Abnormal Maturation Research Articles

GRANULOSA CELL DYSFUNCTION AND IMPAIRED OOCYTE MATURATION PLAY SIGNIFICANT ROLES IN POLYCYSTIC OVARY SYNDROME PATHOGENESIS

The polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women of reproductive age worldwide. It is characterized by hyperandrogenism, ovarian dysfunction, and polycystic ovarian morphology.With a particular focus on granulosa cell dysfunction and abnormal oocyte maturation, this comprehensive review explores the intricate molecular mechanisms driving PCOS pathogenesis. PCOS is characterized by hormonal and metabolic disturbances caused by long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and the insulin-like growth factor 1 (IGF1) signaling pathway.In this review, we discuss the dysregulation of certain lncRNAs, such as NEAT1, and miRNAs, including miR-29a-3p, in PCOS granulosa cells, as well as how these dysregulations affect cell proliferation, insulin sensitivity, and steroidogenesis. This study examines the interaction between non-coding RNAs and the IGF1 system, which reveals an intricate regulatory network involved in follicular development and ovarian function. These pathways are altered in expression and activity, which has implications for how oocytes mature and how fertility is affected.In addition, this review emphasizes the interconnected nature of granulosa cell dysfunction, oocyte maturation defects, and systemic metabolic disturbances in PCOS pathogenesis. Granulosa cells have the potential to be used as a research and therapeutic intervention focus, due to their accessibility and central role in ovarian function.Additionally, we propose future research directions using advanced technologies such as single cell sequencing and multi-omics technologies. According to the review, studies that focus on granulosa cells can help develop novel diagnostic markers, personalized treatment strategies, and potential PCOS-based therapies.In addition to providing insight into the molecular underpinnings of PCOS, this study sets the stage for future investigations aimed at improving diagnosis, management, and treatment.

Trace antibiotic exposure affects murine gut microbiota and metabolism

Gut microbiota is important for host metabolism regulation. Antibiotic exposure disturbs this regulation by affecting the microbiome. Trace levels of antibiotics in water have been widely reported and the impact on gut microbiota remains understudied. We provide evidence of trace antibiotic exposure affecting the host's gut microbiota using a mouse model exposed to trace amounts of azithromycin (AZI) or ciprofloxacin (CIP) in drinking water. AZI exposure in males changed the distribution of gram-positive (Firmicutes and Bacteroidetes) and gram-negative (Proteobacteria, Fusobacteria, and Verrucomicrobia) bacteria at an early age. Both AZI and CIP resulted in abnormal microbiota maturation. Additionally, the production of short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, in females is affected. Serum hormone and metabolome levels shifted after trace antibiotic exposure. AZI and CIP exposure broadly disrupted original host-microbe interaction relationships between the gut microbiota and SCFAs or serum metabolites. In this study, we demonstrated that trace antibiotic exposure was associated with extensive gut microbiota and metabolism perturbation in mice and that the potential health risks in susceptible populations should be considered.

Neural Circuit Remodeling: Mechanistic Insights from Invertebrates.

As nervous systems mature, neural circuit connections are reorganized to optimize the performance of specific functions in adults. This reorganization of connections is achieved through a remarkably conserved phase of developmental circuit remodeling that engages neuron-intrinsic and neuron-extrinsic molecular mechanisms to establish mature circuitry. Abnormalities in circuit remodeling and maturation are broadly linked with a variety of neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. Here, we aim to provide an overview of recent advances in our understanding of the molecular processes that govern neural circuit remodeling and maturation. In particular, we focus on intriguing mechanistic insights gained from invertebrate systems, such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. We discuss how transcriptional control mechanisms, synaptic activity, and glial engulfment shape specific aspects of circuit remodeling in worms and flies. Finally, we highlight mechanistic parallels across invertebrate and mammalian systems, and prospects for further advances in each.

Machine Learning Assessment of Gestational Age in Accelerated Maturation, Delayed Maturation, Villous Edema, Chorangiosis, and Intrauterine Fetal Demise.

Assessment of placental villous maturation is among the most common tasks in perinatal pathology. However, the significance of abnormalities in morphology is unclear and interobserver variability is significant. To develop a machine learning model of placental maturation across the second and third trimesters and quantify the impact of different pathologist-diagnosed abnormalities of villous morphology. Digitize placental villous slides from more than 2500 placentas at 12.0 to 42.6 weeks. Build whole slide learning models to estimate obstetrician-determined gestational age for cases with appropriate maturation and normal morphology. Define the model output as "placental age" and compare it to the chronologic gestational age. Our model showed an r2 of 0.864 and mean absolute error of 1.62 weeks for placentas with appropriate maturation in the test set. Pathologist diagnosis of accelerated maturation was associated with a 2.56-week increase in placental age (±2.91 weeks, P < .001), while delayed maturation was associated with a 0.92-week decrease in placental age (±1.82 weeks, P < .001). Intrauterine fetal demise causes diverse changes to placental age, driven by the nature of the demise. We tested the impact of training a model, using all live births. The resulting r2 was 0.874 and mean absolute error was 1.73 weeks. Furthermore, by including cases with abnormal maturation in the training data, the effect size of accelerated maturation was blunted to only 0.56 ± 2.35 weeks (P < .001). We show that various abnormalities of villous maturation and morphology correlate with abnormalities in placental age. This "no pathologist" model could be useful in situations where pathologists are unavailable or the need for consistency outweighs the utility of expertise.

Influence of Magmatic Intrusion on Abnormal Hydrocarbon Generation and Expulsion of Source Rock: A Case Study of the Dongying Sag, Bohai Bay Basin

AbstractHow gabbro affects the generation and expulsion of hydrocarbons in muddy surrounding rocks is clarified by analyzing thin section, major and trace elements, total organic carbon (TOC), pyrolysis, extracts and vitrinite reflectance data from source rocks in the Chunxi area the Dongying Sag, Bohai Bay Basin, eastern China. The results show that a magma intrusion brings copious heat to the source rocks, which promotes abnormal maturation of organic matter (OM) and rapid hydrocarbon generation. The CH4 and H2 produced by gabbro alteration play a role in hydrocarbon generation of source rocks. The hydrothermal process during magma intrusion provides many different minerals to the source rock, resulting in carbonate‐rich surrounding mudstone. The carbonate and clay minerals produced by volcanic mineral alteration jointly catalyze the hydrocarbon generation of the source rock. The high‐temperature baking of the intrusion results in hydrothermal pressurization and hydrocarbon generation pressurization, causing many fractures in the surrounding rock. The generated oil and gas are discharged through the fractures under diffusion and pressure. Mantle‐derived CO2 is also conducive to the expulsion of hydrocarbons because of its strong enrichment capacity for hydrocarbons.

Evaluation of cerebral fissure depths measured by prenatal ultrasonography in healthy fetuses at 20–24 weeks gestational age

AimWe aimed to establish normal reference ranges for insula, sylvian fissure (SF), parieto-occipital fissure (POF), and calcarine fissure (CF) measured by prenatal ultrasonography (USG) between 20–24 weeks of gestation in healthy fetuses. MethodA total of 186 fetuses in the second trimester were evaluated by transabdominal USG. All measurements were obtained by a single clinician. The study was divided into four subgroups (Group A: 20–20 weeks six days, Group B: 21–21 weeks six days, Group C: 22–22 weeks six days, Group D: 23–23 weeks six days). ResultsEight fetuses (4.23 %) between 20 and 21 weeks of gestation could not be included in the study because the sulcus borders could not be clearly evaluated. Measurements were obtained in all fetuses over 21 weeks of gestation. Reference ranges were obtained for insula, SF, POF, and CF in all fetuses and subgroups. At 20 and 23 weeks and six days gestation, mean insula depth was 14.96 ± 1.62 mm (min 11.0 mm − max 18.9 mm), mean SF depth was 6.96 ± 1.35 mm (min 3.6 mm − max 10.0 mm), mean POF depth was 2.05 ± 0.66 mm (min 1.1 mm − max 5.6 mm) and mean CF depth was 2.42 ± 0.68 mm (min 1.5 mm − 6.1 mm). There was a correlation between the cerebellum and cisterna magna and all fissure depths. ConclusionOur nomograms of healthy fetuses may be helpful in the early detection of cortical maturation abnormalities.

True empty follicle syndrome is a subtype of oocyte maturation abnormalities.

To review the outcomes of in vitro maturation (IVM) and in vitro fertilization (IVF) in women with empty follicle syndrome (EFS). The study evaluated the genetic underpinnings of EFS by analyzing mutations. This retrospective case series involving 17 women with EFS over at least 2 IVF cycles was conducted. The study also employed whole-exome sequencing to analyze the genetic mutations. The treatment approaches included letrozole-primed IVM, follicle-stimulating hormone (FSH)-human chorionic gonadotrophin (hCG)-primed IVM, and conventional IVF. The average female age was 31.5±4.6 years, and the duration of infertility was 7.3±3.5 years. Four patients underwent IVF. IVM oocyte collections yielded oocytes in 12 of 13 subjects. Of these, 75% (9/12) yielded MII oocytes after 48 h of IVM media incubation. Six subjects had fertilized embryos, resulting in a 40.9% intracytoplasmic sperm injection (ICSI) fertilization rate (9 embryos/22 MII oocytes). Genetic analysis revealed mutations in seven patients. This study demonstrated the partial efficacy of letrozole-primed IVM plus growth hormone and FSH-hCG primed IVM protocols. No pregnancies or live births were recorded after IVM. One ongoing pregnancy post-IVF and one spontaneous live birth were observed. Inter-cycle variabilities were observed in women with oocyte maturation abnormalities (OMAs). Almost all patients with EFS had oocytes collected during IVM following IVF. These oocytes have limited potential for maturation, fertilization, and live birth, as demonstrated by the low rates observed after IVM culture and ICSI. These conditions are observed in OMAs due to defects in the oocyte machinery. The proposed flowchart provides a comprehensive classification approach for various forms of EFS.

P08-05 The Role and mechanism of O-GlcNAcylation in abnormalities of oocyte maturation and early embryonic development caused by PFOS exposure

P08-05 The Role and mechanism of O-GlcNAcylation in abnormalities of oocyte maturation and early embryonic development caused by PFOS exposure

Epidermal renewal during the treatment of atopic dermatitis lesions: A study coupling line‐field confocal optical coherence tomography with artificial intelligence quantifications

AbstractObjectiveThis study explores the application of Line‐field Confocal Optical Coherence Tomography (LC‐OCT) imaging coupled with artificial intelligence (AI)‐based algorithms to investigate atopic dermatitis (AD), a common inflammatory dermatosis.Materials and methodsAD acute and chronic lesions (ADL) were compared to clinically healthy‐looking skin (ADNL). LC‐OCT was used noninvasively and in real‐time to image the skin of AD patients during flare‐ups and monitor remissions under topical steroid treatment for 2 weeks. Quantitative parameters were extracted from the images, including morphological and cellular‐level markers of epidermal architecture. A novel cellular‐level parameter, nuclei “atypia,” which quantifies the orderliness of epidermal renewal, was used to highlight abnormal maturation processes.ResultsCompared to healthy skin, AD lesions exhibited significant increases in both epidermal and stratum corneum (SC) thickness, along with a more undulated dermo‐epidermal junction (DEJ). Additionally, keratinocyte nuclei (KN) were larger, less compact, and less organized in lesional areas, as indicated by the atypia parameter. A higher degree of atypia was observed in chronic lesions compared to acute ones. Following treatment, all the parameters normalized to levels observed in healthy skin within 2 weeks, mirroring clinical improvements.ConclusionThis study provides insights into the quantification of epidermal renewal using a noninvasive imaging technique, highlighting differences between ADL/ADNL and acute/chronic lesions. It also presents the AD treatment mechanism, paving the way for future investigations on AD and other skin barrier function‐related conditions.

Diverging Effects of Violence Exposure and Psychiatric Symptoms on Amygdala-Prefrontal Maturation During Childhood and Adolescence

BackgroundViolence exposure during childhood and adolescence is associated with increased prevalence and severity of psychopathology. Neurobiological correlates suggest that abnormal maturation of emotion-related brain circuitry, such as the amygdala-prefrontal cortex (PFC) circuit, may underlie the development of psychiatric symptoms after exposure. However, it remains unclear how amygdala-PFC circuit maturation is related to psychiatric risk in the context of violence. MethodsIn this study, we analyzed individual differences in amygdala-PFC circuit maturity using data collected from the PNC (Philadelphia Neurodevelopmental Cohort) (n = 1133 youths). Neurodevelopment models of amygdala-PFC resting-state functional connectivity were built using deep learning and trained to predict chronological age in typically developing youths (not violence exposed and without a psychiatric diagnosis). Using the brain age gap estimate, an index of relative circuit maturation, patterns of atypical neurodevelopment were investigated. ResultsViolence exposure was associated with delayed maturation of basolateral amygdala (BLA)–PFC circuits, driven by increased BLA–medial orbitofrontal cortex functional connectivity. In contrast, increased psychiatric symptoms were associated with advanced maturation of BLA-PFC functional connectivity, driven by decreased BLA–dorsolateral PFC functional connectivity. ConclusionsDelayed frontoamygdala maturation after exposure to violence suggests atypical, but adaptive, development of threat appraisal processes, potentially reflecting a greater threat generalization characteristic of younger children. Advanced circuit maturation with increasing symptoms suggests divergent neurodevelopmental mechanisms underlying illness after emotion circuits have adapted to adversity, exacerbated by preexisting vulnerabilities to early maturation. Disentangling the effects of adversity and psychopathology on neurodevelopment is crucial for helping youths recover from violence and preventing illness from continuing into adulthood.

Recurrent ocular toxoplasmosis is associated with interferon-gamma deficiency possibly due to genetic origin

ObjectiveOcular toxoplasmosis (OT) can cause posterior uveitis; causes of recurrent OT are not well understood. We explored clinical, immunological and genetic properties associated with recurrent OT.Methods and analysisA recurrent OT...

Brain Age Gap in Early Illness Schizophrenia and the Clinical High-Risk Syndrome: Associations With Experiential Negative Symptoms and Conversion to Psychosis.

Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets. Using structural MRI, we compared the brain age gap among CHR-P (n = 51), ESZ (n = 78), and unaffected comparison participants (UCP; n = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n = 10; CHR-P non-converters; n = 23) and positive and negative symptoms. ESZ showed a greater brain age gap relative to UCP and CHR-P (Ps < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P = .008), but not expressive negative symptom severity. Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia.

Testing the role of unstimulated ın vitro maturation in the developmental potential of immature oocytes in women with oocyte maturation abnormalities.

This study aims to investigate the developmental potential of immature oocytes and questions whether unstimulated in vitro maturation (IVM) can be used as a treatment in women with oocyte maturation abnormalities. This cohort study was conducted between September 2019 and December 2022, and it included 12 women who underwent unstimulated, non-hCG priming IVM.Oocytes were incubated in in vitro maturation medium for 26-48 hours and evaluated to compare their maturation profiles with the immature oocytes retrieved from the same patients in their previous IVF cycles. Among the twelve women in the study, eleven (91.6%) underwent whole exome sequencing (WES) analysis. Of these, ten women presented a total of 18 mutations, excluding Case 1, which had no previous mutation analysis. Of the mutations identified, 9 (50%) were located in the FSHR gene, 5 (27.8%) in the TUBB8 gene, 1 (5.6%) in the ZP1 gene, 1 (5.6%) in the SLFN14 gene, 1 (5.6%) in the AR gene, and 1 (5.6%) in the STEAP3 gene. Apart from one woman with resistant ovary syndrome,none of the women treated with unstimulated in vitro maturation had oocyte maturation . Remarkably, the only patient to achieve oocyte maturation in an unstimulated IVM cycle was Case 11, who had ROS and a single FSHR mutation. Unstimulated non hCG primed IVM has no value in the treatment of OMAS, except in cases with resistant ovary syndrome. However this study led our team to develop novel treatment options based on physiological mechanisms for some subtypes and supraphysiological approach for other subtypes of oocyte maturation abnormalities.

Mild neonatal hypoxia disrupts adult hippocampal learning and memory and is associated with CK2-mediated dysregulation of synaptic calcium-activated potassium channel KCNN2.

Although nearly half of preterm survivors display persistent neurobehavioral dysfunction including memory impairment without overt gray matter injury, the underlying mechanisms of neuronal or glial dysfunction, and their relationship to commonly observed cerebral white matter injury are unclear. We developed a mouse model to test the hypothesis that mild hypoxia during preterm equivalence is sufficient to persistently disrupt hippocampal neuronal maturation related to adult cellular mechanisms of learning and memory. Methods: Neonatal (P2) mice were exposed to mild hypoxia (8%O 2 ) for 30 min and evaluated for acute injury responses or survived until adulthood for assessment of learning and memory and hippocampal neurodevelopment. Neonatal mild hypoxia resulted in clinically relevant oxygen desaturation and tachycardia without bradycardia and was not accompanied by cerebral gray or white matter injury. Neonatal hypoxia exposure was sufficient to cause hippocampal learning and memory deficits and abnormal maturation of CA1 neurons that persisted into adulthood. This was accompanied by reduced hippocampal CA3-CA1 synaptic strength and LTP and reduced synaptic activity of calcium-sensitive SK2 channels, key regulators of spike timing dependent neuroplasticity, including LTP. Structural illumination microscopy revealed reduced synaptic density, but intact SK2 localization at the synapse. Persistent loss of SK2 activity was mediated by altered casein kinase 2 (CK2) signaling. Clinically relevant mild hypoxic exposure in the neonatal mouse is sufficient to produce morphometric and functional disturbances in hippocampal neuronal maturation independently of white matter injury. Additionally, we describe a novel persistent mechanism of potassium channel dysregulation after neonatal hypoxia. Collectively our findings suggest an unexplored explanation for the broad spectrum of neurobehavioral, cognitive and learning disabilities that paradoxically persist into adulthood without overt gray matter injury after preterm birth.

MAST4 regulates stem cell maintenance with DLX3 for epithelial development and amelogenesis

The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.

Effects of pain, sedation and analgesia on neonatal brain injury and brain development

Critically ill newborns experience numerous painful procedures as part of lifesaving care in the Neonatal Intensive Care Unit. However, painful exposures in the neonatal period have been associated with alterations in brain maturation and poorer neurodevelopmental outcomes in childhood. The most frequently used medications for pain and sedation in the NICU are opioids, benzodiazepines and sucrose; these have also been associated with abnormalities in brain maturation and neurodevelopment making it challenging to know what the best approach is to treat neonatal pain. This article provides clinicians with an overview of how neonatal exposure to pain as well as analgesic and sedative medications impact brain maturation and neurodevelopmental outcomes in critically ill infants. We also highlight areas in need of future research to develop standardized neonatal pain monitoring and management strategies.

Brain health in preterm infants: importance of early-life pain and analgesia exposure.

"Everyday" exposures in the neonatal period, such as pain, may impact brain health in preterm infants. Specifically, greater exposure to painful procedures in the initial weeks after birth have been related to abnormalities in brain maturation and growth and poorer neurodevelopmental outcomes in preterm infants. Despite an increasing focus on the importance of treating pain in preterm infants, there is a lack of consensus of optimal approaches to managing pain in this population. This may be due to recent findings suggesting that commonly used analgesic and sedative medications in preterm infants may also have adverse effects of brain maturation and neurodevelopmental outcomes. This review provides an overview of potential impacts of pain and analgesia exposure on preterm brain health while highlighting research areas in need of additional investigations for the development of optimal pain management strategies in this population.

Glutathione peroxidase (GPX1) - Selenocysteine metabolism preserves the follicular fluid's (FF) redox homeostasis via IGF-1- NMD cascade in follicular ovarian cysts (FOCs)

Follicular ovarian cysts (FOCs) are characterized by follicles in the ovaries that are >20 mm in diameter and persist for >10 days without the corpus luteum, leading to anovulation, dysregulation of folliculogenesis and subfertility in humans and livestock species. Despite their clinical significance, the precise impact of FOCs on oocyte reserve, maturation, and quality still needs to be explored. While FOCs are observed in both human and livestock populations, they are notably prevalent in livestock species. Consequently, livestock species serve as valuable models for investigating the molecular intricacies of FOCs. Thus, in this study, using goat FOCs, we performed integrated proteomic, metabolomic and functional analyses to demonstrate that oocyte maturation is hampered due to increased reactive oxygen species (ROS) in FOCs follicular fluid (FF) via downregulation of glutathione peroxidase (GPX1), a critical antioxidant seleno enzyme required to negate oxidative stress. Notably, GPX1 reduction was positively correlated with the FF's decline of free selenium and selenocysteine metabolic enzymes, O-phosphoryl-tRNA (Sec) selenium transferase (SEPSECS) and selenocysteine lyase (SCLY) levels. Adding GPX1, selenocysteine, or selenium to the culture media rescued the oocyte maturation abnormalities caused by FOCs FF by down-regulating the ROS. Additionally, we demonstrate that substituting GPX1 regulator, Insulin-like growth factor-I (IGF-1) in the in vitro maturation media improved the oocyte maturation in the cystic FF by down-regulating the ROS activity via suppressing Non-sense-mediated decay (NMD) of GPX1. In contrast, inhibition of IGF-1R and the target of rapamycin complex 1 (mTORC1) hampered the oocyte maturation via NMD up-regulation. These findings imply that the GPX1 regulation via selenocysteine metabolism and the IGF-1-mediated NMD may be critical for the redox homeostasis of FF. We propose that GPX1 enhancers hold promise as therapeutics for enhancing the competence of FOCs oocytes. However, further in vivo studies are necessary to validate these findings observed in vitro.

Beta Spectral Power during Passive Listening in Preschool Children with Specific Language Impairment

Introduction: Children with specific language impairment (SLI) have difficulties in different speech and language domains. Electrophysiological studies have documented that auditory processing in children with SLI is atypical and probably caused by delayed and abnormal auditory maturation. During the resting state, or different auditory tasks, children with SLI show low or high beta spectral power, which could be a clinical correlate for investigating brain rhythms. Methods: The aim of this study was to examine the electrophysiological cortical activity of the beta rhythm while listening to words and nonwords in children with SLI in comparison to typical development (TD) children. The participants were 50 children with SLI, aged 4 and 5 years, and 50 age matched TD children. The children were divided into two subgroups according to age: (1) children 4 years of age; (2) children 5 years of age. Results: The older group differed from the younger group in beta auditory processing, with increased values of beta spectral power in the right frontal, temporal, and parietal regions. In addition, children with SLI have higher beta spectral power than TD children in the bilateral temporal regions. Conclusion: Complex beta auditory activation in TD and SLI children indicates the presence of early changes in functional brain connectivity.

HOIL-1L deficiency induces cell cycle alteration which causes immaturity of skeletal muscle and cardiomyocytes

HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiated from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiated from control hiPSCs. Further analysis of hiPSC-derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results demonstrate that abnormal cell maturation possibly contribute to the development of myopathy and DCM. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.