Normal Development Research Articles

Pediatric Desmoid Tumor of the Head and Neck: A Systematic Review and Modified Framework for Management by Age Group.

Unlike in adults, pediatric head and neck desmoid tumors (DTs) have greater capacity to interfere with normal anatomical development. Therefore, adequate interventions and management must be defined. We aimed to provide the most comprehensive systematic review on pediatric head and neck DTs to date, including assessment of lesion location predominance, intervention, and management, and examination of any associations between age and outcomes like surgical margin status, recurrence, and complications. A systematic literature review was conducted between January 1990 and December 2023 using PubMed, Scopus, and MEDLINE databases following the Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 guidelines. We aimed to elucidate intervention and management strategies by studying various outcomes in 0-11 and 12-21 year olds. The literature search yielded 44 studies, totaling 121 patients. Most head and neck DTs localized to the mandible, cranium, and neck; occurred early (P = 4.18 years); and underwent local resection with positive margins. Older and younger patients shared no difference in complication or recurrence rates. We found recurrence is likely to occur with positive margins. Because standard treatment of DTs is surgical resection with negative margins, if technically feasible with reasonable associated morbidity, we suggest additional resection of the tumor to achieve negative margins. We also recommend more robust follow-up data collection, not only due to desmoid's high recurrence and data paucity in patients older than 12 years, but also, to better establish best management practices.

Nano-alumina induced developmental and neurobehavioral toxicity in the early life stage of zebrafish, associated with mTOR

The study aims to investigate the effects of nano-alumina (AlNPs) on the early development and neurobehavior of zebrafish and the role of mTOR in this process. After embryos and grown-up larvae exposed to AlNPs from 0 to 200 μg/mL, we examined the development, neurobehavior, AlNPs content, and mTOR pathway genes. Moreover, embryos were randomly administered with control, negative control, mTOR knockdown, AlNPs, and mTOR knockdown + AlNPs, then examined for development, neurobehavior, oxidative stress, neurotransmitters, and development genes. As AlNPs increased, swimming speed and distance initially increased and then decreased; thigmotaxis and panic-avoidance reflex substantially decreased in the high-dose AlNPs group; aluminum and nanoparticles considerably accumulated in the 100 μg/mL AlNPs group; AlNPs at high dose decreased mTOR gene and protein levels, stimulating autophagy via increasing ULK1 and ULK2. mTOR knockdown exacerbated the harm to normal development rate, eye and body length, and neurobehavior induced by AlNPs through raising ROS, SOD, and ACH levels but decreasing AchE activity and development genes. Therefore, AlNPs suppress neurobehavior through downregulating mTOR, and mTOR knockdown further aggravates their early development and neurobehavior loss, suggesting mTOR could be a potential target for the toxicity of AlNPs.

Two New Mouse Alleles of Ocm and Slc26a5

The genes Ocm (encoding oncomodulin) and Slc26a5 (encoding prestin) are expressed strongly in outer hair cells and both are involved in deafness in mice. However, it is not clear if they influence the expression of each other. In this study, we characterise the auditory phenotype resulting from two new mouse alleles, Ocmtm1e and Slc26a5tm1Cre. Each mutation leads to absence of detectable mRNA transcribed from the mutant allele, but there was no evidence that oncomodulin regulates expression of prestin or vice versa. The two mutants show distinctive patterns of auditory dysfunction. Ocmtm1e homozygotes have normal auditory brainstem response thresholds at 4 weeks old followed by progressive hearing loss starting at high frequencies, while heterozygotes show largely normal thresholds until 6 months of age, when signs of worse thresholds are detected. In contrast, Slc26a5tm1Cre homozygotes have stable but raised thresholds across all frequencies tested, 3 to 42 kHz, at least from 4 to 8 weeks old, while heterozygotes have raised thresholds at high frequencies. Distortion product otoacoustic emissions and cochlear microphonics show deficits similar to auditory brainstem responses in both mutants, suggesting that the origin of hearing impairment is in the outer hair cells. Endocochlear potentials are normal in the two mutants. Scanning electron microscopy revealed normal development of hair cells in Ocmtm1e homozygotes but scattered outer hair cell loss even at 4 weeks old when thresholds appeared normal, indicating that there is not a direct relationship between numbers of outer hair cells present and auditory thresholds.

The Effect of Touch and Massage Techniques Applied to Children on Parental Role Perception and Perceived Stress

Aim: The study examined the effects of tactile and massage techniques on the occupational therapist’s perspective on the role perception and stress levels of parents and the changes in children’s sensory processing. Method: A total of 30 children, (18 females and 12 males), aged 3-6, with normal development, and their parents were included in the study. A diverse community sample of mothers (M=33.6±5.521 years) and their preschool-aged children (M=4.5±1.2 years) participated in the study. The following instruments were employed: Parental Stress Index, Self-Perception Scale for Parenting Role, and Sensory Profile Test. Parents were instructed in a number of touch and massage techniques devised by the Occupational Therapist within the framework of Sensory Integration Theory. Following the 15-minute and 20-session implementation period, the parents were then tested. After the sessions were completed, the tests were repeated. Results: The findings indicated that at the end of the study, there was a decrease in parental stress levels, and an increase in parental role perception and children's sensory processing skills (p <0.05). The study demonstrated that touch and massage techniques can positively impact parent-child interaction. Conclusion: Studies examining the potential enduring effects of positive parental touch on stress levels and parental role perception rarely extend beyond infancy. It is believed that research with a larger sample size on this topic would contribute significantly to the existing literature.

Effects of Hindlimb Suspension on the Development of Hip Bone Morphologies in Growing Rats

Abnormal hip bone morphologies are associated with various diseases of the hip joint. Weight bearing, especially during growth, may be important to achieve normal acetabulum development. This study aimed to investigate whether hip bone morphologies were affected by hindlimb suspension (HS) in 4 week-old rats. In HS groups, tail suspension was applied for 0, 2, 4, and 8 weeks. Age-matched rats were used as controls. The complex of hip bones with lumbar and sacral vertebrae were assessed based on morphological indexes using three-dimensional reconstructed images from X-ray computed tomography. Acetabular widths (measured from cranial to caudal) unchanged and depths became larger in both groups with age. Acetabular lengths (from the ventral side to the dorsal side) became larger in control groups but unchanged in HS groups with age. In HS groups, acetabular width, length, and depths were smaller than the control groups at 4 and/or 8 weeks. Acetabular versions became enlarged (rotated inwards) with age in both groups, although this was particularly pronounced in HS groups. Histologically, triradiate cartilage layers in the acetabulum were thinner with age and almost disappeared at 8 weeks in both groups. However, HS decreased Safranin O staining and prolonged the presence of hypertrophic chondrocyte indicating alterations in the chondral ossification processes. Iliac wing angles remained unchanged and anterior superior iliac crest (ASIC) distances increased with age in controls. In contrast, HS groups showed narrowed iliac wing angles with small ASIC distances. These results suggest that reduced mechanical loading during growth can interfere with hip joint formation.

Detailed delineation of the fetal brain in diffusion MRI via multi-task learning.

Diffusion-weighted MRI is increasingly used to study the normal and abnormal development of fetal brain inutero. Recent studies have shown that dMRI can offer invaluable insights into the neurodevelopmental processes in the fetal stage. However, because of the low data quality and rapid brain development, reliable analysis of fetal dMRI data requires dedicated computational methods that are currently unavailable. The lack of automated methods for fast, accurate, and reproducible data analysis has seriously limited our ability to tap the potential of fetal brain dMRI for medical and scientific applications. In this work, we developed and validated a unified computational framework to (1) segment the brain tissue into white matter, cortical/subcortical gray matter, and cerebrospinal fluid, (2) segment 31 distinct white matter tracts, and (3) parcellate the brain's cortex and delineate the deep gray nuclei and white matter structures into 96 anatomically meaningful regions. We utilized a set of manual, semi-automatic, and automatic approaches to annotate 97 fetal brains. Using these labels, we developed and validated a multi-task deep learning method to perform the three computations. Our evaluations show that the new method can accurately carry out all three tasks, achieving a mean Dice similarity coefficient of 0.865 on tissue segmentation, 0.825 on white matter tract segmentation, and 0.819 on parcellation. The proposed method can greatly advance the field of fetal neuroimaging as it can lead to substantial improvements in fetal brain tractography, tract-specific analysis, and structural connectivity assessment.

Sex chromosomes and hormones independently influence healthy brain development but act similarly after cranial radiation

The course of normal development and response to pathology are strongly influenced by biological sex. For instance, female childhood cancer survivors who have undergone cranial radiation therapy (CRT) tend to display more pronounced cognitive deficits than their male counterparts. Sex effects can be the result of sex chromosome complement (XX vs. XY) and/or gonadal hormone influence. The contributions of each can be separated using the four-core genotype mouse model (FCG), where sex chromosome complement and gonadal sex are decoupled. While studies of FCG mice have evaluated brain differences in adulthood, it is still unclear how sex chromosome and sex hormone effects emerge through development in both healthy and pathological contexts. Our study utilizes longitudinal MRI with the FCG model to investigate sex effects in healthy development and after CRT in wildtype and immune-modified Ccl2-knockout mice. Our findings in normally developing mice reveal a relatively prominent chromosome effect prepubertally, compared to sex hormone effects which largely emerge later. Spatially, sex chromosome and hormone influences were independent of one another. After CRT in Ccl2-knockout mice, both male chromosomes and male hormones similarly improved brain outcomes but did so more separately than in combination. Our findings highlight the crucial role of sex chromosomes in early development and identify roles for sex chromosomes and hormones after CRT-induced inflammation, highlighting the influences of biological sex in both normal brain development and pathology.

Comprehensive evaluation of fetal renal ultrasound parameters for fetal growth restriction

ObjectiveThis study aims to investigate variances in renal ultrasound parameters between fetuses experiencing fetal growth restriction (FGR) and those with normal intrauterine development, with the intent to offer actionable insights for clinical management. MethodForty-five pregnant women diagnosed with FGR between 28 and 36 weeks of gestation, who underwent examination at Wenzhou People's Hospital from September 2021 to June 2023, constituted the FGR group. Concurrently, 65 pregnant women with normal intrauterine development at matching gestational weeks formed the control group. Renal ultrasound parameters, encompassing renal artery peak systolic velocity (PSV), end diastolic velocity (EDV), time averaged maximum velocity (TAMX), resistive indices (S/D, PI, RI), ratios of renal volume to gestational age (RV/WEEK) and estimated fetal weight (RV/EFW), vascular indices (VI, FI, VFI), were compared between the two groups. All parameters represented the mean values of bilateral kidneys. ResultIn the FGR group, fetal renal artery PSV (37.71 ± 9.93 cm/s), EDV (6.19 ± 1.50 cm/s), TAMX (15.10 ± 3.83 cm/s), RV/WEEK (0.45 ± 0.12), RV/EFW (7.53 ± 3.24), VI (22.19 ± 15.00), and VFI (5.53 ± 3.63) were significantly lower compared to the control group (PSV: 47.11 ± 11.24 cm/s, EDV: 7.13 ± 2.00 cm/s, TAMX: 17.85 ± 3.85 cm/s, RV/WEEK: 0.66 ± 0.19, RV/EFW:9.20 ± 3.17, VI: 28.67 ± 14.72, VFI: 7.40 ± 3.68). Conversely, fetal renal artery resistive indices (S/D: 9.09 ± 2.58, PI: 2.71 ± 0.56, RI: 0.92 ± 0.04) in the FGR group were notably higher than those in the control group (S/D: 6.22 ± 1.93, PI: 2.20 ± 0.73, RI: 0.87 ± 0.04), with statistical significance (P < 0.05). No significant difference was found in renal FI between the FGR group (26.78 ± 6.59) and the control group (26.89 ± 5.82) (P > 0.05). Receiver operating characteristic (ROC) curve analysis revealed higher diagnostic efficacy for RV/WEEK and RI among individual indicators, while combined parameter application yielded the highest diagnostic efficiency. ConclusionUtilizing a comprehensive evaluation of fetal kidney ultrasound parameters with multiple indices facilitates early screening and diagnosis of FGR fetuses, thereby aiding clinical decision-making and enhancing newborn birth outcomes.

Age-Related Differences in Prestimulus EEG Affect ERPs and Behaviour in the Equiprobable Go/NoGo Task

Detailed studies of the equiprobable auditory Go/NoGo task have allowed for the development of a sequential-processing model of the perceptual and cognitive processes involved. These processes are reflected in various components differentiating the Go and NoGo event-related potentials (ERPs). It has long been established that electroencephalography (EEG) changes through normal lifespan development. It is also known that ERPs and behaviour in the equiprobable auditory Go/NoGo task change from children to young adults, and again in older adults. Here, we provide a novel examination of links between in-task prestimulus EEG, poststimulus ERPs, and behaviour in three gender-matched groups: children (8–12 years), young adults (18–24 years), and older adults (59–74 years). We used a frequency Principal Component Analysis (f-PCA) to estimate prestimulus EEG components and a temporal Principal Component Analysis (t-PCA) to separately estimate poststimulus ERP Go and NoGo components in each age group to avoid misallocation of variance. The links between EEG components, ERP components, and behavioural measures differed markedly between the groups. The young adults performed best and accomplished this with the simplest EEG–ERP–behaviour brain dynamics pattern. The children performed worst, and this was reflected in the most complex brain dynamics pattern. The older adults showed some reduction in performance, reflected in an EEG–ERP–behaviour pattern with intermediate complexity between those of the children and young adults. These novel brain dynamics patterns hold promise for future developmental research.

Heparan sulfate proteoglycans in pathological protein aggregation and brain functionality

Proteoglycans are highly specialized proteins with specific interactive modules in their core proteins, allowing them to engage with a diverse range of cellular and structural proteins, contributing to many varied roles in cell processes. This review examines the roles of heparan sulfate (HS) proteoglycans (HSPGs) in the assembly of pathological protein aggregates in brain tissues, which negatively impact cognitive brain function. While HSPGs play roles in normal brain development, they also contribute to the abnormal accumulation and persistence of protein aggregates in Alzheimer&amp;rsquo;s and Parkinson&amp;rsquo;s diseases (AD and PD), prolonging their neurotoxic effects. HSPG-mediated effects on the innate immune system may also contribute to the development of neuroinflammation and pathogenesis of neurodegenerative changes in the central nervous system. These pathological developments lead to impaired cognition, permanent memory loss in dementia and AD, and an inability of the brain to exert normal neuromuscular control, affecting motor functions and body movement in PD. A deeper understanding of the properties of HS in these degenerative processes is essential for the development of therapeutic measures to treat these conditions. Significant improvements in neuroimaging, next-generation glycosaminoglycan analytical techniques, and functional glycomics hold great promise for elucidating the complexities of HS structure and function. These advancements may significantly aid in the development of HS biotherapeutics to treat these debilitating conditions, which are increasingly impacting the aging global population. While a number of promising therapeutic candidates have already emerged, further research is required to optimize their biotherapeutic applications in this challenging area of pathobiology, bioregulation, and the recovery of neural function.

Embryonic genome instability upon DNA replication timing program emergence

Faithful DNA replication is essential for genome integrity1–4. Under-replicated DNA leads to defects in chromosome segregation, which are common during embryogenesis5–8. However, the regulation of DNA replication remains poorly understood in early mammalian embryos. Here we constructed a single-cell genome-wide DNA replication atlas of pre-implantation mouse embryos and identified an abrupt replication program switch accompanied by a transient period of genomic instability. In 1- and 2-cell embryos, we observed the complete absence of a replication timing program, and the entire genome replicated gradually and uniformly using extremely slow-moving replication forks. In 4-cell embryos, a somatic-cell-like replication timing program commenced abruptly. However, the fork speed was still slow, S phase was extended, and markers of replication stress, DNA damage and repair increased. This was followed by an increase in break-type chromosome segregation errors specifically during the 4-to-8-cell division with breakpoints enriched in late-replicating regions. These errors were rescued by nucleoside supplementation, which accelerated fork speed and reduced the replication stress. By the 8-cell stage, forks gained speed, S phase was no longer extended and chromosome aberrations decreased. Thus, a transient period of genomic instability exists during normal mouse development, preceded by an S phase lacking coordination between replisome-level regulation and megabase-scale replication timing regulation, implicating a link between their coordination and genome stability.

Integrative analysis of transcriptome and metabolome reveals the heterogeneity of ovarian follicles between high-altitude Yak (Bos grunniens) and Low-altitude cattle (Bos taurus)

Differences including reproductive efficiency have been proved existence between high-altitude yak (Bos grunniens) and low-altitude cattle (Bos taurus), however, the discrepancies of ovarian follicles across them are still elusive. In the present study, RNA-seq results exhibited an obvious separation of yak and cattle granulosa cells (GCs), and 2329 differently expressed genes (DEGs) was obtained, with 1297 upregulated and 1032 downregulated DEGs in yaks. Advanced analysis revealed that DEGs were mainly enriched in cellular structure, DNA packaging and remodeling (GO and GSEA), hypoxia adaptability, energy metabolism (KEGG and GSEA), and epigenetic modification of histones (Reactome and GSEA). Metabolite profiles of yak and cattle follicular fluid (FF) were depicted by LC-MS/MS non-target metabolomics, and 350 different metabolites (DMs) were acquired, with 242 upregulated and 108 downregulated DMs in yaks. The KEGG pathway enrichment results demonstrated that DMs were primarily enriched in metabolism including lipid, carbohydrate and nucleic acid metabolism. Finally, twenty-nine pathways were significant enriched via integrative analysis, most of which were associated with metabolism including carbohydrate metabolism (e.g. Glycolysis / Gluconeogenesis) and lipid metabolism (e.g. Sphingolipid metabolism). Of note, the key hypoxia adaptation pathway, HIF-1 signaling pathway, was predominant enriched. Overall, we ascertained that the heterogeneity in ovarian follicles of yaks and cattle was existence, which were mainly reflected on hypoxia adaptation and energy metabolism. These results implied that the above processes were evolved specifically for the normal development of yak follicles under plateau atmosphere.

Regulation of folate transport at the mouse arachnoid barrier

BackgroundFolates are a family of B9 vitamins essential for normal growth and development in the central nervous system (CNS). Transport of folates is mediated by three major transport proteins: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate uptake occurs at the choroid plexus (CP) epithelium through coordinated actions of FRα and PCFT, or directly into brain parenchyma at the vascular blood–brain barrier (BBB), mediated by RFC. Impaired folate transport can occur due to loss of function mutations in FRα or PCFT, resulting in suboptimal CSF folate levels. Our previous reports have demonstrated RFC upregulation by nuclear respiratory factor-1 (NRF-1) once activated by the natural compound pyrroloquinoline quinone (PQQ). More recently, we have identified folate transporter localization at the arachnoid barrier (AB). The purpose of the present study was to further characterize folate transporters localization and function in AB cells, as well as their regulation by NRF-1/PGC-1α signaling and folate deficiency.MethodsIn immortalized mouse AB cells, polarized localization of RFC and PCFT was assessed by immunocytochemical analysis, with RFC and PCFT functionality examined with transport assays. The effects of PQQ treatment on changes in RFC functional expression were also investigated. Mouse AB cells grown in folate-deficient conditions were assessed for changes in gene expression of the folate transporters, and other key transporters and tight junction proteins.ResultsImmunocytochemical analysis revealed apical localization of RFC at the mouse AB epithelium, with PCFT localized on the basolateral side and within intracellular compartments. PQQ led to significant increases in RFC functional expression, mediated by activation of the NRF-1/PGC-1α signalling cascade. Folate deficiency led to significant increases in expression of RFC, MRP3, P-gp, GLUT1 and the tight junction protein claudin-5.ConclusionThese results uncover the polarized expression of RFC and PCFT at the AB, with induction of RFC functional expression by activation of the NRF-1/PGC-1α signalling pathway and folate deficiency. These results suggest that the AB may contribute to the flow of folates into the CSF, representing an additional pathway when folate transport at the CP is impaired.

Gene Misexpression in a Smoc2+ve/Sox2-Low Population in Juvenile Prop1-Mutant Pituitary Gland.

Mutations in the pituitary-specific transcription factor Prophet of Pit-1 (PROP1) are the most common genetic etiology of combined pituitary hormone deficiency (CPHD). CPHD is associated with short stature, attributable to growth hormone deficiency and/or thyroid-stimulating hormone deficiency, as well as hypothyroidism and infertility. Pathogenic lesions impair pituitary development and differentiation of endocrine cells. We performed single-cell RNA sequencing of pituitary cells from a wild-type and a Prop1-mutant P4 female mouse to elucidate population-specific differential gene expression. We observed a Smoc2+ve population that expressed low Sox2, which trajectory analyses suggest are a transitional cell state as stem cells differentiate into endocrine cells. We also detected ectopic expression of Sox21 in these cells in the Prop1df/df mutant. Prop1-mutant mice are known to overexpress Pou3f4, which we now show to be also enriched in this Smoc2+ve population. We sought to elucidate the role of Pou3f4 during pituitary development and to determine the contributions of Pou3f4 upregulation to pituitary disease by utilizing double-mutant mice lacking both Prop1 and Pou3f4. However, our data showed that Pou3f4 is not required for normal pituitary development and function. Double mutants further demonstrated that the upregulation of Pou3f4 was not causative for the overexpression of Sox21. These data indicate loss of Pou3f4 is not a potential cause of CPHD, and further studies may investigate the functional consequence of upregulation of Pou3f4 and Sox21, if any, in the novel Smoc2+ve cell population.

Neuroimaging in Nonsyndromic Craniosynostosis: Key Concepts to Unlock Innovation.

Craniosynostoses (CRS) are caused by the premature fusion of one or more cranial sutures, with isolated nonsyndromic CRS accounting for most of the clinical manifestations. Such premature suture fusion impacts both skull and brain morphology and involves regions far beyond the immediate area of fusion. The combined use of different neuroimaging tools allows for an accurate depiction of the most prominent clinical-radiological features in nonsyndromic CRS but can also contribute to a deeper investigation of more subtle alterations in the underlying nervous tissue organization that may impact normal brain development. This review paper aims to provide a comprehensive framework for a better understanding of the present and future potential applications of neuroimaging techniques for evaluating nonsyndromic CRS, highlighting strategies for optimizing their use in clinical practice and offering an overview of the most relevant technological advancements in terms of diagnostic performance, radiation exposure, and cost-effectiveness.

Intravenous lipid emulsions designed to meet preterm infant requirements increase plasma and tissue levels of docosahexaenoic acid and arachidonic acid in mice

Intravenous lipid emulsions used in preterm infants contain insufficient docosahexaenoic acid (DHA) and arachidonic acid (ARA) to support normal development, resulting in deficiencies that contribute to complications of prematurity and cognitive delay. We sought to investigate the effects of new intravenous lipid emulsions designed to contain sufficient DHA and ARA to meet preterm needs, while avoiding liver toxicity. Three new lipid emulsions (NLE A-C) were laboratory-generated using high pressure homogenization. First, a long-term experiment evaluated the impact on plasma, liver, and frontal cortex fatty acid composition compared to commercially available lipid emulsions. Lipid emulsions were administered via daily orogastric gavage to four-week-old C57Bl/6J mice. Next, liver toxicity was evaluated in a murine model of parenteral nutrition-induced hepatosteatosis. Mice were provided an ad lib fat-free high carbohydrate diet, with intravenous lipid emulsion administration every other day for 19 days. Administration of commercially available lipid emulsions (soybean oil, mixed oil, or fish oil) resulted in decreased plasma and tissue levels of DHA and/or ARA compared to a chow control. The new lipid emulsions demonstrated a dose-response effect in plasma and tissue concentration of DHA and ARA. NLE C (with an approximately even DHA:ARA ratio), compared to chow, maintained similar DHA (19.2±0.3 vs. 19.3±0.3%, P=1.00) and ARA (10.4±0.2 vs. 9.9±0.2% ARA, P=0.75) content in frontal cortex tissue. All three new lipid emulsions prevented biochemical liver injury and pathologist-assessed hepatosteatosis; soybean oil lipid emulsion and mixed oil lipid emulsion treatment resulted in hepatosteatosis in both experiments. Long-term treatment with the new lipid emulsions in juvenile mice resulted in increased plasma and tissue DHA and/or ARA content compared to currently available lipid emulsions. The new lipid emulsions also prevented hepatosteatosis and biochemical liver injury with enteral and parenteral administration.

Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway

Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.

In utero human intestine contains maternally derived bacterial metabolites.

Understanding when host-microbiome interactions are first established is crucial for comprehending normal development and identifying disease prevention strategies. Furthermore, bacterially derived metabolites play critical roles in shaping the intestinal immune system. Recent studies have demonstrated that memory T cells infiltrate human intestinal tissue early in the second trimester, suggesting that intestinal immune education begins in utero. Our previous study reported a unique fetal intestinal metabolomic profile with an abundance of several bacterially derived metabolites and aryl hydrocarbon receptor (AHR) ligands implicated in mucosal immune regulation. To follow up on this work, in the current study, we demonstrate that a number of microbial byproducts present in fetal intestines in utero are maternally derived and vertically transmitted to the fetus. Notably, these bacterially derived metabolites, particularly short chain fatty acids and secondary bile acids, are likely biologically active and functional in regulating the fetal immune system and preparing the gastrointestinal tract for postnatal microbial encounters, as the transcripts for their various receptors and carrier proteins are present in second trimester intestinal tissue through single-cell transcriptomic data.

A Fungicide, Fludioxonil, Formed the Polyploid Giant Cancer Cells and Induced Metastasis and Stemness in MDA-MB-231 Triple-Negative Breast Cancer Cells.

Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10-5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial-mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells.

Apoptosis-dependent head development during metamorphosis of the cnidarian Hydractinia symbiolongicarpus

Apoptosis is a regulated cell death that depends on caspases. It has mainly been studied as a mechanism for the removal of unwanted cells. However, apoptotic cells can induce fate or behavior changes of their neighbors and thereby participate in development. Here, we address the functions of apoptosis during metamorphosis of the cnidarian Hydractinia symbiolongicarpus. We describe the apoptotic profile during metamorphosis of the larva and identify Caspase3/7a, but no other executioner caspases, as essential for apoptosis in this context. Using pharmacological and genetic approaches, we find that apoptosis is required for normal head development. Inhibition of apoptosis resulted in defects in head morphogenesis. Neurogenesis was compromised in the body column of apoptosis-inhibited animals but there was no effect on the survival or proliferation of stem cells, suggesting that apoptosis is required for cellular commitment rather than for the maintenance of their progenitors. Differential transcriptomic analysis identifies TRAF genes as downregulated in apoptosis-inhibited larvae and functional experiments provide evidence that they are essential for head development. Finally, we find no major role for apoptosis in head regeneration in this animal, in contrast to the significance of apoptosis in Hydra head regeneration.