Toxicity of internalized polyalanine to cells depends on aggregation

In polyalanine (PA) diseases, the disease-causing transcription factors contain an expansion of alanine repeats. While aggregated proteins that are responsible for the pathogenesis of neurodegenerative disorders show cell-to-cell propagation and thereby exert toxic effects on the recipient cells, whether this is also the case with expanded PA has not been studied. It is also not known whether the internalized PA is toxic to recipient cells based on the degree of aggregation. In this study, we therefore prepared different degrees of aggregation of a peptide having 13 alanine repeats without flanking sequences of PA disease-causative proteins (13A). The aggregated 13A was spontaneously taken up by neuron-like cultured cells. Functionally, strong aggregates but not weak aggregates displayed a deficit in neuron-like differentiation in vitro. Moreover, the injection of strong but not weak 13A aggregates into the ventricle of mice during the neonatal stage led to enhanced spontaneous motor activity later in life. Thus, PA in the extracellular space has the potential to enter adjacent cells, and may exert toxicity depending on the degree of aggregation.

Volume Overload Initiates an Immune Response in the Right Ventricle at the Neonatal Stage

Background: Pulmonary regurgitation caused by the correction or palliation of pediatric tetralogy of Fallot (TOF) leads to chronic right ventricular (RV) volume overload (VO), which induces adolescent RV dysfunction. A better understanding of the molecular mechanism by which VO initiates neonatal RV remodeling may bring new insights into the post-surgical management of pediatric TOF.Methods and Results: We created a fistula between the abdominal aorta and inferior vena cava on postnatal day 1 (P1) using a rat model to induce neonatal VO. Echocardiography revealed that the velocity and velocity- time-integral of the pulmonary artery (PA) were significantly elevated, and hematoxylin and eosin (H&E) staining showed that the diameter of the RV significantly increased. RNA-seq analysis of the RV on P7 indicated that the top 10 enriched Gene Ontology (GO) terms and the top 20 enriched terms in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were associated with immune responses. Flow-cytometric analysis demonstrated that the number of CD4+and CD8+ immune cells were significantly augmented in the VO group compared with the sham group.Conclusions: A neonatal cardiac VO rat model on P1 was successfully created, providing a platform for studying the molecular biology of neonatal RV under the influence of VO. VO - induces an immune response at the neonatal stage (from P1 to P7), suggesting that immune responses may be an initiating factor for neonatal RV remodeling under the influence of VO and that immunosuppressants may be used to prevent pediatric RV remodeling caused by VO.

Vein of Galen Aneurysmal Malformations in Pediatric Patients Submitted to Endovascular Treatment: Report of 3 Cases

Objective To report three cases of vein of Galen aneurysmal malformation (VGAM) in pediatric patients treated at the hemodynamics lab of Hospital Santa Isabel (HSI) in Blumenau, state of Santa Catarina, Brazil, from 2006 to 2020. Clinical presentation, endovascular treatment, and postprocedure evolution to date are included. Case description Three children aged 5 to 12 months with cardiac, respiratory, or neurological damage in the neonatal stage, were referred to the neurosurgery service and diagnosed with VGAM. The three patients underwent endovascular embolization of the malformation, with different clinical evolution throughout outpatient follow-up. Conclusion Vein of Galen aneurysmal malformations are uncommon vascular abnormalities that, until the advent of endovascular embolization, were associated with high morbidity and mortality rates. Its prognosis is linked with initial clinic, early diagnosis, and timely surgical correction.

Thalamocortical axons regulate neurogenesis and laminar fates in early sensory cortex

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons increase the number of layer 4 neurons in primary sensory areas by enhancing neurogenesis and shifting the fate of superficial layer neurons to that of layer 4 by the neonatal stage. Part of these area-specific roles are played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.

Percutaneous coarctation dilatation under transthoracic echocardiography guidance solely without fluoroscopy in neonate intensive care

Introduction: Neonatal coarctation has to be diagnosed and treated urgently. Actually, the surgical treatment is the main option. The coarctation dilatation is usually achieved under fluoroscopy guidance whenever indicated. Balloon angioplasty could be an alternative approach or transient measure in difficult cases with cardiogenic shock or severe cardiac insufficiency. In the reported case, we prove and discuss the major role of transthoracic echocardiography, which is used solely to guide the coarctation dilatation in neonate environment. Objective: The reported case aims to assess the safety and the efficiency of two-dimensional TEE to guide the dilatation of aortic coarctation in neonate. Case presentation: We describe successful dilatation of neonatal coarctation done exclusively using echocardiography in neonatal ICU at the bed. The procedure duration was 40 minutes (from the puncture to sheath removal). The coarctation was diagnosed easily and well described using TTE with good image quality obtained from supra-sternal plane and upper and left lateral view. TayShak balloon measuring 6 and 8 mm were used with a 0.018 French guided exchange wire. Complete relief of the coarctation was checked by TTE without recording any complication. The follow-up in the third month (the submission time of this manuscript) showed very good results without requiring any surgical intervention or additional restenosis. Conclusion: Our initial experience confirmed the safety and efficiency of coarctation dilatation using TTE as the only guidance tool at the bed in neonatal stage, especially in a case presenting severe metabolic and cardiac failure. This report suggests and encourages other potential applications in neonatology intensive care.

Etiology and surgical management of pediatric acute colon perforation beyond the neonatal stage

Purpose Acute colon perforation is a pediatric surgical emergency. We aimed to analyze the different etiologies and clinical characteristics of acute non-traumatic colon perforation beyond the neonatal period and to identify surgical management and outcomes. Methods This retrospective study included 18 patients admitted with acute colon perforation and who received surgical treatment. Results Age of patients ranged between 1 month and 15 years. Five patients swallowed foreign objects (two swallowed magnets), two had colon perforation secondary to a malignant tumor (both colorectal adenocarcinoma) and two were iatrogenic (one prior colonoscopy, one air enema for intussusception). There was one perforation due to chemotherapy and Amyand’s hernia respectively. The remaining seven patients had unknown etiologies; five of them were diagnosed with colitis. Fifteen (83.3 %) patients underwent open laparotomy, among which four attempted laparoscopy first. Three (16.7 %) patients underwent laparoscopic surgery. Fourteen (77.8 %) patients received simple suture repairs and four (22.2 %) received colonic resections and anastomosis. Four (22.2 %) patients received a protective diverting colostomy and three (16.7 %) received an ileostomy. Conclusions There is a wide range of etiology besides necrotizing enterocolitis and trauma, but a significant portion of children present with unknown etiology. Type of surgery elected should be dependent on the patient’s etiology, disease severity and experience of surgeons.

Mathematical modeling of palatal suture pattern formation: morphological differences between sagittal and palatal sutures

The median palatal suture serves as a growth center for the maxilla; inadequate growth at this site causes malocclusion and dental crowding. However, the pattern formation mechanism of palatal sutures is poorly understood compared with that of calvarial sutures such as the sagittal suture. In the present study, therefore, we compared the morphological characteristics of sagittal and palatal sutures in human bone specimens. We found that palatal suture width was narrower than sagittal suture width, and the interdigitation amplitude of the palatal suture was lower than that of the sagittal suture. These tendencies were also observed in the neonatal stage. However, such differences were not observed in other animals such as chimpanzees and mice. We also used a mathematical model to reproduce the differences between palatal and sagittal sutures. After an extensive parameter search, we found two conditions that could generate the difference in interdigitation amplitude and suture width: bone differentiation threshold $$v_c$$ v c and growth speed c. We discuss possible biological interpretations of the observed pattern difference and its cause.

Autophagy is dispensable for the maintenance of hematopoietic stem cells in neonates

Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to sustain lifelong hematopoiesis. HSCs are preserved in quiescence with low mitochondrial activity. Recent studies indicate that autophagy contributes to HSC quiescence through suppressing mitochondrial metabolism. However, it remains unclear whether autophagy is involved in the regulation of neonatal HSCs, which proliferate actively. In this study, we clarified the role of autophagy in neonatal HSCs using 2 types of autophagy-related gene 7 (Atg7)-conditional knockout mice: Mx1-Cre inducible system and Vav-Cre system. Atg7-deficient HSCs exhibited excess cell divisions with enhanced mitochondrial metabolism, leading to bone marrow failure at adult stage. However, Atg7 deficiency minimally affected hematopoiesis and metabolic state in HSCs at neonatal stage. In addition, Atg7-deficient neonatal HSCs exhibited long-term reconstructing activity, equivalent to wild-type neonatal HSCs. Taken together, autophagy is dispensable for stem cell function and hematopoietic homeostasis in neonates and provide a novel aspect into the role of autophagy in the HSC regulation.

Spatiotemporal Changes in the Gene Expression Spectrum of the β2 Adrenergic Receptor Signaling Pathway in the Lungs of Rhesus Monkeys

Objective β2 adrenergic receptor (ADRB2) agonists mainly participate in regulation of airway function through the ADRB2-G protein-adenylyl cyclase (AC) signaling pathway; however, the key genes associated with this pathway and the spatiotemporal changes in the expression spectrum of some of their subtypes remain unclear, resulting in an insufficient theoretical basis for formulating the dose and method of drug administration for neonates. Methods We performed sampling at different developmental time points in rhesus monkeys, including the embryo stage, neonatal stage, and adolescence. The MiSeq platform was used for sequencing of key genes and some of their subtypes in the ADRB2 signaling pathway in lung tissues, and target gene expression was normalized and calculated according to reads per kilobase million. Results At different lung-developmental stages, we observed expression of phenylethanolamine N-methyltransferase (PNMT), ADRB2, AC, AKAP and EPAC subtypes (except AC8, AKAP4/5), and various phosphodiesterase (PDE) subtypes (PDE3, PDE4, PDE7, and PDE8), with persistently high expression of AC6, PDE4B, and AKAP(1/2/8/9/12/13, and EZR) maintained throughout the lung-developmental process, PNMT, ADRB2, AC(4/6), PDE4B, and AKAP(1/2/8/9/12/13, EZR, and MAP2)were highly expressed at the neonatal stage. Conclusion During normal lung development in rhesus monkeys, key genes associated with ADRB2–G protein–AC signaling and some of their subtypes are almost all expressed at the neonatal stage, suggesting that this signaling pathway plays a role in this developmental stage. Additionally, AC6, PDE4B, and AKAP(1/2/8/9/12/13, and EZR) showed persistently high expression during the entire lung-developmental process, which provides a reference for the development and utilization of key gene subtypes in this pathway.

TRIC-A regulates intracellular Ca2+ homeostasis in cardiomyocytes

Trimeric intracellular cation (TRIC) channels have been identified as monovalent cation channels that are located in the ER/SR membrane. Two isoforms discovered in mammals are TRIC-A (TMEM38a) and TRIC-B (TMEM38b). TRIC-B ubiquitously expresses in all tissues, and TRIC-B−/− mice is lethal at the neonatal stage. TRIC-A mainly expresses in excitable cells. TRIC-A−/− mice survive normally but show abnormal SR Ca2+ handling in both skeletal and cardiac muscle cells. Importantly, TRIC-A mutations have been identified in human patients with stress-induced arrhythmia. In the past decade, important discoveries have been made to understand the structure and function of TRIC channels, especially its role in regulating intracellular Ca2+ homeostasis. In this review article, we focus on the potential roles of TRIC-A in regulating cardiac function, particularly its effects on intracellular Ca2+ signaling of cardiomyocytes and discuss the current knowledge gaps.