Developmental Trajectories Research Articles

Variation in gaze following across the life span: A process-level perspective.

Following eye gaze is fundamental for many social-cognitive abilities, for example, when judging what another agent can or cannot know. While the emergence of gaze following has been thoroughly studied on a group level, we know little about (a) the developmental trajectory beyond infancy and (b) the sources of individual differences. In Study 1, we examined gaze following across the lifespan (N=478 3- to 19-year-olds from Leipzig, Germany; and N=240 20- to 80-year-old international, remotely tested adults). We found a steep performance improvement during preschool years, in which children became more precise in locating the attentional focus of an agent. Precision levels then stayed comparably stable throughout adulthood with a minor decline toward old age. In Study 2, we formalized the process of gaze following in a computational cognitive model that allowed us to conceptualize individual differences in a psychologically meaningful way (N=60 3- to 5-year-olds, 50 adults). According to our model, participants estimate pupil angles with varying levels of precision based on observing the pupil location within the agent's eyes. In Study 3, we empirically tested how gaze following relates to vector following in non-social settings and perspective-taking abilities (N=102 4- to 5-year-olds). We found that gaze following is associated with both of these abilities but less so with other Theory of Mind tasks. This work illustrates how the combination of reliable measurement instruments and formal theoretical models allows us to explore the in(ter)dependence of core social-cognitive processes in greater detail. RESEARCH HIGHLIGHTS: Gaze following develops beyond infancy. The highest precision levels in localizing attentional foci are reached in young adulthood with a slight decrease towards old age. We present a computational model that describes gaze following as a process of estimating pupil angles and the corresponding gaze vectors. The model explains individual differences and recovers signature patterns in the data. To estimate the relation between gaze- and vector following, we designed a non-social vector following task. We found substantial correlations between gaze following and vector following, as well as Level 2 perspective-taking. Other Theory of Mind tasks did not correlate.

Delayed recruitment of activity-dependent bulk endocytosis in Fmr1 knockout neurons.

The presynapse performs an essential role in brain communication via the activity-dependent release of neurotransmitters. However, the sequence of events through which a presynapse acquires functionality is relatively poorly understood, which is surprising, since mutations in genes essential for its operation are heavily implicated in neurodevelopmental disorders. We addressed this gap in knowledge by determining the developmental trajectory of synaptic vesicle (SV) recycling pathways in primary cultures of rat hippocampal neurons. Exploiting a series of optical and morphological assays, we revealed that the majority of nerve terminals displayed activity-dependent calcium influx from 3 days invitro (DIV), immediately followed by functional evoked exocytosis and endocytosis, although the number of responsive nerve terminals continued to increase until the second week invitro. However, the most intriguing discovery was that activity-dependent bulk endocytosis (ADBE) was only observed from DIV 14 onwards. Importantly, optimal ADBE recruitment was delayed until DIV 21 in Fmr1 knockout neurons, which model Fragile X Syndrome (FXS). This implicates the delayed recruitment of ADBE as a potential contributing factor in the development of circuit dysfunction in FXS, and potentially other neurodevelopmental disorders.

The role of lexical and prosodic characteristics of mothers' child-directed speech for the early vocabulary development of Italian children with cochlear implants.

Variability in the vocabulary outcomes of children with cochlear implants (CIs) is partially explained by child-directed speech (CDS) characteristics. Yet, relatively little is known about whether and how mothers adapt their lexical and prosodic characteristics to the child's hearing status (before and after implantation, and compared with groups with normal hearing (NH)) and how important they are in affecting vocabulary development in the first 12 months of hearing experience. To investigate whether mothers of children with CIs produce CDS with similar lexical and prosodic characteristics compared with mothers of age-matched children with NH, and whether they modify these characteristics after implantation. In addition, to investigate whether mothers' CDS characteristics predict children's early vocabulary skills before and after implantation. A total of 34 dyads (17 with NH, 17 with children with CIs; ages = 9-32 months), all acquiring Italian, were involved in the study. Mothers' and children's lexical quantity (tokens) and variety (types), mothers' prosodic characteristics (pitch range and variability), and children's vocabulary skills were assessed at two time points, corresponding to before and 1 year post-CI activation for children with CIs. Children's vocabulary skills were assessed using parent reports; lexical and prosodic characteristics were observed in semi-structured mother-child interactions. Results showed that mothers of children with CIs produced speech with similar lexical quantity but lower lexical variety, and with increased pitch range and variability, than mothers of children with NH. Mothers generally increased their lexical quantity and variety and their pitch range between sessions. Children with CIs showed reduced expressive vocabulary and lower lexical quantity and variety than their peers 12 months post-CI activation. Mothers' prosodic characteristics did not explain variance in children's vocabulary skills; their lexical characteristics predicted children's early vocabulary and lexical outcomes, especially in the NH group, but were not related to later language development. Our findings confirm previous studies on other languages and support the idea that the lexical characteristics of mothers' CDS have a positive effect on children's early measures of vocabulary development across hearing groups, whereas prosodic cues play a minor role. Greater input quantity and quality may assist children in the building of basic language model representations, whereas pitch cues may mainly serve attentional and emotional processes. Results emphasize the need for additional longitudinal studies investigating the input received from other figures surrounding the child and its role for children's language development. What is already known on the subject Mothers' CDS is thought to facilitate and support language acquisition in children with various language developmental trajectories, including children with CIs. Because children with CIs are at risk for language delays and have acoustic processing limitations, their mothers may have to produce a lexically simpler but prosodically richer input, compared to mothers of children with NH. Yet, the literature reports mixed findings and no study to our knowledge has concurrently addressed the role of mothers' lexical and prosodic characteristics for children's vocabulary development before implantation and in the first 12 months of hearing experience. What this study adds to the existing knowledge The study shows that mothers of children with CIs produce input of similar quantity but reduced variety, and with heightened pitch characteristics, compared to mothers of children with NH. There was also a general increase in mothers' lexical quantity and variety, and in their pitch range, between sessions. Only their lexical characteristics predicted children's early vocabulary skills. Their lexical variety predicted children's expressive vocabulary and lexical variety only in the NH group. What are the practical and clinical implications of this work? These findings expand our knowledge about the effects of maternal input and may contribute to the improvement of early family-centred intervention programmes for supporting language development in children with CIs.

Psychosocial and biobehavioral processes underlying the association between prenatal risk factors and child self-regulation.

Over the past few decades, there has been accumulating evidence that prenatal exposure to risk is negatively related to child self-regulation. However, the mechanisms underlying this relationship are unclear. The present study used a multimethod approach to simultaneously examine the mediating role of the developmental trajectories of observed parenting quality (support, stimulation, and structure) and children's functional brain networks (small-worldness) from infancy into the preschool period in a sample of 233 children and their biological mothers. The results revealed a potential sleeper effect: Prenatal exposure to risk was negatively related to child self-regulation during the preschool period, but not during infancy. Parenting quality remained relatively stable over time, whereas small-worldness showed an increase during infancy, followed by a decrease into the preschool age period. These developmental changes did not mediate the relation between prenatal risk and child self-regulation. Prenatal exposure to risk was related to lower levels of maternal support during infancy, but did not affect the development of parenting quality over time. Prenatal risk was also not related to the growth rate of small-worldness in young children. However, the developmental changes in small-worldness predicted individual differences in child self-regulation. These findings suggest that children generally have the potential to benefit from positive postnatal parenting environments, regardless of the levels of prenatal risk. A potential target for intervention efforts based on the current findings might be related to postnatal experiences that impact the development of functional brain networks, which in turn could affect the development of child self-regulation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Late adolescent outcomes of different developmental trajectories of ADHD symptoms in a large longitudinal study.

There exists substantial heterogeneity in the developmental trajectories of ADHD symptoms, with distinctions often made between persistent versus remittent, and early- versus late-onset. However, how these trajectories relate to late adolescent functioning and whether, in particular, later onset trajectories mark a milder subtype remains unclear. Building on earlier work that has examined early life predictors of ADHD symptom trajectories up to age 14, we applied latent class growth analysis to data from the UK Millennium Cohort Study (N = 10,262) to evaluate whether developmental trajectories of ADHD symptoms up to age 17 (from age 3) were similar to those identified up to age 14 and associated with differing levels of impairment in peer victimisation, mental health, substance use, and delinquency outcomes at age 17. Our optimal model included five trajectory groups, labelled unaffected (37.6%), mildly affected (34.8%), subclinical remitting (14.4%), adolescent onset (7.6%), and stable high (5.6%). Adolescent onset and stable high trajectories were similarly impaired across all outcomes, other than substance use. Subclinical remitting individuals were impaired on self-esteem and well-being compared to unaffected individuals. By the end of mid-adolescence, those with a later onset have similar impairments to those following an early onset/persistent trajectory. Residual impairment may remain for those on a remitting trajectory.

A Deep Dynamic Causal Learning Model to Study Changes in Dynamic Effective Connectivity during Brain Development.

Brain dynamic effective connectivity (dEC), characterizes the information transmission patterns between brain regions that change over time, which provides insight into the biological mechanism underlying brain development. However, most existing methods predominantly capture fixed or temporally invariant EC, leaving dEC largely unexplored. Herein we propose a deep dynamic causal learning model specifically designed to capture dEC. It includes a dynamic causal learner to detect time-varying causal relationships from spatio-temporal data, and a dynamic causal discriminator to validate these findings by comparing original and reconstructed data. Our model outperforms established baselines in the accuracy of identifying dynamic causalities when tested on the simulated data. When applied to the Philadelphia Neurodevelopmental Cohort, the model uncovers distinct patterns in dEC networks across different age groups. Specifically, the evolution process of brain dEC networks in young adults is more stable than in children, and significant differences in information transfer patterns exist between them. This study highlights the brain's developmental trajectory, where networks transition from undifferentiated to specialized structures with age, in accordance with the improvement of an individual's cognitive and information processing capability. The proposed model consists of the identification and verification of dynamic causality, utilizing the spatio-temporal fusing information from fMRI. As a result, it can accurately detect dEC and characterize its evolution over age.

A single-cell transcriptomic study of heterogeneity in human embryonic tanycytes

Disruptions in energy homeostasis can lead to diseases like obesity and diabetes, affecting millions of people each year. Tanycytes, the adult stem cells in the hypothalamus, play crucial roles in assisting hypothalamic neurons in maintaining energy balance. Although tanycytes have been extensively studied in rodents, our understanding of human tanycytes remains limited. In this study, we utilized single-cell transcriptomics data to explore the heterogeneity of human embryonic tanycytes, investigate their gene regulatory networks, analyze their intercellular communication, and examine their developmental trajectory. Our analysis revealed the presence of two clusters of β tanycytes and three clusters of α tanycytes in our dataset. Surprisingly, human embryonic tanycytes displayed significant similarities to mouse tanycytes in terms of marker gene expression and transcription factor activities. Trajectory analysis indicated that α tanycytes were the first to be generated, giving rise to β tanycytes in a dorsal–ventral direction along the third ventricle. Furthermore, our CellChat analyses demonstrated that tanycytes generated earlier along the developmental lineages exhibited increased intercellular communication compared to those generated later. In summary, we have thoroughly characterized the heterogeneity of human embryonic tanycytes from various angles. We are confident that our findings will serve as a foundation for future research on human tanycytes.

Lipid biomarkers and stable isotopes uncover paleovegetation changes in extremely species-rich forest-steppe ecosystems, Central Europe

The historical development of the vegetation of semi-dry grasslands in Central Europe is not satisfactorily understood. Long-term continuity of open vegetation or, conversely, deep-past forest phases are considered possible sources of the current extreme species diversity of these ecosystems. We aimed to reveal the trajectory of paleovegetation development in these ecosystems through detailed analysis of terrestrial in-situ soil geoarchives. We measured the bulk soil carbon and nitrogen contents, lipid molecular distribution, and compound-specific stable carbon and hydrogen isotopic signatures of mid- and long-chain n-alkanes extracted from soil and modern plant material tissues (i.e., deciduous and Pinus leaves and grass/herbaceous species).The C23-C33 n-alkane homologues were identified in soils with different abundances. Normally, C27 and C29 n-alkanes were the most abundant homologues in tree-leaf samples, while grass-derived n-alkanes were mostly C31 and C33 homologues. Soils were largely dominated by C29 and C31 n-alkanes. Odd-numbered C27-C33 soil n-alkane δ13C values ranged from -36.2‰ to -23.2‰, whereas their δ2H values showed a wider range of variability that fluctuated from -224‰ to -172‰. Molecular distribution in combination with radiocarbon analysis of soil organic matter (SOM) and δ13C and δ2H values of n-alkanes revealed a large contribution of C3 trees (both deciduous and coniferous trees/pine trees) as the main source of n-alkanes between the late Pleistocene and early Holocene (ca 15,000–8,200 calibrated year before present/cal year BP). A clear shift toward more grassy/herbaceous vegetation was observed from the early Holocene (ca 11,700–8,200 cal year BP) onwards. Distribution patterns of lipids and soil geochemical parameters showed that plants are the main source of SOM and that biodegradation and kinetic isotope fractionation are not the main reasons for 13C enrichment in soil profiles. Past C3 vegetation shifts as well as paleoclimate changes (i.e., aridity) can have played a role in the observed 13C depth profiles.

Phenotyping variability in early socio-communicative skills in young children with autism and its influence on later development.

Children with autism spectrum disorder (ASD) often face challenges in early social communication skills, prompting the need for a detailed exploration of specific behaviors and their impact on cognitive and adaptive functioning. This study aims to address this gap by examining the developmental trajectories of early social communication skills in preschoolers with ASD aged 18-60 months, comparing them to age-matched typically developing (TD) children. Utilizing the early social communication scales (ESCS), the research employs a longitudinal design to capture changes over time. We apply a principal component analysis (PCA) to ESCS variables to identify underlying components, and cluster analysis to identify subgroups based on preverbal communication profiles. The results reveal consistent differences in early social communication skills between ASD and TD children, with ASD children exhibiting reduced skills. PCA identifies two components, distinguishing objects-directed behaviors and social interaction-directed behaviors. Cluster analysis identifies three subgroups of autistic children, each displaying specific communication profiles associated with distinct cognitive and adaptive functioning trajectories. In conclusion, this study provides a nuanced understanding of early social communication development in ASD, emphasizing the importance of low-level behaviors. The identification of subgroups and their unique trajectories contributes to a more comprehensive understanding of ASD heterogeneity. These findings underscore the significance of early diagnosis, focusing on specific behaviors predicting cognitive and adaptive functioning outcomes. The study encourages further research to explore the sequential development of these skills, offering valuable insights for interventions and support strategies.

A Guide for Aspiring Neurology Educators.

Deans of medical schools have diverse roles and responsibilities. In this article, we use the career development trajectories of neurologists who have become education deans in student affairs and curriculum to offer advice to aspiring clinician educators of all levels and backgrounds. Although their roles differ, the advice they share is universal and essential for the career development of future clinician educators. ANN NEUROL 2024.

P-159 Single-cell high-throughput methylation and transcriptomic analysis indicates variations in sensitivity to Folate-mediated one-carbon metabolism in mouse preimplantation embryos

Abstract Study question Do Folate-mediated one-carbon metabolism (FOCM) supplements impose methylating conditions that influence methylation and transcriptomic profiles during preimplantation period of mouse embryos? Summary answer Subtle differences in embryo methylation profiles were induced by FOCM supplements, despite transcriptomic signatures remained stable and selective genes related to metabolism were activated. What is known already Previous human studies of populations affected by seasonal variations in diet including folate availability have shown methylation changes in specific loci known as metastable epialleles (MEs). MEs exhibit stability across tissues, indicating these could be potential biosensors for heightened sensitivity to external methylating influences in early embryonic stages. Despite significant progress in IVF embryo culture conditions, the sensitivity to the outer metabolic environment during the extensive genomic transformation of embryo reprogramming remains inadequately understood. Study design, size, duration This is a prospective experimental study conducted from January 2023 to December 2023. A total of 111 fresh mouse zygotes (F1 hybrid (B6/CBA)) were subjected embryo culture conditions with different FOCM supplies of 5-MTHF and betaine up to expanded blastocyst stage (105 hours). At different timepoints, individual embryos were collected and disaggregated in individual cells for downstream single-cell analysis. Participants/materials, setting, methods Mouse zygotes were collected from the oviduct, washed and culture in KSOM supplemented with 5-MTHF and betaine at respectively concentrations of 50μM and 50μg/mL (THF/bet(50)), 10μM and 10μg/mL (THF/bet(10)) and no supplement till blastocyst stage at 37 °C, 6%CO2 and 5%O2. Individual embryos were collected at 2 cells, 4 cells, 8 cells, Morula and Blastocyst stage and disaggregated into single cells for subsequent single-cell RNAseq (SmartSeq2) and single-cell methylome analysis through Splinted Ligation Adapter Tagging (scSPLAT). Main results and the role of chance The methylation analysis conducted though scSPLAT revealed a comprehensive reduction in global methylation levels throughout developmental stages. Notably, zygotes exhibited a maximal proportion of methylated cytosines at CpG sites, while blastocysts displayed minimal methylation levels, with sporadic increases in isolated cells. Quantitative profiling indicated lower methylation intensities in treated embryos from zygote to 4 cells, followed by a reversal trend from 8 cells to blastocyst, suggestive of an enhanced assimilation of one-carbon metabolism (FOCM) supplements. Transcriptomic profiles obtained through scRNAseq exhibited correlation with developmental trajectories from zygote to blastocyst. However, no discernible variations were attributed to the combined exposure of Betaine and 5-MTHF. Gene enrichment analysis of differentially expressed genes at various timepoints highlighted specific metabolic responses, including mitochondrial oxidative stress and variations in glutathione metabolism. This suggests that the folate forms utilized in this study may possess a protective role as antioxidants, contributing to the observed effects on gene expression during embryonic development. Limitations, reasons for caution The methylation analysis shown in this study was a pilot carried out with low coverage of sequencing deepness, further analysis are ongoing to increase reads coverage. Wider implications of the findings Exposure of mouse embryos to FOCM enhanced global methylation during cell division from 8 cells to blastocyst, indicating heightened assimilation during DNA synthesis. While the transcriptomic signature remained stable, increased expression of genes linked to mitochondrial oxidative stress and glutathione metabolism suggests FOCM’s potential antioxidant role. Trial registration number not applicable

Партнерство государства и бизнеса с использованием офсетного контракта: возможности и препятствия в развитии

The purpose of the study is to identify and disclose opportunities and obstacles in the development of partnership between the state and business using an offset contract. The methodological basis of the study was made up of general scientific methods of cognition of economic processes and phenomena, in particular, the synthesis method (ensured the unification of the essential features, advantages and risks of an offset contract into a single whole), the analysis method (contributed to the identification of the results of using offset contracts in modern Russian conditions), logical methods (helped to identify obstacles to the use of an offset contract in Russia), the expert assessment method (contributed to the proposal of measures to develop the Russian practice of partnership between the state and business, taking into account the possibilities of an offset contract). The main results of the study: the signs, advantages, risks and key indicators of the use of offset contracts in Russia are systematized; obstacles in the development of partnership between the state and business on the basis of an offset contract are highlighted; guided by the possibilities of an offset contract, the trajectory of further development of partnership between the state and business is determined. The theoretical significance of the research lies in the development of the scientific foundations of the use of offset contracts at the present stage of development. The practical significance of the study is related to the possibility of using the results obtained in making managerial decisions to ensure the effective development of partnership between the state and business on the basis of an offset contract.

O-135 The consequences of paternal pre-conceptional health for offspring health and pregnancy outcomes: involvement of the germ-cell epigenome and non-germ cell factors

Abstract Study question Paternal health at conception is important for offspring health. The susceptibility windows within the male reproductive tract and the molecular mechanisms are not completely understood. Summary answer Using mouse genetics, (epi)genomics and in-depth phenotyping, we show that the germ-cell epigenome and components of the seminal fluid are critical for paternal intergenerational effects. What is known already Paternal intergenerational effects are highly conserved across mammals and lower organisms including flies and nematodes. In mammals, the sperm epigenome, as well as the composition of the seminal fluid are sensitive to environmental challenges and influence offspring development and adult phenotypic trajectories. The best known of these mechanisms are DNA methylation and small non-coding RNAs in spermatozoa and the balance between inflammatory and tolerogenic cytokines in the seminal fluid. Small non-coding RNAs are mostly acquired by maturing spermatozoa during the epididymal transit from extracellular vesicle of epididymal epithelial origin, and have the potential to influence embryonic development and offspring health. Study design, size, duration We use two paternal paradigms of pre-conceptional challenge in wild-type C57BL6 mice: high-fat diet feeding for 2 weeks and circadian disruption for 4 weeks before conception. The duration of the environmental challenges has been chosen to meet timing of sperm maturation in the mouse (high-fat diet) or to be the minimum sufficient to induce circadian disruption without overt side effects. Exposed males and their offspring have undergone deep metabolic and molecular phenotyping. Participants/materials, setting, methods We used both bulk and single cell (epi)genomics on exposed males as well as male and female offspring. The molecular phenotyping has been instructed by the results of the metabolic phenotyping performed in collaboration with the German Mouse Clinic, the biggest mouse clinic in Europe, using highly standardized and robust procedures. Importantly, we have used a family-based approach for the data analysis, according to which the experimental n is the exposed father. Main results and the role of chance Paternal circadian disruption achieved by four weeks of day-restricted feeding (food only during the light phase), leads to hyperphagia, hyperglycemia, hypercorticosteronemia and partial circadian disruption in unexposed male offspring. The phenotypes are gender-specific and the females feature partial protection from the paternal effects. Mechanistically, mouse seminal fluid contains corticosterone, whose appearance dynamic follows the organismal circadian rhythm and is blunted upon circadian disruption. Offspring phenotypes are sensitive to the levels of corticosterone in the seminal fluid and consequential to impaired placentation, reduced placental efficiency and fetal growth restriction. Paternal exposure to an acute high-fat diet challenge, instead, leads to a 30% penetrant glucose intolerance phenotype exclusively in male offspring. Mechanistically, this is linked to diet-induced mitochondrial dysfunction in somatic and germ cells and a compensatory burst of mitochondrial DNA transcription in spermatozoa. Mitochondrial DNA encoded small non-coding RNAs accumulate in spermatozoa, are inherited at fertilization, and reprogram early embryo transcription towards premature activation of oxidative metabolism, a predisposing factor to adult-onset glucose intolerance. Importantly, phenotypes and mechanisms are conserved across highly characterized human cohorts. These studies strengthen the importance of paternal health at conception for pregnancy and offspring health and identify germ-cell and non-germ cell factors as potential mechanistic mediators. Limitations, reasons for caution Although we have shown for the first time that stress hormones are present in the seminal fluid and relay paternal stress to the offspring and provided the first example of epigenetic inheritance of sperm small non-coding RNAs, mechanisms are still to be completely uncovered. Complementary mechanisms cannot be excluded. Wider implications of the findings Our findings strengthen the importance of paternal health at conception for pregnancy and offspring health. They also provide potential male tract biomarkers and novel strategies to monitor paternal health at conception and preconception lifestyle interventions aimed at improving pregnancy outcomes and preventing the spread of metabolic disorders through epigenetic inheritance. Trial registration number not applicable

P-048 Morphokinetic analysis and implantation prediction of embryos derived from oocytes microinjected with Artificial Intelligence (AI) real-time assessed sperm

Abstract Study question Is embryo morphokinetic development affected by sperm quality assessed real time during Intracytoplasmic Sperm Injection (ICSI)? Summary answer Embryos derived from oocytes microinjected with low-quality sperm, analyzed by an AI-tool, exhibit a sluggish pace and a diminished potential for successful implantation. What is known already The study of embryo morphokinetics provides insights into the temporal aspects of cell division, which are pivotal for successful implantation. Key parameters such as time of division to 3 cells (t3), time to division to 5 cells (t5), time between division to 3 cells and subsequent division to 4 cells (s2) and duration of cell cycle two, i.e. time between division to 2 cells and division to 3 cells (cc2) are closely associated with implantation potential. Monitoring these markers allows clinicians to select embryos with optimal developmental trajectories, improving the chances of successful implantation and ultimately leading to healthier pregnancies. Study design, size, duration That is a single-centre and non-intervention study of 60 ICSI cycles. Seminal samples were assessed real-time with Sperm identification (SiD) software (v1.0, IVF2.0, LTD). Microinjected oocytes were maintained in culture in time-lapse incubators (EmbryoScope or EmbryoScope Plus). Injected sperm and their corresponding oocytes were individually followed-up to assess early embryo morphokinetics: t3, t5, s2, cc2 (273 total blastocysts) in a four-month period. Participants/materials, setting, methods Sixty ICSI cycles (35 from own oocytes and 25 from egg donation) were studied.418 sperm were assessed with SiD and classified as ‘low’, ‘medium’, ‘good’ or ‘best’, according to their motility parameters. Early embryonic morphokinetics were studied focusing on t3, t5, s2 and cc2 times. Ranges related with best implantation potential were studied according to previous works of our group: t3(34-40h), t5 (45-55h), cc2 (9-12h) and s2 (≤0,76h). Main results and the role of chance No discernible differences were observed in the parameters t3 and t5 among embryos within each sperm quality group. However, significant differences were identified in s2 and cc2 metrics between embryos of distinct sperm quality groups. Specifically, oocytes subjected to microinjection with ‘best’ or ‘good’ sperm exhibited an optimal average cc2 length (10.49 ± 5.12), in stark contrast to embryos derived from oocytes microinjected with ‘medium’ or ‘low’ sperm, which manifested an acelerated developmental pace (8.73 ± 5.55) (p < 0.05). Furthermore, embryos from the ‘best’ and ‘good’ groups displayed significantly shorter s2 lengths (1.16 ± 1.98 and 1.03 ± 1.62) compared to embryos from the ‘low’ group (2.73 ± 3.96). The latter exhibited an extended duration between the 3-cell division and subsequent division to 4 cells (p < 0.05). These findings lead us to infer that embryos arising from oocytes microinjected with ‘best’ or ‘good’ sperm possess superior implantation potential compared to those originating from oocytes microinjected with ‘medium’ or ‘low’ sperm, as indicated by SiD scores. The latter cohort appears to exhibit an alterated morphokinetic development and diminished implantation potential. Limitations, reasons for caution This project is limited by its retrospective and single-centre nature. In addition, studying later embryo morphokinetics parameters could provide a better description of embryo development and its relation with sperm quality assessed real-time. Finally, sperm morphology should also be included in SiD software because of its relation with reproductive success. Wider implications of the findings Selection of high-quality sperm to microinject into the oocytes, supported by real-time analysis, could contribute to improved morphological and kinetic characteristics of embryos, potentially increasing the chances of success in assisted reproductive procedures. In addition, it provides an opportunity to reduce subjectivity and inter-user variability of ICSI procedure. Trial registration number Not applicable

Developmental trajectories of spoken language comprehension and functional communication in children with cerebral palsy: A prospective cohort study.

Developmental trajectories of spoken language comprehension and functional communication in children with cerebral palsy: A prospective cohort study.

Variation and variability in skeletal ossification of the gray short-tailed opossum, Monodelphis domestica

Abstract By reconstructing and comparing the sequence of ontogenetic (embryonic development and post-natal growth) events across species, developmental biologists have gained unique insights into the key processes underlying the evolution of modern lineages and their extinct relatives. However, despite the importance of intraspecific variation to evolutionary transformation and lineage divergence, variation in the sequence of developmental events is seldom acknowledged. Thus, how much variation or variability should be expected during ontogeny remains poorly understood and it is an open question to what extent it impacts interspecific comparisons of developmental patterns. To address this crucial question, we studied the skeletal development of the important biomedical and developmental model organism, Monodelphis domestica. We investigated cranial, forelimb, and hindlimb elements using Ontogenetic Sequence Analysis (OSA) to quantify and assess the full range of variation and variability in the sequence of ossification. Our study documented that previously unrecognized variation exists during M. domestica ontogeny — with over 5000 sequences for the full 92 event analysis. Further, OSA revealed unexpectedly high variability (i.e., the propensity to express variation) in the sequence of ossification for the skull and across the entire skeleton. Reconstructed modal sequences were generally in agreement with previously recognized patterns, including earlier ossification of the facial skeleton and a slight offset between forelimb and hindlimb development. However, the full range of variation shows that the majority of specimens in our analysis followed developmental trajectories distinct from those recovered by prior studies. This level of variation is quite remarkable and demonstrates the importance of assessing intraspecific ontogenetic variation. By quantifying sequence polymorphism and studying how developmental variation and variability differ among species, we can clarify more precisely how developmental patterns differ among species and gain insights into how ontogeny itself evolves.

O-132 A systematic spatial HiPlex proteomics exploration of human testicular tissues from birth to adulthood

Abstract Study question Can we map the key maturation stages of human spermatogonial stem cells (SSCs) within their niche during infancy and puberty? Summary answer Using highplex spatial proteomics, we describe the key cellular events taking place during human testis maturation. What is known already The human testis is a complex “ecosystem” that matures in response to endocrine and exocrine signals and interactions between its diverse cellular components. Unlike animal models, in humans, testicular maturation is a slow process that takes place over more than a decade. In contrast to ovaries, the human testis retains its immature state until the onset of puberty. Single-cell RNA sequencing data has revealed significant developmental changes for germ cell and the somatic niche during infancy and puberty. Study design, size, duration Using the hyperplex imaging technique (CellDIVE) and a panel of 30 protein markers - selected to label key components of the developing human testis - we have systematically analyzed a time series of ∼75 testicular biopsies from boys aged 8 months to adulthood. Following sequential staining and capture of high-resolution images, our analysis pipeline involves the conversion of image into single-cell data, which allows a systematic description of the spatial SSC/niche microenvironment interactions across development. Participants/materials, setting, methods The panel of antibody markers was defined using integrated scRNAseq data and represents all key cell types, including germ cell markers (e.g., MAGEA4), Sertoli cell markers (e.g., SOX9), Leydig cell markers (e.g., INSL3), myoid cell markers (e.g., ACTA2) ... Main results and the role of chance To describe the events occurring during human testicular maturation, we build a Tissue Microarray (TMA) containing ∼75 biopsies of boys of different ages (0-16yrs old) and using an in-house panel of 30 markers for high-dimensional multiplex CELL DIVE images. Our analytical strategy uses Uniform Manifold Approximation and Projection (UMAP) maps to quantify and statistically compare single-cell data. Our marker panel allows us to phenotype testicular cells at different stages of development, including SSCs (state 0 to state 4), Sertoli cells, Leydig cells, and so on. Moreover, employing spatial-latent Dirichlet allocation (LDA), we identified recurrent cellular neighbourhoods (RCNs), revealing distinct cell clusters and their corresponding RCNs. These RCNs reflect recurring spatial arrangements of cells within testicular tissues, allowing us to infer the spatial organization and interplay among different cell types. Additionally, we explored spatial distances and neighbourhood frequencies across different tissues and conducted spatial co-occurrence analysis to assess the likelihood of finding adjacent cell types. The identification of RCNs offers valuable insights into the microenvironmental dynamics and cellular relationships taking place within the developing testis. Looking ahead, we aim to delve into the functional significance of RCNs in shaping the developmental trajectories and physiological processes within human testicular tissues. Limitations, reasons for caution Due to limitations in proteomics techniques, we could only include ∼30 protein markers on our panel. Although the biopsy samples used in our study are all from chemo-naïve patients, it possible that the conditions affecting these paediatric patients may impact the architecture or development of their testicular tissues. Wider implications of the findings Our study provides a systematic approach to study the development and organization of human testicular structures, which will allow to enumerate the cellular content of individual testicular biopsies and infer their stage of maturation, therefore providing a personalised baseline assessment for each patient at the time of cryopreservation. Trial registration number not applicable

Effects of low temperature on growth and metabolism of larval green sturgeon (Acipenser medirostris) across early ontogeny.

Southern Distinct Population Segment (sDPS) green sturgeon spawn solely in one stretch of the Sacramento River in California. Management of this spawning habitat is complicated by cold water temperature requirements for the conservation of winter-run Chinook salmon. This study assessed whether low incubation and rearing temperatures resulted in carryover effects across embryo to early juvenile life stages on scaling relationships in growth and metabolism in northern DPS green sturgeon used as a proxy for sDPS green sturgeon. Fish were incubated and reared at 11°C and 15°C, with a subset experiencing a reciprocal temperature transfer post-hatch, to assess recovery from cold incubation or to simulate a cold-water dam release which would chillrearing larvae. Growth and metabolic rate of embryos and larvae were measured to 118days post hatch. Reciprocal temperature transfers revealed a greater effect of low temperature exposure during larval rearing rather than during egg incubation. While 11°C eggs hatched at a smaller length, log-transformed length-weight relationships showed that these differences in developmental trajectory dissipated as individuals achieved juvenile morphology. However, considerable size-at-age differences persisted between rearing temperatures, with 15°C fish requiring 60days post-hatch to achieve 1g in mass, whereas 11°C fish required 120days to achieve 1g, resulting in fish of the same age at the completion of the experiment with a ca. 37-fold difference in weight. Consequently, our study suggests that cold rearing temperatures have far more consequential downstream effects than cold embryo incubation temperatures. Growth delays from 11°C rearing temperatures would greatly increase the period of vulnerability to predation in larval green sturgeon. The scaling relationship between log-transformed whole-body metabolism and mass exhibited a steeper slope and thus an increased oxygen requirement with size in 11°C reared fish, potentially indicating an energetically unsustainable situation. Understanding how cold temperatures affect green sturgeon ontogeny is necessary to refine our larval recruitment estimations for this threatened species.

Gender Differences in the Path to Medical School Deanship

Women account for only 28% of current US medical school deans. Studying the differences between women and men in their preparation to becoming deans might help to explain this discrepancy. To identify differences in the leadership development experiences between women and men in their ascent to the medical school deanship. In this qualitative study, volunteers from the roster of the Association of American Medical Colleges Council of Deans were solicited and interviewed from June 15 to November 9, 2023. Women deans were recruited first, then men who had been appointed to their deanships at a similar time to their women counterparts were recruited. Deans were interviewed on topics related to number of applications for deanships, prior leadership roles, leadership development, personal factors, and career trajectories. Interviews were coded, and themes were extracted through conventional content analysis. Career and leadership development experiences were elicited using a semistructured interview guide. We interviewed 17 women and 17 men deans, representing 25.8% (34 of 132) of the total population of US medical school deans. Most deans (23 [67.6%]) practiced a medicine-based specialty or subspecialty. No statistically significant differences were found between women and men with regard to years to attain deanship (mean [SD], 2.7 [3.4] vs 3.7 [3.7] years), years as a dean (mean [SD], 5.7 [5.2] vs 6.0 [5.0] years), highest salary during career (mean [SD], $525 769 [$199 936] vs $416 923 [$195 848]), or medical school rankings (mean [SD], 315.5 [394.5] vs 480.5 [448.9]). Their reports indicated substantive gender differences in their paths to becoming a dean. Compared with men, women deans reported having to work harder to advance, while receiving less support and opportunities for leadership positions by their own institutions. Subsequently, women sought leadership development from external programs. Women deans also experienced gender bias when working with search firms. This qualitative study of US medical school deans found that compared with men, women needed to be more proactive, had to participate in external leadership development programs, and had to confront biases during the search process. For rising women leaders, this lack of support had consequences, such as burnout and attrition, potentially affecting the makeup of future generations of medical school deans. Institutional initiatives centering on leadership development of women is needed to mitigate the gender biases and barriers faced by aspiring women leaders.

From building energy modeling to urban building energy modeling: A review of recent research trend and simulation tools

Initiatives aimed at retrofitting the existing buildings stock and constructing Zero Carbon Community (ZCC) have been recognized as highly effective measures for reaching the zero emission carbon goals set by the EU Commission by 2050. The Building Energy Modeling approach focuses only on typical individual building and it is hardly suitable for assessing the performance and the mutual interaction of a group of interconnected buildings In this case the application of Urban Building Energy Modeling (UBEM) is required. Research on UBEM constitutes the foundation for reducing the energy needs of the built environment; however, there is currently a lack of knowledge on UBEM concept, workflow and related simulation tools. This paper has twofold objectives; first presents an in-depth bibliometric analysis, through CiteSpace, to analyze the developmental trajectory of emerging simulation UBEM method. The analysis encompasses the distribution of authors collaborations, geographic and institutional cooperation in publications and research hotspots. Based on this, the paper summarizes the development trends and potential directions for research in the UBEM field. Furthermore, as a second objective, the paper provides a comprehensive analysis of the main UBEM tools with focus on the input and output data, simulation engine and data workflow. The final scope of this study is to offer to urban planners and policymakers a comprehensive framework as a starting point for approaching zero-carbon communities’ from both the concepts and the simulations analysis point of view.