Minor and major spliceosomes control splicing of distinct intron types and are thought to act largely independent of one another. SR proteins are essential splicing regulators mostly connected to the major spliceosome. Here, we show that Srsf10 expression is controlled through an autoregulated minor intron, tightly correlating Srsf10 with minor spliceosome abundance across different tissues and differentiation stages in mammals. Surprisingly, all other SR proteins also correlate with the minor spliceosome and Srsf10, and abolishing Srsf10 autoregulation by Crispr/Cas9-mediated deletion of the autoregulatory exon induces expression of all SR proteins in a human cell line. Our data thus reveal extensive crosstalk and a global impact of the minor spliceosome on major intron splicing.
Insertion of a sufficient number of electrodes is important for a successful use of cochlear implants. We investigated the results of scala vestibuli insertion for cochlear implantation in cases of obstructed scala tympani. In a series of 200 cochlear implantations, scala vestibuli insertion was successfully performed in 4 cases with obstruction of the scala tympani. Etiologies included a temporal bone fracture, severe otosclerosis and malformations of the cochlea. The maximum insertion depth obtained via the scala vestibuli was 30 mm. Postoperative results were comparable to patients in whom conventional scala tympani insertion was performed. No adverse effects related to the site of insertion were observed. Scala vestibuli insertion offers a valuable alternative in cases of obstructed scala tympani that can be employed for a variety of etiologies.
Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b. We show that Ube3b regulates dendritic branching in a cell-autonomous manner.Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning and alterations in social interactions. We further demonstrate that Ube3b ubiquitinates the catalytic γ-subunit of calcineurin (Ppp3cc), the overexpression of which phenocopies the loss of Ube3b with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetic mouse model for KOS.
Neocortical projection neurons are generated by neural progenitor cells (NPCs) within the ventricular and subventricular zone. While early NPCs can give rise to both deep and upper layer neurons, late progenitors are restricted to upper layer neurogenesis. The molecular mechanisms controlling the differentiation potential of early versus late NPCs are unknown. Here, we report a novel function for TrkC-T1, the non-catalytic isoform of the neurotrophin receptor TrkC, that is distinct from TrkC-TK+, the full-length isoform. We provide direct evidence that TrkC-T1 regulates the switch in NPC fate from deep to upper layer neuron production. Elevated levels of TrkC-T1 in early NPCs promote the generation of deep layer neurons. Conversely, downregulation of TrkC-T1 in these cells promotes upper layer neuron fate. Furthermore, we show that TrkC-T1 exerts this control by interaction with the signaling adaptor protein ShcA. TrkC-T1 prevents the phosphorylation of Shc and the downstream activation of the MAP kinase (Erk1/2) pathway. In vivo manipulation of the activity of ShcA or Erk1/2, directly affects cortical neuron cell fate. We thus show that the generation of upper layer neurons by late progenitors is dependent on the downregulation of TrkC-T1 in late progenitor cells and the resulting activation of the ShcA/Erk1/2 pathway.
Background: Necrotizing enterocolitis (NEC) is a serious complication among pre-term infants. Surfactant replacement therapy can help to prevent respiratory distress syndrome (RDS) among very low birth weight (VLBW) pre-term infants. Currently, there are no pharmacoeconomic analyses that estimate the cost savings in preventing RDS among pre-term infants diagnosed with NEC who receive surfactant therapy.Objectives: To estimate the economic impact of the synthetic protein-containing surfactant lucinactant (Surfaxin) and pooled animal-derived surfactants (beractant [Survanta] and poractant alfa [Curosurf]) in the prevention of RDS among surviving pre-term infants weighing 600 to 1,250 grams who have been diagnosed with NEC.Methods: A decision-analytic model was developed using a hospital perspective to estimate the economic impact of initial length of stay in the neonatal intensive care unit (NICU) for pre-term infants with NEC. Clinical outcomes consist of the average initial NICU length of stay from the combined Phase III randomized, controlled clinical trials of surfactant therapy (SELECT and STAR). The cost input was the average cost of treating surviving pre-term infants with medical NEC, U.S. $2,039, the combined level II and level III NICU cost per day (2002).Results: Pre-term infants with NEC who survived and received lucinactant had 2.27 fewer initial NICU days compared to the pooled animal-derived cohort (73.73 versus 76.00 days, respectively). The estimated average cost of an initial NICU stay per infant was U.S. $150,320 for infants receiving lucinactant compared to U.S. $154,948 for infants receiving animal-derived surfactants. Due to fewer NICU days, lucinactant therapy results in a medical cost savings of U.S. $4,628 per infant.Conclusion: Among surviving pre-term infants diagnosed with NEC who received surfactant therapy, the synthetic protein-containing surfactant lucinactant reduced total initial NICU hospital costs when compared to pooled animal-derived surfactants. Anecdotal evidence, however, suggests that cyanotic episodes are more common in neonates sleeping supine. We wanted to determine whether term neonates do indeed have more episodes of intermittent hypoxia in the supine than in the side position. INTERMITTENT HYPOXIA IN SUPINE VERSUS SIDE POSITION IN 1-5 D OLD TERM NEONATESMethods: We enrolled 1-5 day old term neonates in a controlled 2-phase cross-over study design. They were randomised to sleep, for 6 h each, either in supine followed by side position (right or left) or vice versa. Pulse oximeter saturation (SpO2) values and a signal quality indicator were recorded throughout (VitaGuard VG 300 with Masimo SET, Irvine, CA; 2-4 s averaging). Only recordings lasting at least 3 h in either position were included. Desaturation events to Ͻ85% and Ͻ80% SpO2 were analysed, excluding events with poor signal quality.Results: 477 neonates had recordings of sufficient duration. Mean duration of analyzable signal was 4.93 h for supine and 4.89 h for side position. 38% and 75%, respectively, of in...
We report a case of a neonate with sectional narrowing of the spinal cord on the level of T12 to L2 and a deformed vertebral body on a different level, L4. In previously described cases of sectional spinal dysgenesis, the vertebral and spinal cord malformations are usually found on the same level. Our case may represent a new variant of spinal dysgenesis.
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