gebhart/patrepeval huggingface dataset:
The fibre–folate debate in colo-rectal cancer (2006)

Intervention and prospective studies showing no effect of fibre in protection against colo-rectal cancer have challenged consensus recommendations that population intakes of fibre should be increased to reduce the risk of colo-rectal cancer. The European Prospective Investigation of Cancer and Nutrition (EPIC) of 519 978 individuals aged 25-70 years is the largest prospective study of diet and cancer to date worldwide. It incorporates ten different European countries in order to increase heterogeneity in dietary habits and calibration procedures to reduce measurement error. Data for 1065 reported cases of colo-rectal cancer were reported in 2003. There was a 40% reduction in risk for the highest quintile v. lowest quintile of fibre in food after calibration. It has been suggested that these effects were a result of confounding by folate and other factors. Although there are a number of hypotheses to explain why folate should be protective in colo-rectal cancer, a meta-analysis has shown that folate in food may be protective but there is no effect of total folate (i.e. food plus supplements). In a further analysis of 1826 cases in EPIC, identified in the latest follow-up, the inclusion of an additional 761 cases has confirmed the previously published results, with a strong and significant reduction in colo-rectal cancer of approximately 9% reduction in risk for each uncalibrated quintile increase in fibre (P<0.001 for linear trend) compared with an 8% reduction in the previous report, which had not been adjusted for folate. Inclusion of the other covariates (physical activity, alcohol, smoking and red and processed meat) with folate has confirmed this significant inverse association for colon cancer and strengthened the association with left-sided colon cancer (P < 0.001).
Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis (2005)

Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclerosis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experiments using chimeric mice expressing ALS-linked mutations to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuronal cell types on disease phenotype. When perturbed by primary neuronal damage, e.g. expression of SOD-1 mutations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the receptor FGFR1. FGF-1 stimulates nerve growth factor (NGF) expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Nrf2 leads to the expression of antioxidant and cytoprotective enzymes such as heme oxygenase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neurotrophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astrocytes may be a mechanism to eliminate critically damaged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role.
The Saccharomyces cerevisiae Ku Autoantigen Homologue Affects Radiosensitivity Only in the Absence of Homologous Recombination (1996)

In mammalian cells, all subunits of the DNA-dependent protein kinase (DNA-PK) have been implicated in the repair of DNA double-strand breaks and in V(D)J recombination. In the yeast Saccharomyces cerevisiae, we have examined the phenotype conferred by a deletion of HDF1, the putative homologue of the 70-kD subunit of the DNA-end binding Ku complex of DNA-PK. The yeast gene does not play a role in radiation-induced cell cycle checkpoint arrest in G1 and G2 or in hydroxyurea-induced checkpoint arrest in S. In cells competent for homologous recombination, we could not detect any sensitivity to ionizing radiation or to methyl methanesulfonate (MMS) conferred by a hdf1 deletion and indeed, the repair of DNA double-strand breaks was not impaired. However, if homologous recombination was disabled (rad52 mutant background), inactivation of HDF1 results in additional sensitization toward ionizing radiation and MMS. These results give further support to the notion that, in contrast to higher eukaryotic cells, homologous recombination is the favored pathway of double-strand break repair in yeast whereas other competing mechanisms such as the suggested pathway of DNA-PK-dependent direct break rejoining are only of minor importance.
Polymer light-emitting electrochemical cells with frozen p-i-n junction (1997)

The p-i-n junction in a polymer light-emitting electrochemical cell (LEC) is stabilized by cooling the device below the glass transition temperature of the ion-transport polymer. LECs with frozen p-i-n junctions exhibit typical light emitting diode (LED) behavior including diode rectification, unipolar light emission (same polarity as that used for generating the junction), and fast response. The freezeout of ion motion allows polymer LECs to be driven at bias voltages well beyond the electrochemical stability window, and thereby extends the potential applications of polymer LECs to high pixel density, column-row addressable displays.
The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy (2008)

We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation deltaK280 (Tau(RD)/deltaK280), or the deltaK280 plus two proline mutations in the hexapeptide motifs (Tau(RD)/deltaK280/I277P/I308P). The deltaK280 mutation accelerates aggregation ("proaggregation mutant"), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models ("antiaggregation mutant"). The inducible transgene expression was driven by the forebrain-specific CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2-3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [KXGS motifs, targets of the kinase MARK (microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human proaggregation mutant Tau(RD) coaggregates with mouse Tau, coupled with missorting and hyperphosphorylation at multiple sites. When expression of proaggregation Tau(RD) is switched off, soluble and aggregated exogenous Tau(RD) disappears within 1.5 months. However, tangles of mouse Tau, hyperphosphorylation, and missorting remain, suggesting an extended lifetime of aggregated wild-type Tau once a pathological conformation and aggregation is induced by a proaggregation Tau species.
Systemic ciclosporin and tacrolimus in dermatology (2007)

Ciclosporin and tacrolimus are calcineurin inhibiting immunosuppressant agents useful in the treatment of immune-mediated inflammatory dermatoses. Available data and clinical experience demonstrate ciclosporin's efficacy in treating psoriasis, atopic dermatitis, pyoderma gangrenosum, lichen planus, autoimmune bullous disease (in combination with corticosteroids), recalcitrant chronic idiopathic urticaria, and chronic dermatitis of the hands and feet. Although the role of topical tacrolimus in atopic dermatitis is well established, such experience with the oral formulation of tacrolimus has been limited. However, there are several case studies and anecdotal reports of the successful use of oral tacrolimus in various dermatoses. In this article we discuss the utility of systemic ciclosporin and tacrolimus in dermatology.
Evidence for an Essential Lysine in Glucose‐6‐Phosphate Dehydrogenase from Leuconostoc mesenteroides (1975)

1. Pyridoxal 5'-phosphate inhibits glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides reversibly which Ki equals 0.04-0.06 mM. 2. This inhibition is competitive with respect to glucose 6-phosphate and non-competitive with respect to NADP+ or NAD+. Interaction between enzyme and excess pyridoxal 5'-phosphate follows pseudo-first-order kinetics and indicates that one molecule of inhibitor reacts with each active unit of enzyme. 3. Substrate and coenzyme protect the enzyme from inhibition by pyridoxal 5'-phosphate. Dissociation constants for NADP+ and glucose 6-phosphate were determined from their effects on the kinetics of enzyme--inhibitor interaction. 4. Reaction of the enzyme with pyridoxal 5'-phosphate produces a typical Schiff-base absorbance peak at 430 nm. Subsequent reduction with sodium borohydride leads to spectral changes characteristic for the formation of a secondary amine. 5. The irreversibly inactivated enzyme thus produced contains two moles of inhibitor per mole of enzyme (two subunits per mole). After protein hydrolysis, N-6-pyridoxyllysine can be identified by paper chromatography. 6. The enzyme is inhibited irreversibly by 1-fluoro-2,4-dinitrobenzene, even in the presence of excess 2-mercaptoethanol. At least one dinitrophenyl group is bound per active unit of enzyme; 4 to 5 moles of dinitrophenyl group are bound per mole of enzyme. NADP+ AND GLUCOSE 6-PHOSPHATE PROTECT AGAINST INHIBITION BY 1-FLUORO-2,4-DINITROBENZENE. The absorption spectrum of dinitrophenyl-enzyme corresponds to that for dinitrophenylated amino groups. 7. These studies indicate that there is an essential lysine at the active site of the enzyme. It is suggested that the function of this lysine is to bind glucose 6-phosphate. 8. It is proposed that a group of "active lysine" proteins may exist (in analogy with the "active serine" enzymes), which share a common structural feature at their substrate-binding site and to which pyridoxal 5'-phosphate binds specifically.
Service Net-2000: An Intelligent Network Evolution (1991)

Rapid technological changes in the computing and telecommunications industries are expanding customer expectations and service requirements for the public network. Meeting these needs will require several major changes in the network, notably in the areas of high-bandwidth services, faster service-provisioning times (i.e., improved operations, administration, maintenance, and provisioning), and increased network intelligence. In this paper, we describe how AT&T Network Systems plans to use Service Net-2000 to support these changes. The Service Net-2000 architecture will integrate high-capacity switching and data-networking elements with synchronous optical network (SONET) transmission elements under a unified, customer-oriented, common control structure. Because it is evolving directly from today's 5ESS® switch, Service Net-2000 will incorporate all the capabilities of today's real-world intelligent network. By using intelligent network adjuncts, service circuit nodes, and service control points within this architecture, we will be able to offer a broad range of services faster and easier than we can today. These concepts form the basis for future service offerings that will create a more responsive, service-rich public network ready to meet the information movement needs of end users.
Protection of Chickens againstEscherichia coliInfections by DNA Containing CpG Motifs (2003)

Synthetic oligodeoxynucleotides (ODN) containing CpG motifs (CpG-ODN) have been shown to be effective immunoprotective agents in murine models for a variety of viral, intracellular bacterial, and protozoan infections. Until now, the use of CpG-ODN to protect against extracellular bacterial infections has not been reported. The objective of this study was to investigate the effect of CpG-ODN against cellulitis and colibacillosis in broiler chickens, using a well-established model. At 22 days of age, birds received CpG-ODN by either the subcutaneous or intramuscular route. Three days later, a virulent isolate of Escherichia coli was applied to a scratch site on the caudal abdominal skin. Birds were examined for 10 days after the E. coli challenge, and pathological and bacteriological assessments were conducted on all birds. The control group of birds receiving no CpG-ODN((2007)) had a survival rate of 15%. In contrast, groups that received CpG-ODN((2007)), by either subcutaneous or intramuscular injection, had significantly higher survival rates (P < 0.0001). Furthermore, the size of the cellulitis lesion was significantly smaller in groups that received CpG-ODN((2007)) by the subcutaneous route (P < 0.01). A dose of as little as 3.16 micro g of CpG-ODN((2007)), delivered 3 days prior to challenge by either the subcutaneous or intramuscular route, significantly protected birds against E. coli infection (P < 0.01). This study demonstrates that CpG-ODN((2007)) has both local and systemic protective effects in broiler chickens. This is the first time that CpG-ODN((2007)) has been demonstrated to have an immunoprotective effect against an extracellular bacterial infection in any food animal species.
Characterization of Amylolytic Enzyme Activities Associated with the Hyperthermophilic Archaebacterium Pyrococcus furiosus (1990)

The hyperthermophilic archaebacterium Pyrococcus furiosus produces several amylolytic enzymes in response to the presence of complex carbohydrates in the growth medium. These enzyme activities, alpha-glucosidase, pullulanase, and alpha-amylase, were detected in both cell extracts and culture supernatants. All activities were characterized by temperature optima of at least 100 degrees C as well as a high degree of thermostability. The existence of this collection of activities in P. furiosus suggests that polysaccharide availability in its growth environment is a significant aspect of the niche from which it was isolated.
The Surface of Lipid Droplets Is a Phospholipid Monolayer with a Unique Fatty Acid Composition (2002)

We found that caveolin-2 is targeted to the surface of lipid droplets (Fujimoto, T., Kogo, H., Ishiguro, K., Tauchi, K., and Nomura, R. (2001) J. Cell Biol. 152, 1079-1085) and hypothesized that the lipid droplet surface is a kind of membrane. To elucidate the characteristics of the lipid droplet surface, we isolated lipid droplets from HepG2 cells and analyzed them by cryoelectron microscopy and by mass spectrometry. By use of cryoelectron microscopy at the stage temperature of 4.2 K, the lipid droplet surface was observed as a single line without any fixation or staining, indicating the presence of a single layer of phospholipids. This result appeared consistent with the hypothesis that the lipid droplet surface is derived from the cytoplasmic leaflet of the endoplasmic reticulum membrane and may be continuous to it. However, mass spectrometry revealed that the fatty acid composition of phosphatidylcholine and lysophosphatidylcholine in lipid droplets is different from that of the rough endoplasmic reticulum. The ample presence of free cholesterol in lipid droplets also suggests that their surface is differentiated from the bulk endoplasmic reticulum membrane. On the other hand, although caveolin-2beta and adipose differentiation-related protein, both localizing in lipid droplets, were enriched in the low density floating fraction, the fatty acid composition of the fraction was distinct from lipid droplets. Collectively, the result indicates that the lipid droplet surface is a hemi-membrane or a phospholipid monolayer containing cholesterol but is compositionally different from the endoplasmic reticulum membrane or the sphingolipid/cholesterol-rich microdomain.
Loss of the Atp2c1 Secretory Pathway Ca2+-ATPase (SPCA1) in Mice Causes Golgi Stress, Apoptosis, and Midgestational Death in Homozygous Embryos and Squamous Cell Tumors in Adult Heterozygotes (2007)

Loss of one copy of the human ATP2C1 gene, encoding SPCA1 (secretory pathway Ca(2+)-ATPase isoform 1), causes Hailey-Hailey disease, a skin disorder. We performed targeted mutagenesis of the Atp2c1 gene in mice to analyze the functions of this Golgi membrane Ca(2+) pump. Breeding of heterozygous mutants yielded a normal Mendelian ratio among embryos on gestation day 9.5; however, null mutant (Spca1(-/-)) embryos exhibited growth retardation and did not survive beyond gestation day 10.5. Spca1(-/-) embryos had an open rostral neural tube, but hematopoiesis and cardiovascular development were ostensibly normal. Golgi membranes of Spca1(-/-) embryos were dilated, had fewer stacked leaflets, and were expanded in amount, consistent with increased Golgi biogenesis. The number of Golgi-associated vesicles was also increased, and rough endoplasmic reticulum had fewer ribosomes. Coated pits, junctional complexes, desmosomes, and basement membranes appeared normal in mutant embryos, indicating that processing and trafficking of proteins in the secretory pathway was not massively impaired. However, apoptosis was increased, possibly the result of secretory pathway stress, and a large increase in cytoplasmic lipid was observed in mutant embryos, consistent with impaired handling of lipid by the Golgi. Adult heterozygous mice appeared normal and exhibited no evidence of Hailey-Hailey disease; however, aged heterozygotes had an increased incidence of squamous cell tumors of keratinized epithelial cells of the skin and esophagus. These data show that loss of the Golgi Ca(2+) pump causes Golgi stress, expansion of the Golgi, increased apoptosis, and embryonic lethality and demonstrates that SPCA1 haploinsufficiency causes a genetic predisposition to cancer.
The clinical burden of type 2 diabetes in patients with acute coronary syndromes: Prognosis and implications for short- and long-term management (2014)

Type 2 diabetes mellitus (T2DM) is associated with increased morbidity and mortality in patients with acute coronary syndromes (ACS). Cardiometabolic risk factors, including hyperglycaemia, insulin resistance, atherogenic dyslipidaemia, increased visceral fat and inflammation, are associated with increased risk in this population and represent potential targets for treatment. In this review, management strategies for patients with T2DM post-ACS, both in the acute-care setting and in the long-term, are discussed. Although the benefits of long-term, aggressive, multifactorial risk factor modification are well established, a significant burden of recurrent events remains and the search for novel strategies continues. Several studies are assessing the potential cardiovascular (CV) benefits and safety of various classes of newer agents. Of these, AleCardio (aleglitazar), Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE; alogliptin) and Evaluation of LIXisenatide in Acute Coronary Syndrome (ELIXA; lixisenatide) specifically address patients with type 2 diabetes post-ACS. The mechanisms of action of these new therapies and aims of the CV outcome studies are briefly reviewed. The prevalence of type 2 diabetes continues to increase worldwide highlighting the need for new strategies that address the complex underlying processes that drive atherosclerosis and CV events in this high-risk patient population.
Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat (1992)

Injection of basic fibroblast growth factor (bFGF) into the eye, intravitreally or subretinally, delays photoreceptor degeneration in inherited retinal dystrophy in the rat, as does local injury to the retina (Faktorovich et al., 1990). To determine whether this heparin-binding peptide or local injury is effective in any other form of photoreceptor degeneration, we examined their protective roles in light damage. Albino rats of the F344 strain were exposed to 1 or 2 weeks of constant fluorescent light (115-200 footcandles), either with or without 1 microliter of bFGF solution (1150 ng/microliters in PBS) injected intravitreally or subretinally 2 d before the start of light exposure. Uninjected and intravitreally PBS-injected controls showed the loss of a majority of photoreceptor nuclei and the loss of most inner and outer segments after 1 week of light exposure, while intravitreal injection of bFGF resulted in significant photoreceptor rescue. The outer nuclear layer in bFGF-injected eyes was two to three times thicker than in controls, and the inner and outer segments showed a much greater degree of integrity. Following recovery in cyclic light for 10 d after 1 week of constant light exposure, bFGF-injected eyes showed much greater regeneration of photoreceptor inner and outer segments than did the controls. bFGF also increased the incidence of presumptive macrophages, located predominantly in the inner retina, but the evidence suggests they are not directly involved in photoreceptor rescue. Subretinal injection of bFGF resulted in photoreceptor rescue throughout most of the superior hemisphere in which the injection was made, with rescue extending into the inferior hemisphere in many of the eyes. Remarkably, the insertion of a dry needle or injection of PBS into the subretinal space also resulted in widespread photoreceptor rescue, extending through 70% or more of the superior hemisphere, and sometimes into the inferior hemispheres. This implicates the release and widespread diffusion of some endogenous survival-promoting factor from the site of injury in the retina. Our findings indicate that the photoreceptor rescue activity of bFGF is not restricted to inherited retinal dystrophy in the rat, and that light damage is an excellent model for studying the cellular site(s), kinetics, and molecular mechanisms of both the normal function of bFGF and its survival-promoting activity. Moreover, the injury-related rescue suggests that survival-promoting factors are readily available to provide a protective role in case of injury to the retina, presumably comparable to those that mediate the "conditioning lesion" effect in other neuronal systems.
Spatial and Temporal Cellular Responses to Single-Strand Breaks in Human Cells (2003)

DNA single-strand breaks (SSB) are one of the most frequent DNA lesions produced by reactive oxygen species and during DNA metabolism, but the analysis of cellular responses to SSB remains difficult due to the lack of an experimental method to produce SSB alone in cells. By using human cells expressing a foreign UV damage endonuclease (UVDE) and irradiating the cells with UV through tiny pores in membrane filters, we created SSB in restricted areas in the nucleus by the immediate action of UVDE on UV-induced DNA lesions. Cellular responses to the SSB were characterized by using antibodies and fluorescence microscopy. Upon UV irradiation, poly(ADP-ribose) synthesis occurred immediately in the irradiated area. Simultaneously, but dependent on poly(ADP-ribosyl)ation, XRCC1 was translocated from throughout the nucleus, including nucleoli, to the SSB. The BRCT1 domain of XRCC1 protein was indispensable for its poly(ADP-ribose)-dependent recruitment to the SSB. Proliferating cell nuclear antigen and the p150 subunit of chromatin assembly factor 1 also accumulated at the SSB in a detergent-resistant form, which was significantly reduced by inhibition of poly(ADP-ribose) synthesis. Our results show the importance of poly(ADP-ribosyl)ation in sequential cellular responses to SSB.