The Transcriptomic Response of Rat Hepatic Stellate Cells to Endotoxin: Implications for Hepatic Inflammation and Immune Regulation

With their location in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all of the liver cell types both by physical association (cell body as well as cytosolic processes penetrating into sinusoids through the endothelial fenestrations) and by producing several cytokines and chemokines. Bacterial lipopolysaccharide (LPS), circulating levels of which are elevated in liver diseases and transplantation, stimulates HSCs to produce increased amounts of cytokines and chemokines. Although recent research provides strong evidence for the role of HSCs in hepatic inflammation and immune regulation, the number of HSC-elaborated inflammatory and immune regulatory molecules may be much greater then known at the present time. Here we report time-dependent changes in the gene expression profile of inflammatory and immune-regulatory molecules in LPS-stimulated rat HSCs, and their validation by biochemical analyses. LPS strongly up-regulated LPS-response elements (TLR2 and TLR7) but did not affect TLR4 and down-regulated TLR9. LPS also up-regulated genes in the MAPK, NFκB, STAT, SOCS, IRAK and interferon signaling pathways, numerous CC and CXC chemokines and IL17F. Interestingly, LPS modulated genes related to TGFβ and HSC activation in a manner that would limit their activation and fibrogenic activity. The data indicate that LPS-stimulated HSCs become a major cell type in regulating hepatic inflammatory and immunological responses by altering expression of numerous relevant genes, and thus play a prominent role in hepatic pathophysiology including liver diseases and transplantation

Do changes in health reveal the possibility of undiagnosed pancreatic cancer? Development of a risk-prediction model based on healthcare claims data.

Background and objectiveEarly detection methods for pancreatic cancer are lacking. We aimed to develop a prediction model for pancreatic cancer based on changes in health captured by healthcare claims data.MethodsWe conducted a case-control study on 29,646 Medicare-enrolled patients aged 68 years and above with pancreatic ductal adenocarcinoma (PDAC) reported to the Surveillance Epidemiology an End Results (SEER) tumor registries program in 2004-2011 and 88,938 age and sex-matched controls. We developed a prediction model using multivariable logistic regression on Medicare claims for 16 risk factors and pre-diagnostic symptoms of PDAC present within 15 months prior to PDAC diagnosis. Claims within 3 months of PDAC diagnosis were excluded in sensitivity analyses. We evaluated the discriminatory power of the model with the area under the receiver operating curve (AUC) and performed cross-validation by bootstrapping.ResultsThe prediction model on all cases and controls reached AUC of 0.68. Excluding the final 3 months of claims lowered the AUC to 0.58. Among new-onset diabetes patients, the prediction model reached AUC of 0.73, which decreased to 0.63 when claims from the final 3 months were excluded. Performance measures of the prediction models was confirmed by internal validation using the bootstrap method.ConclusionModels based on healthcare claims for clinical risk factors, symptoms and signs of pancreatic cancer are limited in classifying those who go on to diagnosis of pancreatic cancer and those who do not, especially when excluding claims that immediately precede the diagnosis of PDAC

Critical Role of Klf5 in Regulating Gene Expression during Post-Eyelid Opening Maturation of Mouse Corneas

Background: Klf5 plays an important role in maturation and maintenance of the mouse ocular surface. Here, we quantify WT and Klf5-conditional null (Klf5CN) corneal gene expression, identify Klf5-target genes and compare them with the previously identified Klf4-target genes to understand the molecular basis for non-redundant functions of Klf4 and Klf5 in the cornea. Methodology/Principal Findings: Postnatal day-11 (PN11) and PN56 WT and Klf5CN corneal transcriptomes were quantified by microarrays to compare gene expression in maturing WT corneas, identify Klf5-target genes, and compare corneal Klf4- and Klf5-target genes. Whole-mount corneal immunofluorescent staining was employed to examine CD45+ cell influx and neovascularization. Effect of Klf5 on expression of desmosomal components was studied by immunofluorescent staining and transient co-transfection assays. Expression of 714 and 753 genes was increased, and 299 and 210 genes decreased in PN11 and PN56 Klf5CN corneas, respectively, with 366 concordant increases and 72 concordant decreases. PN56 Klf5CN corneas shared 241 increases and 98 decreases with those previously described in Klf4CN corneas. Xenobiotic metabolism related pathways were enriched among genes decreased in Klf5CN corneas. Expression of angiogenesis and immune response-related genes was elevated, consistent with neovascularization and CD45+ cell influx in Klf5CN corneas. Expression of 1574 genes was increased and 1915 genes decreased in WT PN56 compared with PN11 corneas. Expression of ECM-associated genes decreased, while that of solute carrier family members increased in WT PN56 compared with PN11 corneas. Dsg1a, Dsg1b and Dsp were down-regulated in Klf5CN corneas and their corresponding promoter activities were stimulated by Klf5 in transient co-transfection assays. Conclusions/Significance: Differences between PN11 and PN56 corneal Klf5-target genes reveal dynamic changes in functions of Klf5 during corneal maturation. Klf5 contributes to corneal epithelial homeostasis by regulating the expression of desmosomal components. Klf4- and Klf5-target genes are largely distinct, consistent with their non-redundant roles in the mouse cornea. © 2012 Kenchegowda et al

Third Generation Effects on Fermion Mass Predictions in Supersymmetric Grand Unified Theories

Relations among fermion masses and mixing angles at the scale of grand unification are modified at lower energies by renormalization group running induced by gauge and Yukawa couplings. In supersymmetric theories, the $b$ quark and $\tau$ lepton Yukawa couplings, as well as the $t$ quark coupling, may cause significant running if $\tan \beta$, the ratio of Higgs field expectation values, is large. We present approximate analytic expressions for the scaling factors for fermion masses and CKM matrix elements induced by all three third generation Yukawa couplings. We then determine how running caused by the third generation of fermions affects the predictions arising from three possible forms for the Yukawa coupling matrices at the GUT scale: the Georgi-Jarlskog, Giudice, and Fritzsch textures.Comment: phyzzx, 26 pp., 6 figures not included, e-mailable upon request, JHU-TIPAC-93000

A televideo exercise and nutrition program for children with acute lymphoblastic leukemia in maintenance therapy: design and methods

Changes in nutrient intake and decreased exercise resulting from cancer therapies as well as their side effects may be contributing factors in the increased body weight and differences in physical fitness observed in survivors of childhood acute lymphoblastic leukemia (ALL). This article will describe the study protocol for an intervention program designed to improve the physical activity and nutrition behaviors of ALL survivors. Twenty-four children aged between 4 years and 12 years with ALL will be randomized to a 6-month technology-based exercise and nutrition program (TLC4ALLKids) or to enhanced usual care (eUC). The participants randomized to the TLC4ALLKids will participate in weekly, 1-hour coaching sessions on nutrition and physical activity and 1-hour physical activity classes delivered by group video conferencing. Participants will be provided with iPad tablets loaded with video conferencing software and the Healthy Lifestyle Tracking calendar to track daily nutrition and physical activity goals and weight. Both groups will be provided with Fitbit™ Zip to monitor physical activity. To assess feasibility, participant recruitment (achievement of proposed sample size), attendance (per weekly online sessions/assessment sessions), and adherence (number of families at 3 and 6 months) will be evaluated. Outcome measures to assess the intervention will include anthropometrics (weight, height, and waist circumference), physical activity (accelerometry), energy and macronutrient intake (food records), sleep habits (Children's Sleep Habits Questionnaire), and quality of life (Pediatric Quality of Life Inventory) will be obtained at baseline, 3 months, and 6 months. Semi-structured interviews will be used to gather information about ways to improve the program and overcome barriers to participation. If successful, the TLC4ALLKids intervention will provide a means to educate and improve the health behaviors of ALL survivors that can be delivered remotely and conveniently to participants

First Constraints on Source Counts at 350 Microns

We have imaged a $\sim$6 arcminute$^2$ region in the Bo\"otes Deep Field using the 350 $\mu$m-optimised second generation Submillimeter High Angular Resolution Camera (SHARC II), achieving a peak 1$\sigma$ sensitivity of $\sim$5 mJy. We detect three sources above 3$\sigma$, and determine a spurious source detection rate of 1.09 in our maps. In the absence of $5\sigma$ detections, we rely on deep 24 $\mu$m and 20 cm imaging to deduce which sources are most likely to be genuine, giving two real sources. From this we derive an integral source count of 0.84$^{+1.39}_{-0.61}$ sources arcmin$^{-2}$ at $S>13$ mJy, which is consistent with 350 $\mu$m source count models that have an IR-luminous galaxy population evolving with redshift. We use these constraints to consider the future for ground-based short-submillimetre surveys.Comment: accepted for publication in The Astrophysical Journa

In Quest of Educational Quality in the UAE

Quality assurance started as a corporate-related process in the 1960s but later became a highly sought-after objective in educational and academic contexts. The growing interest in quality assurance has been the result of government and business expectations, as well as competition in the higher education marketplace. One such growing market for quality assurance is the United Arab Emirates, where public formal education has only existed since the 1970s. This chapter focuses on the quest for what can be considered as the Holy Grail within the context of each of the previous chapters in this edited book, namely, quality education. The chapter offers a synopsis of the fast-paced developments and ongoing activities in quality assurance in education in the United Arab Emirates. Federal and emirate-based initiatives will be presented and discussed while reflecting on lessons learned and offering recommendations whenever possible

Centerscope

Centerscope, formerly Scope, was published by the Boston University Medical Center "to communicate the concern of the Medical Center for the development and maintenance of improved health care in contemporary society.