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The neuromuscular junction (NMJ) consists of three components, namely presynaptic motor neurons, postsynaptic muscle fibers and perisynaptic Schwann cells (PSCs). The role of Schwann cells (SCs) in regulating NMJ structural and functional development remains unclear. In this study, mice with conditional inactivation of neurofibromin 1 (Nf1) and phosphatase and tensin homolog (Pten), specifically in SCs, resulted in delayed NMJ maturation that led to delayed muscle growth, recapitulating the muscular dystrophy condition observed in human neurofibromatosis type I syndrome (NF1) patients. Expression levels of NMJ development related molecules such as cholinergic receptor, nicotinic, alpha polypeptide 1 (Chrna1), agrin (Agrn), dystrophin, muscular dystrophy (Dmd), laminin, beta 2 (Lamb2) and dystroglycan 1 (Dag1) were also downregulated. To further explore the molecular alterations in these SCs, NF1- and PTEN-related pathways were analyzed in mutant sciatic nerves. As expected, hyperactive RAS/PI3K/AKT/mTOR signaling pathways were identified, suggesting the importance of these pathways for NMJ development, and subsequent muscle maturation.

Epidemics and pandemics of influenza are characterized by rapid global spread mediated by non-mutually exclusive transmission modes. The relative significance between contact, droplet, and airborne transmission is yet to be defined, a knowledge gap for implementing evidence-based infection control measures. We devised a transmission chamber that separates virus-laden particles by size and determined the particle sizes mediating transmission of influenza among ferrets through the air. Ferret-to-ferret transmission was mediated by airborne particles larger than 1.5 μm, consistent with the quantity and size of virus-laden particles released by the donors. Onward transmission by donors was most efficient before fever onset and may continue for 5 days after inoculation. Multiple virus gene segments enhanced the transmissibility of a swine influenza virus among ferrets by increasing the release of virus-laden particles into the air. We provide direct experimental evidence of influenza transmission via droplets and fine droplet nuclei, albeit at different efficiency.

Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of soft tissue neoplasm with extremely poor prognosis and no effective medical options currently available. MPNSTs can occur either sporadically or in association with the neurofibromatosis type 1 (NF1) syndrome. Importantly, activation of RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and WNT/CTNNB1 signaling pathways has been reported in both NF1‐related and late‐stage sporadic MPNSTs. In this study, we found that DAW22, a natural sesquiterpene coumarin compound isolated from Ferula ferulaeoides (Steud.) Korov., could inhibit cell proliferation and colony formation in five established human MPNST cancer cell lines. Further molecular mechanism exploration indicated that DAW22 could target the main components in the MPNST tumorigenic pathways: namely suppress phosphorylation of AKT and ERK, and reduce levels of non‐phospho (active) CTNNB1. Using the xenograft mouse model transplanted with human MPNST cancer cell line, daily treatment with DAW22 for 25 days was effective in reducing tumor growth. These results support DAW22 as an alternative therapeutic compound for MPNST treatment by affecting multiple signaling transduction pathways in its disease progression. In this study, we evaluated the anti‐tumor effect of natural compound DAW22 on malignant peripheral nerve sheath tumors (MPNSTs) using both in vitro and in vivo approaches. The anti‐tumor effect was caused by the induction of apoptosis and targeting of AKT, ERK, and CTNNB1 signaling pathways. These results support DAW22 as an alternative therapeutic compound for MPNST treatment by affecting multiple signaling transduction pathways in its disease progression.

Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.

Malignant peripheral nerve sheath tumors ( MPNST s) are an aggressive form of soft tissue neoplasm with extremely poor prognosis and no effective medical options currently available. MPNST s can occur either sporadically or in association with the neurofibromatosis type 1 ( NF 1) syndrome. Importantly, activation of RAS / RAF / MEK / ERK , PI 3K/ AKT / mTOR , and WNT / CTNNB 1 signaling pathways has been reported in both NF 1‐related and late‐stage sporadic MPNST s. In this study, we found that DAW 22, a natural sesquiterpene coumarin compound isolated from Ferula ferulaeoides (Steud.) Korov ., could inhibit cell proliferation and colony formation in five established human MPNST cancer cell lines. Further molecular mechanism exploration indicated that DAW 22 could target the main components in the MPNST tumorigenic pathways: namely suppress phosphorylation of AKT and ERK , and reduce levels of non‐phospho (active) CTNNB 1. Using the xenograft mouse model transplanted with human MPNST cancer cell line, daily treatment with DAW 22 for 25 days was effective in reducing tumor growth. These results support DAW 22 as an alternative therapeutic compound for MPNST treatment by affecting multiple signaling transduction pathways in its disease progression.

Primary cultures of adult rat dorsal root ganglia (DRG) were prepared to examine the properties of prostacyclin (IP) receptors and prostaglandin E2 (EP) receptors in sensory neurones. IP receptor agonists, cicaprost and iloprost, stimulated adenylyl cyclase activity with EC50 values of 22 and 28 nM, respectively. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) were 7 fold less potent than cicaprost and iloprost, with PGE2 displaying a lower maximal response. Adenylyl cyclase activation by iloprost, PGE1 and PGE2, but not by forskolin, was highly dependent on DRG cell density. Although the potency of iloprost and PGE2 for stimulating adenylyl cyclase was unchanged, their maximal responses were significantly increased at low cell density. Both IP and EP2/4 receptors could be down‐regulated by agonist pretreatment, however the presence of cyclo‐oxygenase (COX) inhibitors did not prevent this apparent down‐regulation of IP and EP2/4 receptors at high DRG cell densities. Stimulation of adenylyl cyclase by the neuropeptide calcitonin gene‐related peptide was also decreased at high DRG cell density, whereas the responses to β‐adrenoceptor agonists were increased at high DRG cell density. Addition of nerve growth factor (NGF), or the addition of anti‐neurotrophin antibodies during the 5‐day culture of DRG cells, had no effect on IP receptor‐mediated responses. These results indicate that Gs‐coupled receptors involved in nociception are regulated in a variable manner in adult rat sensory neurones, and that this cell density‐dependent regulation may be agonist‐independent for IP and EP2/4 receptors. British Journal of Pharmacology (2001) 133, 13–22; doi:10.1038/sj.bjp.0704028

Cystic fibrosis is caused by mutations in the gene encoding an ion-transport protein, the cystic-fibrosis transmembrane conductance regulator (CFTR). Defective secretion of anions is the primary cause of many of the clinical manifestations of cystic fibrosis, including pancreatic insufficiency. We aimed to identify a molecular mechanism from which a new method to circumvent defective pancreatic secretion could be derived. Multiple-human-tissue RT-PCR and semiquantitative RT-PCR analyses were used to examine gene expression. An antisense technique was used in conjunction with radioimmunoassay, Fura-2 spectrofluorometry, immunohisto-chemistry, and the short-circuit current technique (Ussing chamber) for elucidation of gene function and its application in rescuing defective pancreatic secretion. We cloned a newly identified gene, NYD-SP27, which has structural similarity to an isoform of phospholipase C. NYD-SP27 was expressed endogenously in human pancreatic-duct cells and upregulated in cystic fibrosis. Suppression of NYD-SP27, by transfection of its antisense into human cystic-fibrosis pancreatic-duct cells, resulted in augmentation of phospholipase-C-coupled calcium-ion release and protein kinase C activity, improvement in the amount of mutated CFTR reaching the plasma membrane, and restoration of cAMP-activated pancreatic anion secretion. NYD-SP27 exerts an inhibitory effect on phospholipase-C-coupled processes that depend on calcium ions and protein kinase C, including CFTR trafficking and function. Its upregulation in pancreatic-duct cells may reveal a previously unsuspected defect in cystic fibrosis contributing to pancreatic insufficiency, and thus represents a new target for pharmacological intervention in cystic fibrosis.