Development Function Research Articles

Therapeutic value of homeoprotein signaling pathways.

Cell signaling based on homeoprotein transfer is a pathway with developmental and physiological functions. For a few transcription factors of this family, primarily ENGRAILED1, ENGRAILED2 and OTX2, their physiological functions have led to therapeutic strategies in animal models of human diseases, including Parkinson's disease, amyotrophic lateral sclerosis, amblyopia and anxiety-related disorders. In mesencephalic dopaminergic neurons which degenerate in Parkinson's disease, ENGRAILED1/2 have cell autonomous activities, but their transducing properties enables their use as therapeutic proteins. In contrast, in spinal alpha-motoneurons, which are lost in amyotrophic lateral sclerosis, ENGRAILED1 is supplied by V1 interneurons. Thus, its use as a therapeutic protein to protect alpha-motoneurons against degeneration mimics its normal non-cell autonomous neurotrophic activity. OTX2, synthesized and secreted by the choroid plexus, is transferred to parvalbumin interneurons and exerts regulatory functions controlling cerebral cortex plasticity. Understanding the latter OTX2 function has led to strategies for manipulating visual acuity and anxiety-like behavior in adult mice. In this review, we describe these cases and what is known about the involved molecular mechanisms. Because the transduction sequences are conserved in most of the few hundred homeoproteins, we argue how this family of molecules constitutes an important reservoir of physiological knowledge, with potential consequences in the search for new therapeutic strategies.

Organ-level distribution tandem mass spectrometry analysis of three structural types of brassinosteroids in rapeseed.

Brassinosteroids (BRs) are a class of naturally occurring steroidal phytohormones mediating a wide range of pivotal developmental and physiological functions throughout the plant's life cycle. Therefore, it is of great significance to determine the content and the distribution of BRs in plants.Regretfully, although a large number of quantitative methods for BRs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) have been reported, the in planta distribution of BRs is still unclear because of their lower contents in plant tissues and the lack of effective ionizable groups in their chemical structures. We stablished a novel analytical method of BRs based on C18 cartridge solid-phase extraction (SPE) purification, 4-(dimethylamino)-phenylboronic acid (DMAPBA) derivatization, and online valve-switching system coupled with ultra-high performance liquid chromatography-electro spray ionization-triple quadrupole mass spectrometry (UHPLC-ESI-MS/MS). This method has been used to quantify three structural types of BRs (epibrassinolide, epicastasterone, and 6-deoxo-24-epicastaster one) in different organs of Brassica napus L. (rapeseed). We obtained the contents of three structural types of BRs in various organ tissues of rapeseed. The contents of three BRs in rapeseed flowers were the highest, followed by tender pods. The levels of three BRs all decreased during the maturation of the organs. We outlined the spatial distribution maps of three BRs in rapeseed based on these results, so as to understand the spatial distribution of BRs at the visual level. Our results provided useful information for the precise in situ localization of BRs in plants and the metabolomic research of BRs in future work. The in planta spatial distribution of BRs at the visual level has been studied for the first time.

Griboyedov’s Ball in the System of Historical Ballroom Dancing Traditions

The article deals with the ballroom dance practice peculiar to the culture of Russian society of the early 18th—19th century. Ball tradition is a “polyfunctional sociocultural phenomenon”, realizing important functions of culture, activating the process of aesthetic and ethical education of a personality involved in historical ball events. Historical ball culture is one of the forms of sociocultural practice of the nobility, which participated in dance celebrations according to the established ball structure, having a ceremonial form and its own aesthetic stylistics. One of the main motives for the fascination with balls was the aspiration of a part of the educated nobility for its own socialization within the estate. The period of flourishing of the ballroom dancing tradition fell on the second half of the 18th — first half of the 19th century. After the Imperial Court Ball in 1904 in the Winter Palace of St. Petersburg, the tradition of this type of festivities was interrupted. In the 1980s and early 1990s, through the efforts of enthusiastic constructors, ballroom dance programmes began to revive. In modern Russia, the institute of historical ballroom dancing clubs has been formed, and an institutional environment of entities engaged in the study and promotion of historical ballroom traditions is gradually forming.Ballroom culture is characterized by a whole range of developmental functions that contribute to the formation of a socially adapted personality. The author proposes to supplement the communicative and marketing group of functions, inherent in the revival of historical ballroom traditions, with the function of social mythologization. To prove this thesis, the author defines the properties of ball culture as a social myth, which possesses rationality (consciousness), conceptual development (ceremoniality), aesthetic orientation, the presence of intension, communication, presentation or marketing purposes of the groups of people involved in it.The symbolic experience of re-enactors in recreating historical dances is largely mythologemic in nature, appealing to some of today’s youth and adults. Passionate about ballroom culture under the guidance of experienced choreographers, they create memorable aesthetic ballroom symbols, involving patrons and supporters in the process. Griboyedov’s historical ballroom dance programmes are part of the institutional environment considered in this article, correspond to the style of the noble era, have a ceremonial and entertaining context and contribute to the promotion of the cultural heritage of the great Russian playwright and diplomat A.S. Griboyedov.

Validation of factor structure of the neurodevelopmental parent report for outcome monitoring in down syndrome: confirmatory factor analysis.

The Neurodevelopmental Parent Report for Outcome Monitoring (ND-PROM), initially developed to monitor developmental and behavioral functions in children with autism spectrum disorder (ASD), assesses symptoms across a wide range of domains relevant in Down syndrome (DS). Psychometric properties of ND-PROM were assessed in 385 individuals with DS and 52 with a combined diagnosis of DS and ASD (DS+ASD), whose caregivers completed the ND-PROM questionnaire for a clinical visit in a specialized Down syndrome program at a tertiary pediatric hospital. Confirmatory factor analysis was conducted to evaluate the internal structure validity of the ND-PROM. Measurement invariance was assessed, with a comparison group of 246 individuals with ASD, and latent mean differences between the DS and ASD-only groups, as well as the combined DS+ASD groups, were assessed. Findings support the existence of the 12 clinically-derived factors in the DS population: Expressive Language, Receptive Language, Adaptive skills/Toileting, Social Emotional Understanding, Social Interaction, Independent Play, Sensory Processes, Challenging Behaviors, Impulse/ADHD, and Mental Health. Differences in response patterns of development and behaviors were observed between those with DS and those with ASD, including those with DS having higher abilities in nonverbal communication, social emotional understanding, and social interaction, and fewer restricted and repetitive behaviors and interests, impulsivity or ADHD symptoms, and mental health concerns compared to those with ASD. Individuals in the DS+ASD group had more difficulties with expressive and receptive language, nonverbal and social communication, social interaction, independent play, and adaptive skills than either the DS-only group or the ASD-only groups. The ND-PROM has a desirable factor structure and is a valid and clinically useful tool that captures a range of distinct and independent areas of developmental and behavioral functioning in DS, for individuals with and without an ASD diagnosis.

Developing Sex: From Recremental Semen to Developmental Endocrinology.

During the 1890s, animal development became associated with glandular activity, with profound implications for pediatric nosology and treatment. The significance of this endocrinological turn of developmental physiology and pathophysiology in part hinges on an often-overlooked continuity with ubiquitous early modern medical thought concerning semen as a recrementitious (reabsorbed) nutrient or stimulant. Mid-19th-century interests in adult sexual physiology were increasingly nerve-centered and antihumoral. Scattered empirical, particularly veterinarian, interests in gonadal developmental functions failed to moderate these explanatory trends. While Brown-Séquard's rejuvenation experiments still offered no clear starting point for a developmental endocrinology, in 1892 Gaston Variot and Paul Bezançon more explicitly deduced a testicular developmental endocrinological function from various observations on testicular ectopy and a local form of animal "demi-castration." Ensuing interest in thethyroid, thethymus and in thetesticles led to various working conceptions of their respective and putatively reciprocal developmental properties, including the idea of a thyroid-testis axis. From 1896, the pubertal affliction of chlorosis became the subject of multiple opotherapeutic approaches, providing an experimental basis for theories of ovarian internal secretion. Polyglandular therapy, piloted for divergent developmental conditions, remained routine until the 1930s despite the biological inefficacy of many endocrine products.

Multiscale Mineralization in the Leopard Gecko Eggshell

AbstractReptilian (non‐avian) eggshell biomineralization is markedly different from avian eggshells. Despite discontinuous/variable mineralization, the reptilian eggshell (like in birds) is responsible for protective and developmental functions of the egg as part of a highly successful reproduction strategy. Using multiscale imaging and characterization methods including X‐ray and electron microscopy/tomography, a 3D overview of eggshell ultrastructure in the gekkotan Eublepharis macularius – the common leopard gecko is provided. Eggshell mineral is shown to be sensitive to aqueous preparations, where cryogenic methods are essential for accurate mineral and organic preservation. Interwoven with the mineral are underlying organic fibers involved in the formation of complex hierarchical order in the eggshell, including nucleation and growth of mineral. The calcitic mineral phase of the eggshell takes on three microstructural motifs at the shell surface: nodular scutes (≈40 µm), intermittent blunt or star‐shaped mineral rosettes (≈1 mm), and smaller mineral corollas (≈10 µm). Individual scutes have two hierarchical mineral structures – mineral nanospheres (≈500 nm) and mineral nanodomains (≈40 nm). Diverse and variable biomineralization features of reptilian eggshells likely reflect the importance of differences in ecology and physiology on egg formation, survival, and eggshell mechanics, and are likely related to hydration sensitivity, structural organic‐inorganic interactions, and mineral polymorphism.

Developmental patterning function of GNOM ARF-GEF mediated from the cell periphery.

The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its closest homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study largely extend the current notions of GN function. We show that GN, but not GNL1, localizes to the cell periphery at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that the cell periphery is the major site of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations en route to the cell periphery. A study of GN-GNL1 chimeric ARF-GEFs indicates that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps toward the elucidation of the mechanism underlying unique cellular and development functions of GNOM.

Dynamics of miRNA accumulation during C. elegans larval development.

Temporally and spatially controlled accumulation underlies the functions of microRNAs (miRNAs) in various developmental processes. In Caenorhabditis elegans, this is exemplified by the temporal patterning miRNAs lin-4 and let-7, but for most miRNAs, developmental expression patterns remain poorly resolved. Indeed, experimentally observed long half-lives may constrain possible dynamics. Here, we profile miRNA expression throughout C. elegans postembryonic development at high temporal resolution, which identifies dynamically expressed miRNAs. We use mathematical models to explore the underlying mechanisms. For let-7, we can explain, and experimentally confirm, a striking stepwise accumulation pattern through a combination of rhythmic transcription and stage-specific regulation of precursor processing by the RNA-binding protein LIN-28. By contrast, the dynamics of several other miRNAs cannot be explained by regulation of production rates alone. Specifically, we show that a combination of oscillatory transcription and rhythmic decay drive rhythmic accumulation of miR-235, orthologous to miR-92 in other animals. We demonstrate that decay of miR-235 and additional miRNAs depends on EBAX-1, previously implicated in target-directed miRNA degradation (TDMD). Taken together, our results provide insight into dynamic miRNA decay and establish a resource to studying both the developmental functions of, and the regulatory mechanisms acting on, miRNAs.

Glutathione safeguards TET-dependent DNA demethylation and is critical for the acquisition of totipotency and pluripotency during preimplantation development.

During early development, both genome-wide epigenetic reprogramming and metabolic remodeling are hallmark changes of normal embryogenesis. However, little is known about their relationship and developmental functions during the preimplantation window, which is essential for the acquisition of totipotency and pluripotency. Herein, we reported that glutathione (GSH), a ubiquitous intracellular protective antioxidant that maintains mitochondrial function and redox homeostasis, plays a critical role in safeguarding postfertilization DNA demethylation and is essential for establishing developmental potential in preimplantation embryos. By profiling mitochondria-related transcriptome that coupled with different pluripotency, we found GSH is a potential marker that is tightly correlated with full pluripotency, and its beneficial effect on prompting developmental potential was functionally conformed using invitro fertilized mouse and bovine embryos as the model. Mechanistic study based on preimplantation embryos and embryonic stem cells further revealed that GSH prompts the acquisition of totipotency and pluripotency by facilitating ten-eleven-translocation (TET)-dependent DNA demethylation, and ascorbic acid (AsA)-GSH cycle is implicated in the process. In addition, we also reported that GSH serves as an oviductal paracrine factor that supports development potential of preimplantation embryos. Thus, our results not only advance the current knowledge of functional links between epigenetic reprogramming and metabolic remodeling during preimplantation development but also provided a promising approach for improving current invitro culture system for assisted reproductive technology.

First characterization of the nuclear receptor superfamily in the Mediterranean mussel Mytilus galloprovincialis: developmental expression dynamics and potential susceptibility to environmental chemicals.

Endocrine-disrupting chemicals (EDCs) represent a global threat to human health and the environment. In vertebrates, lipophilic EDCs primarily act by mimicking endogenous hormones, thus interfering with the transcriptional activity of nuclear receptors (NRs). The demonstration of the direct translation of these mechanisms into perturbation of NR-mediated physiological functions in invertebrates, however, has rarely proven successful, as the modes of action of EDCs in vertebrates and invertebrates seem to be distinct. In the present work, we investigated the members of the NR superfamily in a bivalve mollusk, the Mediterranean mussel Mytilus galloprovincialis. In addition to annotating the M. galloprovincialis NR complement, we assessed the potential developmental functions and susceptibility to EDC challenge during early development by gene expression analyses. Our results indicate that a majority of mussel NRs are dynamically expressed during early development, including receptors characterized by a potential susceptibility to EDCs. This study thus indicates that NRs are major regulators of early mussel development and that NR-mediated endocrine disruption in the mussel could be occurring at a larger scale and at earlier stages of the life cycle than previously anticipated. Altogether, these findings will have significant repercussions for our understanding of the stability of natural mussel populations. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.

Plant cuticles repress organ initiation and development during skotomorphogenesis in Arabidopsis

After germination in the dark, plants produce a shoot apical hook and closed cotyledons to protect the quiescent shoot apical meristem (SAM), which is critical for seedling survival during skotomorphogenesis. The factors that coordinate these processes, particularly SAM repression, remain enigmatic. Plant cuticles, multilayered structures of lipid components on the outermost surface of the aerial epidermis of all land plants, provide protection against desiccation and external environmental stresses. Whether and how cuticles regulate plant development are still unclear. Here, we demonstrate that mutants of BODYGUARD1 (BDG1) and long-chain acyl-CoA synthetase2 (LACS2), key genes involved in cutin biosynthesis, produce a short hypocotyl with an opened apical hook and cotyledons in which the SAM is activated during skotomorphogenesis. Light signaling represses expression of BDG1 and LACS2, as well as cutin biosynthesis. Transcriptome analysis revealed that cuticles are critical for skotomorphogenesis, particularly for the development and function of chloroplasts. Genetic and molecular analyses showed that decreased HOOKLESS1 expression results in apical hook opening in the mutants. When hypoxia-induced expression of LITTLE ZIPPER2 at the SAM promotes organ initiation in the mutants, the de-repressed expression of cell-cycle genes and the cytokinin response induce the growth of true leaves. Our results reveal previously unrecognized developmental functions of the plant cuticle during skotomorphogenesis and demonstrate a mechanism by which light initiates photomorphogenesis through dynamic regulation of cuticle synthesis to induce coordinated and systemic changes in organ development and growth during the skotomorphogenesis-to-photomorphogenesis transition.

Striking a growth-defense balance: Stress regulators that function in maize development.

Maize (Zea mays) cultivation is strongly affected by both abiotic and biotic stress, leading to reduced growth and productivity. It has recently become clear that regulators of plant stress responses, including the phytohormones abscisic acid (ABA), ethylene (ET), and jasmonic acid (JA), together with reactive oxygen species (ROS), shape plant growth and development. Beyond their well established functions in stress responses, these molecules play crucial roles in balancing growth and defense, which must be finely tuned to achieve high yields in crops while maintaining some level of defense. In this review, we provide an in-depth analysis of recent research on the developmental functions of stress regulators, focusing specifically on maize. By unraveling the contributions of these regulators to maize development, we present new avenues for enhancing maize cultivation and growth while highlighting the potential risks associated with manipulating stress regulators to enhance grain yields in the face of environmental challenges.

Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation.

Background: IL-35 potently inhibits immune responses both in vivo and in vitro. However, the specific characteristics of IL-35-producing cells, including their developmental origin, cellular phenotype, and function, are unknown. Methods: By using a novel IL-35 reporter mouse (Ebi3-Dre-Thy1.1) and double transgenic fate-mapping reporter mice (35EbiT-Rosa26-rox-tdTomato reporter mice or Foxp3 fate-mapping system), we tracked and analyzed the differentiation and developmental trajectories of Tr35 cells in vivo. And then we investigated the therapeutic effects of OVA-specific Tr35 cells in an OVA-induced allergic airway disease model. Results: We identified a subset of cells, denoted Tr35 cells, that secrete IL-35 but do not express Foxp3. These cells have high expression of molecules associated with T-cell activation and can inhibit T-cell proliferation in vitro. Our analyses showed that Tr35 cells are a distinct subpopulation of cells that are independent of Tr1 cells. Tr35 cells exhibit a unique gene expression profile and tissue distribution. The presence of Thy1.1 (Ebi3) expression in Tr35 cells indicates their active secretion of IL-35. However, the proportion of ex-Tr35 cells (Thy1.1-) is significantly higher compared to Tr35 cells (Thy1.1+). This suggests that Tr35 cells possess the ability to regulate IL-35 expression rapidly in vivo. Tr35 cells downregulated the expression of the inflammatory cytokines IL-4, IFN-γ and IL-17A. However, once Tr35 cells lost IL-35 expression and became exTr35 cells, the expression of inflammatory cytokines was upregulated. Importantly, our findings indicate that Tr35 cells have therapeutic potential. In an OVA-induced allergic airway disease mouse model, Tr35 cell reinfusion significantly reduced airway hyperresponsiveness and histopathological airway and lung inflammation. Conclusions: We have identified a subset of Tregs, Tr35 cells, that are distinct from Tr1 cells. Tr35 cells can dynamically regulate the secretion of inflammatory cytokines by controlling IL-35 expression to regulate inflammatory immune responses.

Інтенсифікація інтелектуального розвитку дітей дошкільного віку засобами сюжетно-рольових та дидактичних ігор

The article defines the essence of a child’s intellectual development: the implementation of thinking and logical operations, tasks, situations and problems, obtaining results and conclusions. An analysis of theoretical and methodological research on the research topic was carried out. The spiritual-cultural, moral-ethical, artistic-visual, aesthetic, speech-developing, historical-local lore, logical-mathematical, natural-informative didactic potential of various games was determined. The stages of involvement of a preschool child in educational processes for the intensification of intellectual development are highlighted. The implementation of educational, educational and developmental educational functions through the use of story role-playing, didactic games in the educational process of preschool in different age groups is indicated. The basis of the organization of story role-playing games by preschoolers through their observation of the work of doctors, cooks, farmers, teachers, as well as the activities of people of various professions is singled out. Pedagogical conditions for the intellectual development of preschool children by means of didactic games are identified: thinking through the content of educational and didactic material, planning and organizing the procedural conduct of didactic games, stimulating the generalization of acquired knowledge by preschoolers and consolidation of new material; creating situations and selecting elements of didactic games; cognitive and developmental direction of preschoolers’ abilities; development of sensory, logical-mathematical, speech-cultural and artistic-creative abilities; division of didactic games into simpler elementary parts, as well as synthesis into complex tasks; revealing the prospects of using knowledge in everyday life and in non-standard situations. The types of didactic games for the intellectual development of preschool children have been determined: games with objects (toys), natural material, board-printed and word games.

Microgravity Inhibits Cell Proliferation and Promotes Senescence and Apoptosis in Embryonic Stem Cells

With advancements in deep space exploration missions, long-term spaceflights pose potential hazards to the reproductive and developmental functions of astronauts. Embryonic stem cells (ESCs), which are crucial to the development and growth of individual organisms, are observably altered by a microgravity environment. However, the role and mechanisms of microgravity in other activities of ESCs are still unclear. Here, mouse embryonic stem cells (mESCs) were used to investigate and understand the effect of microgravity on their activities. Combined with the SJ-10 satellite and random position machine, which were utilized for spaceflight and microgravity simulation, respectively, the bioinformatic tools were also used to assess the effect that microgravity might have on mESC activities. Based on differentially expressed genes (DEGs) analysis, 114 DEGs were significantly up-regulated and 859 DEGs were significantly down-regulated in mESCs after being subjected to spaceflight. The activities, such as cell proliferation, senescence, and apoptosis, were selected and confirmed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. It demonstrated a reduced proliferation capability of mESCs but increased the number of senescent and apoptotic cells after being subjected to simulated microgravity. Real-time polymerase chain reaction analysis of the screened activity-related DEGs demonstrated approximately consistent trends of these gene expressions in both spaceflight and simulated microgravity, as was predicted by bioinformatics analysis. Overall, these findings suggest that microgravity inhibits the proliferation of mESCs and induces senescence and apoptosis, shedding light on the impact of microgravity on the fundamental functions of mESCs in reproductive and embryonic development.

Neurobehavioral toxic effects and mechanisms of 2-aminobenzothiazole exposure on zebrafish

2-Aminobenzothiazole (NTH), a benzothiazole derivative, exhibits potent biochemical activities and plays a significant role in modern industry. Widespread and intensive utilization of NTH has led to its detection in aquatic environments, encompassing both groundwater and surface water. Despite its wide usage, the effect of NTH on developmental neurotoxicity in aquatic organisms remains uncharted. Therefore, the aim of this investigation was to create exposure models for short- and long-term studies in order to analyze the neurobehavioral toxic impact of NTH (0, 50, 500, and 5000 μg/L) on zebrafish, which includes motor function, anxiety, and memory performance, as well as to examine the mechanism of neurotoxicity. The results revealed a significant suppression of initial embryonic mobility by NTH. However, during short-term exposure experiments, it did not significantly impact the developmental neurobehavioral functions of zebrafish. In addition, significant effects on zebrafish were observed after long-term exposure to 50 and 500 μg/L NTH, mainly impacting locomotion, social behavior, anxiety, and cognitive functions. Moreover, NTH caused oxidative damage in adult zebrafish brain tissue, which was accompanied by abnormal expression of oxidative damage-related genes. Furthermore, the Real-Time PCR results indicated a significant suppression of genes related to exposure to NTH, specifically those in the GABA synthesis pathway (gabrg2, gad2, gad1b, and abat) and the 5-HT synthesis pathway (tph2, tph1b, pet1, and htr1aa). Taken together, this study demonstrates for the first time that chronic exposure to NTH decreases the expression of genes associated with the zebrafish GABA synthesis pathway and the 5-HT synthesis pathway. This suppression is accompanied by oxidative damage, ultimately resulting in neurobehavioral changes related to motor ability, anxiety, and memory performance.

Intellectual function of a productive social character

The humanistic-psychological aspect of the problem of the totalitarianism psychological basis, in particular racism, is the formation of resistance to totalitarian ideas among the citizens of those states that have chosen the path of social progress. It is shown that this basis is formed by conscious and unconscious conformists and individuals who are unable to understand socio-political and socio-economic realities on their own due to a low IQ level. Thus, it has been proven that the formation of psychological resistance to totalitarian ideas should be based not on the development of the intellect, but on character education. If intelligence is not only the IQ level, but also a derivative of a person’s independence and courage, and stupidity and dullness – from fear and subordination, then what is needed is not an increase in “intelligence”, but the education of a productive social character of citizens, which is characterized by independence, persistence, love of life in all its healthy and beautiful manifestations. Therefore, the intellectual function of a productive social character is its constant focus on solving socio-political tasks, solving social problems from the standpoint of humanistic spiritual values. The primary condition of formation of such a character is the development of the ability to love, which is born in the process of communication with a child, saturated with generous manifestations of sincere love, from its birth. Then there is a full-fledged gaming activity (“fair game”). Satisfaction the benevolent self-regulation in such a game corresponds to the emotion-motivational center of decency as an essential component of a virtuous social character, therefore, which accelerates its development. he age-related transition of the leading developmental function from communication to play does not reduce the power of sincere love for a child in terms of enriching his biophilia. A sufficient condition for a child’s full-fledged development is his cognitive activity, which requires significant mental and volitional efforts, which are most effectively motivated by the curiosity of the learning process. Students should be primarily got interested by the content of the subjects of the artistic-aesthetic cycle, because a full-fledged artistic-aesthetic activity is interesting, exciting, creative, and because their main task is precisely the education of a spiritual orientation of a personality. Self-actualization is a person’s work on himself, which powerfully develops biophilia. Personalities who are self-actualized love their work, enjoy their professional competence and self-realization, which is a significant component of biophilia. A set of self traits is developed in them, that perfectly correspond to a productive social character.

'All the progressive forms of life are built up on the attraction of sex': Development and the social function of the sexual instinct in late 19th- and early 20th-century Western European sexology.

This article explores the relationship between sexual science and evolutionary models of human development and progress. It examines the ways in which late 19th- and early 20th-century Western European sexual scientists constructed the sexual instinct as an evolutionary force that not only served a reproductive purpose, but was also pivotal to the social, moral, and cultural development of human societies. Sexual scientists challenged the idea that non-reproductive sexualities were necessarily perverse, pathological, or degenerative by linking sexual desire to the evolution of sociality, often focusing on forms of relationality and care that exceeded biological kinship. As a result, non-reproductive sexual expressions, including homosexual and non-reproductive heterosexual behaviours, were interpreted as manifestations of a sexual instinct operating in the service of human development. These claims were reliant on cross-cultural and historical comparisons of sexual values, behaviours, and customs that rehearsed and reinforced imperial narratives of development premised on racialized, gendered, and classed hierarchies. Sexual scientists mapped diverse sexual behaviours in terms of their perceived evolutionary benefits, contributing to colonial narratives that distinguished between different cultures according to imagined trajectories of development. These contestations around the sexual instinct and its developmental functions played a vital role in allowing sexual science to authorize itself as a field of knowledge that promised to provide expertise required to manage sexual life and secure the global development of human civilization.

Notch1 Regulates Hepatic Thrombopoietin Production

Notch signaling is highly conserved and regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production has not been described. We noted that mice with a deficiency in hepatic Notch1 had thrombocytopenia, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of circulating platelets and impaired megakaryocyte differentiation and maturation. Addition of exogenous TPO rescued megakaryocyte maturation and circulating platelet numbers. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes. RNA-seq analysis showed significantly reduced JAK-STAT signaling. JAK2/STAT3 phosphorylation and TPO production was also impaired in purified cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron.

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.