Cullin-RING E3 ubiquitin ligase 4 regulates neurite morphogenesis during neurodevelopment.

Neuritogenesis is crucial for establishing proper neuronal connections during brain development; its failure causes neurodevelopmental defects. Cullin-RING E3 ubiquitin ligase complexes participate in various neurodevelopmental processes by regulating protein stability. We demonstrated the regulatory function of Cullin-RING E3 ubiquitin ligase 4 (CRL4) in neurite morphogenesis during early neurodevelopment. Cul4a and Cul4b, the core scaffold proteins of CRL4, exhibit high expression and activation within the cytosol of developing neurons, regulated by neuronal stimulation through N-methyl D-aspartate (NMDA) receptor signaling. CRL4 also interacts with cytoskeleton-regulating proteins involved in neurite morphogenesis. Notably, genetic depletion and inhibition of cytosolic CRL4 enhance neurite extension and branching in developing neurons. Conversely, Cul4a overexpression suppresses basal and NMDA-enhanced neuritogenesis. Furthermore, CRL4 and its substrate adaptor regulate the polyubiquitination and proteasomal degradation of doublecortin protein. Collectively, our findings suggest that CRL4 ensures proper neurite morphogenesis in developing neurons by regulating cytoskeleton-regulating proteins.

The Third Extracellular Loop of Mammalian Odorant Receptors Is Involved in Ligand Binding.

Mammals recognize chemicals in the air via G protein-coupled odorant receptors (ORs). In addition to their orthosteric binding site, other segments of these receptors modulate ligand recognition. Focusing on human hOR1A1, which is considered prototypical of class II ORs, we used a combination of molecular modeling, site-directed mutagenesis, and in vitro functional assays. We showed that the third extracellular loop of ORs (ECL3) contributes to ligand recognition and receptor activation. Indeed, site-directed mutations in ECL3 showed differential effects on the potency and efficacy of both carvones, citronellol, and 2-nonanone.

Odorant Receptors Containing Conserved Amino Acid Sequences in Transmembrane Domain 7 Display Distinct Expression Patterns in Mammalian Tissues.

Mammalian genomes are well established, and highly conserved regions within odorant receptors that are unique from other G-protein coupled receptors have been identified. Numerous functional studies have focused on specific conserved amino acids motifs; however, not all conserved motifs have been sufficiently characterized. Here, we identified a highly conserved 18 amino acid sequence motif within transmembrane domain seven (CAS-TM7) which was identified by aligning odorant receptor sequences. Next, we investigated the expression pattern and distribution of this conserved amino acid motif among a broad range of odorant receptors. To examine the localization of odorant receptor proteins, we used a sequence-specific peptide antibody against CAS-TM7 which is specific to odorant receptors across species. The specificity of this peptide antibody in recognizing odorant receptors has been confirmed in a heterologous in vitro system and a rat-based in vivo system. The CAS-TM7 odorant receptors localized with distinct patterns at each region of the olfactory epithelium; septum, endoturbinate and ectoturbinate. To our great interests, we found that the CAS-TM7 odorant receptors are primarily localized to the dorsal region of the olfactory bulb, coinciding with olfactory epithelium-based patterns. Also, these odorant receptors were ectopically expressed in the various non-olfactory tissues in an evolutionary constrained manner between human and rats. This study has characterized the expression patterns of odorant receptors containing particular amino acid motif in transmembrane domain 7, and which led to an intriguing possibility that the conserved motif of odorant receptors can play critical roles in other physiological functions as well as olfaction.

Administration of steroids after 34 weeks of gestation enhances fetal lung maturity profiles.

OBJECTIVE: To estimate the effect of antenatal glucocorticoid administration on fetal lung maturity in pregnancies with known fetal lung immaturity between the 34th and 37th weeks of gestation. STUDY DESIGN: Pregnancies between 34(0/7) and 36(6/7) weeks undergoing amniocentesis to determine fetal lung maturity were targeted. Women with negative results (TDx-FLM-II <45 mg/g) were randomly assigned to intramuscular glucocorticoid injection or no treatment. A repeat TDx-FLM-II test was obtained 1 week after enrollment. RESULTS: Thirty-two women who met inclusion criteria were randomly assigned. Seven women delivered within a week of testing for fetal lung maturity, and were excluded from the analysis. Ten received glucocorticoid and 15 did not. Women assigned to glucocorticoids had a mean increase TDx-FLM-II in 1 week of 28.37 mg/g. Women assigned to no-treatment had an increase of 9.76 mg/g (P < .002). CONCLUSION: A single course of intramuscular glucocorticoids after 34 weeks in pregnancies with documented fetal lung immaturity significantly increases TDx- FLM-II.

A vascular graft for endometrial cancer groin recurrence.

BACKGROUND: Recurrent groin metastases from endometrial cancer that invades the femoral vasculature is debilitating and provides a management dilemma. CASE: We present the first case of endometrial cancer with metastatic disease to the groin vasculature palliated with percutaneous endovascular embolization and stent grafting. CONCLUSION: Endovascular surgery provides an alternative option in those with metastatic endometrial cancer of the groin to improve the patient's quality of life by avoiding a major surgery with difficult postoperative recovery and prolonging the timecourse until the next major bleed.