tbuckley/cabot-search huggingface dataset:
Apple miRNAs and tasiRNAs with novel regulatory networks
Authors: Rui Xia, Hong Zhu, Yong-qiang An, Eric P Beers, Zongrang Liu
Journal: Genome biology (2012)

Abstract Background MicroRNAs (miRNAs) and their regulatory functions have been extensively characterized in model species but whether apple has evolved similar or unique regulatory features remains unknown. Results We performed deep small RNA-seq and identified 23 conserved, 10 less-conserved and 42 apple-specific miRNAs or families with distinct expression patterns. The identified miRNAs target 118 genes representing a wide range of enzymatic and regulatory activities. Apple also conserves two TAS gene families with similar but unique trans -acting small interfering RNA (tasiRNA) biogenesis profiles and target specificities. Importantly, we found that miR159, miR828 and miR858 can collectively target up to 81 MYB genes potentially involved in diverse aspects of plant growth and development. These miRNA target sites are differentially conserved among MYB s, which is largely influenced by the location and conservation of the encoded amino acid residues in MYB factors. Finally, we found that 10 of the 19 miR828-targeted MYB s undergo small interfering RNA (siRNA) biogenesis at the 3' cleaved, highly divergent transcript regions, generating over 100 sequence-distinct siRNAs that potentially target over 70 diverse genes as confirmed by degradome analysis. Conclusions Our work identified and characterized apple miRNAs, their expression patterns, targets and regulatory functions. We also discovered that three miRNAs and the ensuing siRNAs exploit both conserved and divergent sequence features of MYB genes to initiate distinct regulatory networks targeting a multitude of genes inside and outside the MYB family.
G protein–coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice
Authors: Olivia Osborn, Da Young Oh, Joanne McNelis, Manuel Sanchez-Alavez, Saswata Talukdar, Min Lu, PingPing Li, Lucinda Thiede, Hidetaka Morinaga, Jane J. Kim, Jan Heinrichsdorff, Sarah Nalbandian, Jachelle M. Ofrecio, Miriam Scadeng, Simon Schenk, John Hadcock, Tamas Bartfai, Jerrold M. Olefsky
Journal: Journal of Clinical Investigation (2012)

Obesity-induced inflammation is a key component of systemic insulin resistance, which is a hallmark of type 2 diabetes. A major driver of this inflammation/insulin resistance syndrome is the accumulation of proinflammatory macrophages in adipose tissue and liver. We found that the orphan GPCR Gpr21 was highly expressed in the hypothalamus and macrophages of mice and that whole-body KO of this receptor led to a robust improvement in glucose tolerance and systemic insulin sensitivity and a modest lean phenotype. The improvement in insulin sensitivity in the high-fat diet-fed (HFD-fed) Gpr21 KO mouse was traced to a marked reduction in tissue inflammation caused by decreased chemotaxis of Gpr21 KO macrophages into adipose tissue and liver. Furthermore, mice lacking macrophage expression of Gpr21 were protected from HFD-induced inflammation and displayed improved insulin sensitivity. Results of in vitro chemotaxis studies in human monocytes suggested that the defect in chemotaxis observed ex vivo and in vivo in mice is also translatable to humans. Cumulatively, our data indicate that GPR21 has a critical function in coordinating macrophage proinflammatory activity in the context of obesity-induced insulin resistance.
Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes
Authors: Sarah Brice Russo, Catalin F. Baicu, An Van Laer, Tuoyu Geng, Harinath Kasiganesan, Michael R. Zile, L. Ashley Cowart
Journal: Journal of Clinical Investigation (2012)

Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de novo sphingolipid synthesis. However, it is not known whether these effects are mediated by bulk SFAs and sphingolipids or by individual lipid species. In this report, we demonstrate that a diet high in SFA induced cardiac hypertrophy, left ventricular systolic and diastolic dysfunction, and autophagy in mice. Furthermore, treatment with the SFA myristate, but not palmitate, induced hypertrophy and autophagy in adult primary cardiomyocytes. De novo sphingolipid synthesis was required for induction of all pathological features observed both in vitro and in vivo, and autophagy was required for induction of hypertrophy in vitro. Finally, we implicated a specific ceramide N-acyl chain length in this process and demonstrated a requirement for (dihydro)ceramide synthase 5 in cardiomyocyte autophagy and myristate-mediated hypertrophy. Thus, this report reveals a requirement for a specific sphingolipid metabolic route and dietary SFAs in the molecular pathogenesis of lipotoxic cardiomyopathy and hypertrophy.
Staphylococcus aureus spa type t437: identification of the most dominant community-associated clone from Asia across Europe
Authors: C. Glasner, G. Pluister, H. Westh, J.P. Arends, J. Empel, E. Giles, F. Laurent, F. Layer, L. Marstein, A. Matussek, A. Mellmann, M. Pérez-Vásquez, E. Ungvári, X. Yan, H. Žemličková, H. Grundmann, J.M. van Dijl
Journal: Clinical Microbiology and Infection (2014)

<h2>Abstract</h2> Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) belonging to the multilocus sequence type clonal complex 59 (MLST CC59) is the predominant community-associated MRSA clone in Asia. This clone, which is primarily linked with the <i>spa</i> type t437, has so far only been reported in low numbers among large epidemiological studies in Europe. Nevertheless, the overall numbers identified in some Northern European reference laboratories have increased during the past decade. To determine whether the <i>S. aureus</i> t437 clone is present in other European countries, and to assess its genetic diversity across Europe, we analysed 147 <i>S. aureus</i> t437 isolates from 11 European countries collected over a period of 11 years using multiple locus variable number tandem repeat fingerprinting/analysis (MLVF/MLVA) and MLST. Additionally 16 <i>S. aureus</i> t437 isolates from healthy carriers and patients from China were included. Most isolates were shown to be monophyletic with 98% of the isolates belonging to the single MLVA complex 621, to which nearly all included isolates from China also belonged. More importantly, all MLST-typed isolates belonged to CC59. Our study implies that the European <i>S. aureus</i> t437 population represents a genetically tight cluster, irrespective of the year, country and site of isolation. This underpins the view that <i>S. aureus</i> CC59 has been introduced into several European countries, not being restricted to particular geographical regions or specific host environments. The European <i>S. aureus</i> t437 isolates thus bear the general hallmarks of a high-risk clone.
Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a <i>Phellodendron Amurense</i> Bark Extract
Authors: Addanki P. Kumar, Shylesh Bhaskaran, Manonmani Ganapathy, Katherine Crosby, Michael D. Davis, Peter Kochunov, John Schoolfield, I-Tien Yeh, Dean A. Troyer, Rita Ghosh
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Development of prostate cancer prevention strategies is an important priority to overcome high incidence, morbidity, and mortality. Recently, we showed that Nexrutine, an herbal extract, inhibits prostate cancer cell proliferation through modulation of Akt and cAMP-responsive element binding protein (CREB)–mediated signaling pathways. However, it is unknown if Nexrutine can be developed as a dietary supplement for the prevention of prostate cancer. In this study, we used the transgenic adenocarcinoma of mouse prostate (TRAMP) model to examine the ability of Nexrutine to protect TRAMP mice from developing prostate cancer. Experimental Design: Eight-week-old TRAMP mice were fed with pelleted diet containing 300 and 600 mg/kg Nexrutine for 20 weeks. Efficacy of Nexrutine was evaluated by magnetic resonance imaging at 18 and 28 weeks of progression and histologic analysis of prostate tumor or tissue at the termination of the experiment. Tumor tissue was analyzed for modulation of various signaling molecules. Results: We show that Nexrutine significantly suppressed palpable tumors and progression of cancer in the TRAMP model. Expression of total and phosphorylated Akt, CREB, and cyclin D1 was significantly reduced in prostate tissue from Nexrutine intervention group compared with tumors from control animals. Nexrutine also inhibited cyclin D1 transcriptional activity in androgen-independent PC-3 cells. Overexpression of kinase dead Akt mutant or phosphorylation-defective CREB inhibited cyclin D1 transcriptional activity. Conclusions: The current study shows that Nexrutine-mediated targeting of Akt/CREB–induced activation of cyclin D1 prevents the progression of prostate cancer. Expression of CREB and phosphorylated CREB increased in human prostate tumors compared with normal tissue, suggesting their potential use as prognostic markers.
Reply to C. Twelves et al
Authors: Ann H. Partridge, R. Bryan Rumble, Ian E. Smith
Journal: Journal of Clinical Oncology (2015)

We would like to thank Twelves et al for their insightful comments regarding the recently published American Society of Clinical Oncology clinical practice guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2–negative (or unknown) advanced breast cancer. We agree with the distinction drawn between treatment of physician’s choice (TPC) and best supportive care, and we agree that TPC should be considered an appropriate active control arm. The challenge in determining the appropriate category into which to place trials with a TPC arm is that, potentially, TPC could also include options like combination treatment, best supportive care, or observation alone. We tried to eliminate any confusion concerning which trials made comparisons against a control versus best supportive care or observation alone in the Results section and in the descriptions of the trials.
Plasma from human mothers of fetuses with severe arthrogryposis multiplex congenita causes deformities in mice
Authors: Leslie Jacobson, Agata Polizzi, Gillian Morriss-Kay, Angela Vincent
Journal: Journal of Clinical Investigation (1999)

Arthrogryposis multiplex congenita (AMC) is characterized by fixed joint contractures and other deformities, sometimes resulting in fetal death. The cause is unknown in most cases, but some women with fetuses affected by severe AMC have serum antibodies that inhibit fetal acetylcholine receptor (AChR) function, and antibodies to fetal antigens might play a pathogenic role in other congenital disorders. To investigate this possibility, we have established a model by injecting pregnant mice with plasma from four anti-AChR antibody–positive women whose fetuses had severe AMC. We found that human antibodies can be transferred efficiently to the mouse fetus during the last few days of fetal life. Many of the fetuses of dams injected with AMC maternal plasmas or Ig were stillborn and showed fixed joints and other deformities. Moreover, similar changes were found in mice after injection of a serum from one anti-AChR antibody–negative mother who had had four AMC fetuses. Thus, we have confirmed the role of maternal antibodies in cases of AMC associated with maternal anti-AChR, and we have demonstrated the existence of pathogenic maternal factors in one other case. Importantly, this approach can be used to look at the effects of other maternal human antibodies on development of the fetus.
Meta-analysis of primary target genes of peroxisome proliferator-activated receptors
Authors: Merja Heinäniemi, J Oskari Uski, Tatjana Degenhardt, Carsten Carlberg
Journal: Genome biology (2007)

Peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the development of diseases, such as obesity, cardiovascular disease, type 2 diabetes and cancer. Here, an in silico screening method is presented, which incorporates experiment- and informatics-derived evidence, such as DNA-binding data of PPAR subtypes to a panel of PPAR response elements (PPREs), PPRE location relative to the transcription start site (TSS) and PPRE conservation across multiple species, for more reliable prediction of PPREs.In vitro binding and in vivo functionality evidence agrees with in silico predictions, validating the approach. The experimental analysis of 30 putative PPREs in eight validated PPAR target genes indicates that each gene contains at least one functional, strong PPRE that occurs without positional bias relative to the TSS. An extended analysis of the cross-species conservation of PPREs reveals limited conservation of PPRE patterns, although PPAR target genes typically contain strong or multiple medium strength PPREs. Human chromosome 19 was screened using this method, with validation of six novel PPAR target genes.An in silico screening approach is presented, which allows increased sensitivity of PPAR binding site and target gene detection.
Medical management of Crohn’s disease
Authors: J R Fraser Cummings, Satish Keshav, Simon P L Travis
Journal: BMJ (2008)

#### Summary points

Crohn’s disease is a chronic, relapsing and remitting inflammatory condition of the gastrointestinal tract. Treatment has changed radically over the past decade with the introduction of biological therapy and increased use of immunomodulators. Awareness of the therapeutic potential and associated adverse events is necessary both for offering benefit and for protecting patients from undue risks from these treatments.

The median population incidence of the disease is 6.7 (range 1.6 to 14.6) cases per 100 000 annually and prevalence is 140 (10-199) cases per 100 000 in the West.1 About 690 000 people in Europe, including about 90 000 people in the United Kingdom, have the disease, with estimated healthcare costs of €3.04bn (£2.4bn; $4.8bn) and £300m a year respectively.2

The disease presents at any age, although usually at age 16-30 years; it has a disproportionate effect on economically active individuals. Common presenting symptoms include diarrhoea, abdominal pain, weight loss, and fatigue. The disease is characterised by transmural intestinal inflammation, with occasional extraintestinal features such as …
Association Between Serum Ferritin, Hemoglobin, Iron Intake, and Diabetes in Adults in Jiangsu, China
Authors: Zumin Shi, Xiaoshu Hu, Baojun Yuan, Xiaoqun Pan, Haakon E. Meyer, Gerd Holmboe-Ottesen
Journal: Diabetes Care (2006)

To investigate the association between iron status, iron intake, and diabetes among Chinese adults.This cross-sectional household survey was carried out in 2002 in Jiangsu Province, China. The sample contained 2,849 men and women aged > or =20 years with a response rate of 89.0%. Iron intake was assessed by food weighing plus consecutive individual 3-day food records. Fasting plasma glucose (FPG), serum ferritin, and hemoglobin were measured.The prevalence of anemia was 18.3% in men and 31.5% in women. Mean hemoglobin and serum ferritin increased across groups with increasing FPG. The prevalence of anemia among women was 15.0% in individuals with FPG >7.0 mmol/l compared with 32.6% in individuals with FPG <5.6 mmol/l. There was a similar, however not significant, trend among men. In women, after adjusting for known risk factors, the odds ratio (OR) of diabetes was 2.15 (95% CI 1.03-4.51) for subjects in the upper quartile of hemoglobin compared with the rest, and the corresponding OR for the upper quartile of serum ferritin was 3.79 (1.72-8.36). Iron intake was positively associated with diabetes in women; fourth quartile intake of iron yielded an OR of 5.53 (1.47-20.44) compared with the first quartile in the multivariate analyses. In men, similar trends were suggested, although they were not statistically significant.Iron status and iron intake was independently associated with risk of diabetes in Chinese women but not in men.
P176 GWAS IDENTIFIES NOVEL SUSCEPTIBILITY LOCI ON CHR4Q28.1 FOR PROGNOSIS OF HEPATITIS B VIRUS RELATED HEPATOCELLULAR CARCINOMA
Authors: N.H. Park, S.W. Jung, J.W. Shin, B.R. Park, C.J. Kim, J.E. Lee, E.S. Shin, J.A. Kim, Y.H. Chung
Journal: Journal of Hepatology (2014)
Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas
Authors: MJ van den Bent, JS Wefel, D Schiff, MJB Taphoorn, K Jaeckle, L Junck, T Armstrong, A Choucair, AD Waldman, T Gorlia, M Chamberlain, BG Baumert, MA Vogelbaum, DR Macdonald, DA Reardon, PY Wen, SM Chang, AH Jacobs
Journal: The Lancet Oncology (2011)
Measurement of the stiffness of endoscopes---a plea for commonality
Authors: G D BELL
Journal: Gut (2001)

Editor,—In a previous issue ((2000) Gut 46:801–8.[OpenUrl][1][PubMed][2]), Brooker and colleagues described their experience with an exciting new variable stiffness colonoscope. They made the point that a stiffer colonoscope shaft reduces recurrent looping but makes passage through an angulated sigmoid more difficult and causes more stretching and hence pain when loops do occur. Conversely, the more flexible thinner paediatric instruments are better for negotiating a fixed or narrow sigmoid colon but then tend to allow recurrent loop formation later in the procedure. Their randomised trial using either a standard Olympus CF200HL (13.3 mm shaft diameter) or a prototype (Olympus XCF-SH230L—12.9 mm shaft diameter) variable stiffness colonoscope looked very promising although in one case a paediatric Olympus PCF230I (11.3 mm shaft diameter) was required … [1]: {openurl}?query=rft.jtitle%253DMedical%2B%2526%2Bbiological%2Bengineering%2B%2526%2Bcomputing%26rft.stitle%253DMed%2BBiol%2BEng%2BComput%26rft.aulast%253DWehrmeyer%26rft.auinit1%253DJ.%2BA.%26rft.volume%253D36%26rft.issue%253D4%26rft.spage%253D475%26rft.epage%253D479%26rft.atitle%253DColonoscope%2Bflexural%2Brigidity%2Bmeasurement.%26rft_id%253Dinfo%253Apmid%252F10198532%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10198532&link_type=MED&atom=%2Fgutjnl%2F49%2F1%2F154.1.atom
Reducing the exome search space for Mendelian diseases using genetic linkage analysis of exome genotypes
Authors: Katherine R Smith, Catherine J Bromhead, Michael S Hildebrand, A Eliot Shearer, Paul J Lockhart, Hossein Najmabadi, Richard J Leventer, George McGillivray, David J Amor, Richard J Smith, Melanie Bahlo
Journal: Genome biology (2011)

Many exome sequencing studies of Mendelian disorders fail to optimally exploit family information. Classical genetic linkage analysis is an effective method for eliminating a large fraction of the candidate causal variants discovered, even in small families that lack a unique linkage peak. We demonstrate that accurate genetic linkage mapping can be performed using SNP genotypes extracted from exome data, removing the need for separate array-based genotyping. We provide software to facilitate such analyses.
The canalicular bile salt exporting protein BSEP is not expressed in patients with progressive familial intrahepatic cholestasis type 2.
Authors: P Jansen, Etienne Sokal, G Hooiveld, E Jacquemin, H van Goor, J Koning, F Kuipers, F Stellaard, M. Hadchouel, M. Muller
Journal: Hepatology (1998)
T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells
Authors: Linda Fahlén, Simon Read, Leonid Gorelik, Stephen D. Hurst, Robert L. Coffman, Richard A. Flavell, Fiona Powrie
Journal: The Journal of Experimental Medicine (2005)

CD4+CD25+ regulatory T (T reg) cells play a pivotal role in control of the immune response. Transforming growth factor-β (TGF-β) has been shown to be required for T reg cell activity; however, precisely how it is involved in the mechanism of suppression is poorly understood. Using the T cell transfer model of colitis, we show here that CD4+CD45RBhigh T cells that express a dominant negative TGF-β receptor type II (dnTβRII) and therefore cannot respond to TGF-β, escape control by T reg cells in vivo. CD4+CD25+ T reg cells from the thymus of dnTβRII mice retain the ability to inhibit colitis, suggesting that T cell responsiveness to TGF-β is not required for the development or peripheral function of thymic-derived T reg cells. In contrast, T reg cell activity among the peripheral dnTβRII CD4+CD25+ population is masked by the presence of colitogenic effector cells that cannot be suppressed. Finally, we show that CD4+CD25+ T reg cells develop normally in the absence of TGF-β1 and retain the ability to suppress colitis in vivo. Importantly, the function of TGF-β1−/− T reg cells was abrogated by anti–TGF-β monoclonal antibody, indicating that functional TGF-β can be provided by a non–T reg cell source.
Upregulation of class I major histocompatibility complex gene expression in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo.
Authors: R A Pereira, D C Tscharke, A Simmons
Journal: The Journal of Experimental Medicine (1994)

Major histocompatibility complex (MHC) deficiency is typical of almost all resident cells in normal neural tissue. However, CD8+ T cells, which recognize antigenic peptides in the context of class I MHC molecules, are known to mediate clearance of herpes simplex virus (HSV) from spinal ganglia of experimentally infected mice, leading to the hypothesis that class I expression in the peripheral nervous system must be upregulated in response to HSV infection. In addressing this hypothesis it is shown, in BALB/c (H-2d) mice, that normally deficient class I transcripts transiently accumulate in peripheral nerve Schwann cells, ganglionic satellite cells, and primary sensory neurons, indicating that in each of these cell types class I expression is regulated at the transcriptional level in vivo. Furthermore, for 3-4 wk after infection, H-2Kd/Dd antigens are expressed by satellite and Schwann cells but not neurons, suggesting additional posttranscriptional regulation of class I synthesis in neurons. Alternatively, the class I RNAs induced in neurons may not be derived from classical class I genes. Factors regulating H-2 class I expression emanate from within infected ganglia, probably from infected neurons themselves. However, induction of class I molecules was not maintained during latency, when viral gene expression in neurons is restricted to a single region within the virus repeats. These data have implications for the long-term survival of cells in HSV-infected neural tissue.