Notch1 intracellular domain suppresses APP intracellular domain—Tip60–Fe65 complex mediated signaling through physical interaction

AbstractThe amyloid beta-precursor protein (APP) and the Notch receptor are both type 1 integral transmembrane proteins, and both are cleaved by presenilin-dependent gamma-secretase activity. In this study, we have demonstrated that the Notch intracellular domain (Notch1-IC) suppresses APP-intracellular domain (AICD)-mediated ROS generation and cell death after being processed by gamma secretase. Notch1-IC physically interacts with AICD, Fe65, and Tip60, thereby disrupting the association of the AICD–Fe65–Tip60 trimeric transcription activator complex in AICD signaling. AICD–Fe65–Tip60 mediated reactive oxygen species generation was found to be suppressed by Notch1-IC. Furthermore, AICD–Fe65–Tip60 was shown to mediate cell death in human neuroblastoma cells, and the overexpression of Notch1-IC inhibited cell death induced by AICD–Fe65–Tip60. Collectively, our findings indicate that Notch1-IC plays the role of a negative regulator in AICD signaling via the disruption of the AICD–Fe65–Tip60 trimeric complex

Endophytic fungal association via gibberellins and indole acetic acid can improve plant growth under abiotic stress: an example of Paecilomyces formosus LHL10

<p>Abstract</p> <p>Background</p> <p>Endophytic fungi are little known for exogenous secretion of phytohormones and mitigation of salinity stress, which is a major limiting factor for agriculture production worldwide. Current study was designed to isolate phytohormone producing endophytic fungus from the roots of cucumber plant and identify its role in plant growth and stress tolerance under saline conditions.</p> <p>Results</p> <p>We isolated nine endophytic fungi from the roots of cucumber plant and screened their culture filtrates (CF) on gibberellins (GAs) deficient mutant rice cultivar <it>Waito-C </it>and normal GAs biosynthesis rice cultivar Dongjin-byeo. The CF of a fungal isolate CSH-6H significantly increased the growth of <it>Waito-C </it>and Dongjin-byeo seedlings as compared to control. Analysis of the CF showed presence of GAs (GA₁, GA₃, GA₄, GA₈, GA₉, GA₁₂, GA₂₀and GA₂₄) and indole acetic acid. The endophyte CSH-6H was identified as a strain of <it>Paecilomyces formosus </it>LHL10 on the basis of phylogenetic analysis of ITS sequence similarity. Under salinity stress, <it>P. formosus </it>inoculation significantly enhanced cucumber shoot length and allied growth characteristics as compared to non-inoculated control plants. The hypha of <it>P. formosus </it>was also observed in the cortical and pericycle regions of the host-plant roots and was successfully re-isolated using PCR techniques. <it>P. formosus </it>association counteracted the adverse effects of salinity by accumulating proline and antioxidants and maintaining plant water potential. Thus the electrolytic leakage and membrane damage to the cucumber plants was reduced in the association of endophyte. Reduced content of stress responsive abscisic acid suggest lesser stress convened to endophyte-associated plants. On contrary, elevated endogenous GAs (GA₃, GA₄, GA₁₂and GA₂₀) contents in endophyte-associated cucumber plants evidenced salinity stress modulation.</p> <p>Conclusion</p> <p>The results reveal that mutualistic interactions of phytohormones secreting endophytic fungi can ameliorate host plant growth and alleviate adverse effects of salt stress. Such fungal strain could be used for further field trials to improve agricultural productivity under saline conditions.</p

Targeted delivery of iron oxide nanoparticle-loaded human embryonic stem cell-derived spherical neural masses for treating intracerebral hemorrhage

This study evaluated the potential of iron oxide nanoparticle-loaded human embryonic stem cell (ESC)-derived spherical neural masses (SNMs) to improve the transportation of stem cells to the brain, ameliorate brain damage from intracerebral hemorrhage (ICH), and recover the functional status after ICH under an external magnetic field of a magnet attached to a helmet. At 24 h after induction of ICH, rats were randomly separated into three experimental groups: ICH with injection of phosphate-buffered saline (PBS group), ICH with intravenous injection of magnetosome-like ferrimagnetic iron oxide nanocubes (FION)-labeled SNMs (SNMs* group), and ICH with intravenous injection of FION-labeled SNMs followed by three days of external magnetic field exposure for targeted delivery by a magnet-embedded helmet (SNMs*+Helmet group). On day 3 after ICH induction, an increased Prussian blue-stained area and decreased swelling volume were observed in the SNMs*+Helmet group compared with that of the other groups. A significantly decreased recruitment of macrophages and neutrophils and a downregulation of pro-inflammatory cytokines followed by improved neurological function three days after ICH were observed in the SNMs*+Helmet group. Hemispheric atrophy at six weeks after ICH was significantly decreased in the SNMs*+Helmet group compared with that of the PBS group. In conclusion, we have developed a targeted delivery system using FION tagged to stem cells and a magnet-embedded helmet. The targeted delivery of SNMs might have the potential for developing novel therapeutic strategies for ICH.

X-linked Opitz G/BBB Syndrome: Identification of a Novel Mutation and Prenatal Diagnosis in a Korean Family

X-linked Opitz G/BBB syndrome (XLOS; MIM 300000) is a rare multiple congenital anomaly disorder that is characterized by facial anomalies, laryngeal/tracheal/esophageal defects and genitourinary abnormalities. XLOS is caused by mutations in the MID1 gene which encodes a microtubule-associated RING-Bbox-Coiled-coil (RBCC) protein. We recently found a four-year Korean male patient who was suspected of having XLOS. Mutation analysis of the MID1 gene in the patient and his mother demonstrated that the patient had a novel insertion mutation (c.1798_1799insC), and his mother was a heterozygous carrier of the mutation. After identification of the causative mutation in this family, prenatal diagnosis of two consecutive fetuses were successfully undertaken. This is the first report on a genetically confirmed case of XLOS in Korea

Radiological Spectrum of Hepatic Mesenchymal Hamartoma in Children

OBJECTIVE: A hepatic mesenchymal hamartoma is an uncommon benign tumor in children and little is known about the spectrum of its radiological features. The purpose of this study is to describe the spectrum of radiological features of a hepatic mesenchymal hamartoma in children. MATERIALS AND METHODS: Thirteen children with a pathologically confirmed hepatic mesenchymal hamartoma (M:F = 7:6; mean age, 3 years 2 months) were included in our study. Ultrasonography (US) was performed in nine patients including color and power Doppler US (n = 7). CT scans were performed in all patients. We evaluated the imaging findings of the hepatic mesenchymal hamartomas and the corresponding pathological features. RESULTS: Each patient had a single tumor (mean diameter: 13 cm [1.8-20 cm]). On CT and/or US, four patients (31%) had a "multiseptated cystic tumor", five patients (38%) had a "mixed solid and cystic tumor", and four patients (31%) had a "solid tumor." The septa of the cystic portion were thin in the multiseptated cystic tumors and irregularly thick in the mixed solid and cystic tumors as seen on US. On a post-contrast CT scan, solid portions or thick septa of the tumors showed heterogeneous enhancement. The amount of hepatocytes was significantly different among the three tumor groups according to the imaging spectrum (p = 0.042). CONCLUSION: A hepatic mesenchymal hamartoma in children can show a wide spectrum of radiological features, from a multiseptated cystic tumor to a mixed solid and cystic tumor, and even a solid tumor

Activated forkhead transcription factor inhibits neointimal hyperplasia after angioplasty through induction of p27

OBJECTIVE: We examined the effects of FKHRL1 (forkhead transcription factor in rhabdomyosarcoma like-1) overexpression on vascular smooth muscle cell (VSMC) proliferation, apoptosis, and cell cycle, in vitro, and the role of FKHRL1 and p27 in the pathophysiology of neointimal growth after balloon angioplasty, in vivo. Furthermore, we tested whether FKHRL1 overexpression can inhibit neointimal hyperplasia in a rat carotid artery model. METHODS AND RESULTS: Adenovirus expressing the constitutively active FKHRL1 (FKHRL1-TM; triple mutant) with 3 Akt phosphorylation sites mutated was transfected to subconfluent VSMCs. FKHRL1 overexpression in cultured VSMCs increased p27 expression, leading to G1 phase cell-cycle arrest and increased apoptosis. In vivo, the phosphorylation of FKHRL1 increased significantly 3 hours after balloon injury and decreased thereafter, with the subsequent downregulation of p27. Although the phosphorylation of FKHRL1 was greatest at 3 hours, the downregulation of p27 showed a temporal delay, only slightly starting to decrease after 3 hours and reaching a nadir at 72 hours after balloon injury. Gene transfer of FKHRL1-TM increased p27, decreased proliferation, and increased apoptosis of VSMCs, which resulted in a marked reduction in neointima formation (intima-to-media ratio: 0.31+/-0.13 versus 1.17+/-0.28, for FKHRL1-TM versus Adv-GFP; P<0.001). CONCLUSIONS: Balloon angioplasty leads to the phosphorylation of FKHRL1 and decreased expression of p27, thereby promoting a proliferative phenotype in VSMCs in vitro and in vivo. This study reveals the importance of FKHRL1 in proliferation and viability of VSMCs and suggests that it may serve as a molecular target for interventions to reduce neointima formation after angioplasty

Oral food challenges in children

Many patients assume that allergic reactions against foods are responsible for triggering or worsening their allergic symptoms. Therefore, it is important to identify patients who would benefit from an elimination diet, while avoiding unnecessary dietary restrictions. The diagnosis of food allergy depends on the thorough review of the patients's medical history, results of supplemented trials of dietary elimination, and in vivo and in vitro tests for measuring specific IgE levels. However, in some cases the reliability of such procedures is suboptimal. Oral food challenges are procedures employed for making an accurate diagnosis of immediate and occasionally delayed adverse reactions to foods. The timing and type of the challenge, preparation of patients, foods to be tested, and dosing schedule should be determined on the basis of the patient's history, age, and experience. Although double-blind, placebo-controlled food challenges(DBPCFC) are used to establish definitively if a food is the cause of adverse reactions, they are time-consuming, expensive and troublesome for physician and patients. In practice, An open challenge controlled by trained personnel is sufficient especially in infants and young children. The interpretation of the results and follow-up after a challenge are also important. Since theses challenges are relatively safe and informative, controlled oral food challenges could become the measure of choice in children

Comparison of the Efficacy and Tolerability between Same-day Picosulfate and Split-dose Polyethylene Glycol Bowel Preparation for Afternoon Colonoscopy: A Prospective, Randomized, Investigator-blinded Trial

Background/AimsIn the present study, we evaluated the efficacy and tolerability between same-day bowel preparation protocols using 2 sachets of Picosulfate and a 4 L split-dose polyethylene glycol (PEG) bowel preparation for afternoon colonoscopy.MethodsThe study had a single-center, prospective, randomized, and investigator-blinded, non-inferiority design. We evaluated bowel preparation quality according to the Ottawa scale, patient tolerability, compliance, incidence of adverse events, sleep quality, and polyp/adenoma detection rate.ResultsAmong the 196 patients analyzed (mean age, 55.3 years; 50.3% men), 97 received the same-day regimen of 2 sachets of picosulfate (group A) and 99 received the 4 L split-dose PEG regimen (group B). The Ottawa score of the total colon was 4.05±1.56 in group A and 3.80±1.55 in group B (P=0.255). The proportion of patients having adequate bowel preparation in the same-day picosulfate group (61.5%) was slightly less than the 4 L PEG group (71.3%); however, the difference was not statistically significant (P=0.133). Tolerability of the group A regimen was superior to that of the group B regimen (P<0.000). The same-day picosulfate regimen was associated with fewer adverse events, such as abdominal bloating (P=0.037) and better sleep quality (P<0.000).ConclusionsThe same-day picosulfate regimen and the 4 L split-dose PEG regimen had similar efficacy in bowel preparation for afternoon colonoscopy. However, the same-day picosulfate regimen was easier to administer, produced fewer adverse events, and enabled better sleep quality