tbuckley/cabot-search huggingface dataset:
Independent Birth of a Novel TRIMCyp in Tupaia belangeri with a Divergent Function from Its Paralog TRIM5
Authors: Dan Mu, Hui Yang, Jia-Wu Zhu, Feng-Liang Liu, Ren-Rong Tian, Hong-Yi Zheng, Jian-Bao Han, Peng Shi, Yong-Tang Zheng
Journal: Molecular Biology and Evolution (2014)

The origin of novel genes and their evolutionary fates are long-standing questions in evolutionary biology. These questions become more complicated for genes conserved across various lineages, such as TRIM5, an antiretroviral restriction factor and a retrovirus capsid sensor in immune signaling. TRIM5 has been subjected to numerous pathogenic challenges and undergone dynamic evolution, making it an excellent example for studying gene diversification. Previous studies among several species showed that TRIM5 gained genetic and functional novelty in a lineage-specific manner, either through gene duplication or a cyclophilin A retrotransposing into the TRIM5 locus, creating the gene fusion known as TRIM5-Cyclophilin A (TRIMCyp). To date, the general pattern of TRIM5 across the mammalian lineage remains elusive. In this study, we surveyed 36 mammalian genomes to verify a potentially novel TRIM5 pattern that uniquely seems to have occurred in tree shrews (Tupaia belangeri), and found that both gene duplication and retrotransposition worked jointly to form a specific TRIM5/TRIMCyp cluster not found among other mammals. Evolutionary analyses showed that tree shrew TRIMCyp (tsTRIMCyp) originated independently in comparison with previously reported TRIMCyps and underwent strong positive selection, whereas no signal of positive selection was detected for other tree shrew TRIM5 (tsTRIM5) genes. Functional assay results suggest a functional divergence between tsTRIMCyp and its closest paralog TRIM5-4, likely reflecting different fates under diverse evolutionary forces. These findings present a rare example of novel gene origination resulting from a combination of gene duplication, retrotransposition, and exon shuffling processes, providing a new paradigm to study genetic innovations and evolutionary fates of duplicated genes.
Complement 5a Receptor Inhibition Improves Renal Allograft Survival
Authors: Faikah Gueler, Song Rong, Wilfried Gwinner, Michael Mengel, Verena Bröcker, Sylvia Schön, Tim Friedrich Greten, Heiko Hawlisch, Thomas Polakowski, Karsten Schnatbaum, Jan Menne, Hermann Haller, Nelli Shushakova
Journal: Journal of the American Society of Nephrology (2008)

Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.
Weight loss pressure on a 5 year old wrestler
Authors: R A Sansone, R Sawyer
Journal: British Journal of Sports Medicine (2004)

The case is reported of a 5 year old boy who was pressured to lose weight in order to wrestle at a lower weight class. Although a minority of athletes engage in unhealthy weight management practices, this is an unusual case because of the age of the athlete and the influential role of a parent.
Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma
Authors: S Tanaka
Journal: Gut (2005)

<b>Background and aims:</b> Cyclooxygenase 2 (COX-2) expression in subepithelial macrophages of colorectal adenoma has been suggested as the first in a series of steps leading to colorectal tumorigenesis. We tested the hypothesis that chemokines released from human colorectal adenoma epithelium might be involved in COX-2 expression in macrophages of the lamina propria. <b>Methods:</b> Endoscopic samples of sporadic colorectal adenomas were tested by enzyme linked immunosorbent assay for chemokines involved in macrophage chemotaxis. Localisation of adenoma macrophage chemoattractant protein 1 (MCP-1) and COX-2 were determined by immunohistochemistry. The effects of MCP-1, in the presence or absence of celecoxib, on COX-2 expression, and prostaglandin (PG) E<sub>2</sub> and vascular endothelial growth factor (VEGF) release, were examined in human macrophages isolated from peripheral blood. <b>Results:</b> MCP-1 levels were markedly higher in adenoma with mild-moderate dysplasia (129.7 (19.9) pg/mg protein) and severe dysplasia (227.9 (35.4) pg/mg protein) than in normal colonic mucosa (55.8 (4.2) pg/mg protein). Other chemokine levels, macrophage inflammatory proteins (MIP)-1α and MIP-1β, and the chemokine regulated on activation of normal T cell expressed and secreted (RANTES) did not vary significantly between adenoma and normal mucosa. MCP-1 levels in both adenoma and normal colonic mucosa increased significantly three hours after tissue cultivation in vitro. MCP-1 immunoreactivity was restricted to the adenoma epithelium, with no reactivity seen in adjacent normal epithelial cells. MCP-1 stimulated COX-2 expression and PGE<sub>2</sub> and VEGF release in human macrophages. Celecoxib, a selective COX-2 inhibitor, inhibited MCP-1-induced PGE<sub>2</sub> and VEGF release in macrophages. Addition of exogenous PGE<sub>2</sub> reversed this inhibitory effect on VEGF release, suggesting that MCP-1 in adenoma epithelial cells might be involved in COX-2 expression and subsequent macrophage activation. <b>Conclusions:</b> MCP-1 in colorectal adenoma epithelial cells might be involved in macrophage migration and COX-2 expression, leading to the subsequent development of colonic adenoma.
Impact of Regular Physical Activity on the NAD(P)H Oxidase and Angiotensin Receptor System in Patients With Coronary Artery Disease
Authors: Volker Adams, Axel Linke, Nicolle Kränkel, Sandra Erbs, Stephan Gielen, Sven Möbius-Winkler, Jan F. Gummert, Friedrich Wilhelm Mohr, Gerhard Schuler, Rainer Hambrecht
Journal: Circulation (2005)

Background— In patients with stable coronary artery disease, physical exercise training (ET) improves endothelial dysfunction. A potential mechanism mediating the enhanced vasomotor function is a reduced breakdown of endothelium-derived nitric oxide by reactive oxygen species (ROS). The aim of the present study was to analyze the impact of ET on sources of ROS generation in the left internal mammary artery of patients with symptomatic coronary artery disease. Methods and Results— In left internal mammary artery rings sampled during bypass surgery from 45 patients randomized to either a training (n=22) or an inactive control (n=23) group, the mRNA expression of NAD(P)H oxidase subunits, NAD(P)H oxidase activity, and ROS production were assessed. In addition, endothelial function, expression of angiotensin II (Ang II) receptor type 1 and 2 (AT 1 -R and AT 2 -R), and Ang II-mediated vasoconstriction were determined. ET resulted in a significant lower expression of gp91 phox (23.1±0.5 versus 69.1±18.1 arbitrary units, training versus control), p22 phox (0.7±0.3 versus 2.0±0.5 arbitrary units), and Nox4 (2.7±1.2 versus 5.4±1.0 arbitrary units). Enzymatic activity (2.1±0.3 versus 4.9±0.4 mU/mg) and ROS generation (0.02±0.01 versus 0.06±0.02 arbitrary units) were significantly lower in the training compared with the control group. On a functional level, ET resulted in improved acetylcholine-mediated vasodilatation and a 49% reduction in Ang II–induced vasoconstriction, accompanied by lower AT 1 -R (3.7±0.8 versus 16.6±5.7 arbitrary units, training versus control) and higher AT 2 -R (7.8±2.5 versus 1.6±0.7 arbitrary units) mRNA expression. Conclusions— ET reduces vascular expression of NAD(P)H oxidase and AT 1 -R, resulting in decreased local ROS generation. These molecular effects converge in a reduced Ang II–mediated vasoconstriction.
A Zebrafish Model to Study and Therapeutically Manipulate Hypoxia Signaling in Tumorigenesis
Authors: Kirankumar Santhakumar, Emma C. Judson, Philip M. Elks, Sarah McKee, Stone Elworthy, Ellen van Rooijen, Sarah S. Walmsley, Stephen A. Renshaw, Simon S. Cross, Fredericus J.M. van Eeden
Journal: Cancer Research (2012)

Abstract Hypoxic signaling is a central modulator of cellular physiology in cancer. Core members of oxygen-sensing pathway including the von Hippel-Lindau tumor suppressor protein (pVHL) and the hypoxia inducible factor (HIF) transcription factors have been intensively studied, but improved organismal models might speed advances for both pathobiologic understanding and therapeutic modulation. To study HIF signaling during tumorigenesis and development in zebrafish, we developed a unique in vivo reporter for hypoxia, expressing EGFP driven by prolyl hydroxylase 3 (phd3) promoter/regulatory elements. Modulation of HIF pathway in Tg(phd3::EGFP) embryos showed a specific role for hypoxic signaling in the transgene activation. Zebrafish vhl mutants display a systemic hypoxia response, reflected by strong and ubiquitous transgene expression. In contrast to human VHL patients, heterozygous Vhl mice and vhl zebrafish are not predisposed to cancer. However, upon exposure to dimethylbenzanthracene (DMBA), the vhl heterozygous fish showed an increase in the occurrence of hepatic and intestinal tumors, a subset of which exhibited strong transgene expression, suggesting loss of Vhl function in these tumor cells. Compared with control fish, DMBA-treated vhl heterozygous fish also showed an increase in proliferating cell nuclear antigen-positive renal tubules. Taken together, our findings establish Vhl as a genuine tumor suppressor in zebrafish and offer this model as a tool to noninvasively study VHL and HIF signaling during tumorigenesis and development. Cancer Res; 72(16); 4017–27. ©2012 AACR.
Marching to the beat of different drummers: individual airway response diversity
Authors: R.H. Brown
Journal: European Respiratory Journal (2004)

The complicated structures of the lungs can be viewed in the most simplistic form as airways, vessels, and nerves. These structures work together to perform the marvellous feat of respiration and gas exchange. During disease states, one of these structures is impaired, either temporarily or permanently, and respiration and gas exchange are hindered. Asthma is a disease that primarily affects the airways. In asthma, while the aetiology may be varied, and remains a source of scientific controversy, the final common process is constriction of the airway smooth muscle, airway narrowing, and decreased ventilation that, in the severest form, can lead to death. The causes for this pathological constriction of the airways in asthmatics compared to healthy subjects are elusive and remain an area of intense research.

It is well recognised that the airway tree structure throughout the lungs is not uniform in structure or composition 1. On the simplest level, the airways change in size from the trachea to the alveoli 2. In addition, the cellular composition of the airways changes along the airway tree. For example, the amount of airway smooth muscle, cartilage, and nerves progressively decreases along the airway tree. Therefore, it is logical to suggest that the airways along the tree would not respond in a homogeneous manner in health or disease. However, the next step in the understanding of the heterogeneous response of the airways is not so intuitive.

Most investigators accept the idea of heterogeneity along the airway tree 3–5. However, the …
The Peptidyl-Isomerase Pin1 Regulates p27kip1 Expression through Inhibition of Forkhead Box O Tumor Suppressors
Authors: Arjan B. Brenkman, Peter L.J. de Keizer, Niels J.F. van den Broek, Petra van der Groep, Paul J. van Diest, Armando van der Horst, Alida M.M. Smits, Boudewijn M.T. Burgering
Journal: Cancer Research (2008)

The Forkhead box O (FOXO) protein family is an evolutionarily conserved subclass of transcription factors recently identified as bona fide tumor suppressors. Preventing the accumulation of cellular damage due to oxidative stress is thought to underlie its tumor-suppressive role. Oxidative stress, in turn, also feedback controls FOXO4 function. Regulation of this process, however, is poorly understood but may be relevant to the ability of FOXO to control tumor suppression. Here, we characterize novel FOXO4 phosphorylation sites after increased cellular oxidative stress and identify the isomerase Pin1, a protein frequently found to be overexpressed in cancer, as a critical regulator of p27(kip1) through FOXO4 inhibition. We show that Pin1 requires these phosphorylation events to act negatively on FOXO4 transcriptional activity. Consistent with this, oxidative stress induces binding of Pin1 to FOXO, thereby attenuating its monoubiquitination, a yet uncharacterized mode of substrate modulation by Pin1. We have previously shown that monoubiquitination is involved in controlling nuclear translocation in response to cellular stress, and indeed, Pin1 prevents nuclear FOXO4 accumulation. Interestingly, Pin1 acts on FOXO through stimulation of the activity of the deubiquitinating enzyme HAUSP/USP7. Ultimately, this results in decreased transcriptional activity towards target genes, including the cell cycle arrest gene p27(kip1). Notably, in a primary human breast cancer panel, low p27(kip1) levels inversely correlated with Pin1 expression. Thus, Pin1 is identified as a novel negative FOXO regulator, interconnecting FOXO phosphorylation and monoubiquitination in response to cellular stress to regulate p27(kip1).
Statin-Induced Cholesterol Lowering and Plaque Regression After 6 Months of Magnetic Resonance Imaging–Monitored Therapy
Authors: João A.C. Lima, Milind Y. Desai, Henning Steen, William P. Warren, Sandeep Gautam, Shenghan Lai
Journal: Circulation (2004)

Background— Statin therapy reduces adverse outcomes, with a minimal decrease in vessel stenosis. Magnetic resonance imaging (MRI) noninvasively detects atherosclerotic plaque (AP) reduction. We hypothesized that statin-induced AP regression can be monitored by MRI and detected earlier than previously reported and is significantly associated with its lipid-lowering effect. Methods and Results— APs in thoracic aorta were measured by combined surface/transesophageal MRI in 27 patients (treated with simvastatin 20 to 80 mg daily) before and after 6 months of therapy. AP volume and luminal dimensions were measured from 6 cross sections used to construct a 2.4-cm 3D volume of the aorta that included plaque and lumen. Method reproducibility was studied in 10 patients imaged twice, 1 week apart. AP volume was reduced from 3.3±0.1.4 to 2.9±1.4 cm 3 at 6 months ( P &lt;0.02), whereas luminal volume increase was less accentuated (from 12.0±3.9 to 12.2±3.7 cm 3 , P &lt;0.06). LDL cholesterol decreased by 23% (from 125±32 to 97±27 mg/dL, P &lt;0.05) in 6 months. AP regression (plaque volume/area reduction) was significantly related to LDL cholesterol reduction ( P &lt;0.02 and P &lt;0.005, respectively), and luminal volume increase was inversely related to LDL cholesterol reduction ( P &lt;0.04). Plaque volume measurement was highly reproducible (intraclass correlation R =0.98 and variability=4.8%). Intraobserver (0.91) and interobserver (0.81) concordances were documented for plaque volume assessment. Conclusions— AP regression and reverse remodeling can be detected accurately by MRI 6 months after statin therapy initiation, and it is strongly associated with LDL cholesterol reduction.
Aldosterone Action and Sodium- and Potassium-Activated Adenosine Triphosphatase in Toad Bladder
Authors: James H. Hill, Nadim Cortas, Mackenzie Walser
Journal: Journal of Clinical Investigation (1973)

Urinary hemibladders obtained from toads soaked in water or saline were treated with aldosterone, 10(-6) M, either 1(1/2) or 16 h after mounting. After 2(1/2) h exposure to the hormone, short-circuit current was increased by 110-192% and open-circuit potential by 20-44% as compared with untreated paired hemibladders. Mucosal cells were then assayed for sodium-potassium-stimulated adenosine triphosphatase (ATPase). No increase occurred in activity per milligram protein or in the portion of total activity dependent on sodium. Activity at low sodium concentrations was also measured and analyzed by means of the Hill equation in terms of K, the apparent dissociation constant of the enzyme-sodium complex, and n, a number that expresses the degree of interaction between binding sites. Neither K nor n was significantly altered by aldosterone. A few experiments were also carried out at low ATP concentrations (0.3 mM); again no change in sodium-dependent activity was noted. The results indicate that aldosterone does not stimulate sodium transport by increasing the quantity of sodium-potassium adenosine triphosphatase in mucosal cells or the dependence of this activity on sodium or ATP concentrations.
Huriez syndrome: case report with a detailed analysis of skin dendritic cells
Authors: C. Guerriero, C. Albanesi, G. Girolomoni, C. De Simone, R. Capizzi, P. Amerio, A. Tulli
Journal: British Journal of Dermatology (2000)

Journal Article Huriez syndrome: case report with a detailed analysis of skin dendritic cells Get access C. Guerriero, C. Guerriero Department of Dermatology, Catholic University of the Sacred Heart, Largo A.Gemelli 8, 00168 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar C. Albanesi, C. Albanesi Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar G. Girolomoni, G. Girolomoni Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar C. De Simone, C. De Simone Department of Dermatology, Catholic University of the Sacred Heart, Largo A.Gemelli 8, 00168 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar R. Capizzi, R. Capizzi Department of Dermatology, Catholic University of the Sacred Heart, Largo A.Gemelli 8, 00168 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar P. Amerio, P. Amerio Department of Dermatology, Catholic University of the Sacred Heart, Largo A.Gemelli 8, 00168 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar A. Tulli A. Tulli Department of Dermatology, Catholic University of the Sacred Heart, Largo A.Gemelli 8, 00168 Rome, Italy Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 143, Issue 5, 1 November 2000, Pages 1091–1096, https://doi.org/10.1046/j.1365-2133.2000.03793.x Published: 01 November 2000
The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention
Authors: John P Alao
Journal: Molecular Cancer (2007)

Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed.
Ectopic pregnancies after infertility treatment: modern diagnosis and therapeutic strategy
Authors: Herve Fernandez, Amelie Gervaise
Journal: Human Reproduction Update (2004)

Ectopic pregnancy (EP) is a major event in a woman's reproductive life. It complicates infertility treatment and must be recognized early to simplify the treatment strategy, which must always be directed towards optimizing subsequent fertility. Epidemiological findings indicate that tubal history and smoking are the principal risk factors of those EP that are considered reproductive (rather than contraceptive) failures. Adding together the attributable risks for EP allows the construction of a risk scale to determine its probability for any given patient. This risk calculation makes it easier to establish a diagnostic strategy that uses abdominal and transvaginal ultrasound and hCG assays. Progesterone assays are useful only for determining the activity of the pregnancy but do not help to identify its site. Conservative treatment is to be preferred unless the EP occurs on a known hydrosalpinx. All the treatment trials and the Cochrane database meta-analysis show that medical treatment with methotrexate, preferably multidose, is equivalent in efficacy to conservative treatment with laparoscopy in the populations studied. Heterotopic pregnancies, which occur most often after assisted reproduction technology (1-3%), should preferably be treated by salpingectomy except in interstitial sites. There is no consensus that IVF is indicated after EP. The patient's age is probably the determining factor: fertility treatment should not be delayed to an age where the results would be altered, especially with the risk of a recurrent EP.
Long term follow-up in patients with pulmonary alveolar proteinosis
Authors: Yulia Ilkovich, Lubov Novikova, Olga Baranova, Ivetta Dvorakovskaya, Andrey Bazhanov
Journal: European Respiratory Journal (2011)

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by respiratory failure due to surfactant accumulation within the lung. PAP is currently treated by whole lung lavage (WLL).  Since 1977, our cohort is 52 (35 male, 17 female) idiopathic PAP patients. Median age - 37±9 y.o. Most patients are current or former smokers (64%) and have occupational history (55%). Most patients have moderate impairments in functional parameters (mean DLCO - 65±15% pred., mean pulmonary artery systolic pressure - 30±6 mm Hg).  The majority of patients (88.4%) received WLL therapy. 3 patients (5.8%) had segmental lavage, 3 patients (5.8%) - N-acetylcysteine (NAC) as monotherapy. The average number of WLL procedures was 2 (1-7). 34.6% received only one WLL and demonstrated long-term improvement after the procedure.  5-years survival rate is 100%. Spontaneous resolution was observed in 2 patients (3.8%) on NAC treatment. In most cases the course of PAP was slowly progressive. 8 patients (15.4%) had rapid progressive deterioration with respiratory failure despite repeated WLL. Predictors of fast progression were estimated. No associations with gender, age, smoking status were found. Long antibiotics and corticosteroids (CS) intake due to incorrect diagnoses before PAP diagnostic (p  Avoiding of delayed diagnosis/incorrect treatment increases the probability of long symptom-free period after WLL.