gebhart/patrepeval huggingface dataset:
Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. (1986)

Regulation of the production of erythropoietin occurs in the kidney and liver largely through control of accumulation of erythropoietin mRNA. Erythropoietin mRNA was first detected in kidneys at 1.5 h postanemia and reached a plateau value at least 200-fold above the control value by 4 to 8 h. A 20-base sequence immediately upstream from the reported erythropoietin mRNA initiation site is complementary to a hypervariable sequence in 18S rRNA.
Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation (1998)

The classification of diabetes mellitus and the tests used for its diagnosis were brought into order by the National Diabetes Data Group of the USA and the second World Health Organization Expert Committee on Diabetes Mellitus in 1979 and 1980. Apart from minor modifications by WHO in 1985, little has been changed since that time. There is however considerable new knowledge regarding the aetiology of different forms of diabetes as well as more information on the predictive value of different blood glucose values for the complications of diabetes. A WHO Consultation has therefore taken place in parallel with a report by an American Diabetes Association Expert Committee to re-examine diagnostic criteria and classification. The present document includes the conclusions of the former and is intended for wide distribution and discussion before final proposals are submitted to WHO for approval. The main changes proposed are as follows. The diagnostic fasting plasma (blood) glucose value has been lowered to > or =7.0 mmol l(-1) (6.1 mmol l(-1)). Impaired Glucose Tolerance (IGT) is changed to allow for the new fasting level. A new category of Impaired Fasting Glycaemia (IFG) is proposed to encompass values which are above normal but below the diagnostic cut-off for diabetes (plasma > or =6.1 to <7.0 mmol l(-1); whole blood > or =5.6 to <6.1 mmol l(-1)). Gestational Diabetes Mellitus (GDM) now includes gestational impaired glucose tolerance as well as the previous GDM. The classification defines both process and stage of the disease. The processes include Type 1, autoimmune and non-autoimmune, with beta-cell destruction; Type 2 with varying degrees of insulin resistance and insulin hyposecretion; Gestational Diabetes Mellitus; and Other Types where the cause is known (e.g. MODY, endocrinopathies). It is anticipated that this group will expand as causes of Type 2 become known. Stages range from normoglycaemia to insulin required for survival. It is hoped that the new classification will allow better classification of individuals and lead to fewer therapeutic misjudgements.
Active and passive immunization to protect against antibiotic associated caecitis in hamsters. (1983)

The administration of clindamycin to hamsters induces a lethal enterocolitis as a consequence of toxins produced in the alimentary tract by Clostridium difficile. The lethal and cytopathic effects of C. difficile toxins are neutralized in vitro by C. sordellii antitoxin and hamsters may be protected against clindamycin induction of caecitis by passive immunization using C. sordellii antitoxin. To examine active immunization using C. difficile and C. sordellii toxoids, groups of male and female Syrian hamsters were immunized on two occasions and challenged by parenteral clindamycin. A concentrated C. difficile toxoid protected 90% of females and 78% of males; the degree of protection per group decreased with dilution of the toxoid used for immunization. A similar degree of protection was observed in female hamsters immunized with a bivalent vaccine prepared from the partially purified toxins A and B of C. difficile. Immunization using a C. sordellii toxoid protected between 100 and 25% of females per group and between 50 and 12.5% of males per group.
Three-Dimensional Structure of the Zinc-Containing Phosphotriesterase with the Bound Substrate Analog Diethyl 4-Methylbenzylphosphonate, (1996)

Phosphotriesterase from Pseudomonas diminuta catalyzes the hydrolysis of paraoxon and related acetylcholinesterase inhibitors with rate enhancements that approach 10(12). The enzyme requires a binuclear metal center for activity and as isolated contains 2 equiv of zinc per subunit. Here we describe the three-dimensional structure of the Zn2+/Zn2+-substituted enzyme complexed with the substrate analog diethyl 4-methylbenzylphosphonate. Crystals employed in the investigation belonged to the space group C2 with unit cell dimensions of a = 129.6 A, b = 91.4 A, c = 69.4 A, beta = 91.9 degrees, and two subunits in the asymmetric unit. The model was refined by least-squares analysis to a nominal resolution of 2.1 A and a crystallographic R-factor of 15.4% for all measured X-ray data. As in the previously reported structure of the cadmium-containing enzyme, the bridging ligands are a carbamylated lysine residue (Lys 169) and a hydroxide. The zinc ions are separated by 3.3 A. The more buried zinc ion is surrounded by His 55, His 57, Lys 169, Asp 301, and the bridging hydroxide in a trigonal bipyramidal arrangement as described for the cadmium-substituted enzyme. Unlike the octahedral coordination observed for the more solvent-exposed cadmium ion, however, the second zinc is tetrahedrally ligated to Lys 169, His 201, His 230, and the bridging hydroxide. The diethyl 4-methylbenzylphosphonate occupies a site near the binuclear metal center with the phosphoryl oxygen of the substrate analog situated at 3.5 A from the more solvent-exposed zinc ion. The aromatic portion of the inhibitor binds in a fairly hydrophobic pocket. A striking feature of the active site pocket is the lack of direct electrostatic interactions between the inhibitor and the protein. This most likely explains the broad substrate specificity exhibited by phosphotriesterase. The position of the inhibitor within the active site suggests that the nucleophile for the hydrolysis reaction is the metal-bound hydroxide.
Gaucher's disease: a disease with chronic stimulation of the immune system. (1982)

Concentrations of IgA, IgG, and IgM were measured in 25 patients with Gaucher's disease. The mean of each was significantly higher than that generally observed in healthy adults. A direct correlation was noted between IgA and IgG concentrations and age. Patients who underwent splenectomy had IgM concentrations significantly lower than those of persons who did not. In two of 25 patients, multiple myeloma of the nonsecretory type developed. The migration inhibition factor (MIF) test performed with the lymphocytes of our patients was positive to glucocerebroside in four of 17 patients, to glucocerebrosidase in four of 19 patients, and to the extracts of the spleen of a patient with Gaucher's disease in three of eight patients. The results of al MIF tests were negative in six control subjects with splenomegaly of other causes. Our results suggest that in Gaucher's disease there is chronic stimulation of the humoral immune system. The first expression of this stimulation is the production of polyclonal immunoglobulins and, in due time, the development of monoclonal immunoglobulin as well as multiple myeloma.
NF-κB as a therapeutic target in neurodegenerative diseases (2007)

NF-kappaB is a transcription factor that regulates numerous physiological functions, and that is involved in the pathogenesis of various diseases. In the nervous system there is evidence supporting a dual role of NF-kappaB in neurodegenerative diseases; activation of NF-kappaB in neurons promotes their survival, whereas activation in glial and immune cells mediates pathological inflammatory processes. The reason for such a dichotomy lies in the complexity of the NF-kappaB system. Emerging research has begun to dissect the pathways leading to the activation of the different NF-kappaB proteins, and the gene targets of NF-kappaB, in cells of the nervous system. In this article the authors discuss recent findings concerning the roles of NF-kappaB in the pathogenesis of several neurodegenerative disorders, and its potential as a pharmaceutical target for these disorders.
Current Diagnostic Modalities for Vulnerable Plaque Detection (2007)

Rupture of vulnerable plaques is the main cause of acute coronary syndrome and myocardial infarction. Identification of vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize such plaques. Several diagnostic methods are currently tested to detect vulnerable plaques. Angiography has a low discriminatory power to identify the vulnerable plaque, but does provide information about the entire coronary tree and serves as guide for invasive imaging techniques and therapy. Angioscopy offers a direct visualization of the plaque surface and intra-luminal structures like thrombi and tears. However, angioscopy is difficult to perform, invasive and only the proximal part of the vessels can be investigated. IVUS (intravascular ultrasound) provides some insight into the composition of plaques. The detection of vulnerable plaques is mainly based on series of case reports with a lack of prospectivity and follow-up. Palpography, an IVUS derived technique, reveals information, which is not recognizable in IVUS. It can differentiate between deformable and non-deformable tissue, which enables the technique to detect vulnerable plaques with a positive predictive value. The clinical value of palpography is currently under investigation. Thermography assesses the temperature heterogeneity as an indicator of the metabolic state of the plaque. A coincidence of temperature rise and localization of vulnerable plaque was suggested. OCT (optical coherence tomography) can provide images with ultrahigh resolution utilizing the back-reflection of near-infrared light from optical interfaces in tissue. Drawbacks are the low penetration depth into tissue and the absorbance of light by blood. Raman spectroscopy can provide quantification about the molecular composition of the plaque. Long acquisition time, the low penetration depth and light absorbance by blood limit the performance of the technique. Another light emitting technique is NIR (near infrared spectroscopy), which identifies lipid loaded plaques and is tested currently in clinical trials. Non-invasive MRI (magnetic resonance imaging) and multislice spiral computed tomography (MSCT), with their excellent ability to identify lipid-rich tissue, have been utilized to characterize potentially vulnerable plaques foremost in non-moving structures like the carotid arteries. Due to the resolution of the techniques small plaque structure cannot be assessed. The role of non-invasive imaging in vulnerable plaque detection is currently under investigation. Several invasive and non-invasive techniques are currently under development to assess the vulnerable plaque. Most of the techniques show exiting features, but none have proven their value in an extensive in vivo validation and all have a lack of prospective data.
Prophylactic and therapeutic vaccination with dendritic cells against hepatitis C virus infection (2005)

Antigen uptake and presentation capacities enable DC to prime and activate T cells. Recently, several studies demonstrated a diminished DC function in hepatitis C virus (HCV) infected patients showing impaired abilities to stimulate allogenic T cells and to produce IFN-gamma in HCV infected patients. Moreover, DC of patients who have resolved HCV infection behave like DC from healthy donors responding to maturation stimuli, decrease antigen uptake, up-regulate expression of appropriate surface marker, and are potent stimulators of allogenic T cells. A number of studies have demonstrated in tumour models and models of infectious diseases strong induction of immune responses after DC vaccination. Because DC are essential for T-cell activation and since viral clearance in HCV infected patients is associated with a vigorous T-cell response, we propose a new type of HCV vaccine based on ex vivo stimulated and matured DC loaded with HCV specific antigens. This vaccine circumvents the impaired DC maturation and the down regulated DC function of HCV infected patients in vivo by giving the necessary maturation stimuli and the HCV antigens in a different setting and location ex vivo. Strong humoral and cellular immune responses were detected after HCV core DC vaccination. Furthermore, DC vaccination shows partial protection in a therapeutic and prophylactic model of HCV infection. In conclusion, mice immunized with HCV core pulsed DC generated a specific antiviral response in a mouse HCV challenge model. Our results indicate that HCV core pulsed DC may serve as a new modality for immunotherapy of HCV especially in chronically infected patients.
Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40-ligand (1996)

Blockade of costimulation through the B7-CD28 pathway by CTLA4Ig can lead to Ag-specific T cell tolerance. Most models studied to date involve a Th1-dependent response. To investigate whether the tolerizing effects of CTLA4Ig might vary depending upon the cytokine nature of the immune response, we studied its effects on contact hypersensitivity (CHS) in response to two allergens. In BALB/c mice, both 2,4-dinitrofluorobenzene (DNFB) and FITC induce CHS. However, the DNFB response is Th1-predominant, while the FITC response is Th2 predominant. CTLA4Ig treatment during primary sensitization induced long-lasting unresponsiveness to DNFB, with 88% and 76% inhibition of primary (first challenge) and secondary (re-sensitization and re-challenge) CHS, respectively. In contrast, CTLA4Ig inhibited primary CHS to FITC by over 82% but had little effect on secondary CHS. Consistent with its effects on CHS, the suppressive effect of CTLA4Ig on Th2 cells was short-lived in FITC-sensitized mice, while Th1-like cytokine-secreting cells remained reduced in DNFB-sensitized mice, even when the animals were rechallenged with DNFB. The addition of anti-CD40L Ab to CTLA4Ig was able to induce long-lasting unresponsiveness to FITC, indicating the ability of cells mounting this Th2 response to receive costimulatory signals through either pathway. In conclusion, CHS can be mediated by both Th1 and Th2 cells, and the ability of CTLA4Ig to lead to long-standing nonresponsiveness in this model depends on the nature (i.e., cytokine profile) of the immune response.
Structural insights into human Kif7, a kinesin involved in Hedgehog signalling (2012)

Kif7, a member of the kinesin 4 superfamily, is implicated in a variety of diseases including Joubert, hydrolethalus and acrocallosal syndromes. It is also involved in primary cilium formation and the Hedgehog signalling pathway and may play a role in cancer. Its activity is crucial for embryonic development. Kif7 and Kif27, a closely related kinesin in the same subfamily, are orthologues of the Drosophila melanogaster kinesin-like protein Costal-2 (Cos2). In vertebrates, they work together to fulfil the role of the single Cos2 gene in Drosophila. Here, the high-resolution structure of the human Kif7 motor domain is reported and is compared with that of conventional kinesin, the founding member of the kinesin superfamily. These data are a first step towards structural characterization of a kinesin-4 family member and of this interesting molecular motor of medical significance.
Targeted Delivery of Antisense Oligodeoxynucleotide and Small Interference RNA into Lung Cancer Cells (2006)

Selective gene inhibition by antisense oligodeoxynucleotide (AS-ODN) or by small interference RNA (siRNA) therapeutics promises the treatment of diseases that cannot be cured by conventional drugs. However, antisense therapy is hindered due to poor stability in physiological fluids and limited intracellular uptake. To address these problems, a ligand targeted and sterically stabilized nanoparticle formulation has been developed in our lab. Human lung cancer cells often overexpress the sigma receptor and, thus, can be targeted with a specific ligand such as anisamide. AS-ODN or siRNA against human survivin was mixed with a carrier DNA, calf thymus DNA, before complexing with protamine, a highly positively charged peptide. The resulting particles were coated with cationic liposomes consisting of DOTAP and cholesterol (1:1, molar ratio) to obtain LPD (liposome-polycation-DNA) nanoparticles. Ligand targeting and steric stabilization were then introduced by incubating preformed LPD nanoparticles with DSPE-PEG-anisamide, a PEGylated ligand lipid developed earlier in our lab, by the postinsertion method. Nontargeted nanoparticles coated with DSPE-PEG were also prepared as a control. Antisense activities of nanoparticles were determined by survivin mRNA down-regulation, survivin protein down-regulation, ability to trigger apoptosis in tumor cells, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to anticancer drugs. We found that tumor cell delivery and antisense activity of PEGylated nanoparticles were sequence dependent and rely on the presence of anisamide ligand. The uptake of oligonucleotide in targeted, PEGylated nanoparticles could be competed by excess free ligand. Our results suggest that the ligand targeted and sterically stabilized nanoparticles can provide a selective delivery of AS-ODN and siRNA into lung cancer cells for therapy.
Intramolecular Repression of Mouse Heat Shock Factor 1 (1998)

The pathway leading to transcriptional activation of heat shock genes involves a step of heat shock factor 1 (HSF1) trimerization required for high-affinity binding of this activator protein to heat shock elements (HSEs) in the promoters. Previous studies have shown that in vivo the trimerization is negatively regulated at physiological temperatures by a mechanism that requires multiple hydrophobic heptad repeats (HRs) which may form a coiled coil in the monomer. To investigate the minimal requirements for negative regulation, in this work we have examined mouse HSF1 translated in rabbit reticulocyte lysate or extracted from Escherichia coli after limited expression. We show that under these conditions HSF1 behaves as a monomer which can be induced by increases in temperature to form active HSE-binding trimers and that mutations of either HR region cause activation in both systems. Furthermore, temperature elevations and acidic buffers activate purified HSF1, and mild proteolysis excises fragments which form HSE-binding oligomers. These results suggest that oligomerization can be repressed in the monomer, as previously proposed, and that repression can be relieved in the apparent absence of regulatory proteins. An intramolecular mechanism may be central for the regulation of this transcription factor in mammalian cells, although not necessarily sufficient.
Dynamic network decoding revisited (2009)

We present a dynamic network decoder capable of using large cross-word context models and large n-gram histories. Our method for constructing the search network is designed to process large cross-word context models very efficiently and we address the optimization of the search network to minimize any overhead during run-time for the dynamic network decoder. The search procedure uses the full LM history for lookahead, and path recombination is done as early as possible. In our systematic comparison to a static FSM based decoder, we find the dynamic decoder can run at comparable speed as the static decoder when large language models are used, while the static decoder performs best for small language models. We discuss the use of very large vocabularies of up to 2.5 million words for both decoding approaches and analyze the effect of weak acoustic models for pruning.
Activated Protein C-catalyzed Proteolysis of Factor VIIIa Alters Its Interactions within Factor Xase (1996)

Factor VIIIa, the cofactor for the factor IXa-dependent conversion of factor X to factor Xa, is proteolytically inactivated by activated protein C (APC). APC cleaves at two sites in factor VIIIa, Arg336, near the C terminus of the A1 subunit; and Arg562, bisecting the A2 subunit (Fay, P., Smudzin, T., and Walker, F. (1991) J. Biol. Chem. 266, 20139-20145). Factor VIIIa increased the fluorescence anisotropy of fluorescein-Phe-Phe-Arg factor IXa (Fl-FFR-FIXa; Kd = 42.4 nM), whereas cleavage of factor VIIIa by APC eliminated this property. Isolation of the APC-cleaved A1/A3-C1-C2 dimer (A1336/A3-C1-C2), and the fragments derived from cleaved A2 subunit (A2N/A2C), permitted dissection of the roles of individual cleavages in cofactor inactivation. Intact A1/A3-C1-C2 dimer increased Fl-FFR-FIXa anisotropy and bound factor X in a solid phase assay, while these activities were absent in the A1336/A3-C1-C2. However, the residues removed by this cleavage, Met337 Arg372, did not directly participate in these functions since neither a synthetic peptide to this sequence nor an anti-peptide polyclonal antibody blocked these activities using intact dimer. CD spectral analysis of the intact and truncated dimers indicated reduced alpha and/or beta content in the latter. The A1/A3-C1-C2 dimer plus A2 subunit reconstitutes cofactor activity and produced a factor VIIIa-like effect on the anisotropy of Fl-FFR-FIXa. However, when A2 was replaced by the A2N/A2C fragments, the resulting fluorescence signal was equivalent to that observed with the dimer alone. These results indicate that APC inactivates the cofactor at two levels within the intrinsic factor Xase complex. Cleavage of either subunit modulates the factor IXa active site, suggesting an essential synergy of interactive sites in factor VIIIa. Furthermore, cleavage of the A1 site alters the conformation of a factor X binding site within that subunit, thereby reducing the affinity of cofactor for substrate.
The oocyte population is not renewed in transplanted or irradiated adult ovaries (2008)

No evidence was found to support the hypothesis that progenitor cells from extra-ovarian sources can repopulate the adult ovary. The findings are consistent with the conventional view that a limited number of oocytes are formed before birth and declines with age. The study did not, however, rule out the possibility that germline stem cells may reside in the adult ovary.
Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials (2015)

Cancer Research UK, Medical Research Council.
Isolierung und Strukturermittlung der neuen Cyclosporine E, F, G, H und I (1982)

Isolation and Structure Determination of the New Cyclosporins E, F, G, H und I The cyclosporins, a new group of biologically active metabolites, are produced by the fungus Tolypocladium inflatum GAMS (formerly designated as Trichoderma polysporum [LINK EX PERS.] RIFAI). They represent neutral cyclic oligopeptides composed of 11 amino acids. In addition to the already described cyclosporins A–D new minor compounds, cyclosporins E–I, have now been isolated from the crude cyclosporin‐complex by applying extensive chromatographical separation procedures. The structures of the new compounds have been determined by spectroscopical evidence, hydrolytic cleavage and chemical correlation reactions as well as by X‐ray analysis of suitable derivatives. Cyclosporins A, B, C, D and G differ from each other only in the nature of the amino acid no. 2. Cyclosporins E and I are N ‐demethylated congeners of cyclosporins A and D respectively, Cyclosporin F has been recognized as deoxycyclosporin A, whereas Cyclosporin H represents an epimeric form of cyclosporin A and contains N ‐methyl‐D‐valine in position 11.