Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development.

Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.

Indian American rhinoplasty: an emerging ethnic group.

BACKGROUND: The goal of this article is to help U.S. plastic surgeons better understand why Indian American rhinoplasty is different from other ethnic rhinoplasties in their practice. The study is composed of three parts: a review of the cultural perspectives of Indian Americans toward aesthetic surgery, an investigation into the aesthetic ideals of the Indian American nose, and an overview of operative strategies to achieve these ideals. METHODS: A total of 35 Indian Americans who were dissatisfied with their nasal appearance were analyzed, 15 prospectively and 20 retrospectively. Group 1 consists of 15 Indian American women who were unhappy with the appearance of their nose. Standard photographs and anthropometric measurements were taken. Anterior and lateral photographic views were morphed to the patient's subjective ideal. Actual and ideal images were compared and analyzed. Group 2 consists of a retrospective review of 20 consecutive Indian American rhinoplasty cases with a follow-up of 1 to 6 years. RESULTS: The majority of the group 1 participants complained of a dorsal "hump," a downwardly rotated tip, and/or a large nose. The average subjective ideal nasolabial angle was determined to be 101.6 degrees. Based on the authors' analysis, three categories of nasal deformities were identified and operative strategies are discussed. Evaluation of the 20 clinical cases indicated that a more conservative surgical approach is warranted in these patients. CONCLUSIONS: Indian American rhinoplasty patients present a challenging range of nasal deformities requiring careful surgical planning. A clear understanding of the patient's desires is essential to achieving patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Interposition grafting of popliteal artery cystic adventitial disease: case report.

Cystic adventitial disease of the popliteal artery is a rare cause of leg claudication occurring primarily in young adults. We report a case of a 41-year-old athletic man who presented with rapidly progressive left leg claudication. Using duplex ultrasound and magnetic resonance angiography, a diagnosis of popliteal artery cystic adventitial disease was made. The cystic popliteal artery was resected and replaced using a prosthetic interposition graft. At the 1.5-year follow-up, the cysts have recurred; however, the related symptoms have not. This is in contrast to a previously reported case of interposition saphenous vein grafting requiring resection due to invasion by recurrent cysts within 6 months.

R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.

The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/beta-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.

Management of sternal wounds with bilateral pectoralis major myocutaneous advancement flaps in 114 consecutively treated patients: refinements in technique and outcomes analysis.

Because life-threatening sternal wound complications can occur following sternotomy, the optimal management of sternal wound infections remains an important topic. To decrease morbidity following operative treatment of these patients, the authors made a number of refinements in their treatment protocol over the past several years, particularly with regard to the extent of débridement, method of flap apposition, and management of drains. The purpose of this study was to obtain specific outcomes data by reviewing a large series of patients treated by a single surgeon. In this series of 114 consecutive sternal wounds treated by the senior author (Ascherman), patients were managed almost exclusively with débridement and immediate closure with bilateral pectoralis major myocutaneous advancement flaps. There were no intraoperative deaths. The 30-day perioperative mortality rate was 7.9 percent, with only one death directly related to sternal infection. Nineteen patients (16.7 percent) experienced postoperative morbidity, including partial wound dehiscences (5 percent), skin edge necrosis (5 percent), and seromas (3.5 percent). The authors advocate single-stage management of complicated sternal wounds with immediate débridement and bilateral pectoralis major myocutaneous advancement flaps. The procedure is rapid and effective. Refinements in technique have significantly lowered morbidity.

The core membrane fusion complex governs the probability of synaptic vesicle fusion but not transmitter release kinetics.

Synaptic vesicle fusion is driven by the formation of a four-helical bundle composed of soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptors (SNAREs). Exactly how the structural interactions that lead to the formation of this complex relate to neurotransmitter release is not well understood. To address this question, we used a strategy to "rescue" synaptic transmission after proteolytic cleavage of the synaptosome-associated protein of 25 kDa (SNAP-25) by botulinum neurotoxin E (BoNtE). Transfection of CA3 hippocampal pyramidal cells with BoNtE-resistant SNAP-25 restored synaptic transmission. Additional mutations that alter the interaction between SNAP-25 C-terminal coil and the other SNARE coils dramatically reduce transmitter release probability but leave the kinetics of synaptic responses unaltered. These data indicate that at synapses, SNARE interactions are necessary for fusion but are not the rate-limiting step of neurotransmission.