.v1
Subject: Biology And Life Sciences, Horticulture Keywords: salt tolerant genotypes; wild tomato; developmental stages; seed germination
Online: 8 December 2023 (03:12:47 CET)
Tomato is considered moderately sensitive to salinity, which detracts from the quality and yield of its fruit; therefore, wild populations have been used as a genetic resource. The aim of this research was to identify lines derived from wild tomato populations with tolerance to salinity during the germination and seedling stages. During germination, 52 wild lines and 2 commercial hybrids were subjected to 150 mM and 0 mM NaCl and evaluated. The test was carried out for 20 days in a germination chamber with constant darkness, temperature of 25±2 °C and relative humidity of 80±4%. At the seedling stage, 22 wild tomato lines with the best performance in the germination test and 2 commercial hybrids were evaluated for 12 days in a floating raft system. Concentrations of 175 mM and 0 mM NaCl were used. Seventeen tolerant genotypes were identified at one of both developmental stages, while one genotype showed tolerance at both stages. These results indicate that there are different response mechanisms in each developmental stage. Native tomatoes play an important role in the identification of tolerant genotypes since they can be used as genetic resources for obtaining commercial genotypes with salt tolerance or as potential rootstocks.
ARTICLE | doi:10.20944/preprints202310.0167.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Developmental Coordination Disorder; DCD; Genetics; Movement Disorders; Pathogenetic Spectrum.
Online: 4 October 2023 (07:48:17 CEST)
Developmental Coordination Disorder (DCD) is a neurodevelopmental condition characterized by non-progressive central motor impairments. Mild movement disorder features have been observed in DCD. Until now, the etiology of DCD remains unclear. Recent studies suggested a genetic substrate in some patients with DCD, but comprehensive knowledge about associated genes and underlying pathogenetic mechanisms is still lacking. In this study, we first identified genes described in literature in patients with a diagnosis of DCD according to the official diagnostic criteria. Second, we exposed the underlying pathogenetic mechanisms of DCD, by investigating tissue- and temporal gene expression patterns and brain-specific biological mech-anisms. Third, we explored putative shared pathogenetic mechanisms between DCD and frequent movement disorders with a known genetic component, including ataxia, chorea, dystonia, and myoclonus. We identified 12 genes associated with DCD in literature, which are ubiquitously expressed in the central nervous system throughout brain development. These genes are involved in cellular processes, neural signaling and nervous system development. There was a remarkable overlap (62%) in pathogenetic mechanisms between DCD-associated genes and genes linked with movement disorders. Our findings suggest that some patients might have a genetic etiology of DCD, which could be considered part of a pathogenetic movement disorder spectrum.
ARTICLE | doi:10.20944/preprints202110.0337.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine 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 And Life Sciences, Animal Science, Veterinary Science And 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 And Life Sciences, Anatomy And Physiology 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.
REVIEW | doi:10.20944/preprints202311.1719.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: Dravet Syndrome; developmental epileptic encephalopathy; genetics; targeted therapy; epilepsy syndrome
Online: 28 November 2023 (08:12:09 CET)
Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.
ARTICLE | doi:10.20944/preprints202309.2097.v1
Subject: Biology And Life Sciences, Toxicology Keywords: cellular dynamics; multicellular agent-based model; computer simulation; developmental toxicity.
Online: 29 September 2023 (12:02:33 CEST)
Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the compucell3d.org modeling environment to simulate epithelial-mesenchymal transition of epiblast cells and self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, posterior/extraembryonic). Cell fate in the model is determined by an autonomous homeobox (HOX) clock driven by morphogenetic signals (e.g., FGF, WNT, ATRA, CDX). Executing the model renders a quantitative cell-level computation of mesodermal subpopulations and consequences of perturbation based on known embryogeny. For example, synthetic perturbation of the control network rendered altered phenotypes (cybermorphs) mirroring experimental mouse embryology, with 50% reductions in FGF4, FGF8 and BMP4 signaling resulting in 86%, 98% and 59% reductions, respectively in the posterior mesodermal population, while ATRA exposure also resulted in a 78% decrease in this population. This model enables integration of in vitro chemical bioactivity data for specific molecular targets with known embryology to test mechanistic veracity and quantitative prediction of altered development.
ARTICLE | doi:10.20944/preprints202308.0492.v1
Subject: Biology And Life Sciences, Plant Sciences Keywords: long sunshine; Medicago truncatula; developmental period; transcriptome analysis; functional annotation
Online: 7 August 2023 (11:54:19 CEST)
To explore the expression characteristics and biological functions of related genes of medicago terrestris under long day conditions, and to lay a foundation for revealing the molecular mechanism of medicago terrestris under long day conditions. The leaves of 'R108' tribulus Medicago sativa at branch stage (A), bud stage (B), initial flowering stage (C) and full flowering stage (D) were sequenced by RNA-Seq technology. The genome of Medicago sativa, a related species of Tribulus tribulus, was used as a reference genome for sequence comparison. The transcriptomes of three adjacent periods (A vs B, B vs C, C vs D) were analyzed for differentially expressed genes and photoperiod related differentially expressed genes were screened. A total of 6875 differentially expressed genes were detected. GO functional analysis showed that differentially expressed genes were mainly involved in biological processes, cell components and molecular functions, among which the most differentially expressed genes were involved in cell components. KEGG enrichment analysis showed that differentially expressed genes were mainly involved in circadian rhythm, photosynthesis - antenna protein, ribosome metabolism and other pathways. The number of single nucleotide variants detected by cSNP analysis was 312875, and the frequency of A/G and C/T were the highest. The function of eggNOG was divided into 23 categories, with a total of 26745 genes having similarities, 9008 genes were classified as function unknown, 2669 genes were classified as signal transduction mechanism, 2194 genes were classified as transcription, etc. In different developmental stages (A vs B, B vs C, C vs D), 3463 up-regulated and 3412 down-regulated differentially expressed genes were found. The difference between up-regulated and down-regulated genes was the most obvious between bud stage and initial flowering stage. In addition, a total of 79 flowering genes were found, of which 51 differential genes were screened out to participate in photoperiodic regulation pathway, 23 differential genes were up-regulated, and 28 differential genes were down-regulated. The ratio of gene-LOC11410562(GI), gene-LOC11435974(CO), gene-LOC11422615(TOC1) and gene-LOC11432385(LHY) was higher than that of gene-LOC25500742(PHYA) and gene-LOC11 431402(ELF3), gene-LOC11434778(Col13), gene-LOC25498015(Col6), and gene-LOC11415514(Col9) were preexpressed. The above differentially expressed genes were significantly expressed in different development stages of Terrestris alfalfa, which laid a foundation for further study of the molecular mechanism of Terrestris alfalfa.
ARTICLE | doi:10.20944/preprints202009.0290.v1
Subject: Biology And Life Sciences, Ecology, Evolution, Behavior And Systematics 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: Biology And Life Sciences, Cell And 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 And Life Sciences, 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.
ARTICLE | doi:10.20944/preprints202309.1113.v1
Subject: Computer Science And Mathematics, Information Systems Keywords: Sustainable Developmental Goal; Sustainable City; Industry 4.0; Multi-Criteria Decision Making
Online: 18 September 2023 (04:03:00 CEST)
Due to a shortage of funding and other market challenges, Small and Medium-sized Enterprises (SMEs) have a tough time adopting new technologies. Numerous technological obstacles nega-tively impact the long-term commercial achievement of SMEs. The deployment of Industry 4.0 might resolve several technological challenges. A sustainable city is a difficult structure whose economical, societal, and ecological components interact and compete with one another. There is a dearth of actual methodologies for measuring interaction. The objective of Industry 4.0 is to obtain a better degree of performance effectiveness and profitability, and greater automation. Conse-quently, the purpose of the research is to determine the influence of Industry 4.0 in fostering economic efficiency in small and medium enterprises' sustainability. A Sustainable City using Multi-Criteria Decision Making (SC-MCDM) system is designed in this research to test and achieve sustainable developmental goals. This paper then gives a technique for calculating the interaction between various standards, such as static interactions and dynamical pattern resemblance, as well as the weight variables of every indication generated by the connection. Furthermore, the ap-plication of the suggested technique is proved by assessing the sustainable development goals of twelve Chinese cities within the Triple Bottom Line (TBL) paradigm. From a geographic-temporal viewpoint, spatial variations in city sustainability reveal regional inequalities in sustainability. Indicator scores suggest that the lack of research spending, falling financing in stationary assets, shortage of financial development, and inadequate shared transit are the most significant limiting factors for most communities. Furthermore, the growth of tertiary industries, the improvement of energy performance, the expansion of green areas, and the reduction of pollution emissions are the key driving forces for enhancing sustainability. Compared to other methodologies, Multi-Criteria Decision Making (MCDM) considers the interplay between conditions, which is an excellent way to assess the sustainability of a city. The experimental findings show the impact of MCDM and sustainability to achieve sustainable development goals.
ARTICLE | doi:10.20944/preprints202305.0139.v1
Subject: Social Sciences, Education Keywords: handwriting; developmental coordination disorder; dysgraphia; psychomotor therapy; effectiveness of psychomotor therapy
Online: 3 May 2023 (10:54:55 CEST)
In Switzerland, psychomotor therapy (PMT) is a standard treatment for children with graphomotor impairments, but scientific evidence of its effectiveness is rare. To investigate the effectiveness of PMT, we conducted a randomized field trial (RFT). The sample consisted of 121 first and second graders with graphomotor impairments, some of whom met the criteria of developmental coordination disorder, while the remaining suffered from developmental dysgraphia. The treatments lasted over 5 months. Handwriting fluency and consistency were measured five times on a digitizing tablet. All participating children completed a self-concept interview, and a standardized fine motor performance test twice. Psychomotor therapy significantly improved the fine motor skills of the therapy group compared to those of the waiting group. However, there was no evidence that the treated children improved more than the waiting children in terms of their graphomotor skills such as frequency, automaticity, and consistency of forming letters. Finally, the children of the therapy group showed partial improvements in their handwriting self-concept, while those of the waiting group children remained stable. This short-term RFT demonstrated the effectiveness of PMT in terms of fine motor skills and some aspects of the handwriting self-concept but showed no effects on handwriting fluency and consistency.
REVIEW | doi:10.20944/preprints202207.0436.v1
Subject: Biology And Life Sciences, Anatomy And 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: Biology And Life Sciences, Biochemistry And Molecular Biology 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/preprints202307.2004.v1
Subject: Social Sciences, Psychology Keywords: Autism Spectrum Disorder (ASD); Havighurst developmental tasks; life histories methodology; young people; adults
Online: 28 July 2023 (11:53:11 CEST)
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition, characterized by persistent deficits in communication/social interaction and restricted and repetitive patterns of behavior, interests or activities. It is usually identified in childhood, despite late diagnoses in cases of greater functionality. Havighurst proposes a set of fundamental tasks throughout the life cycle, whose achievement is probably compromised in the ASD, even though it lacks scientific evidence. This study innovates, as it is based on Havighurst's theoretical model for understanding the development process of three adults and one young person, diagnosed with ASD level I, at different life stages. Through the methodology of life histories, interviews were subject to content analysis. Results pointed out the early detection and interventions importance, minimizing adversities, above all by those who had late diagnoses. Self-perceived success, not expected, was found in some development tasks (e.g. conscience and morality development). Also were noticed expected limitations related to ASD (e.g. difficulties in relationships with peers and in the labor market inclusion). Probably, in cases of greater severity and less functionality/autonomy, there would be greater failure in development tasks. It is crucial to improve research on this developmental model and on the factors that delay the diagnosis, including cases of different levels of severity.
ARTICLE | doi:10.20944/preprints202306.0587.v1
Subject: Social Sciences, Language And Linguistics Keywords: Grammar; clause complexity; longitudinal study; Specific Language Impairment (SLI); Developmental Language Disorder (DLD).
Online: 8 June 2023 (04:41:09 CEST)
This paper addresses the grammatical challenges associated with the development of clause complexity, focusing on the performance of a group of monolingual Spanish-speaking schoolchildren with Specific Language Impairment/Developmental Language Disorder (SLI/DLD) in a longitudinal corpus of oral narrative samples. The study examines the presence of interclause relations of subordination and equivalence (hypotaxis and parataxis) in language samples of two groups: an experimental group made up of 24 schoolchildren with SLI/DLD and a control group made up of 24 schoolchildren with typical development (TD). The results show that while both groups use parataxis as the most common relation between clauses in all school grades, there is a significant decrease in paratactic relations and a significant increase in hypotactic relations from first to fourth grade of primary education. Although the development patterns are highly similar, the SLI/DLD group shows greater difficulties in mastering more complex (hypotactic) relations in fourth grade compared to the control group, indicating that they are less sophisticated in the use of these types of complex relations. These findings suggest that focused support on the most complex structures is needed towards the fourth grade of primary education, given the demands of the school academic register from 6 and 7 years of age, and the potential problems that the development of clause complexity can cause in school-age children.
ARTICLE | doi:10.20944/preprints202111.0013.v1
Subject: Biology And Life Sciences, Biochemistry And 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/preprints202208.0355.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health 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/preprints202011.0737.v1
Subject: Social Sciences, 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 And Pharmacology, Pediatrics, Perinatology And Child Health 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 And Life Sciences, Biochemistry And Molecular Biology 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: Biology And Life Sciences, Cell And 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: Social Sciences, Cognitive Science 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/preprints202302.0160.v2
Subject: Environmental And Earth Sciences, Oceanography Keywords: Keywords: Developmental dyslexia; attentional dyslexia; Hebrew; migrations between words; phonological output buffer; orthographic-visual analyzer; reading
Online: 20 March 2023 (04:08:07 CET)
Abstract: Letter migrations between words in reading aloud (e.g., reading "cane love" as "lane love" or "lane cove") are known to result from a deficit in the visual-orthographic analysis and characterize attentional dyslexia. In spontaneous speech, individuals with impairment in the phonological output buffer may show migrations of phonemes between words. The purpose of this study was to examine whether migrations between words in reading aloud can also result from a deficit in the phonological output buffer, to explore the characteristics of migrations resulting from orthographic input and from phonological output deficits, and to examine methods to distinguish these two sources. Using tasks of reading aloud of 92-182 word pairs, we identified 18 adults and adolescents with developmental dyslexia who made between-word letter migrations in reading aloud, significantly more than age-matched controls (372 adults and 26 7th-graders). To distinguish between orthographic-input and phonological-output sources for these migrations, we administered a test assessing orthographic-input without spoken-output (written-semantic-decision on 140 migratable word pairs) and a test of repetition of 36 auditorily-presented migratable word pairs, assessing spoken output without orthographic-input (and word span tests). These tests indicated that the migrations of ten of the participants with dyslexia resulted from an orthographic-input deficit, and for the other eight participants, migrations resulted from a phonological-output deficit. We identified several differences between the two types of between-word errors: first, whereas the individuals with attentional dyslexia made omissions of a letter that appeared in the same position in the two words, the phonological output buffer group did not make such omissions. In addition, the groups differed in the origin of migration: orthographic input migrations involve letters that are orthographically adjacent, whereas phonological output migrations involve phonemes that have just been spoken or that are prepared together in the phonological buffer for production. This was manifested in that migrations from the line below and from two lines above occurred only in the orthographic input deficit group, and migrations occurred from a word vertically close to the target in the orthographic input group but from a word that has just been spoken (placed diagonally to the target) in the phonological output group. This study thus indicates that between-word migrations in reading-aloud can result not only from attentional dyslexia, but also from a phonological output buffer deficit, and offers ways to distinguish between the two.
ARTICLE | doi:10.20944/preprints202208.0135.v1
Subject: Medicine And Pharmacology, Pharmacology And 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.
ARTICLE | doi:10.20944/preprints201804.0216.v1
Subject: Social Sciences, 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.
REVIEW | doi:10.20944/preprints202308.2196.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: microbiome; cognitive bacteria; embodied cognition; behavior; holobiont; meditation; Internet of Microbes (IOM); developmental programming; quantum states; hologenome
Online: 1 September 2023 (03:29:46 CEST)
Microbes are the most prevalent and widely-distributed life form on planet Earth. They are also cognitive organisms with memory and superior problem-solving skills that use quantum phase transitions during their remarkably-effective gathering and dissemination of information. This narrative review explores the biological ramifications of human holobionts physically embodying the human microbiome and connecting to the Internet of Microbes (IOM) beyond our body. Within the review, we consider: 1) the ways in which our microbial co-partners exerted control over our ancestors and continue to influence our current human generation, 2) how they mold virtually every key aspect of our life and even remain with our body in death and 3) how inward-looking contemplative tools such as meditation and embodied cognition provide an ideal opportunity to connect to the microbial information super highway and tap the full range of human holobiont capacities.
REVIEW | doi:10.20944/preprints202110.0233.v1
Subject: Medicine And Pharmacology, Pharmacology And 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 And Pharmacology, Psychiatry And Mental Health 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/preprints202312.0654.v1
Subject: Civil Engineering, Engineering Keywords: Non-Structural Elements (NSE); Life Cycle Cost Assessment; Social Life Cycle Assessment; Resilience; Sustainable Developmental Goals (SDG’ s)
Online: 11 December 2023 (06:01:48 CET)
The response of building elements during earthquakes has been an area of concern for different researchers around the world. The NSEs are the first elements to attain failure, the buildings after damages in safety priority are classified as in “Life Safety” mode, but in reality, they are in “Collapse Safety” mode and the occupants inside the buildings are in a state of “Non-Life Safety” as a result of falling of the hazardous NSE’s like cladding's, partitions, hanging objects. In addition to the Life Cycle Cost Assessment (LCCA), the Social Life Cycle Assessment (SLCA) is overlooked by the majority of the researchers, the community must be prepared to respond to an event more efficiently without any major casualties or loss of life. It is expected that by the end of 2050, almost double the construction will take place, the embodied energy during the pre-construction, post-construction and demolition generates a lot of CO2s into the environment, hence sustainability should be given due importance, helping in the achievement of Sustainable Developmental Goals (SDGs).
ARTICLE | doi:10.20944/preprints202310.1085.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: endogenous neuromodulation; neurofeedback; Infra-Low frequency; slow cortical potential; intrinsic connectivity networks; infra-slow fluctuations; EEG biofeedback; developmental trauma
Online: 17 October 2023 (11:24:17 CEST)
Clinical work conducted over the last seventeen years at the EEG Institute in Los Angeles and by other neurofeedback providers around the world has demonstrated the utility of extending frequency-based neurofeedback deep into the infra-low frequency (ILF) region, using the method of endogenous neuromodulation described herein. The method is characterized by the absence of any overt reinforcements, which makes it possible to extend the clinical reach to extremely low frequencies. As the training frequency is lowered, the signal becomes more difficult to discriminate, and ultimately it can only be discerned by the brain itself, in the process of endogenous neuromodulation. The method emulates how the brain does skill learning in general: It must observe itself performing the skill, with feedback on its performance. While the immediate target of ILF neurofeedback is enhanced self-regulatory competence--with symptomatic relief and functional recovery the secondary consequences, progressive lowering of the target frequencies has led to improved outcomes in application to challenging dysfunctions such as episodic suicidality, migraine, seizures, and bipolar mood swings. The work has also yielded insights into how the frequency domain is organized. The training proceeds best at frequencies that are specific to each individual, and these are referred to as optimal response frequencies (ORFs). These frequencies differ for various placements but stand in two fixed relationships to one another, one that holds over the EEG spectral range, and another that holds over the entire ILF range. Training in the ILF region engages the dynamics of the glial-neuronal networks, which govern tonic, resting state regulation. The collective clinical experience with ILF neuromodulation within a large practitioner network supports the case for making protocol-based, individualized ‘homeodynamic’ regulation a therapeutic priority, particularly for our most impacted clinical populations: addiction, trauma formations, traumatic brain injury, and the dementias. The case is made for further outcome studies and foundational research.
ARTICLE | doi:10.20944/preprints202309.0971.v1
Subject: Social Sciences, Behavior Sciences Keywords: processing speed; developmental trajectories; primary school education; cross-country longitudinal study; mixed effects growth modeling; latent class growth modeling
Online: 14 September 2023 (08:46:02 CEST)
This cross-country four-year longitudinal study investigated the development of processing speed throughout primary school education. The analyses were conducted on data collected from 441 schoolchildren in Grades 1, 2, 3 and 4 (aged 6.42 to 11.85 years) in the Kyrgyzstan and Russia. Mixed effects growth modeling was applied to estimate average and individual growth trajectories for processing speed at two cross-country samples. Latent class growth modeling was conducted to identify different types of growth trajectories for processing speed and to compare the distribution of the types within the analyzed samples. According to the results, processing speed significantly increases across primary school years. The trajectory is characterized by nonlinear changes with more intensive growth between Grades 1 and 2, which later slows down until Grade 4. There were no significant cross-country differences in the initial score of processing speed or developmental changes in processing speed across primary school years. The development of processing speed is described by a model with three quadratic growth types but minimally differs. It is concluded that in both samples, the development of processing speed may be characterized by homogeneity, with the most intensive growth from Grade 1 to Grade 2 and subsequent linear improvement until Grade 4.
REVIEW | doi:10.20944/preprints202103.0245.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology 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 And Pharmacology, Immunology And Allergy 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: Social Sciences, 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
ARTICLE | doi:10.20944/preprints202205.0280.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology 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.
ARTICLE | doi:10.20944/preprints202310.0053.v1
Subject: Biology And Life Sciences, Aging Keywords: aging vs survival; DNA damage; double-stranded breaks; Gompertz-Makeham Law; developmental regulatory redundancy; tradeoffs vs emergent properties; fecundity; reproductive fitness; redundancy reliabiiity; programmed aging
Online: 2 October 2023 (08:08:57 CEST)
Formulating a novel concept about the origin of human aging has been constrained by the dominance of a “classic theory” that was proposed nearly 70 years ago. Despite concern over the validity of some of its assumptions, the theory remained basic to our understanding of aging’s relationship with natural selection (NS). However, the logic upon which it rests was tested and subsequently challenged. The present theory describes the single cause of human aging consistent with Darwin’s evolutionary requirement for selection of adaptive traits. It describes an emergent property of the developmental program (DP), that is expressed upon completion of ontogenesis. It involves redundant expression of regulatory processes from the last stage of the DP. That mechanism subsequently preserves a non-aging, stable interval of unchanging NS during which reproductive fitness is achieved. Thereafter, loss of DP regulatory redundancy due to reliability limits, stochastic mutation accumulation, reproductive and a specific type of DNA damage, initiates aging which causes an inexorable decline in strength of NS to begin. It starts approximately a decade later than proposed in the classic theory. Since reproduction and aging are inextricably linked by the same emergent property, selection of that regulatory mechanism makes both traits products of NS.
REVIEW | doi:10.20944/preprints202005.0472.v1
Subject: Biology And Life Sciences, 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: Biology And Life Sciences, Biochemistry And Molecular Biology 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.