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This paper examined the relationship among countermovement jump (CMJ), football category, chronological age, relative age, and pubertal development status to investigate which parameter could be better associated with jumping performance. We tested 259 young male football players (14.9 ± 1.8 yrs; 169.7 ± 9.8 cm; 60.6 ± 11.3 kg; 20.9 ± 2.6 kg m−2) belonging to elite football academies. One-sample chi-square tests were used to test the uniformity of distributions of the proportions of players in each year quarter (relative age effect, RAE) for the whole sample and stratified for each football age category (U14, U15, U17, and U19). One-way ANOVAs were used to test the associations among a) categories, RAE, and CMJ, and b) the pubertal status category and CMJ. Pearson's correlation assessed the relationship among variables. The birth distribution among the year's quarters significantly differed from the expected proportion of 25 % of participants each quarter (χ2 = 41.74; p

Objectives: This study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations. Methods: We leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis. Results: Alpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression. Conclusions: Our study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.

Football is a team sport played worldwide and specific competition demands are needed since young categories. Several physiological and psychological aspects could influence the selection process, and adolescent investigations still be necessary. This retrospective study aims to compare anthropometric and performance features between selected and unselected adolescent footballers. The sample size was 78 players from U10 to U12 categories. Maturation, RAE, anthropometry, and physical performance (repeated sprint ability (RSA), 15-m sprint, countermovement jump (CMJ) and Harre's test) were evaluated (mean ± SD). 33.3 % of players were selected (height = 144.06 ± 6.74 cm, weight = 35.38 ± 4.56 kg) and 66.7 % were unselected (height = 143.06 ± 8.34 cm, weight = 35.94 ± 6.24 kg). Selected U10 were leaner and got the peak of height velocity (APHV) earlier (p

Adipogenesis is a process that differentiates new adipocytes from precursor cells and is tightly regulated by several factors, including many transcription factors and various post-translational modifications. Recently, new roles of adipogenesis have been suggested in various diseases. However, the molecular mechanisms and functional modulation of these adipogenic genes remain poorly understood. This review summarizes the regulatory factors and modulators of adipogenesis and discusses future research directions to identify novel mechanisms regulating adipogenesis and the effects of adipogenic regulators in pathological conditions. The master adipogenic transcriptional factors PPARγ and C/EBPα were identified along with other crucial regulatory factors such as SREBP, Kroxs, STAT5, Wnt, FOXO1, SWI/SNF, KLFs, and PARPs. These transcriptional factors regulate adipogenesis through specific mechanisms, depending on the adipogenic stage. However, further studies related to the in vivo role of newly discovered adipogenic regulators and their function in various diseases are needed to develop new potent therapeutic strategies for metabolic diseases and cancer.

Baccaurea ramiflora has an unstable ripening period. Herein, five typical periods of fruit ripening of ‘LR’ Baccaurea ramiflora were analyzed by non-targeted metabolomics techniques. The results showed that ripening started 73 days after flowering and reached the ripening criterion at 93 days, a total of 451 differential metabolites were identified for the five periods. KEGG enrichment pathway showed that significant changes in citric acid were significantly correlated with changes in the downstream substance spermine (R2 = 0.9068, y = −5.49 + 0.66×), while citric acid (R2 = 0.9982) and spermine (R2 = 0.9841) were negatively correlated with the sugar-acid ratio. Citric acid was the main component of titratable acid and spermine (R2 = 0.9991) was positively correlated with titratable acid. We speculated that citric acid is a key taste marker for fruit ripening in ‘LR’ B. ramiflora. The results of the study provide new metabolic evidence for flavor changes and scientific basis for their quality improvement and exploitation in B. ramiflora.

Neutrophils as first line defender initiate a cascade of healing process immediately after muscle injury. At muscle injury site, neutrophils remove damaged muscle fibers and recruit other immune cells and these functions show in mature neutrophils. In the previous study, physical exercise can mediate neutrophils’ functional changes such as phagocytosis and chemotaxis, though there is no research on how exercise-induced neutrophils contribute the muscle regeneration.In this present study, we investigated the maturation of neutrophils after 4 weeks of mouse treadmill exercise and assessed wound healing assay to evaluate whether treatment with exercise-activated neutrophils is effective for skeletal muscle repair in vitro. In the exercise group, significantly higher mRNA levels of maturation markers compared to the sedentary group and exercise-activated neutrophils improved wound healing of mouse muscle cells.To confirm at the human cell level, based on the well-known fact that exercise increases circulating cortisol levels, neutrophil-like cells were treated with dexamethasone (dHL60 + dex) as exercise mimetics. dHL60 + dex had significantly higher mRNA levels of neutrophil maturation marker and improved wound healing of human skeletal muscle cells compared to the control. These findings suggest that exercise affects neutrophil maturation and that exercise-induced neutrophils contribute to skeletal muscle repair in vitro.

Background: For adolescent soccer players, good sprinting and jumping abilities are crucial for their athletic performance. The application of plyometric training on boosting explosive strength in adolescent soccer players is contingent upon the maturation phase, which can mediate the training-induced adaptations. Purpose: This systematic review and meta-analysis aim to explore the maturation effect of plyometric training on the lower limb explosive power of adolescent soccer players, with vertical countermovement jump (CMJ) and 20-m sprint as the main outcome indicators. Methods: An extensive search of the literature was carried out on various databases including PubMed, Web of Science, Scopus, ProQuest, and the China National Knowledge Infrastructure (CNKI), covering the time period from the establishment of each database to February 6, 2023. The search was conducted using English keywords such as ‘Plyometric,’ ‘Adolescent,’ ‘football,’ and ‘Explosive strength.’ This study utilized the Cochrane risk of bias assessment tool to conduct a standardized quality evaluation of all the included literature. Additionally, the Review Manager 5.4 software was employed to perform data analysis on all the extracted data. Results: A total of 17 studies involving 681 adolescent soccer players aged 10 to 19 were included. Plyometric training significantly improved CMJ performance across different maturation stages, especially in the post-peak height velocity stage (POST-PHV) [MD = 4.35, 95 % CI (2.11, 6.59), P

Neurons are believed to be non-proliferating cells. However, neuronal stem cells are still present in certain areas of the adult brain, although their proliferation diminishes with age. Just as with other cells, their proliferation and differentiation are modulated by various mechanisms. These mechanisms are foundational to the strategies developed to induce neuronal proliferation and differentiation, with potential therapeutic applications for neurodegenerative diseases. The most common among these diseases are Parkinson's disease and Alzheimer's disease, associated with the formation of β-amyloid (Aβ) aggregates which cause a reduction in the number of neurons. Compounds such as LiCl, 4-aminothiazoles, Pregnenolone, ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFκB, Wnt, BDNF, and NPAS3. Moreover, combinations of these compounds can potentially transform somatic cells into neurons. This transformation process involves the activation of neuron-specific transcription factors such as NEUROD1, NGN2, ASCL1, and SOX2, which subsequently leads to the transcription of downstream genes, culminating in the transformation of somatic cells into neurons. Neurodegenerative diseases are not the only conditions where inducing neuronal proliferation could be beneficial. Consequently, the impact of pro-proliferative compounds on neurons has also been researched in mouse models of Alzheimer's disease.

Introduction: Understanding the critical factors for the maturation of human induced pluripotent stem cell (hiPSC)-derived cardiac tissue is important for further development of culture techniques. Rotating flow culture, where the tissues float in the culture medium by balancing its gravitational settling and the medium flow generated in rotating disk-shaped culture vessels, is one of culture systems used for tissue engineering. It has previously been demonstrated that rotating flow culture leads to the formation of matured cardiac tissue with higher levels of function and structure than the other culture systems. However, the detailed mechanisms underlying the maturation of cardiac tissue remain unclear. This study investigated the maturation process of hiPSC-derived cardiac tissue in rotating flow culture with a focus on morphological changes in the tissue, which is a trigger for maturation. Methods: The cardiac tissue, which consisted of cardiomyocytes derived from hiPSCs, was cultured on the 3D scaffold of poly (lactic-co-glycolic) acid (PLGA)-aligned nanofibers, in rotating flow culture for 5 days. During the culture, the time profile of projected area of tissue and formation of maturation marker proteins (β-myosin heavy chain and Connexin-43), tissue structure, and formation of nuclear lamina proteins (Lamin A/C) were compared with that in static suspension culture. Results: The ratio of the projected area of tissue significantly decreased from Day 0 to Day 3 due to tissue shrinkage. In contrast, Western blot analysis revealed that maturation protein markers of cardiomyocytes significantly increased after Day 3. In addition, in rotating flow culture, flat-shaped nuclei and fiber-like cytoskeletal structures were distributed in the surface region of tissue where medium flow was continuously applied. Moreover, Lamin A/C, which are generally formed in differentiated cells owing to mechanical force across the cytoskeleton and critically affect the maturation of cardiomyocytes, were significantly formed in the tissue of rotating flow culture. Conclusions: In this study, we found that spatial heterogeneity of tissue structure and tissue shrinkage occurred in rotating flow culture, which was not observed in static suspension culture. Moreover, from the quantitative analysis, it was also suggested that tissue shrinkage in rotating flow culture contributed its following tissue maturation. These findings showed one of the important characteristics of rotating flow culture which was not revealed in previous studies.

Summary: Characterizing cell identity in complex tissues such as the human retina is essential for studying its development and disease. While retinal organoids derived from pluripotent stem cells have been widely used to model development and disease of the human retina, there is a lack of studies that have systematically evaluated the molecular and cellular fidelity of the organoids derived from various culture protocols in recapitulating their in vivo counterpart. To this end, we performed an extensive meta-atlas characterization of cellular identities of the human eye, covering a wide range of developmental stages. The resulting map uncovered previously unknown biomarkers of major retinal cell types and those associated with cell-type-specific maturation. Using our retinal-cell-identity map from the fetal and adult tissues, we systematically assessed the fidelity of the retinal organoids in mimicking the human eye, enabling us to comprehensively benchmark the current protocols for retinal organoid generation.

Study Objectives: Sleep slow wave activity, as measured using EEG delta power (

The oocyte is the basis of life, supporting development from a fertilized cell to an independent multicellular organism. The oocyte’s competence to drive the first cell cycles postfertilization are critical to embryonic survival and subsequent successful pregnancy. Coupled with the complex processes of follicle assembly, activation, differentiation, growth, and terminal maturation, oocyte developmental competence is gradually acquired during oocyte growth and meiotic maturation. Most reproduction management technologies and interventions are centered around these highly coordinated processes, targeting the ovarian follicle and the oocyte within. Thus, our objective was to highlight key aspects of oocyte and follicle development in cattle, and to discuss recent advances in oocyte and follicle-centered reproductive biotechnologies.

Summary: Signaling via N-methyl-d-aspartate receptors (NMDARs) is critical for the maturation of glutamatergic synapses, partly through a developmental switch from immature synapses expressing primarily GluN2B- and GluN3A-containing subtypes to GluN2A-rich mature ones. This subunit switch is thought to underlie the synaptic stabilization of NMDARs necessary for neural network consolidation. However, the cellular mechanisms controlling the NMDAR exchange remain unclear. Using a combination of single-molecule and confocal imaging and biochemical and electrophysiological approaches, we show that surface GluN3A-NMDARs form a highly diffusive receptor pool that is loosely anchored to synapses. Remarkably, changes in GluN3A subunit expression selectively alter the surface diffusion and synaptic anchoring of GluN2A- but not GluN2B-NMDARs, possibly through altered interactions with cell surface receptors. The effects of GluN3A on NMDAR surface diffusion are restricted to an early time window of postnatal development in rodents, allowing GluN3A subunits to control the timing of NMDAR signaling maturation and neuronal network refinements.

The metabolic reasons for rambutan taste variations during maturity are unknown. Here, we obtained a unique rambutan cultivar Baoyan No.2 (BY2) with a strong yellow pericarp and excellent taste, the sugar-acid ratios of which ranged from 21.7 to 94.5 during maturation. Widely targeted metabolomics analysis was performed to reveal the metabolic reasons behind these taste variations. The results showed that 51 metabolites were identified as common different metabolites (DMs), including 16 lipids, 12 amino acids and others. Among them, the abundance level of 3,4-digalloylshikimic acid exhibited a positive correlation with the titratable acids (R2 = 0.9996) and a negative correlation with the sugar-acid ratio (R2 = 0.9999). Therefore, it could be a taste biomarker of BY2 rambutan. Moreover, all DMs were enriched in “galactose metabolism”, “fructose and mannose metabolism” and “biosynthesis of amino acids” pathways, which predominantly accounted for the taste variation. Our findings provided new metabolic evidence for the taste variation of rambutan.

Background and Aims: An interactive regulatory network assembled through the induction and downregulation of distinct transcription factors governs acinar cell maturation. Understanding how this network is built is relevant for protocols of directed pancreatic acinar differentiation. The murine transcription factor Prox1 is highly expressed in multipotent pancreatic progenitors and in various mature pancreatic cell types except for acinar cells. In this study, we investigated when is Prox1 expression terminated in developing acinar cells and the potential involvement of its activity in acinar cell specification/differentiation. We also investigated the effects of sustained Prox1 expression in acinar maturation and maintenance. Methods: Prox1 acinar expression was analyzed by immunofluorescence and confocal microscopy. Prox1-null embryos (Prox1GFPCre/Δ), Prox1AcOE transgenic mice, histologic and immunostaining methods, transmission electron microscopy, functional assays, and quantitative RNA and RNA-sequencing methods were used to investigate the effects of Prox1 functional deficiency and sustained Prox1 expression in acinar maturation and homeostasis. Results: Immunostaining results reveal transient Prox1 expression in newly committed embryonic acinar cells. RNA-sequencing demonstrate precocious expression of multiple “late” acinar genes in the pancreas of Prox1GFPCre/Δ embryos. Prox1AcOE transgenic mice carrying sustained Prox1 acinar expression have relatively normal pancreas development. In contrast, Prox1AcOE adult mice have severe pancreatic alterations involving reduced acinar gene expression, abnormal acinar secretory granules, acinar atrophy, increased endoplasmic reticulum stress, and mild chronic inflammation. Conclusion: Prox1 transient expression in early acinar cells is necessary for correct sequential gene expression. Prox1 expression is terminated in developing acinar cells to complete maturation and to preserve homeostasis.

The application of a no-touch technique to create an autologous radiocephalic arteriovenous fistula might improve the patency rate. In the present report, we have expanded the concept of the no-touch technique by introducing a modified no-touch technique in which we preserve the perivenous vascular tissue, followed by a functional end-to-side anastomosis to create a radiocephalic arteriovenous fistula with early maturation for hemodialysis.

Schizophrenia, a debilitating disorder with typical manifestation of clinical symptoms in early adulthood, is characterized by cognitive impairments in executive processes such as in working memory (WM). However, there is a rare case of individuals with early-onset schizophrenia (EOS) starting before their 18th birthday, while WM and its neural substrates are still undergoing maturation. Using the WM n-back task with functional magnetic resonance imaging, we assessed the functional neurodevelopment of WM in adolescents with EOS and age- and gender-matched typically developing controls. Participants underwent neuroimaging in the same scanner twice, once at age 17 and at 21 (mean interscan interval = 4.3 years). General linear model analysis was performed to explore WM neurodevelopmental changes within and between groups. Psychopathological scores were entered in multiple regressions to detect brain regions whose longitudinal functional change was predicted by baseline symptoms in EOS. WM neurodevelopment was characterized by widespread functional reductions in frontotemporal and cingulate brain areas in patients and controls. No between-group differences were found in the trajectory of WM change. Baseline symptom scores predicted functional neurodevelopmental changes in frontal, cingulate, parietal, occipital, and cerebellar areas. The adolescent brain undergoes developmental processes such as synaptic pruning, which may underlie the refinement WM of network. Prefrontal and parietooccipital activity reduction is affected by clinical presentation of symptoms. Using longitudinal neuroimaging methods in a rare diagnostic sample of patients with EOS may help the advancement of neurodevelopmental biomarkers intended as pharmacological targets to tackle WM impairment.

The palynological and geochemical analyses were carried out on shales samples in borehole and outcrop sections of the southern Bida and northern Anambra basins respectively. These analyses aimed at evaluating the hydrocarbon prospectivity of the basins. The results of total organic carbon (TOC) of 0.30–9.01 wt% in Patti Shale interval of Agbaja section in southern Bida Basin revealed a high TOC, depicting a substantial organic matter in the source rock. TOC of 0.82–2.56 wt% for Patti Shale in Ahoko outcrops (southern Bida Basin) show relatively moderate TOC which revealed a fair organic matter in the source beds. TOC of 0.44–0.95 wt% of Mamu Shales in Ojodu outcrops in northern Anambra Basin indicates a moderate to poor TOC which suggests fair to poor organic matter in the source rock. Hydrogen Index (HI) range of 45- 153 mgHC/grock with producible hydrocarbon (S2) of 2.60–5.00 mgHC/grock reveals very good source rock potentials in the Agbaja section. HI of 0.08–0.57 mgHC/grock, S2 of 0.12 mgHC/grock in Ahoko and HI of Mamu Shales of 30–136 mgHC/grock, S2 of 0.14–0.90 mgHC/grock in Ojodu outcrop, both revealed poor to fair source rock potentials. The results of vitrinite reflectance (Ro) and maximum temperature (Tmax) range (0.30 to 0.55% and 420 to 435 °C, respectively) suggest a low to relatively high thermal maturity index in both frontier basins. The thermal maturity of the shales in Agbaja borehole sections is moderate to high, although from record no petroleum has been produced from the sections in the basin. From the organic matter type, the kerogen is classified as type II/III and IV for both basins. The palynological results propose the Maastrichtian age for both basins, regarding the rich accumulation concerning micro-florals; Psilatricolporites prolatus, Florentinia laciniata seghiris, Echitriporite trianguliformis, Arecipites sp. Monoporite, Triporites. Dinocysts belonging to the Spiniferites, and Deflandreacean dinoflagellate, and Acritaarchs of Polipodiaceosporite retigularis, Acripite sp., which were analyzed from the shale intervals in the basins; suggest a Cretaceous age, marginal marine-continental environments, paleovegetation, and humid climate. Finally, the palynological, and geochemical analysis results will contribute knowledge that will be useful for hydrocarbons exploration in these frontier basins in Nigeria.

Biological environments present a complex array of metal-binding ligands. Metal-binding proteins have been the overwhelming focus of study because of their important and well-defined biological roles. Consequently, the presence of functional low molecular weight (LMW) metal-ligand complexes has been overlooked in terms of their roles in metallobiochemistry, particularly within cells. Recent studies in microbial systems have illuminated the different roles of L-histidine in nickel uptake, gene expression, and metalloenzyme maturation. In this focused critical review, these roles are surveyed in the context of the coordination chemistry of Ni(II) ions and the amino acid histidine, and the physico-chemical properties of nickel complexes of histidine. These complexes are fundamentally important to cellular metal homeostasis and further work is needed to fully define their contributions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The words that children learn change over time in predictable ways. The first words that infants acquire are generally ones that are both frequent and highly imageable. Older infants also learn words that are more abstract and some that are less common. It is unclear whether this pattern is attributable to maturational factors (i.e., younger children lack sufficiently developed cognitive faculties needed to learn abstract words) or linguistic factors (i.e., younger children lack sufficient knowledge of their language to use grammatical or contextual cues needed to figure out the meaning of more abstract words). The present study explores this question by comparing vocabulary acquisition in 53 preschool-aged children (M = 51 months, range = 30-76 months) who were adopted from China and Eastern Europe after two and half years of age and 53 vocabulary-matched infant controls born and raised in English speaking families in North America (M = 24 months, range = 16-33 months). Vocabulary was assessed using the MB-CDI Words and Sentences form, word frequency was estimated from the CHILDES database, and imageability was measured using adult ratings of how easily words could be pictured mentally. Both groups were more likely to know words that were both highly frequent and imageable (resulting in an over-additive interaction). Knowledge of a word was also independently affected by the syntactic category that it belongs to. Adopted preschoolers' vocabulary was slightly less affected by imageability. These findings were replicated in a comparison with a larger sample of vocabulary-matched controls drawn from the MB-CDI norming study (M = 22 months, range = 16-30 months; 33 girls). These results suggest that the patterns of acquisition in children's early vocabulary are primarily driven by the accrual of linguistic knowledge, but that vocabulary may also be affected by differences in early life experiences or conceptual knowledge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Failure to achieve timely arteriovenous fistulae (AVFs) utilization due to excessive depth (>6 mm) remains an ongoing concern for dialysis access. This study evaluates the outcomes of radiocephalic (RCF) and brachiocephalic (BCF) fistula elevation required for access utilization., Methods: A retrospective review of all patients undergoing first-time autologous access over 10 years was undertaken. RCF and BCF were analyzed, and cases of initial access failure due to depth alone were selected for study. Primary and staged brachio-basilic AVF were excluded. Outcomes of early thrombosis, line placement, maturation (successful progression to hemodialysis [HD), reintervention, and functional dialysis (continuous HD for 3 consecutive months) were examined., Results: From January 2012 to December 2022, 1733 patients (67% female; mean age, 61 ± 14 years) underwent autologous AVF placement. Of these, 298 patients (17%) had depth-related AVF access issues (BCF, 71% and RCF, 29%). Nineteen percent of these AVFs underwent a primary balloon-assisted maturation (BAM), and 2% had side branch coil embolization before consideration for elevation. The average time to intervention for depth was 11 ± 4 weeks after primary creation. During elevation, side branch ligation occurred in 38% of cases, and 15% underwent intraoperative BAM, The pre-elevation depth was 8.2 ± 3.1 mm, and the mean post-elevation depth was 4.7 ± 2.9 mm (P = .002). Early thrombosis (<18 days) occurred in 4% of cases. There was no mortality, and the 30-day major adverse cardiac event rate was 2%, with a 30-day morbidity of 5%, which was driven by wound issues. Six percent of the AVFs underwent follow-up BAM within 3 months. Mean maturation of the AVFs was 74% ± 3% vs 72% ± 3% (P = .58) for the elevation vs no-elevation groups at 24 weeks, respectively. However, there was an increase in tunneled central line placement in pre-emptive fistula patients due to the delay in maturation (elevation, 17% vs no-elevation, 8%; P = .008). There was a mean successful access time of 6 ± 3 weeks after elevation (16 ± 4 weeks after access creation). There was a median of 2.4 secondary interventions per year after elevation compared with a median of 2.7 secondary interventions per year without elevation. Mean access functionality was 68% ± 8% vs 75% ± 8% at 3 years for the elevation vs no-elevation groups, respectively (P = .25)., Conclusions: Elevation of deep BCF and RCF occurs late after placement but can be successfully achieved with low morbidity and satisfactory long-term functionality. It results in an increase in tunneled central line placement in pre-emptive fistula patients. Elevation is a valuable adjunct to AVF maturation and enhances an autologous access policy., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Biological maturation can be defined as the timing and tempo of progress to achieving a mature state. The estimation of age of peak height velocity (PHV) or percentage of final estimated adult stature attainment (%EASA) is typically used to inform the training process in young athletes. In youth soccer, maturity-related changes in anthropometric and physical fitness characteristics are diverse among individuals, particularly around PHV. During this time, players are also at an increased risk of sustaining an overuse or growth-related injury. As a result, the implementation of training interventions can be challenging. The purpose of this review was to (1) highlight and discuss many of the methods that can be used to estimate maturation in the applied setting and (2) discuss the implications of manipulating training load around PHV on physical development and injury risk. We have provided key stakeholders with a practical online tool for estimating player maturation status (Supplementary Maturity Estimation Tools). Whilst estimating maturity using predictive equations is useful in guiding the training process, practitioners should be aware of its limitations. To increase the accuracy and usefulness of data, it is also vital that sports scientists implement reliable testing protocols at predetermined time-points.

Resumen: Antecedentes: Los nevos de localizaciones especiales («nevi of special sites» [NOSS]) son lesiones melanocíticas benignas que se presentan en ubicaciones particulares. Aunque las características histológicas de los NOSS ya han sido descritas, sus especificaciones inmuno-fenotípicas no han sido del todo definidas. Objetivos: Describir las características clínico-patológicas de una serie de casos de NOSS y determinar su perfil inmunohistoquímico. Materiales y métodos: Se evaluaron 35 NOSS, utilizando técnicas de tinción con inmunoperoxidasa como marcador melanocítico (S100, Melan-A y HMB45) y de proliferación (Ki-67). Resultados: Todos los casos de NOSS mostraron cambios arquitectónicos alarmantes (proliferación melanocítica lentiginosa llamativa, irregularidades, conglomerado y cohesión de los nidos) y atipia citológica (melanocitos grandes con núcleos vesiculares, citoplasma claro y presencia de pigmento melánico fino), características que podrían llevar al diagnóstico equivocado de nevo atípico o, incluso, de melanoma. Todos los casos de NOSS mostraron una expresión difusa de las proteínas S100 y Melan-A. El Ki-67 de los melanocitos névicos fue extremadamente bajo. La expresión de la proteína HMB45 se limitó a los melanocitos junturales y a los dérmicos superficiales. Conclusiones: Los NOSS pueden presentar características histológicas que simulan nevos atípicos o melanomas, por lo que es importante tomar en cuenta esto para evitar errores diagnósticos. La expresión de la proteína HMB45 en los NOSS indica que sus melanocitos tienen un fenotipo activado. La disminución de la expresión de la proteína HMB45 en los NOSS, siguiendo un gradiente descendiente desde la zona de la unión hacia la zona dérmica más profunda indica una maduración inmunohistoquímica. Abstract: Background: Nevi of special sites (NOSS) are benign melanocytic lesions that occur at particular sites. Although the histological features of NOSS have been described, their immunophenotypic features have not been fully characterized. Aims: To present the clinicopathological characteristics of a case series of NOSS and to characterize their immunohistochemical profile. Materials and methods: Thirty-five NOSS were assessed using immunoperoxidase staining techniques for the melanocytic (S100, Melan-A, and HMB45) and proliferation (Ki-67) markers Results: All of the cases of NOSS showed concerning architectural changes (prominent lentiginous melanocytic proliferation, irregularities, crowdedness, and dyhesiveness of the nests), and cytological atypia (large nevomelanocytes with vesicular nuclei, clear cytoplasm, and dusty melanin pigment) that can lead to a misdiagnosis of atypical nevi or even melanomas. All of the cases of NOSS showed diffuse expression of S100 and Melan-A proteins. Ki-67 labeling index of the nevomelanocytes was extremely low. HMB45 protein expression was limited to the junctional and superficial dermal nevomelanocytes. Conclusions: NOSS can show histological features that can easily mimic atypical nevi or melanomas and this diagnostic consideration should be kept in mind to avoid their misdiagnosis. The expression of HMB45 protein in NOSS indicates that their nevomelanocytic cells have an activated phenotype. The decreased HMB45 protein expression following a gradient from junctional to deeper dermal localization in NOSS is indicative of their immunohistochemical maturation.

Obestatin is a gastrointestinal peptide having wide-ranging effects on cell proliferation; however, its mechanism of action remains poorly understood. Thus, the aim of the study was to elucidate the effect of exogenous obestatin on the postnatal structural development of the small intestine. Seven-day-old piglets with an average BW of 1.56 ± 0.23 kg were divided into four groups (n = 10) that received intragastrically obestatin (2, 10 or 15 μg/kg BW) or vehicle. After a 6-day experimental period, morphological analysis of gastrointestinal tract and small intestine wall (mitosis and apoptosis indexes, histomorphometry of mucosa and muscularis layers) was performed. The study revealed a seemingly incoherent pattern of the histological structure of the small intestine among the experimental groups, suggesting that the effect of obestatin is both intestinal segment specific and dose dependent. Histomorphometric analysis of the small intestine showed that higher doses of obestatin seem to promote the structural development of the duodenum while simultaneously hindering the maturation of more distal parts of the intestine. Intragastric administration of obestatin increased the crypt mitotic index in all segments of the small intestine with the strongest pro-mitotic activity following the administration of obestatin at a dose of 10 and 15 μg/kg BW. The significant differences in the number of apoptotic cells in the intestinal villi among the groups were observed only in proximal jejunum and ileum. In conclusion, it seems that obestatin shows a broad-spectrum of activity in the gastrointestinal tract of newborn piglets, being able to accelerate its structural development. However, the varied effect depending on the intestinal segment or the concentration of exogenous obestatin causes that further research is needed to clarify the exact mechanism of this phenomenon.

ABSTRACT: Changes in the metabolic fingerprint of plasma during the onset of lay in broiler breeders were investigated. We used metabolomics to identify biomarkers of sexual maturity and to provide a comprehensive understanding of breeder metabolome during the pullet to hen transition period. A total of 36 pullets were used, in which 30 pullets were randomly assigned to one of 10 unique growth trajectories and 6 birds were assigned to an unrestricted group. The growth trajectories were designed using a 3-phase Gompertz growth model with 10 levels of BW gain in the prepubertal and pubertal growth phases ranging from the breeder-recommended target BW to 22.5% higher, in 2.5% increments. The BW trajectories were applied to each individual bird using a precision feeding (PF) system, which collected BW and feed intake data for each individual bird. The birds were classified based on age at first egg (AFE), and 12 pullets were chosen from the lower and upper AFE extremes (early and late onset of lay) at 18, 20, 22, 24, and 26 wk of age to run repeated blood plasma metabolomic assays. The metabolomic profile data were collected using a direct-injection liquid chromatography-tandem mass spectrometry and steroid assays. Univariate analysis identified 87 differential metabolites between the early- and late-onset of lay groups at 24 wk of age and 104 differential metabolites between the pullet and hen groups. Further investigation of differential metabolites showed 15 potential biomarkers for pullet to hen transition by analyzing the receiver operating characteristic (ROC) curve, mainly consisting of carnitine and choline metabolites. Differential metabolites during the pullet to hen transition were mainly associated with lipid, energy, and amino acid metabolism pathways, which gave clues to the physiological and metabolic shifts resulting from sexual maturation. At 24 wk of age, the main pathways involved in differentiation of the early- and late-onset of lay groups were related to lipid and amino acid metabolism. These metabolites could be involved in biosynthesis of egg yolk precursors in the liver.

Artificial reproduction of northern pike Esox lucius is impeded by the likelihood of obtaining only a small volume of sperm of inconsistent quality. A controlled-release hormone delivery system has the potential to enhance sperm production while avoiding multiple injections The objective of this study was to investigate the effects of mammalian gonadotropin-releasing hormone agonist (mGnRHa) incorporated into poly(lactic-co-glycolic acid) (PLGA) microparticles on milt production, spermatozoon characteristics, and secretion of 17β-estradiol (E2), 11-keto testosterone (11-KT), and testosterone in northern pike. Fish were divided into four groups and injected with 2 mg/kg BW carp pituitary extract (CPE), 20 µg/kg BW mGnRHa in PLGA microparticles, or 20 µg/kg BW mGnRHa plus 20 mg/kg BW metoclopramide (MET) in PLGA microparticles (PLGA + MET), along with a control group injected with 1 ml/kg 0.9% NaCl. At 48 h postinjection, the volume of milt produced was significantly greater in groups treated with CPE and PLGA + MET than in other groups. At 96 h postinjection, all hormone-treated groups exhibited significantly higher spermatozoon average velocity than recorded in the control group. Spermatozoon motility was significantly increased (P

Prematurity can result in widespread neurodevelopmental impairment, with the impact of premature extrauterine exposure on brain function detectable in infancy. A range of neurodynamic and haemodynamic functional brain measures have previously been employed to study the neurodevelopmental impact of prematurity, with methodological and analytical heterogeneity across studies obscuring how multiple sensory systems are affected. Here, we outline a standardised template analysis approach to measure evoked response magnitudes for visual, tactile, and noxious stimulation in individual infants (n = 15) using EEG. By applying these templates longitudinally to an independent cohort of very preterm infants (n = 10), we observe that the evoked response template magnitudes are significantly associated with age-related maturation. Finally, in a cross-sectional study we show that the visual and tactile response template magnitudes differ between a cohort of infants who are age-matched at the time of study but who differ according to whether they are born during the very preterm or late preterm period (n = 10 and 8 respectively). These findings demonstrate the significant impact of premature extrauterine exposure on brain function and suggest that prematurity can accelerate maturation of the visual and tactile sensory system in infants born very prematurely. This study highlights the value of using a standardised multi-modal evoked-activity analysis approach to assess premature neurodevelopment, and will likely complement resting-state EEG and behavioural assessments in the study of the functional impact of developmental care interventions.

Objective: Islets of Langerhans contain heterogeneous populations of insulin-producing β-cells. Surface markers and respective antibodies for isolation, tracking, and analysis are urgently needed to study β-cell heterogeneity and explore the mechanisms to harness the regenerative potential of immature β-cells. Methods: We performed single-cell mRNA profiling of early postnatal mouse islets and re-analyzed several single-cell mRNA sequencing datasets from mouse and human pancreas and islets. We used mouse primary islets, iPSC-derived endocrine cells, Min6 insulinoma, and human EndoC-βH1 β-cell lines and performed FAC sorting, Western blotting, and imaging to support and complement the findings from the data analyses. Results: We found that all endocrine cell types expressed the cluster of differentiation 81 (CD81) during pancreas development, but the expression levels of this protein were gradually reduced in β-cells during postnatal maturation. Single-cell gene expression profiling and high-resolution imaging revealed an immature signature of β-cells expressing high levels of CD81 (CD81high) compared to a more mature population expressing no or low levels of this protein (CD81low/-). Analysis of β-cells from different diabetic mouse models and in vitro β-cell stress assays indicated an upregulation of CD81 expression levels in stressed and dedifferentiated β-cells. Similarly, CD81 was upregulated and marked stressed human β-cells in vitro. Conclusions: We identified CD81 as a novel surface marker that labels immature, stressed, and dedifferentiated β-cells in the adult mouse and human islets. This novel surface marker will allow us to better study β-cell heterogeneity in healthy subjects and diabetes progression.

Endogenous cortical fluctuations captured by electroencephalograms (EEGs) reflect activity in large-scale brain networks that exhibit dynamic patterns over multiple time scales. Developmental changes in the coordination and integration of brain function leads to greater complexity in population level neural dynamics. In this study we examined multiscale entropy, a measure of signal complexity, in resting-state EEGs in a large (N = 405) cross-sectional sample of children and adolescents (9–16 years). Our findings showed consistent age-dependent increases in EEG complexity that are distributed across multiple temporal scales and spatial regions. Developmental changes were most robust as the age gap between groups increased, particularly between late childhood and adolescence, and were most prominent over fronto-central scalp regions. These results suggest that the transition from late childhood to adolescence is characterized by age-dependent changes in the underlying complexity of endogenous brain networks.

Nobiletin is a natural flavonoid found in citrus fruits with beneficial effects, including anti-inflammatory, anti-cancer and anti-oxidation effects. The aim of this study was to investigate whether nobiletin improves mitochondrial function in porcine oocytes and examine the underlying mechanism. Oocytes enclosed by cumulus cells were cultured in TCM-199 for 44 h with 0.1% dimethyl sulfoxide (control), or supplemented with 5, 10, 25, and 50 μM of nobiletin (Nob5, Nob10, Nob25, and Nob50, respectively). Oocyte maturation rate was significantly enhanced in Nob10 (70.26 ± 0.45%) compared to the other groups (control: 60.12 ± 0.47%; Nob5: 59.44 ± 1.63%; Nob25: 63.15 ± 1.38%; Nob50: 46.57 ± 1.19%). The addition of nobiletin reduced the levels of reactive oxygen species and increased glutathione levels. Moreover, Nob10 promoted mitochondrial biogenesis by upregulating the protein levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α). This resulted in an increase in the number of active mitochondria, mitochondrial DNA copy number, mitochondrial membrane potential, and ATP production, thereby enhancing mitochondrial function. The protein level of p53 decreased, followed by the phosphorylation of B-cell lymphoma 2, suggesting a reduction in mitochondria-mediated apoptosis in the Nob10 group. Additionally, the release of cytochrome c from the mitochondria was significantly diminished along with a decrease in the protein expression of caspase 3. Thus, nobiletin has a great potential to promote the in vitro maturation of porcine oocytes by suppressing oxidative stress and promoting mitochondrial function through the upregulation of the SIRT1/PGC-1α signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dengue virus (DENV) envelope protein plays crucial role in virus entry and maturation of virus during infection. Maturation of DENV occurs in the trans Golgi network at slightly acidic pH which is close to pKa of histidine. When exposed to the acidic environment of the late secretory pathway, dengue virus particles go through a significant conformational change, whereby interactions of structural proteins envelope (E) and prM proteins are reorganised and enable furin protease to cleave prM resulting in mature virus. In order to study the role of histidine of E protein in DENV maturation, we mutated 7 conserved histidine residues of envelope protein and assessed the percent of budding using viral like particle (VLP) system. Histidine mutants; H144A, H244A, H261A and H282A severely disrupted VLP formation without any significant change in expression in cell and its oligomerization ability. Treatment with acidotropic amine reversed the defect for all 4 mutants suggesting that these histidines could be involved in maturation and release. Over expression of capsid protein slightly enhanced VLP release of H244A and H261A. Similarly, furin over expression increased VLP release of these mutants. Co-immunoprecipitation studies revealed that prM and E interaction is lost for H244A, H261A and H282A mutants at acidic pH but not at neutral pH indicating that they could be involved in histidine switch during maturation at acidic pH. Detailed analysis of the mutants could provide novel insights on the interplay of envelop protein during maturation and aid in target for drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In postpartum dairy cows, lipopolysaccharide (LPS) derived from gram-negative bacteria causes uterine or mammary inflammation, resulting in low fertility. The present study aimed to investigate the effect of LPS on the in vitro growth (IVG), steroidogenesis, and maturation of oocyte-cumulus-granulosa cell complexes (OCGCs) derived from bovine early antral follicles. OCGCs were isolated from bovine early antral follicles (0.5-1 mm in diameter) and cultured in vitro for 12 days using media containing 0 (control), 0.01, or 1 μg/mL of LPS. The viability, cavity formation, and oocyte diameter of the OCGCs, as well as the concentrations of estradiol (E 2 ) and progesterone (P 4 ) in the IVG culture media, were determined. After IVG culture, oocytes collected from viable OCGCs were matured in vitro (IVM) in a medium without LPS. The nuclear maturation rate and the mitochondrial membrane potential of oocytes were determined. Bovine oocytes and cumulus-granulosa complexes derived from early antral follicles expressed genes encoding LPS receptor complex, such as toll-like receptor 4 (TLR4). Immunohistochemistry analysis further localized TLR4 expression predominantly in follicular granulosa and theca cells of early antral follicles. The viability of OCGCs and cavity formation in OCGCs were lower in the 0.01 and 1 μg/mL LPS groups than in the control group. No significant difference in oocyte diameter was observed between the treatment groups throughout the culture period. Moreover, E 2 production was suppressed in the 0.01 and 1 μg/mL LPS groups from Days 4-8, whereas P 4 production increased in the 1 μg/mL LPS group from Days 0-8. The nuclear maturation rate after IVM was lower in the 0.01 and 1 μg/mL LPS groups than in the control group. The mitochondrial membrane potential of post-IVM oocytes was lower in the 0.01 and 1 μg/mL LPS groups than in the control group. Taken together, these results indicate that LPS inhibited the growth and steroidogenesis of OCGCs and the meiosis and mitochondrial function of oocytes derived from early antral follicles. This study suggests that the detrimental effects of LPS on developing oocytes may contribute to long-term decreased fertility in postpartum dairy cows., Competing Interests: Declaration of competing interest None of the authors have any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Insight into neuroembryology, developmental neuroanatomy and neurophysiology distinguish the diagnostic approaches of paediatric from adult neurologists and general paediatricians. These fundamental disciplines of basic neuroscience could be more effectively taught during paediatric neurology and most residency programmes, that will strengthen career-long learning. Interdisciplinary training of fetal-neonatal neurology within these programs requires working knowledge of neuroembryology applied to maternal reproductive health influencing the maternal-placental-fetal triad, neonate, and young child. Systematic didactic teaching of development in terms of basic neuroscience with neuropathological context would better address needed clinical skill sets to be incorporated into paediatric neurology and neonatology residencies to address brain health and diseases across childhood. Trainees need to recognize the continuity of development, established by maternal reproductive health before conception with gene -environment influences over the first 1000 days. Considerations of neuroembryology that explain earlier brain development during the first half of pregnancy enhances an understanding of effects throughout gestation through parturition and into neonatal life. Neonatal EEG training enhances these clinical descriptions by applying serial EEG-state analyses of premature neonates through early childhood to recognize evolving patterns associated with neuronal maturation and synaptogenesis. Neuroimaging studies offer comparisons of normal structural images with malformations and destructive lesions to correlate with clinical and neurophysiological findings. This analysis better assesses aberrant developmental processes in the context of neuroembryology. Time-specific developmental events and semantic precision are important for accurate phenotypic descriptions for a better understanding of etiopathogenesis with maturation. Certification of paediatric neurology training programme curricula should apply practical knowledge of basic neuroscience in the context of nervous system development and maturation from conception through postnatal time periods. Interdisciplinary fetal-neonatal neurology training constitutes an important educational component for career-long learning., Competing Interests: Declaration of competing interest The authors have no financial disclosures or conflicts of interest to declare. In our laboratory, fetal autopsy tissues are always treated with respect., (Copyright © 2024. Published by Elsevier Ltd.)

The ability to effectively suppress motor response tendencies is essential for focused and goal-directed behavior. Here, we tested the hypothesis that developmental improvement in the ability to cancel a motor response is reflected by maturational changes in the white matter underlying the right presupplementary motor area (preSMA) and posterior inferior frontal gyrus (IFG), two cortical key areas of the fronto-basal ganglia “stopping” network. Eighty-eight typically-developing children and adolescents, aged 7–19 years, were longitudinally assessed with the stop-signal task (SST) and diffusion tensor imaging (DTI) of the brain over a period of six years. Participants were examined from two to nine times with an average of 6.6 times, resulting in 576 SST-DTI datasets. We applied tract-based spatial statistics to extract mean fractional anisotropy (FA) from regions-of-interest in the white matter underlying the right IFG (IFGFA) and right preSMA (preSMAFA) at each time point. Motor response cancelation performance, estimated with the stop-signal reaction time (SSRT), improved with age. Initially well performing children plateaued around the age of 11 years, while initially poor performers caught up at the age of 13–14 years. White matter microstructure continued to mature across the investigated age range. Males generally displayed linear maturational trajectories, while females displayed more curvilinear trajectories that leveled off around 12–14 years of age. Maturational increases in right preSMAFA but not right IFGFA were associated with developmental improvements in SSRT. This association differed depending on the mean right preSMAFA across the individual maturational trajectory. Children with lower mean right preSMAFA exhibited poorer SSRT performance at younger ages but steeper developmental trajectories of SSRT improvement. Children with higher mean right preSMAFA exhibited flatter trajectories of SSRT improvement along with faster SSRT already at the first assessments. The results suggest that no further improvement in motor response cancellation is achieved once a certain level of maturity in the white matter underlying the right preSMA is reached. Similar dynamics may apply to other behavioral read-outs and brain structures and, thus, need to be considered in longitudinal MRI studies designed to map brain structural correlates of behavioral changes during development.

White matter maturation is a nonlinear and heterogeneous phenomenon characterized by axonal packing, increased axon caliber, and a prolonged period of myelination. While current in vivo diffusion MRI (dMRI) methods, like diffusion tensor imaging (DTI), have successfully characterized the gross structure of major white matter tracts, these measures lack the specificity required to unravel the distinct processes that contribute to microstructural development. Neurite orientation dispersion and density imaging (NODDI) is a dMRI approach that probes tissue compartments and provides biologically meaningful measures that quantify neurite density index (NDI) and orientation dispersion index (ODI). The purpose of this study was to characterize the magnitude and timing of major white matter tract maturation with NODDI from infancy through adolescence in a cross-sectional cohort of 104 subjects (0.6–18.8 years). To probe the regional nature of white matter development, we use an along-tract approach that partitions tracts to enable more fine-grained analysis. Major white matter tracts showed exponential age-related changes in NDI with distinct maturational patterns. Overall, analyses revealed callosal fibers developed before association fibers. Our along-tract analyses elucidate spatially varying patterns of maturation with NDI that are distinct from those obtained with DTI. ODI was not significantly associated with age in the majority of tracts. Our results support the conclusion that white matter tract maturation is heterochronous process and, furthermore, we demonstrate regional variability in the developmental timing within major white matter tracts. Together, these results help to disentangle the distinct processes that contribute to and more specifically define the time course of white matter maturation.

Summary: We demonstrate that cortical interneurons derived from ventral eminences, including the caudal ganglionic eminence, undergo programmed cell death. Moreover, with the exception of VIP interneurons, this occurs in a manner that is activity-dependent. In addition, we demonstrate that, within interneurons, Calcineurin, a calcium-dependent protein phosphatase, plays a critical role in sequentially linking activity to maturation (E15–P5) and survival (P5–P20). Specifically, embryonic inactivation of Calcineurin results in a failure of interneurons to morphologically mature and prevents them from undergoing apoptosis. By contrast, early postnatal inactivation of Calcineurin increases apoptosis. We conclude that Calcineurin serves a dual role of promoting first the differentiation of interneurons and, subsequently, their survival.

Background: Diabetes mellitus is characterized by loss or dysfunction of insulin-producing β-cells in the pancreas, resulting in failure of blood glucose regulation and devastating secondary complications. Thus, β-cells are currently the prime target for cell-replacement and regenerative therapy. Triggering endogenous repair is a promising strategy to restore β-cell mass and normoglycemia in diabetic patients. Potential strategies include targeting specific β-cell subpopulations to increase proliferation or maturation. Alternatively, transdifferentiation of pancreatic islet cells (e.g. α- or δ-cells), extra-islet cells (acinar and ductal cells), hepatocytes, or intestinal cells into insulin-producing cells might improve glycemic control. To this end, it is crucial to systematically characterize and unravel the transcriptional program of all pancreatic cell types at the molecular level in homeostasis and disease. Furthermore, it is necessary to better determine the underlying mechanisms of β-cell maturation, maintenance, and dysfunction in diabetes, to identify and molecularly profile endocrine subpopulations with regenerative potential, and to translate the findings from mice to man. Recent approaches in single-cell biology started to illuminate heterogeneity and plasticity in the pancreas that might be targeted for β-cell regeneration in diabetic patients. Scope of review: This review discusses recent literature on single-cell analysis including single-cell RNA sequencing, single-cell mass cytometry, and flow cytometry of pancreatic cell types in the context of mechanisms of endogenous β-cell regeneration. We discuss new findings on the regulation of postnatal β-cell proliferation and maturation. We highlight how single-cell analysis recapitulates described principles of functional β-cell heterogeneity in animal models and adds new knowledge on the extent of β-cell heterogeneity in humans as well as its role in homeostasis and disease. Furthermore, we summarize the findings on cell subpopulations with regenerative potential that might enable the formation of new β-cells in diseased state. Finally, we review new data on the transcriptional program and function of rare pancreatic cell types and their implication in diabetes. Major conclusion: Novel, single-cell technologies offer high molecular resolution of cellular heterogeneity within the pancreas and provide information on processes and factors that govern β-cell homeostasis, proliferation, and maturation. Eventually, these technologies might lead to the characterization of cells with regenerative potential and unravel disease-associated changes in gene expression to identify cellular and molecular targets for therapy.

Working memory (WM), the ability to hold information on-line to guide planned behavior, improves through adolescence in parallel with continued maturation of critical brain systems supporting cognitive control. Initial developmental neuroimaging studies with one or two timepoints have provided important though varied results limiting our understanding of which and how neural systems change during this transition into mature WM. In this study, we leverage functional magnetic resonance imaging (fMRI) longitudinal data spanning up to 9 years in 129 normally developing individuals to identify which systems demonstrate growth changes that accompany improvements in WM performance. We used a memory guided saccade task that allowed us to probe encoding, pure maintenance, and retrieval neural processes of WM. Consistent with prior research, we found that WM performance continued to improve into the early 20's. fMRI region of interest (ROI) analyses revealed developmental (1) increases in sensorimotor-related (encoding/retrieval) activity in visual cortex from childhood through early adulthood that were associated with WM accuracy and (2) decreases in sustained (maintenance) activity in executive regions from childhood through mid-adolescence that were associated with response latency in childhood and early adolescence. Together these results provide compelling evidence that underlying the maturation of WM is a transition from reliance on executive systems to specialized regions related to the domain of mnemonic requirements of the task leading to optimal performance.

We hypothesized that the neonatal rat heart would bring transplanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to maturity as it grows to adult size. In neonatal rat heart, engrafted hiPSC derivatives developed partially matured myofibrils after 3 months, with increasing cell size and sarcomere length. There was no difference between grafts from hiPSC-CMs or hiPSC-derived cardiac progenitors (hiPSC-CPs) at 3 months, nor was maturation influenced by infarction. Interestingly, the infarcted adult heart induced greater human cardiomyocyte hypertrophy and induction of cardiac troponin I expression than the neonatal heart. Although human cardiomyocytes at all time points were significantly smaller than the host rat cardiomyocytes, transplanted neonatal rat cardiomyocytes reached adult size and structure by 3 months. Thus, the adult rat heart induces faster maturation than the neonatal heart, and human cardiomyocytes mature more slowly than rat cardiomyocytes. The slower maturation of human cardiomyocytes could be related to environmental mismatch or cell-autonomous factors.

Experience-dependent synapse refinement is essential for functional optimization of neural circuits. However, how sensory experience sculpts excitatory synaptic transmission is poorly understood. Here, we show that despite substantial remodeling of synaptic connectivity, AMPAR-mediated synaptic transmission remains at equilibrium during the critical period in the mouse primary visual cortex. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin-binding protein important for synaptic plasticity. With normal visual experience, loss of Ng decreased AMPAR-positive synapse numbers, prevented AMPAR-silent synapse maturation, and increased spine elimination. Importantly, visual deprivation halted synapse loss caused by loss of Ng, revealing that Ng coordinates experience-dependent AMPAR-silent synapse conversion to AMPAR-active synapses and synapse elimination. Loss of Ng also led to sensitized long-term synaptic depression (LTD) and impaired visually guided behavior. Our synaptic interrogation reveals that experience-dependent coordination of AMPAR-silent synapse conversion and synapse elimination hinges upon Ng-dependent mechanisms for constructive synaptic refinement during the critical period.

Background: Establishing long-term arteriovenous access is an important component in the long-term care of a patient with end-stage renal disease. The increasing frequency of obesity is reported to impact the access management of end-stage renal disease patients. This study aims to evaluate the outcomes of arteriovenous fistulae (AVF) in obese and nonobese patients., Methods: A retrospective review of all patients over ten years with primary autogenous AVF (radiocephalic, brachiocephalic, and brachial-basilic) was undertaken at a single center. Patients were subcategorized by body mass index into nonobese, class I, II, and III obesity. Outcomes of maturation (successful progression to hemodialysis), reintervention, functional dialysis (continuous hemodialysis for 3 consecutive months), and patency were examined., Results: From January 1999 to December 2019, 2311 patients (67% female; mean age, 61 ± 15 years) underwent primary AVF placement (12% radiocephalic, 53% brachiocephalic, and 35% brachial basilic). Forty-one percent were nonobese, 29% had class I obesity, 19% had class II obesity, and 11% had class III obesity. The majority of patients were diabetic and Hispanic. The 30-day major adverse cardiovascular event rate was elevated in class II (0.20%) and class III (0.50%) obesity compared with class I obesity (0.15%) and nonobese (0.05%). The 30-day morbidity rate was higher in all classes of obesity (0.5% vs0.3% vs 0.2% vs 0.05% for class III vs class II vs class I obesity and nonobese, respectively). Early thrombosis was significantly increased in class II (9%) and class III obesity (12%) compared with class I obesity (5%) and nonobese (3%). There was a two-fold increase in procedures to effect maturation in class II (51%) and class III (74%) obesity compared with class I obesity (22%) and nonobese (34%). Secondary patency at 3 years was significantly lower in class III (62 ± 4%) and class II (79 ± 3%) compared with class I obesity (87 ± 2%) and nonobese (93 ± 4%). All classes of obesity required significantly more secondary Interventions per year compared with nonobese (3.9 vs 3.1 vs 2.5 vs 1.4 secondary interventions per year for class III vs class II vs class I obesity and nonobese, respectively)., Conclusions: Advancing obesity class is associated with an increased number of procedures to achieve AVF maturation and is associated with poorer patency and functionality as the category of obesity advances., Competing Interests: Disclosures None., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (Vmax) and affinity (Km) in children 0–10 years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS), to identify factors predicting NAT2 Vmax and Km by examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both Vmax and Km and superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥5.3 years. Thus, enzyme efficiency was constrained by substrate concentration, genes, and age. Since MARS output is in the form of basis functions and equations, it allows multiscale systems modeling from the level of cellular chemical reactions to whole body physiological parameters, by automatic selection of significant predictors by the algorithm.

Enhancing the maturation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) will facilitate their applications in disease modeling and drug discovery. Previous studies suggest that cell alignment could enhance hPSC-CM maturation; however, the robustness of this approach has not been well investigated. To this end, we examined if the anisotropic orientation of hPSC-CMs imposed by the underlying aligned fibers within a 3D microenvironment could improve the maturation of hPSC-CMs. Enriched hPSC-CMs were cultured for two weeks on Matrigel-coated anisotropic (aligned) and isotropic (random) polycaprolactone (PCL) fibrous scaffolds, as well as tissue culture polystyrenes (TCPs) as a control. As expected, hPSC-CMs grown on the two types of fibrous scaffolds exhibited anisotropic and isotropic orientations, respectively. Similar to cells on TCPs, hPSC-CMs cultured on these scaffolds expressed CM-associated proteins and were pharmacologically responsive to adrenergic receptor agonists, a muscarinic agonist, and a gap junction uncoupler in a dose-dependent manner. Although hPSC-CMs grown on anisotropic fibrous scaffolds displayed the highest expression of genes encoding a number of sarcomere proteins, calcium handling proteins and ion channels, their calcium transient kinetics were slower than cells grown on TCPs. These results suggest that electrospun anisotropic fibrous scaffolds, as a single method, have limited effect on improving the maturation of hPSC-CMs.

Probiotic bacteria are widely used in functional foods or as dietary supplements. However, the signalling pathways by which they promote beneficial effects on the immune system are not fully understood. The effects of six different probiotics on monocyte-derived dendritic cells (MoDCs) were examined in this study. We found that Lactobacillus rhamnosus triggered full maturation of MoDCs, whereas L. fermentum induced a state of semi-maturation, and Bifidobacterium lactis strains barely modified MoDC basal state. Analysis of expression of genes associated with Toll-like receptor signalling revealed that B. lactis strains induced a weak pro-inflammatory response, and L. fermentum did not affect gene expression of downstream pathways, whereas it increased the expression of cytokines related with STAT3 pathway. Further insight into the pathways triggered by probiotics would facilitate a more appropriate use of probiotics to restore homeostasis in different immune disorders, like inflammatory bowel disease or allergies.

Background: Individuals with autism spectrum disorder (ASD) show atypical brain activity, perhaps due to delayed maturation. Previous studies examining the maturation of auditory electrophysiological activity have been limited due to their use of cross-sectional designs. The present study took a first step in examining magnetoencephalography (MEG) evidence of abnormal auditory response maturation in ASD via the use of a longitudinal design. Methods: Initially recruited for a previous study, 27 children with ASD and nine typically developing (TD) children, aged 6- to 11-years-old, were re-recruited two to five years later. At both timepoints, MEG data were obtained while participants passively listened to sinusoidal pure-tones. Bilateral primary/secondary auditory cortex time domain (100 ms evoked response latency (M100)) and spectrotemporal measures (gamma-band power and inter-trial coherence (ITC)) were examined. MEG measures were also qualitatively examined for five children who exhibited “optimal outcome”, participants who were initially on spectrum, but no longer met diagnostic criteria at follow-up. Results: M100 latencies were delayed in ASD versus TD at the initial exam (~19 ms) and at follow-up (~18 ms). At both exams, M100 latencies were associated with clinical ASD severity. In addition, gamma-band evoked power and ITC were reduced in ASD versus TD. M100 latency and gamma-band maturation rates did not differ between ASD and TD. Of note, the cohort of five children that demonstrated “optimal outcome” additionally exhibited M100 latency and gamma-band activity mean values in-between TD and ASD at both timepoints. Though justifying only qualitative interpretation, these “optimal outcome” related data are presented here to motivate future studies. Conclusions: Children with ASD showed perturbed auditory cortex neural activity, as evidenced by M100 latency delays as well as reduced transient gamma-band activity. Despite evidence for maturation of these responses in ASD, the neural abnormalities in ASD persisted across time. Of note, data from the five children whom demonstrated “optimal outcome” qualitatively suggest that such clinical improvements may be associated with auditory brain responses intermediate between TD and ASD. These “optimal outcome” related results are not statistically significant though, likely due to the low sample size of this cohort, and to be expected as a result of the relatively low proportion of “optimal outcome” in the ASD population. Thus, further investigations with larger cohorts are needed to determine if the above auditory response phenotypes have prognostic utility, predictive of clinical outcome.