Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition.

Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause endemic and pandemic acute viral gastroenteritis. Previously, we reported that many HuNoV strains require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. BA was not essential for the replication of a pandemic-causing GII.4 HuNoV strain. We found the hydrophobic BA glycochenodeoxycholic acid (GCDCA) promotes the replication of the BA-dependent strain GII.3 in jejunal enteroids. Furthermore, we found that inhibition of the G-protein-coupled BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), by JTE-013, reduced GII.3 infection dose-dependently and inhibited GII.3 cellular uptake in enteroids. Herein, we sought to determine whether S1PR2 is required for other BA-dependent HuNoV strains, the BA-independent GII.4, and whether S1PR2 is required for BA-dependent HuNoV infection in HIEs from other small intestinal segments. We found a second S1PR2 inhibitor, GLPG2938, reduces GII.3 infection dose-dependently, and an S1PR2 agonist (CYM-5520) enhances GII.3 replication in the absence of GCDCA. GII.3 replication also is abrogated in the presence of JTE-013 and CYM-5520. JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not GII.4 Sydney (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. Finally, GII.3 infection of duodenal, jejunal, and ileal lines derived from the same individual is reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoVs exploit BA effects on S1PR2 to infect the entire small intestine.IMPORTANCEHuman noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA-independent strain, all require S1PR2 for infection. In addition, BA-dependent infection requires S1PR2 in multiple segments of the small intestine. Together, these results indicate that S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.

Plasmonic Cavity-Catalysis by Standing Hot Carrier Waves.

Manipulating active sites of catalysts is crucial but challenging in catalysis science and engineering. Beyond the design of the composition and structure of catalysts, the confined electromagnetic field in optical cavities has recently become a promising method for catalyzing chemical reactions via strong light-matter interactions. Another form of confined electromagnetic field, the charge density wave in plasmonic cavities, however, still needs to be explored for catalysis. Here, we present an unprecedented catalytic mode based on plasmonic cavities, called plasmonic cavity-catalysis. We achieve direct control of catalytic sites in plasmonic cavities through standing hot carrier waves. Periodic catalytic hotspots are formed because of localized energy and carrier distribution and can be well tuned by cavity geometry, charge density, and excitation angle. We also found that the catalytic activity of the cavity mode increases several orders of magnitude compared with conventional plasmonic catalysis. We ultimately demonstrate that the locally concentrated long-lived hot carriers in the standing wave mode underlie the formation of the catalytic hotspots. Plasmonic cavity-catalysis provides a new approach to manipulate the catalytic sites and rates and may expand the frontier of heterogeneous catalysis.

Cyclic Oxime Esters as Deconstructive Bifunctional Reagents for Cyanoalkyl Esterification of 1,6-Enynes.

A concise copper catalysis strategy for the addition-cyclization of cyclic oxime esters across 1,6-enynes with high stereoselectivity to generate 1-indanones bearing an all-carbon quaternary center is reported. In this process, single-electron reduction of cyclic oxime esters enables deconstructive carbon-carbon cleavage to provide a key cyanopropyl radical poised for the addition-cyclization. This reaction is redox-neutral, exhibits good functional group compatibility, and features 100% atomic utilization. This process driven by copper catalyst makes readily available cyclic oxime esters as bifunctional reagents to demonstrate convergent synthesis.

Shigellosis outbreak among MSM living with HIV: a case-control study in Taiwan, 2015-2016.

OBJECTIVES: Outbreaks of shigellosis among men who have sex with men (MSM) have been reported since the late 1990s. HIV infection is an important risk factor. Since 2014, the global shigellosis epidemic has intensified. Whether chemsex (the use of crystal methamphetamine, γ-hydroxybutyrate or mephedrone to enhance sex) is a new risk factor has not been previously examined. METHODS: We conducted a population-based, case-control study in Taiwan. Acute shigellosis cases diagnosed during the 2015 outbreak among MSM living with HIV were compared with those without shigellosis. CD4+ counts, plasma viral load (pVL), gonorrhoea, syphilis and amoebiasis records were obtained from the Notifiable Disease Surveillance System database. We invited cases/controls to provide information on illicit drug use and sexual behaviours, using a structured questionnaire. RESULTS: Seventy-five shigellosis cases were compared with 225 controls. High pVL (>100 000 copies/mL; adjusted OR (aOR): 4.9, 95% CI 1.4 to 16.9), gonorrhoea (aOR: 29.4, 95% CI 2.3 to 340.2) and syphilis (aOR: 4.3, 95% CI 1.6 to 11.6) were independent risk factors of shigellosis. Twenty shigellosis cases and 59 controls completed the questionnaire. Oral-to-anal sex (aOR: 15.5, 95% CI 3.6 to 66.7), chemsex (aOR: 5.6, 95% CI 1.4 to 22.7) and poppers use (aOR: 10.9, 95% CI 1.9 to 64.2) within 12 months were independent behavioural risk factors of shigellosis. CONCLUSIONS: Chemsex is a new risk factor for shigellosis among MSM living with HIV, as identified in the 2015-2016 outbreak. Additional risk factors include poppers use, sexual risk behaviours and high pVL. Further studies on chemsex among MSM, which is a rising public health concern, are urgently required.

Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition.

Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause both endemic and pandemic acute viral gastroenteritis. Previously we reported that many strains of HuNoV require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. Of note, BA was not essential for replication of a pandemic-causing GII.4 HuNoV strain. Using the BA-requiring strain GII.3, we found that the hydrophobic BA GCDCA induces multiple cellular responses that promote replication in jejunal enteroids. Further, we found that chemical inhibition of the G-protein coupled receptor, sphingosine-1- phosphate receptor 2 (S1PR2), by JTE-013 reduced both GII.3 infection in a dose- dependent manner and cellular uptake in enteroids. Herein, we sought to determine if S1PR2 is required by other BA-dependent HuNoV strains and BA-independent GII.4, and if S1PR2 is required for BA-dependent HuNoV infection in other segments of the small intestine. We found JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not the GII.4 Sydney variant (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. GII.3 infection of duodenal, jejunal and ileal lines derived from the same individual was also reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoV exploit the activation of S1PR2 by BA to infect the entire small intestine. Importance: Human noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA- independent strain, all required S1PR2 for infection. Additionally, BA-dependent infection required S1PR2 in multiple segments of the small intestine. Together these results indicate S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.

MEMO: dataset and methods for robust multimodal retinal image registration with large or small vessel density differences.

The measurement of retinal blood flow (RBF) in capillaries can provide a powerful biomarker for the early diagnosis and treatment of ocular diseases. However, no single modality can determine capillary flowrates with high precision. Combining erythrocyte-mediated angiography (EMA) with optical coherence tomography angiography (OCTA) has the potential to achieve this goal, as EMA can measure the absolute RBF of retinal microvasculature and OCTA can provide the structural images of capillaries. However, multimodal retinal image registration between these two modalities remains largely unexplored. To fill this gap, we establish MEMO, the first public multimodal EMA and OCTA retinal image dataset. A unique challenge in multimodal retinal image registration between these modalities is the relatively large difference in vessel density (VD). To address this challenge, we propose a segmentation-based deep-learning framework (VDD-Reg), which provides robust results despite differences in vessel density. VDD-Reg consists of a vessel segmentation module and a registration module. To train the vessel segmentation module, we further designed a two-stage semi-supervised learning framework (LVD-Seg) combining supervised and unsupervised losses. We demonstrate that VDD-Reg outperforms existing methods quantitatively and qualitatively for cases of both small VD differences (using the CF-FA dataset) and large VD differences (using our MEMO dataset). Moreover, VDD-Reg requires as few as three annotated vessel segmentation masks to maintain its accuracy, demonstrating its feasibility.

Electrochemical selective annulative amino-ketalization and amino-oxygenation of 1,6-enynes.

A new electrochemical selective annulative amino-ketalization and amino-oxygenation of 1,6-enynes with disulfonimides and alcohols is reported, producing a series of functionalized benzofurans under catalyst- and oxidant-free conditions. The annulative aminoketalization proceeds with simple short-chain alcohols such as methanol, ethanol and n-propanol as O-nucleophilic reagents, while the reaction occurs in the annulative aminooxygenation direction in the presence of water and large steric sec-butyl alcohol (SBA).

Cultural Adaptation and Validation of Mullen Scales of Early Learning in Taiwanese children with Autism Spectrum Disorder, Global Developmental Delay, and Typically Developing Children.

BACKGROUND: The Mullen Scales of Early Learning (MSEL) is a standardized comprehensive developmental assessment tool for children aged 0-68 months. However, few Asia-based studies have explored cultural and linguistic adaptations of the MSEL or investigated its psychometric properties in populations with autism spectrum disorder (ASD). AIMS: This study evaluated the reliability and validity of the MSEL-Taiwan version (MSEL-T) for Taiwanese children with ASD, global developmental delay (GDD), and typical development (TD). METHODS AND PROCEDURES: The MSEL items were translated and modified according to the language and culture in Taiwan. In total, 191 children (ASD, 69; GDD, 36; and TD, 86) aged 19-68 months were assessed using the MSEL-T and Peabody Developmental Motor Scales 2 (PDMS-2) at enrollment, followed by the assessments of Vineland Adaptive Behavior Scale-Chinese version (VABS-C) at the age of 36 months or later. OUTCOMES AND RESULTS: All subscales were verified to have good interrater reliability and internal consistency, and subscale scores indicated moderate to high correlations with PDMS-2 and VABS-C scores. Significant differences in MSEL-T scores were observed between same-aged pairs of children with TD and GDD and between pairs of children with TD and ASD. CONCLUSIONS AND IMPLICATIONS: The findings provide evidence of validity and reliability of the MSEL-T. And it is suggested that the culturally and linguistically adapted MSEL-T is a good tool for the clinical assessment of children with and without ASD.

Gene Expression Analysis of Environmental Temperature and High-Fat Diet-Induced Changes in Mouse Supraclavicular Brown Adipose Tissue.

Obesity, a dysregulation of adipose tissue, is a major health risk factor associated with many diseases. Brown adipose tissue (BAT)-mediated thermogenesis can potentially regulate energy expenditure, making it an attractive therapeutic target to combat obesity. Here, we characterize the effects of cold exposure, thermoneutrality, and high-fat diet (HFD) feeding on mouse supraclavicular BAT (scBAT) morphology and BAT-associated gene expression compared to other adipose depots, including the interscapular BAT (iBAT). scBAT was as sensitive to cold induced thermogenesis as iBAT and showed reduced thermogenic effect under thermoneutrality. While both scBAT and iBAT are sensitive to cold, the expression of genes involved in nutrient processing is different. The scBAT also showed less depot weight gain and more single-lipid adipocytes, while the expression of BAT thermogenic genes, such as Ucp1, remained similar or increased more under our HFD feeding regime at ambient and thermoneutral temperatures than iBAT. Together, these findings show that, in addition to its anatomical resemblance to human scBAT, mouse scBAT possesses thermogenic features distinct from those of other adipose depots. Lastly, this study also characterizes a previously unknown mouse deep neck BAT (dnBAT) depot that exhibits similar thermogenic characteristics as scBAT under cold exposure and thermoneutrality.

Methylantcinate A induces tumor specific growth inhibition in oral cancer cells via Bax-mediated mitochondrial apoptotic pathway.

An ergostane type triterpenoid methylantcinate A (MAA) isolated from the fruiting bodies of Antrodia camphorata inhibited the growth of oral cancer cell lines OEC-M1 and OC-2 in a dose-dependent manner, without cytotoxic to normal oral gingival fibroblast cells. The major mechanism of growth inhibition was apoptosis induction, as shown by flow cytometric analysis of annexin V-FITC and propidium iodide staining, caspase-3 activation and DNA fragmentation. The increased expression of pro-apoptotic Bax, poly-(ADP-ribose) polymerase cleavage, and activated caspase-3 and decreased expression of anti-apoptotic Bcl-2 and Bcl-xL were also observed. These results provide the first evidence that the anti-oral cancer effects of MAA may involve a mechanism through the mitochondrial dependent pathway. Thus, results reported here may offer further impulse to the development of MAA analogues as potential chemotherapeutic targets for oral cancer complications.

NTF3 Is a Novel Target Gene of the Transcription Factor POU3F2 and Is Required for Neuronal Differentiation.

POU-homeodomain transcription factor POU3F2 is a critical transcription factor that participates in neuronal differentiation. However, little is known about its downstream mediators. Here genome-wide analyses of a human neuronal differentiation cell model, NT2D1, suggested neurotrophin-3 (NTF3), a key mediator of neuronal development during the early neurogenic period, as a putative regulatory target of POU3F2. Western blot, cDNA microarray, and real-time quantitative PCR analyses showed that POU3F2 and NTF3 were upregulated during neuronal differentiation. Next-generation-sequence-based POU3F2 chromatin immunoprecipitation-sequencing and genome-wide in silico prediction demonstrated that POU3F2 binds to the NTF3 promoter during neuronal differentiation. Furthermore, unidirectional deletion or mutation of the binding site of POU3F2 in the NTF3 promoter decreased promoter-driven luciferase activity, indicating that POU3F2 is a positive regulator of NTF3 promoter activity. While NTF3 knockdown resulted in decreased viability and differentiation of NT2D1 cells, and POU3F2 knockdown downregulated NTF3 expression, recombinant NTF3 significantly rescued viable neuronal cells from NTF3- or POU3F2-knockdown cell cultures. Moreover, immunostaining showed colocalization of POU3F2 and NTF3 in developing mouse neurons. Thus, our data suggest that NTF3 is a novel target gene of POU3F2 and that the POU3F2/NTF3 pathway plays a role in the process of neuronal differentiation.

Characterization of protein arginine methyltransferases in porcine brain.

Protein arginine methylation is a posttranslational modification involved in various cellular functions including cell signaling, protein subcellular localization and transcriptional regulation. We analyze the protein arginine methyltransferases (PRMTs) that catalyze the formation of methylarginines in porcine brain. We fractionated the brain extracts and determined the PRMT activities as well as the distribution of different PRMT proteins in subcellular fractions of porcine brain. The majority of the type I methyltransferase activities that catalyze the formation of asymmetric dimethylarginines was in the cytosolic S3 fraction. High specific activity of the methyltransferase was detected in the S4 fraction (high-salt stripping of the ultracentrifugation precipitant P3 fraction), indicating that part of the PRMT was peripherally associated with membrane and ribosomal fractions. The amount and distribution of PRMT1 are consistent with the catalytic activity. The elution patterns from gel filtration and anion exchange chromatography also indicate that the type I activity in S3 and S4 are mostly from PRMT1. Our results suggest that part of the type I arginine methyltransferases in brains, mainly PRMT1, are sequestered in an inactive form as they associated with membranes or large subcellular complexes. Our biochemical analyses confirmed the complex distribution of different PRMTs and implicate their regulation and catalytic activities in brain.

[Base Activation of Peroxymonosulfate for the Degradation of Ciprofloxacin in Water].

The degradation of ciprofloxacin (CIP) in a base activated peroxymonosulfate (PMS) system was investigated. Results showed that a base activated PMS system can efficiently remove CIP. Singlet oxygen (1 O2) and superoxide anion radical (O2-·) were confirmed to be the major reactive oxygen species through radical quenching experiments. The NaOH concentration, PMS concentration, reactive temperature, and coexisting anions also affected CIP removal. Both NaOH and PMS concentration presented a dual effect, which was highly concentration dependent. An improvement in reactive temperature accelerated CIP degradation, and the calculated activation energy (Ea) was determined to be 5.09 kJ·mol-1 through the fitting of the Arrhenius equation. Different anions had different effects on CIP degradation. No obvious change in CIP concentration was observed when Cl-, SO42-, and NO3- were introduced. H2PO42- inhibited the degradation, but CO32- significantly promoted it. Ten oxidation products were identified through UPLC-MS/MS analysis, and the piperazine ring in the molecular structure of CIP was preferentially attacked by reactive oxygen species in the base activated PMS system.

Egr-1 deficiency protects from renal inflammation and fibrosis.

UNLABELLED: NF-κB and TGFß play critical roles in renal inflammation and fibrosis, and their regulation in the kidney is thus of great interest. Early growth response-1 (Egr-1), a transcription factor belonging to the immediate early gene family, has been found to regulate inflammation and fibrosis in non-kidney tissues, but its role in renal failure has not been clear. In this study, wild-type and Egr1 (-/-) mice were fed with an adenine-enriched diet to induce tubulointerstitial nephritis (TIN), and primary tubular epithelial cells (PTECs) were treated with pro-inflammatory and pro-fibrotic cytokines. Kidney tissues from patients with or without renal failure were stained for Egr-1. Our results showed that Egr-1 expression was upregulated in the kidney with TIN, and the tubular epithelial cell is the primary site for Egr-1 upregulation and nuclear translocation. Egr1 (-/-) mice were protected from renal failure, reflected by low levels of serum urea and creatinine. The protective effect was related to an attenuation of tubular injury, immune cell infiltration, NF-κB activity, and cytokine/chemokine expressions in the kidney. Renal fibrotic area and TGFß signaling were also reduced in Egr1 (-/-) mice. In vitro study showed that Egr-1 deficiency attenuated the ordinary responses of PTECs to TNFα and TGFß. Importantly, Egr-1 is of clinical significance since the activity of Egr-1 in renal tubular cells was upregulated in renal failure patients. Our study highlights the integrative role of Egr-1 in renal inflammation and fibrosis. Thus, Egr-1 may serve as a therapeutic target for human kidney diseases. KEY MESSAGES: Renal failure activates Egr-1 in human and mouse tubular cells. Egr-1 deficiency attenuates NF-κB and TGFß-mediated renal inflammation/fibrosis. Egr1 (-/-) PTECs respond weakly to pro-inflammatory or pro-fibrotic stimulation.

Candida albicans DBF4 gene inducibly duplicated by the mini-Ura-blaster is involved in hypha-suppression.

The opportunistic human fungal pathogen Candida albicans is a natural diploid that does not have a complete sexual cycle. The ability to switch between diverse cellular forms is important to its virulence. Here, we describe the characterization of the C. albicans DBF4 gene, a Saccharomyces cerevisiae homolog that encodes a regulatory subunit of Cdc7 kinase that is known to initiate DNA replication. We made a C. albicans strain, with one DBF4 allele deleted by the mini-Ura-blaster and the other controlled by a repressible promoter. We also found a third CaDBF4 copy that was later verified to be inducibly duplicated by targeted recombination with the min-Ura-blaster. Surprisingly, the strain deleted with the third CaDBF4 copy exhibited hyphal growth under repressed conditions. We conclude that the CaDBF4 gene is prone to being duplicated by the mini-Ura-blaster and that it suppresses hyphal growth in C. albicans.

Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy.

Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4(-/-) mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN.

Luteolin modulates 6-hydroxydopamine-induced transcriptional changes of stress response pathways in PC12 cells.

The neurotoxin 6-hydroxydopamine (6-OHDA), which causes transcriptional changes associated with oxidative and proteotoxic stress, has been widely used to generate an experimental model of Parkinson's disease. The food-derived compound luteolin has multi-target actions including antioxidant, anti-inflammatory and neurotrophic activities. The aim of this study is to investigate how luteolin affects 6-OHDA-mediated stress response pathways. The results showed that when PC12 cells were pre-treated with luteolin (20 µM) 30 min prior to 6-OHDA (100 µM) exposure, 6-OHDA-induced ROS overproduction, cytotoxicity, caspase-3 activation, and mRNA expression of BIM, TRB3 and GADD34 were significantly attenuated. Moreover, 6-OHDA-mediated cell cycle arrest and transcription of p53 target genes, p21, GADD45α and PUMA, were reduced by luteolin. Luteolin also significantly down-regulated 6-OHDA-mediated unfolded protein response (UPR), leading to decreases in phospho-eIF2α, ATF4, GRP78 and CHOP. In addition, luteolin attenuated 6-OHDA-induced Nrf2-mediated HO-1 and GCLC. Taken together, these results suggest that diminishing intracellular ROS formation and down-regulation of p53, UPR and Nrf2-ARE pathways may be involved in the neuroprotective effect of luteolin.

Anti-inflammatory effect and mechanism of the green fruit extract of Solanum integrifolium Poir.

The green fruit of Solanum integrifolium Poir. has been used traditionally as an anti-inflammatory and analgesic remedy in Taiwanese aboriginal medicine. The goal of this study is to evaluate the anti-inflammatory activity and mechanism of the green fruit extract of S. integrifolium. A bioactivity-guided fractionation procedure was developed to identify the active partition fraction. The methanol fraction (ME), with the highest phenolic content, exhibited the strongest inhibitory effect against LPS-mediated nitric oxide (NO) release and cytotoxicity in RAW264.7 macrophages. ME also significantly downregulated the expression of LPS-induced proinflammatory genes, such as iNOS, COX-2, IL-1ß, IL-6, CCL2/MCP-1, and CCL3/MIP1α. Moreover, ME significantly upregulated HO-1 expression and stimulated the activation of extracellular-signal-regulated kinase 1/2 (ERK1/2). Pretreatment of cells with the HO-1 inhibitor zinc protoporphyrin and MEK/ERK inhibitor U0126 attenuated ME's inhibitory activity against LPS-induced NO production. Taken together, this is the first study to demonstrate the anti-inflammatory activity of green fruit extract of S. integrifolium and its activity may be mediated by the upregulation of HO-1 expression and activation of ERK1/2 pathway.

The predominant protein arginine methyltransferase PRMT1 is critical for zebrafish convergence and extension during gastrulation.

Protein arginine methyltransferase (PRMT)1 is the predominant type I methyltransferase in mammals. In the present study, we used zebrafish (Danio rerio) as the model system to elucidate PRMT1 expression and function during embryogenesis. Zebrafish prmt1 transcripts were detected from the zygote period to the early larva stage. Knockdown of prmt1 by antisense morpholino oligo (AMO) resulted in delayed growth, shortened body-length, curled tails and cardiac edema. PRMT1 protein level, type I protein arginine methyltransferase activity, specific asymmetric protein arginine methylation and histone H4 R3 methylation all decreased in the AMO-injected morphants. The morphants showed defective convergence and extension and the abnormalities were more severe at the posterior than the anterior parts. Cell migration defects suggested by the phenotypes were not only observed in the morphant embryos, but also in a cellular prmt1 small-interfering RNA knockdown model. Rescue of the phenotypes by co-injection of wild-type but not catalytic defective prmt1 mRNA confirmed the specificity of the AMO and the requirement of methyltransferase activity in early development. The results obtained in the present study demonstrate a direct link of early development with protein arginine methylation catalyzed by PRMT1.

Computational models of distributed aberration in ultrasound breast imaging.

Two methods for simulation of ultrasound wavefront distortion are introduced and compared with aberration produced in simulations using digitized breast tissue specimens and a conventional multiple time-shift screen model. In the first method, aberrators are generated using a computational model of breast anatomy. In the second method, 10 to 12 irregularly shaped, strongly scattering inclusions are superimposed on the multiple-screen model to create a screen-inclusion model. Linear 2-D propagation of a 7.5-MHz planar, pulsed wavefront through each aberrator is computed using a first-order k-space method. The anatomical and screen-inclusion models reproduce two characteristics of arrival-time fluctuations observed in simulations using the digitized specimens that are not represented in simulations using the multiple-screen model: non-Gaussian first-order statistics and sharp changes in the rms arrival-time fluctuation as a function of propagation distance. The anatomical and screen-inclusion models both produce energy- level fluctuations similar to the digitized specimens, but the anatomical model more closely matches the pulse-shape distortion produced by the specimens. Both aberration models can readily be extended to 3-D, and the screen-inclusion model has the advantage of simplicity of implementation. Both models should enable more rigorous evaluation of adaptive focusing algorithms than is possible using conventional time-shift screen models.