tbuckley/cabot-search huggingface dataset:
Localization of Olfactomedin-Related Glycoprotein Isoform (BMZ) in the Golgi Apparatus of Glomerular Podocytes in Rat Kidneys
Authors: DAISUKE KONDO, TADASHI YAMAMOTO, EISHIN YAOITA, PATRIA E. DANIELSON, HIDEYUKI KOBAYASHI, KAZUFUMI OHSHIRO, HARUKO FUNAKI, YU KOYAMA, HIDEHIKO FUJINAKA, KATSUTOSHI KAWASAKI, J. GREGOR SUTCLIFFE, MASAAKI ARAKAWA, ITARU KIHARA
Journal: Journal of the American Society of Nephrology (2000)

Abstract. A gene encoding olfactomedin-related glycoprotein was isolated from rat glomerulus despite its prior identification as a neuron-specific gene. The mRNA expression was remarkably intense in renal glomerulus and brain and faint in the lung and eye among rat systemic organs. Although the brain contained four mRNA variants (AMY, AMZ, BMY, and BMZ) transcribed from a single gene, the glomerulus, lung, and eye expressed only two variants (BMZ and BMY). The glycoprotein was intensely immunolocalized in glomerular podocytes and neurons by using an antibody against synthetic peptide of the M region, but weak in endothelial cells of the kidney and lung. Bronchiolar epithelial cells in the lung, and ciliary, corneal, and iris epithelial cells in the eye were also stained. Immunogold electron microscopy revealed selective localization of olfactomedin-related glycoprotein at the Golgi apparatus in podocytes. In glomerular culture, the staining was also intense at a juxtanuclear region in synaptopodin-positive epithelial cells of irregular shape (phenotypic feature of podocytes), whereas it was weak in synaptopodin-negative ones of cobblestone-like appearance (phenotypic feature of parietal epithelial cells of Bowman's capsule). Interestingly, Western blot analysis identified an intense band corresponding to BMZ isoform and another faint band corresponding to BMY isoform in the glomerulus, whereas the intensity of these two bands were nearly equal in the lung and eye. In the brain, four bands corresponding to four isoforms were observed apparently. Computer sequence analysis predicted coiled-coil structures in the secondary structure of the glycoprotein similar to those in Golgi autoantigens, suggesting significant roles in the unique functions of the Golgi apparatus in rat podocytes and neurons.
Elf-1 Contributes to the Function of the Complex Interleukin (IL)-2–responsive Enhancer in the Mouse IL-2 Receptor α Gene
Authors: Irina Serdobova, Maria Pla, Patrick Reichenbach, Peter Sperisen, Jacques Ghysdael, Anne Wilson, Jonathan Freeman, Markus Nabholz
Journal: The Journal of Experimental Medicine (1997)

Lymphocytes regulate their responsiveness to IL-2 through the transcriptional control of the IL-2Rα gene, which encodes a component of the high affinity IL-2 receptor. In the mouse IL-2Rα gene this control is exerted via two regulatable elements, a promoter proximal region, and an IL-2–responsive enhancer (IL-2rE) 1.3 kb upstream. In vitro and in vivo functional analysis of the IL-2rE in the rodent thymic lymphoma-derived, CD4−CD8− cell line PC60 demonstrated that three separate elements, sites I, II, and III, were necessary for IL-2 responsiveness; these three sites demonstrate functional cooperation. Site III contains a consensus binding motif for members of the Ets family of transcription factors. Here we demonstrate that Elf-1, an Ets-like protein, binds to site III and participates in IL-2 responsiveness. In vitro site III forms a complex with a protein constitutively present in nuclear extracts from PC60 cells as well as from normal CD4−CD8− thymocytes. We have identified this molecule as Elf-1 according to a number of criteria. The complex possesses an identical electrophoretic mobility to that formed by recombinant Elf-1 protein and is super-shifted by anti–Elf-1 antibodies. Biotinylated IL-2rE probes precipitate Elf-1 from PC60 extracts provided site III is intact and both recombinant and PC60-derived proteins bind with the same relative affinities to different mutants of site III. In addition, by introducing mutations into the core of the site III Ets-like motif and comparing the corresponding effects on the in vitro binding of Elf-1 and the in vivo IL-2rE activity, we provide strong evidence that Elf-1 is directly involved in IL-2 responsiveness. The nature of the functional cooperativity observed between Elf-1 and the factors binding sites I and II remains unresolved; experiments presented here however suggest that this effect may not require direct interactions between the proteins binding these three elements.
Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas
Authors: Camilla Pilati, Mohamed Amessou, Michel P. Bihl, Charles Balabaud, Jeanne Tran Van Nhieu, Valérie Paradis, Jean Charles Nault, Tina Izard, Paulette Bioulac-Sage, Gabrielle Couchy, Karine Poussin, Jessica Zucman-Rossi
Journal: The Journal of Experimental Medicine (2011)

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.
A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages
Authors: Maëlle Carraz, Akino Jossang, Jean-François Franetich, Anthony Siau, Liliane Ciceron, Laurent Hannoun, Robert Sauerwein, François Frappier, Philippe Rasoanaivo, Georges Snounou, Dominique Mazier
Journal: PLoS Medicine (2006)

The global spread of multidrug-resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s.Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 muM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 muM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 muM, TI 46, and IC50 42.4 muM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages.A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.
Experiences, Views, and Support Needs of Family Members of People With Hypoglycemia Unawareness: Interview Study
Authors: Julia Lawton, David Rankin, Jackie Elliott, Simon R. Heller, Helen A. Rogers, Nicole De Zoysa, Stephanie Amiel
Journal: Diabetes Care (2013)

OBJECTIVE Hypoglycemia unawareness (HU) affects ∼25% of people with type 1 diabetes. People with HU are often reliant on family to detect hypoglycemia and treat severe episodes. We explored the impact of HU on family members’ lives, their involvement in preventing and managing hypoglycemia, and their information and support needs. RESEARCH DESIGN AND METHODS This study employed an exploratory, qualitative design comprising in-depth interviews with 24 adult family members of persons with type 1 diabetes and HU. RESULTS Family members described restricting their lives so that they could help the person with HU detect and treat hypoglycemia. Some described being very physically afraid of their partner/relative when they had a hypoglycemic episode due to their aggressive and argumentative behavior and personality changes; this could also make treatment administration difficult. Family members also reported feeling anxious and worried about the safety of the person with HU, particularly when they were left unsupervised. These concerns were often precipitated by traumatic events, such as discovering the person with HU in a coma. Family members could neglect their own health and well-being to care for the person with HU and resentment could build up over time. Family members highlighted extensive, unmet needs for information and emotional support; however, some struggled to recognize and accept their own need for help. CONCLUSIONS Our findings reveal a caregiver group currently “in the shadow of the patient” and in urgent need of information and emotional support. Raising awareness among health care professionals is essential, and developing proactive support for family should be considered.
Oesophageal hiatus hernia in three generations of one family
Authors: I. J. Carre, P. Froggatt
Journal: Gut (1970)

A family is described in which eight members in three successive generations had a sliding type of oesophageal hiatus hernia (or partial thoracic stomach) as a sole anomaly. The trait in this family behaved as a strict dominant, manifesting the segregation of a single abnormal autosomal gene. Other possible aetiologies are discussed but considered unlikely.
Increased susceptibility to thiazide-induced hyponatremia in the elderly.
Authors: B A Clark, R P Shannon, R M Rosa, F H Epstein
Journal: Journal of the American Society of Nephrology (1994)

Hyponatremia is a common cause of morbidity in the elderly, and thiazide diuretics are often implicated. Eleven healthy young volunteers, eight healthy old volunteers, and five elderly patients with a history of thiazide-induced hyponatremia were studied to determine susceptibility to thiazide-induced hypoosmolality in age. Each of the healthy subjects ingested a water load (20 mL/kg) after 3 days of hydrochlorothiazide (HCTZ) (100 mg/day) or placebo. Although there were no differences in minimum Uosm between young and old, the healthy old had lower hourly free water clearances (CH2O) as compared with the young and a greater decline in serum osmolality in response to water loading (P < 0.05). HCTZ impaired minimum urine osmolality and CH2O and delayed recovery of serum osmolality after the water load in both healthy young and old (P < 0.005, placebo versus HCTZ), but the impairment in the latter two parameters was greater in the healthy elderly (P < 0.05, young versus old). Vasopressin levels were not different between healthy young and old (1.9 +/- 0.3 versus 2.0 +/- 1.0 pm with placebo; 3.0 +/- 0.7 versus 4.4 +/- 1.0 with HCTZ). Five of the young subjects were restudied after the addition of ibuprofen (400 mg thrice daily) to the thiazide and placebo regimens. Creatinine clearance was not changed, but free water clearance and serum osmolality after water loading were significantly reduced to a degree similar to that seen in the elderly subjects on the thiazide regimen (P < 0.05), suggesting an important role for renal prostaglandins in the defense against hyponatremia.
Quantitative Proteomics Analysis Identifies Mitochondria as Therapeutic Targets of Multidrug-Resistance in Ovarian Cancer
Authors: Xiulan Chen, Shasha Wei, Ying Ma, Jie Lu, Gang Niu, Yanhong Xue, Xiaoyuan Chen, Fuquan Yang
Journal: Theranostics (2014)

Doxorubicin is a widely used chemotherapeutic agent for the treatment of a variety of solid tumors.However, resistance to this anticancer drug is a major obstacle to the effective treatment of tumors.As mitochondria play important roles in cell life and death, we anticipate that mitochondria may be related to drug resistance.Here, stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic strategy was applied to compare mitochondrial protein expression in doxorubicin sensitive OVCAR8 cells and its doxorubicin-resistant variant NCI_ADR/RES cells.A total of 2085 proteins were quantified, of which 122 proteins displayed significant changes in the NCI_ADR/RES cells.These proteins participated in a variety of cell processes including cell apoptosis, substance metabolism, transport, detoxification and drug metabolism.Then qRT-PCR and western blot were applied to validate the differentially expressed proteins quantified by SILAC.Further functional studies with RNAi demonstrated TOP1MT, a mitochondrial protein participated in DNA repair, was involved in doxorubicin resistance in NCI_ADR/RES cells.Besides the proteomic study, electron microscopy and fluorescence analysis also observed that mitochondrial morphology and localization were greatly altered in NCI_ADR/RES cells.Mitochondrial membrane potential was also decreased in NCI_ADR/RES cells.All these results indicate that mitochondrial function is impaired in doxorubicin-resistant cells and mitochondria play an important role in doxorubicin resistance.This research provides some new information about doxorubicin resistance, indicating that mitochondria could be therapeutic targets of doxorubicin resistance in ovarian cancer cells.
Lymphocytes bearing Fc gamma receptors in rheumatoid arthritis. IV. Increased numbers and activation of Facb-R+ cells after immunisation of healthy individuals.
Authors: N.J Goulding, L.J Eales, N.D Hall
Journal: Annals of the Rheumatic Diseases (1986)

Mononuclear cells expressing Fc gamma receptors that form Facb rosettes are increased in the peripheral blood of patients with rheumatoid arthritis compared with controls. Healthy individuals with a positive skin response to tuberculin showed a marked increase in numbers of circulating Facb-R+ cells three days after challenge, returning to baseline after seven days. No response was observed in subjects showing a negative skin test. A similar increase in Facb-R+ cell numbers was measured after intramuscular injection of another specific antigen, tetanus toxoid. In addition to this enhancement of Facb-R+ cell numbers, evidence has been obtained that these cells are in an activated state postimmunisation as judged by acquisition of low density and increased expression of class II MHC antigens. Apparently identical changes in Facb-R+ cell numbers and activation may be induced in vitro either by culturing sensitised mononuclear cells with specific antigen for three days or by an overnight incubation of normal cells with gamma-interferon (gamma-IFN). By analogy, therefore, the increased numbers of Facb-R+ cells in patients with rheumatoid arthritis are probably induced by gamma-interferon generated as part of an antigen driven immune response. In this context it is interesting that patients with Felty's syndrome, in whom neutropenia increases susceptibility to infections leading to the possibility of further stimulation of the immune system by micro-organisms, have particularly high levels of circulating Facb-R+ cells.
Adrenergic Stimulation of Renin Secretion in the Isolated Perfused Rat Kidney
Authors: ROBERT VANDONGEN, W. STANLEY PEART, GRAHAME W. BOYD
Journal: Circulation Research (1973)

To avoid complicating systemic effects, the influence of adrenergic hormones on renin secretion was examined in the isolated rat kidney perfused with Krebs-dextran solution at a constant mean pressure and flow rate. Isoproterenol and glucagon produced a consistent increase in renin secretion without a change in perfusion pressure and flow. Similarly the increase in renin secretion with norepinephrine, which was associated with intense vasoconstriction and raised perfusion pressure, was still observed after the vasoconstrictive effect was abolished with phenoxybenzamine. Isoproterenol- stimulated renin secretion, unaffected by phenoxybenzamine, was markedly suppressed by dl -propranolol but not by d -propranolol. The failure of dl -propranolol to suppress the renin response to glucagon confirms observations in other tissues and suggests involvement of other receptors or alternative mechanisms. These findings support a direct intrarenal effect of adrenergic hormones on renin secretion, and this effect may be mediated specifically by beta receptors in the case of catecholamines.
Strictures in Crohn’s disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin
Authors: C M Gelbmann, S Mestermann, V Gross, M Köllinger, J Schölmerich, W Falk
Journal: Gut (1999)

BACKGROUND/AIMS Intestinal fibrosis and stricture formation is an unresolved problem in Crohn’s disease. The aim of this study was to investigate whether mast cells accumulate in these tissues and whether their localisation is associated with extracellular matrix components. METHODS Mast cells were visualised by immunohistochemical staining of the mast cell specific proteases chymase and tryptase. Their localisation in relation to extracellular matrix components was shown by immunohistochemical double labelling. RESULTS In strictures in Crohn’s disease, a striking accumulation of mast cells was seen particularly in the hypertrophied and fibrotic muscularis propria, with a mean (SEM) mast cell number of 81.3 (14.9) v 1.5 (0.9)/mm 2 in normal bowel (p&lt;0.0005). All mast cells in the muscularis propria were colocalised with patches of laminin. In contrast, in the submucosa, laminin was exclusively found in the basal lamina of blood vessels where many adherent mast cells were seen. No colocalisation of mast cells was found with fibronectin or vitronectin. CONCLUSIONS The large accumulation of mast cells in the muscle layer of strictured bowel suggests a functional role for these cells in the hypertrophic and fibrotic response of the smooth muscle cells. The colocalisation with laminin indicates a mechanism of interaction between smooth muscle cells and mast cells that may be important in the role of mast cells in the process of fibrosis.
Multimodal Functional Neuroimaging: Integrating Functional MRI and EEG/MEG
Authors: Bin He, Zhongming Liu
Journal: IEEE Reviews in Biomedical Engineering (2008)

Noninvasive functional neuroimaging, as an important tool for basic neuroscience research and clinical diagnosis, continues to face the need of improving the spatial and temporal resolution. While existing neuroimaging modalities might approach their limits in imaging capability mostly due to fundamental as well as technical reasons, it becomes increasingly attractive to integrate multiple complementary modalities in an attempt to significantly enhance the spatiotemporal resolution that cannot be achieved by any modality individually. Electrophysiological and hemodynamic/metabolic signals reflect distinct but closely coupled aspects of the underlying neural activity. Combining fMRI and EEG/MEG data allows us to study brain function from different perspectives. In this review, we start with an overview of the physiological origins of EEG/MEG and fMRI, as well as their fundamental biophysics and imaging principles, we proceed with a review of the major advances in the understanding and modeling of neurovascular coupling and in the methodologies for the fMRI-EEG/MEG simultaneous recording. Finally, we summarize important remaining issues and perspectives concerning multimodal functional neuroimaging, including brain connectivity imaging.
THE ENZYMATIC NATURE OF C'1r
Authors: George B. Naff, Oscar D. Ratnoff
Journal: The Journal of Experimental Medicine (1968)

Human C'1, a macromolecular complex composed of three subunits, is the zymogen for at least two distinct enzymes. Preparations of one subunit, C'1r, functioned as a protease which converted another subunit, C'1s, to C'1 esterase. The conversion of C'1s to C'1 esterase by C'1r was blocked by Liquoid, phenyl methylsulfonyl fluoride, and calcium ions, but not by soybean trypsin inhibitor, hirudin, or heparin. Preparations of C'1r also possessed two additional functions, i.e., the ability to hydrolyze certain synthetic amino acid esters and to participate in immune hemolysis. Evidence was presented which indicates that these three functions are properties of a single entity, C'1r, but not of the same portion of its molecular structure. These observations suggest that C'1r has at least two active sites, one for its reaction with C'1q, an additional subunit of C'1, and one for its reaction with C'1s; together, the three subcomponents, C'1q, C'1r, and C'1s, form a single functional unit, the first component of complement.
Relevance of JAK2V617F positivity to hematological diseases - survey of samples from a clinical genetics laboratory
Authors: Wanming Zhao, Rufei Gao, Jiyun Lee, Shu Xing, Wanting T Ho, Xueqi Fu, Shibo Li, Zhizhuang J Zhao
Journal: Journal of Hematology & Oncology (2011)

JAK2V617F is found in the majority of patients with Ph- myeloproliferative neoplasms (MPNs) and has become a valuable marker for diagnosis of MPNs. However, it has also been found in many other hematological diseases, and some studies even detected the presence of JAK2V617F in normal blood samples. This casts doubt on the primary role of JAK2V617F in the pathogenesis of MPNs and its diagnostic value. In the present study, we analyzed JAK2V617F positivity with 232 normal blood samples and 2663 patient blood, bone marrow, and amniotic fluid specimens obtained from a clinical genetics laboratory by using a simple DNA extraction method and a sensitive nested allele-specific PCR strategy. We found JAK2V617F present in the majority (78%) of MPN patients and in a small fraction (1.8-8.7%) of patients with other specific hematological diseases but not at all in normal healthy donors or patients with non-hematological diseases. We also revealed associations of JAK2V617F with novel as well as known chromosomal abnormalities. Our study suggests that JAK2V617F positivity is associated with specific hematological malignancies and is an excellent diagnostic marker for MPNs. The data also indicate that the nested allele-specific PCR method provides clinically relevant information and should be conducted for all cases suspected of having MPNs as well as for other related diseases.