tbuckley/cabot-search huggingface dataset:
Molecular Evolution of the Metazoan PHD–HIF Oxygen-Sensing System
Authors: Kalle T. Rytkönen, Tom A. Williams, Gillian M. Renshaw, Craig R. Primmer, Mikko Nikinmaa
Journal: Molecular Biology and Evolution (2011)

Metazoans rely on aerobic energy production, which requires an adequate oxygen supply. During reduced oxygen supply (hypoxia), the most profound changes in gene expression are mediated by transcription factors known as hypoxia-inducible factors (HIFs). HIF alpha proteins are commonly posttranslationally regulated by prolyl-4-hydroxylase (PHD) enzymes, which are direct "sensors" of cellular oxygen levels. We examined the molecular evolution of the metazoan PHD–HIF oxygen-sensing system by constructing complete phylogenies for PHD and HIF alpha genes and used computational tools to characterize the molecular changes underlying the functional divergence of PHD and HIF alpha duplicates. The presence of PHDs in metazoan genomes predates the emergence of HIF alphas. Our analysis revealed an unexpected diversity of PHD genes and HIF alpha sequence characteristics in invertebrates, suggesting that the simple oxygen-sensing systems of Caenorhabditis and Drosophila may not be typical of other invertebrate bilaterians. We studied the early vertebrate evolution of the system by sequencing these genes in early-diverging cartilaginous fishes, elasmobranchs. Cartilaginous fishes appear to have three paralogs of both PHD and HIF alpha. The novel sequences were used as outgroups for a detailed molecular analysis of PHD and HIF alpha duplicates in a major air-breathing vertebrate lineage, the mammals, and a major water-breathing vertebrate lineage, the teleosts. In PHDs, functionally divergent amino acid sites were detected near the HIF alpha-binding channel and beta2beta3 loop that defines its substrate specificity. In HIF alphas, more functional divergence was found in teleosts than in mammals, especially in the HIF-1 alpha PAS domain and HIF-2 alpha oxygen-dependent degradation (ODD) domains, which interact with PHDs. Overall, in the vertebrates, elevated substitution rates in the HIF-2 alpha N-terminal ODD domain, together with a functional divergence associated with the known differences in PHD2 versus PHD1/3 substrate specificity, have contributed to the tighter oxygen-sensitive regulation of HIF-1 alpha than that of HIF-2 alpha.
Subtype-Specific <i>FBXW7</i> Mutation and <i>MYCN</i> Copy Number Gain in Wilms' Tumor
Authors: Richard D. Williams, Reem Al-Saadi, Tasnim Chagtai, Sergey Popov, Boo Messahel, Neil Sebire, Manfred Gessler, Jenny Wegert, Norbert Graf, Ivo Leuschner, Mike Hubank, Chris Jones, Gordan Vujanic, Kathy Pritchard-Jones
Journal: Clinical Cancer Research (2010)

Wilms' tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX, and TP53. However, the majority of cases do not harbor mutations in these genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP).We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation-dependent Probe Amplification, or fluorescence in situ hybridization.We identified FBXW7, an E3 ubiquitin ligase component, as a novel Wilms' tumor gene, mutated or deleted in approximately 4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1. We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%).Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms' tumor.
Robotic Leg Control with EMG Decoding in an Amputee with Nerve Transfers
Authors: Levi J. Hargrove, Ann M. Simon, Aaron J. Young, Robert D. Lipschutz, Suzanne B. Finucane, Douglas G. Smith, Todd A. Kuiken
Journal: New England Journal of Medicine (2013)

The clinical application of robotic technology to powered prosthetic knees and ankles is limited by the lack of a robust control strategy. We found that the use of electromyographic (EMG) signals from natively innervated and surgically reinnervated residual thigh muscles in a patient who had undergone knee amputation improved control of a robotic leg prosthesis. EMG signals were decoded with a pattern-recognition algorithm and combined with data from sensors on the prosthesis to interpret the patient's intended movements. This provided robust and intuitive control of ambulation--with seamless transitions between walking on level ground, stairs, and ramps--and of the ability to reposition the leg while the patient was seated.
Podocyte-Specific Overexpression of the Antioxidant Metallothionein Reduces Diabetic Nephropathy
Authors: Shirong Zheng, Edward C. Carlson, Lu Yang, Patricia M. Kralik, Yun Huang, Paul N. Epstein
Journal: Journal of the American Society of Nephrology (2008)

Podocytes are critical components of the selective filtration barrier of the glomerulus and are susceptible to oxidative damage. For investigation of the role of oxidative stress and podocyte damage in diabetic nephropathy, transgenic mice that overexpress the antioxidant protein metallothionein (MT) specifically in podocytes (Nmt mice) were produced. MT expression was increased six- and 18-fold in glomeruli of two independent lines of Nmt mice, and podocyte-specific overexpression was confirmed. Glomerular morphology and urinary albumin excretion were normal in Nmt mice. OVE26 transgenic mice, a previously reported model of diabetic nephropathy, were crossed with Nmt mice to determine whether an antioxidant transgene targeted to podocytes could reduce diabetic nephropathy. Double-transgenic OVE26Nmt mice developed diabetes similar to OVE26 mice, but MT overexpression reduced podocyte damage, indicated by more podocytes, less glomerular cell death, and higher density of podocyte foot processes. In addition, expansion of glomerular and mesangial volume were significantly less in OVE26Nmt mice compared with OVE26 mice. Four-month-old OVE26Nmt mice had a 70 to 90% reduction in 24-h albumin excretion, but this protection does not seem to be permanent. These results provide evidence for the role of oxidative damage to the podocyte in diabetic mice and show that protection of the podocyte can reduce or delay primary features of diabetic nephropathy.
Overexpressed cyclin D3 contributes to retaining the growth inhibitor p27 in the cytoplasm of thyroid tumor cells
Authors: Gustavo Baldassarre, Barbara Belletti, Paola Bruni, Angelo Boccia, Francesco Trapasso, Francesca Pentimalli, Maria Vittoria Barone, Gennaro Chiappetta, Maria Teresa Vento, Stefania Spiezia, Alfredo Fusco, Giuseppe Viglietto
Journal: Journal of Clinical Investigation (1999)

The majority of thyroid carcinomas maintain the expression of the cell growth suppressor p27, an inhibitor of cyclin-dependent kinase-2 (Cdk2). However, we find that 80% of p27-expressing tumors show an uncommon cytoplasmic localization of p27 protein, associated with high Cdk2 activity. To reproduce such a situation, a mutant p27 devoid of its COOH-terminal nuclear-localization signal was generated (p27-NLS). p27-NLS accumulates in the cytoplasm and fails to induce growth arrest in 2 different cell lines, indicating that cytoplasm-residing p27 is inactive as a growth inhibitor, presumably because it does not interact with nuclear Cdk2. Overexpression of cyclin D3 may account in part for p27 cytoplasmic localization. In thyroid tumors and cell lines, cyclin D3 expression was associated with cytoplasmic localization of p27. Moreover, expression of cyclin D3 in thyroid carcinoma cells induced cytoplasmic retention of cotransfected p27 and rescued p27-imposed growth arrest. Endogenous p27 also localized prevalently to the cytoplasm in normal thyrocytes engineered to stably overexpress cyclin D3 (PC-D3 cells). In these cells, cyclin D3 induced the formation of cytoplasmic p27–cyclin D3–Cdk complexes, which titrated p27 away from intranuclear complexes that contain cyclins A–E and Cdk2. Our results demonstrate a novel mechanism that may contribute to overcoming the p27 inhibitory threshold in transformed thyroid cells.
Differential Effects of Human Granulocyte Colony-Stimulating Factor (hG-CSF) and Thrombopoietin on Megakaryopoiesis and Platelet Function in hG-CSF Receptor-Transgenic Mice
Authors: Feng-Chun Yang, Kohichiro Tsuji, Atsushi Oda, Yasuhiro Ebihara, Ming-jiang Xu, Azusa Kaneko, Sachiyo Hanada, Tetsuo Mitsui, Akira Kikuchi, Atsushi Manabe, Sumiko Watanabe, Yasuo Ikeda, Tatsutoshi Nakahata
Journal: Blood (1999)
Antihypertensive Treatment and Resistant Hypertension in Patients With Type 1 Diabetes by Stages of Diabetic Nephropathy
Authors: Raija Lithovius, Valma Harjutsalo, Carol Forsblom, Markku Saraheimo, Per-Henrik Groop
Journal: Diabetes Care (2013)

To assess blood pressure (BP) control, antihypertensive treatment, and prevalence of resistant hypertension (RH) in patients with type 1 diabetes stratified by stage of diabetic nephropathy.This cross-sectional study included a nationally representative cohort of patients with type 1 diabetes (N = 3,678) from the Finnish Diabetic Nephropathy Study (FinnDiane). The data were linked to the Drug Prescription Register to obtain purchases of antihypertensive drugs 6 months prior to the baseline visit. The treatment targets were based on the American Diabetes Association guidelines. RH was defined as failure to reach BP target despite the use of three or more antihypertensive drugs of different classes (one of which was a diuretic).In patients with normal albumin excretion rate, 14.1% were on antihypertensive treatment and 74.6% of them had uncontrolled BP despite treatment. The corresponding figures were 60.5 and 71.2% for the microalbuminuric patients, 90.3 and 80.0% for the macroalbuminuric patients, 88.6 and 88.1% for dialysis, and 91.2 and 90.4% for kidney-transplanted patients. The prevalence of RH was 1.2% in the normoalbuminuric, 4.7% in the microalbuminuric, 28.1% in the macroalbuminuric, 36.6% in the dialysis, and 26.3% in the kidney transplant groups. Age (odds ratio 1.04 [95% CI 1.02-1.05]), estimated glomerular filtration rate (0.97 [0.96-0.97]), waist-to-hip ratio (1.44 [1.15-1.80]), triglycerides (1.19 [1.01-1.40]), microalbuminuria (2.58 [1.43-4.67]), and macroalbuminuria (5.61 [3.20-9.84]) were independently associated with RH.The prevalence of uncontrolled hypertension and RH increases with advanced diabetic nephropathy. These data suggest that there is an urgent need for improvement of antihypertensive treatment.
Syndrome(s) X
Authors: BrianM. Frier, BasilF. Clarke, IanF. Godsland, MichaelF. Oliver, J.D. Dean, C.J.H. Jones, S.J. Hutchison, J.R. Peters, A.H. Henderson, H.J. Roberts, StevenL. Shumak, Tim Dornan, Peter Nicol
Journal: The Lancet (1991)
The prediction of benefit from pulmonary rehabilitation: setting, training intensity and the effect of selection by disability
Authors: M. D. Morgan
Journal: Thorax (1999)

This study tested the hypothesis that severity of respiratory disability may affect the outcome of pulmonary rehabilitation.In this randomized, controlled study, 126 patients with chronic obstructive pulmonary disease (COPD) were stratified for dyspnoea using the Medical Research Council (MRC) dyspnoea score into MRC3/4 (Moderate) (n=66) and MRC 5 (Severe) dyspnoeic (n=60) groups.The patients were randomly assigned to an eight week programme of either exercise plus education (Exercise group) or education (Control group).Education and exercise programmes for the moderately dyspnoeic patients were carried out in a hospital outpatient setting.Severely dyspnoeic patients were all treated at home.Those in the Exercise group received an individualized training programme.There was a significant improvement in shuttle walking distance in the moderate dyspnoeic group, who received exercise training; baseline (mean±SEM) 191±22 m, post-rehabilitation 279±22 m (p<0.001).There was no improvement in exercise performance in the severely dyspnoeic patients receiving exercise.Neither group of control patients improved.Health status, assessed by the Total Chronic Respiratory Disease Questionnaire score, increased in the moderately dyspnoeic patients receiving exercise from 80±18 to 95±17 (p<0.0001) after rehabilitation.Much smaller changes were seen in the other three groups.Improvement in exercise performance and health status in patients with chronic obstructive pulmonary disease after an exercise programme depends on the initial degree of dyspnoea.
Circulating Bone Morphogenetic Protein 1–3 Isoform Increases Renal Fibrosis
Authors: Lovorka Grgurevic, Boris Macek, David R. Healy, Amy L. Brault, Igor Erjavec, Antonio Cipcic, Ivica Grgurevic, Dunja Rogic, Kresimir Galesic, Jelena Brkljacic, Ranka Stern-Padovan, Vishwas M. Paralkar, Slobodan Vukicevic
Journal: Journal of the American Society of Nephrology (2011)

Bone morphogenetic proteins (BMPs) participate in organ regeneration through autocrine and paracrine actions, but the existence and effects of these proteins in the systemic circulation is unknown. Using liquid chromatography–mass spectrometry, we identified BMP6, GDF15, and the BMP1–3 isoform of the Bmp1 gene in plasma samples from healthy volunteers and patients with CKD. We isolated the endogenous BMP1–3 protein and demonstrated that it circulates as an active enzyme, evidenced by its ability to cleave dentin matrix protein-1 in vitro. In rats with CKD, administration of recombinant BMP1–3 increased renal fibrosis and reduced survival. In contrast, administration of a BMP1–3-neutralizing antibody reduced renal fibrosis, preserved renal function, and increased survival. In addition, treating with the neutralizing antibody was associated with low plasma levels of TGFβ1 and connective tissue growth factor. In HEK293 cells and remnant kidneys, BMP1–3 increased the transcription of collagen type I, TGFβ1, β-catenin, and BMP7 via a BMP- and Wnt-independent mechanism that involved signaling through an integrin β1 subunit. The profibrotic effect of BMP1–3 may, in part, be a result of the accompanied decrease in decorin (DCN) expression. Taken together, inhibition of circulating BMP1–3 reduces renal fibrosis, suggesting that this pathway may be a therapeutic target for CKD.
Interleukin 4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic for human autologous melanoma.
Authors: Y Kawakami, S A Rosenberg, M T Lotze
Journal: The Journal of Experimental Medicine (1988)

Addition of IL-4 (1,000 U/ml) to either high or low concentrations of IL-2 augmented tumor-infiltrating lymphocytes (TIL) growth from human melanoma. Weekly restimulation with irradiated tumor cells in conjunction with IL-4 allowed enhanced growth of TIL. With low-dose IL-2 (10 U/ml) and IL-4, expanded TIL had little cytolytic activity against Daudi or allogeneic tumors. Further, IL-4 augmented the total lytic activity against autologous tumors in most cases. With high-dose IL-2 (1,000 U/ml), IL-4 addition decreased nonspecific killing activity against Daudi or allogeneic melanomas in many cases, and reciprocally augmented cytolytic activity against the autologous melanoma in many cases. This suggests the possible use of IL-4 in cancer therapy, especially in adoptive cellular immunotherapy using TIL or in conjunction with IL-2 administration.
Cytonuclear Evolution of Rubisco in Four Allopolyploid Lineages
Authors: Lei Gong, Mischa Olson, Jonathan F. Wendel
Journal: Molecular Biology and Evolution (2014)

Allopolyploidization in plants entails the merger of two divergent nuclear genomes, typically with only one set (usually maternal) of parental plastidial and mitochondrial genomes and with an altered cytonuclear stoichiometry. Thus, we might expect cytonuclear coevolution to be an important dimension of allopolyploid evolution. Here, we investigate cytonuclear coordination for the key chloroplast protein rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), which is composed of nuclear-encoded, small subunits (SSUs) and plastid-encoded, large subunits. By studying gene composition and diversity as well as gene expression in four model allopolyploid lineages, Arabidopsis, Arachis, Brassica, and Nicotiana, we demonstrate that paralogous nuclear-encoded rbcS genes within diploids are subject to homogenization via gene conversion and that such concerted evolution via gene conversion characterizes duplicated genes (homoeologs) at the polyploid level. Many gene conversions in the polyploids are intergenomic with respect to the diploid progenitor genomes, occur in functional domains of the homoeologous SSUs, and are directionally biased, such that the maternal amino acid states are favored. This consistent preferential maternal-to-paternal gene conversion is mirrored at the transcriptional level, with a uniform transcriptional bias of the maternal-like rbcS homoeologs. These data, repeated among multiple diverse angiosperm genera for an important photosynthetic enzyme, suggest that cytonuclear coevolution may be mediated by intergenomic gene conversion and altered transcription of duplicated, now homoeologous nuclear genes.
Maternal X Chromosome, Visceral Adiposity, and Lipid Profile
Authors: Phillip L. Van, Vladimir K. Bakalov, Andrew R. Zinn, Carolyn A. Bondy
Journal: JAMA (2006)

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A prospective single centre study comparing computed tomography pneumocolon against colonoscopy in the detection of colorectal neoplasms
Authors: Y M Miao, Z Amin, J Healy, P Burn, N Murugan, D Westaby, T G Allen-Mersh
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> To determine the sensitivity and specificity of computed tomography (CT) pneumocolon in the detection of colorectal neoplasms. <h3>METHODS</h3> A total of 201 consecutive patients with colorectal symptoms or requiring surveillance for colorectal neoplasms underwent both conventional colonoscopy and CT pneumocolon. <h3>RESULTS</h3> On conventional colonoscopy 13 invasive colorectal carcinomas were detected in 13 patients, and 118 polyps in 63 patients (14 polyps were ⩾1 cm in diameter, 25 were 6–9 mm, and 79 were ⩽5 mm). CT pneumocolon detected all 13 cancers, two false positive cancers, but only 20 polyps (seven were ⩾1 cm). This resulted in a sensitivity of 100% (95% confidence interval (CI) 87–100%) and specificity of 99% (95% CI 97–100%) for detection of invasive carcinoma, and a sensitivity of 73% (95% CI 56–90%) and specificity of 94% (95% CI 91–98%) for detection of invasive carcinoma and/or ⩾1 cm polyps. CT pneumocolon also identified invasive carcinoma not seen at colonoscopy because of incomplete examination in three patients, and detected metastases in six colorectal carcinoma patients and extracolonic carcinoma in a further seven patients. <h3>CONCLUSIONS</h3> CT pneumocolon had a high sensitivity and specificity for detection of invasive colorectal carcinoma but not colorectal polyps. CT pneumocolon may be suitable for initial investigation of patients with symptoms of colorectal malignancy.
PGC-1 Coactivators in Cardiac Development and Disease
Authors: Glenn C. Rowe, Aihua Jiang, Zolt Arany
Journal: Circulation Research (2010)

The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last 10 years have seen a resurgent interest in cardiac intermediary metabolism and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-γ coactivator (PGC)-1 family of proteins plays a central role in these pathways. The mechanisms by which PGC-1 proteins regulate transcriptional networks and are regulated by physiological cues, as well as the roles they play in cardiac development and disease, are reviewed here.
The Evolutionary Origin of Xanthomonadales Genomes and the Nature of the Horizontal Gene Transfer Process
Authors: Iñaki Comas, Andrés Moya, Rajeev K. Azad, Jeffrey G. Lawrence, Fernando Gonzalez-Candelas
Journal: Molecular Biology and Evolution (2006)

Determining the influence of horizontal gene transfer (HGT) on phylogenomic analyses and the retrieval of a tree of life is relevant for our understanding of microbial genome evolution. It is particularly difficult to differentiate between phylogenetic incongruence due to noise and that resulting from HGT. We have performed a large-scale, detailed evolutionary analysis of the different phylogenetic signals present in the genomes of Xanthomonadales, a group of Proteobacteria. We show that the presence of phylogenetic noise is not an obstacle to infer past and present HGTs during their evolution. The scenario derived from this analysis and other recently published reports reflect the confounding effects on bacterial phylogenomics of past and present HGT. Although transfers between closely related species are difficult to detect in genome-scale phylogenetic analyses, past transfers to the ancestor of extant groups appear as conflicting signals that occasionally might make impossible to determine the evolutionary origin of the whole genome.
Prejudice reduction, collective action, and then what?
Authors: Dominic Abrams, Milica Vasiljevic, Hazel M. Wardrop
Journal: Behavioral and Brain Sciences (2012)

Abstract Despite downsides, it must, on balance, be good to reduce prejudice. Despite upsides, collective action can also have destructive outcomes. Improving intergroup relations requires multiple levels of analysis involving a broader approach to prejudice reduction, awareness of potential conflict escalation, development of intergroup understanding, and promotion of a wider human rights perspective.