gebhart/patrepeval huggingface dataset:
A quantitative indicator diagram for lytic polysaccharide monooxygenases reveals the role of aromatic surface residues in HjLPMO9A regioselectivity (2017)

Lytic polysaccharide monooxygenases (LPMOs) have changed our understanding of lignocellulosic degradation dramatically over the last years. These metalloproteins catalyze oxidative cleavage of recalcitrant polysaccharides and can act on the C1 and/or C4 position of glycosidic bonds. Structural data have led to several hypotheses, but we are still a long way from reaching complete understanding of the factors that determine their divergent regioselectivity. Site-directed mutagenesis enables the investigation of structure-function relationship in enzymes and will be of major importance in unraveling this intriguing matter. In this context, it is crucial to have an enzyme assay or screening approach with a direct correlation with the desired functionality. LPMOs render this search extra challenging due to their insoluble substrates, complex pattern of reaction products and lack of synthetic standards of most oxidized products. Here, we describe a regioselectivity indicator diagram based on the time-course of only 2 HPAEC-PAD signals. The diagram was successfully used to confirm the hypothesis that aromatic surface residues influence the C1/C4 oxidation ratio in Hypocrea jecorina LPMO9A. Consequently, the diagram should become a valuable tool in the search towards better understanding and engineering of regioselectivity in LPMOs.
A Rating‐Scale Method for Determining Absolute Taste Thresholds (1962)

SUMMARY Absolute taste thresholds for salt and sweetness were determined by a combination of ascending‐series and rating‐scale methods: for salt a value only very slightly under previous quoted figures was obtained, for sugar a value of .002 p/p was obtained. The results also permitted a scaling of each taste description on the rating‐scales in terms of both j.n.d's above threshold and solution concentrations. Previous workers have doubted whether there is one single absolute threshold for taste: the present results suggest a number of thresholds in an ascending series may be defined operationally.
PIM kinases are progression markers and emerging therapeutic targets in diffuse large B-cell lymphoma (2012)

This work demonstrates that PIM expression in DLBCL is associated with activation of the JAK/STAT signalling pathway and with the proliferative activity. The correlation of nuclear PIM1 expression with disease stage and the modest response to small-molecule inhibitors suggests that PIM kinases are progression markers rather than primary therapeutic targets in DLBCL.
Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men. (1996)

Effectiveness of a simultaneous inhibition of cholesterol absorption and synthesis, caused by sitostanol ester margarine and pravastatin, was studied to control mild hypercholesterolemia in men with non-insulin-dependent diabetes mellitus (NIDDM) (n = 8). Margarine, 24 g daily, was a basal dietary treatment. Four 7-week intervention periods included margarine, sitostanol (3 g/day) ester margarine, pravastatin (40 mg/day), and sitostanol ester margarine plus pravastatin in a random order. Pravastatin lowered serum total (-32%) and LDL cholesterol (-38%) and apolipoprotein B (-39%) because of enhanced removal (+20%) and decreased production (-26%) of LDL apolipoprotein B, and reduced synthesis (-9%) and turnover (-8%) of cholesterol, which resulted in reduced biliary cholesterol seretion (-18%). Even though serum triglycerides were lowered by 28%, VLDL, IDL, and light and dense LDL became triglyceride-enriched. Despite increasing cholesterol synthesis, sitostanol lowered LDL cholesterol (-14%) by inhibiting cholesterol absorption (-68%) and LDL apolipoprotein B production rate (-20%). Combination of pravastatin and sitostanol ester lowered serum total, VLDL, IDL, and LDL cholesterol and LDL apolipoprotein B by the highest rate, 35%, 50%, 35%, 44%, and 45% from the control margarine period, respectively, because of reduced apolipoprotein B transport rate (but unchanged removal), in both the total and dense LDL subfractions. HDL cholesterol and apolipoprotein A-I kinetics were unchanged. In spite of decreased absorption, cholesterol synthesis was not compensatorily increased. In conclusion, simultaneous inhibition of cholesterol absorption and synthesis lowers LDL cholesterol and apolipoprotein B by 44-45% solely through inhibition of LDL apolipoprotein B production rate in hypercholesterolemic NIDDM patients. A combination of statin to sitostanol ester margarine-resistant patients offers a safe and effective measure to normalize abnormally high cholesterol values, probably with a lowered statin dose.
The Manchester prototype dataflow computer (1985)

The Manchester project has developed a powerful dataflow processor based on dynamic tagging. This processor is large enough to tackle realistic applications and exhibits impressive speedup for programs with sufficient parallelism.
Differential Effects of Acute and Extended Infusions of Glucagon-Like Peptide-1 on First- and Second-Phase Insulin Secretion in Diabetic and Nondiabetic Humans (2003)

Extended administration of GLP-1 not only augments glucose-stimulated insulin secretion, but also shifts the dynamics of the insulin response to earlier release in both diabetic and nondiabetic humans. The restitution of some FPIR in subjects with type 2 diabetes is associated with significantly improved glucose tolerance. These findings demonstrate the benefits of a 3-h infusion of GLP-1 on beta-cell function beyond those of an acute insulin secretagogue, and support the development of strategies using continuous or prolonged GLP-1 receptor agonism for treating diabetic patients.
Tocilizumab: a novel therapy for patients with large-vessel vasculitis (2011)

In this small group of patients with LVV, treatment with TCZ was effective and well tolerated. Further, larger studies are required to confirm our findings.
Treatment of Severe Constipation Improves Parkinsonʼs Disease (PD) Symptoms (2009)

Purpose: Constipation is common in idiopathic PD which affects motor skills, speech and other functions. Constipation may precede PD by up to 10 years and constipation is a risk factor in developing PD.(1) One hypothesis points to a neurotoxin in bowel flora that contributes to the progression of this disease.(2) We report intriguing observations in one PD patient treated for constipation using a novel approach. Case: A 73y old man with a 4y history of severe constipation and PD presented with constipation developing shortly after the PD diagnosis in 2004. He reported bloating with 1-2 stools/week requiring high doses of docusate sodium and psyllium husks. He exhibited marked pillrolling hand tremor, micrographia, positive glabellar tap reflex and cogwheel rigidity while on carbidopa/levodopa combination. He started a combination of vancomycin, metronidazole and colchicine for his treatment-resistant constipation in May 2008. At 21 days he reported his constipation to be markedly improved, defecating daily with ease and no bloating. He also noticed a dramatic improvement in his Parkinson's symptoms with visible decrease in tremor commencing from about 10 days into therapy. By November 2008 and March 2009 on continuous therapy he reported 1 stool/d, no persistent tremors and there was no detectable cogwheel rigidity with absence of glabellar tap reflex. By May 2009 the patient reported a single episode of tremor which lasted 5 minutes. He is continuing 1.2 g metronidazole, 1 g vancomycin and 1 mg colchicine daily. Reduction of the carbidoba/levodopa resulted in occasional tremor ‘attacks’ and a low dose was continued. Discussion: This case reports an unexpected and dramatic symptom reduction in PD with treatment of the constipation, unachievable with current best therapies. It may be a clue to the causality in a subset of PD. Treatment-resistant constipation may be a preceding marker of PD perhaps related to the underlying pathophysiologic process. (1) Bacterial and fungal toxins have been shown to inhibit proteasomes resulting in PD-like syndrome in rat models (2) Injection of Nocardia asteroides (NA) into mice resulted in PD-like syndrome and NA genes were demonstrated in brain tissue of PD patients. (3) Vancomycin originated from Nocardia orientalis and may be acting in the gut flora to suppress a related pathogen's release of its toxins and may help uncover the riddle of PD. Such simple therapy may improve quality of life in many patients with PD. References: 1. Abbott RD, et al. Neurology 2001;57:456-62. 2. Harder B. Sci News 2004; ISSN 0036-8423. 3. LeWitt PA, et al. Mov Disord 2004; 19 (suppl 9): S222. Disclosure: Prof Thomas Borody - Director/Proprietary ownership: Centre for Digestive Diseases Pty Ltd. Margaux Torres - Employee: Centre for Digestive Diseases Pty Ltd Jordana Campbell - Employee: Centre for Digestive Diseases Pty Ltd Lauren Hills - Employee: Centre for Digestive Diseases Pty Ltd Sahisha Ketheeswaran - Employee: Centre for Digestive Disease Pty Ltd.
Body-Mass Index and Mortality in a Prospective Cohort of U.S. Adults (1999)

The risk of death from all causes, cardiovascular disease, cancer, or other diseases increases throughout the range of moderate and severe overweight for both men and women in all age groups. The risk associated with a high body-mass index is greater for whites than for blacks.
Endocrine therapy of advanced carcinoma of the prostate (1993)

Increasing evidence suggests that growth of the prostatic tissue is regulated by a network of hormones and growth factors, in which androgens play the prominent role. Hormonal manipulation remains the core of treatment for locally advanced and metastatic prostate cancer. Achievement of a complete androgen blockade, by surgical or medical means or a combination of both, offers superior results in palliative management of advanced disease. Management of hormonal refractory cancer, however, remains a challenge to clinicians.
Activation of the Serum Response Element and 12-O-Tetradecanoylphorbol-13-Acetate Response Element by the Activated c-raf-1 Protein in a Manner Independent of Protein Kinase C (1989)

Transfection of the cDNA encoding the activated c-raf-1 protein or addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) or dibutyryl cAMP to NIH/3T3 cells activated the c-fos gene enhancer linked to the chloramphenicol acetyltransferase or luciferase reporter gene. Prolonged treatment of NIH/3T3 cells with phorbol 12,13-dibutyrate caused down-regulation of protein kinase C. In these cells, addition of TPA did not stimulate the c-fos gene enhancer any more, but transfection of the c-raf-1 cDNA or addition of dibutyryl cAMP still stimulated the c-fos gene enhancer to the same extent as those induced in the control cells. Transfection of the c-raf-1 cDNA or addition of TPA to NIH/3T3 cells stimulated the serum response element and TPA response element but not the cAMP response element. In contrast, addition of dibutyryl cAMP to NIH/3T3 cells stimulated the cAMP response element but not the serum response element or TPA response element. These results indicate that the activated c-raf-1 protein stimulates the serum response element and TPA response element in a manner independent of protein kinase C and cAMP-dependent protein kinase. Since the c-fos gene enhancer has been shown to contain the serum response element and cAMP response element, it is most likely that the c-raf-1 protein is involved in the regulation of c-fos gene expression through the serum response element.
Poly(ethylenimine-co-l-lactamide-co-succinamide):  A Biodegradable Polyethylenimine Derivative with an Advantageous pH-Dependent Hydrolytic Degradation for Gene Delivery (2002)

A biodegradable gene transfer vector has been synthesized by linking several low molecular weight (MW) polyethylenimine (PEI, 1200 Da) blocks using an oligo(L-lactic acid-co-succinic acid) (OLSA, 1000 Da). The resulting copolymer P(EI-co-LSA) (8 kDa) is soluble in water and degrades via base-catalyzed hydrolytic cleavage of amide bonds. With regard to its application as a gene transfer agent, the polymer showed an interesting pH dependency of degradation. At pH 5, when DNases are highly active, the degradation proceeds at a slower rate than at a physiological pH of 7.4. PEI and P(EI-co-LSA) spontaneously formed complexes with plasmid DNA. Whereas the complexes formed with PEI were not stable and aggregated, forming particles of up to 1 microm hydrodynamic diameter, P(EI-co-LSA) formed complexes, which were about 150 nm in size and of narrow size distribution. The latter complexes were stable, due to their high surface charge (zeta-potential + 18 mV). Similar to low MW PEI, the copolymer exhibited a low toxicity profile. At the same time, the copolymer showed a significant enhancement of transfection activity in comparison to the low MW PEI. This makes P(EI-co-LSA) a promising candidate for long-term gene therapy where biocompatibility and biodegradability become increasingly important.
A [RuII(bipy)3]-[1,9-diamino-3,7-diazanonane-4,6-dione] two-component system, as an efficient ON–OFF luminescent chemosensor for Ni2+ and Cu2+ in water, based on an ET (energy transfer) mechanism (1999)

A dioxo-tetramine ligand (1,9-diamino-3,7-diazanonane-4,6-dione ≡ dioxo-2,3,2-tet) has been appended to a RuII(bipy)3 unit. This new system, 2, is water-soluble and capable of sensing Cu2+ and Ni2+ cations thanks to the strong quenching of the Ru(bipy)3 fluorescence, which takes place when a metal cation is coordinated by the dioxo-2,3,2-tet binding unit. Coordination requires the energetically expensive deprotonation of the amide nitrogens, so that only Cu2+ and Ni2+ are able to promote it among the series of divalent first-row transition metal cations. Moreover, the complexation reaction is pH-dependent and one can distinguish between the two metal cations on working at the proper pH. The quenching mechanism has been examined by measuring the lifetime of the excited state of the ruthenium luminophore both on the metal-free and metal-complexed system and by flash photolysis experiments carried out on the complexed systems. The results clearly indicate that an energy transfer mechanism holds both for the Cu2+ and Ni2+ complex. The characterization of 2 as a water soluble ON–OFF sensor for copper and nickel has also been checked for its lowest detection limit, finding that these two metals can be detected down to a 10–7 M concentration. Moreover, also system 3, containing a dioxo-2,3,2-tet ligand and the ReI(CO)3bipy(Cl) luminophore, has been examined as another possible water-soluble ON–OFF fluorescent sensor for the same transition metal cations. Again, only Cu2+ and Ni2+ are bound with a pH-dependent equilibrium, but incomplete luminescence quenching was observed, which prevented the determination of the quenching mechanism.
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes (2004)

Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.
Longitudinal piezoelectric coefficient measurement for bulk ceramics and thin films using pneumatic pressure rig (1999)

A pneumatic pressure rig was designed to measure the effective d33 coefficient of thin film piezoelectrics by applying a known stress and monitoring the induced charge. It was found that the stress state imposed included components both perpendicular and parallel to the film plane. The later were due to friction and could largely be relieved through sliding of the O-rings to their equilibrium positions for a given pressure. The induced charge stabilized as equilibrium was reached and most of it was produced by the normal component of the stress. By minimizing the surface friction and compensating for the remnant in-plane stress, very good agreement was obtained among the d33 values measured by the Berlincourt method, double-beam interferometry and this method for a bulk lead zirconate titanate (PZT) sample. The d33 value of PZT thin films made by sol-gel processing was also measured. The as deposited films usually showed very weak piezoelectricity with d33 values ranging from 0 to 10 pC/N, indicating little pre-existing alignment of the domains. With increasing poling field, the d33 value also increased and saturated at poling fields exceeding three times the coercive field. Typically, films with thicknesses around 1 μm had d33 values of 100 pC/N. Good agreement between double-beam interferometry and this technique was also obtained for thin films. The small difference between the two measurements is attributed to the effect of mechanical boundary conditions on the effective d33 coefficient.
Pasteurella multocida isolated from rabbits and swine: serologic types and toxin production. (1986)

Pasteurella multocida isolates from rabbits and swine of different geographic origins were serologically grouped and typed. Similar capsule serogroups and somatic serotypes were common to both species. Selected serotypes of both serogroups A and D were tested for toxin production. Toxin-producing isolates from both rabbits and swine were found in serogroup D, but not serogroup A. A correlation was not found between somatic serotype and the capability of an isolate to produce toxin. Noncapsulated variants derived from parent capsulated toxin-producing isolates also produced toxin. The capability of an isolate to produce a toxin did not necessarily make it virulent. The toxins from rabbit and swine P multocida of different geographic origins were antigenically similar. Cell lysis was compared with sonication as a method to release cell-associated toxin for biochemical purification. The toxin was purified from lysates by ammonium sulfate precipitation, followed by ion exchange and gel-filtration chromatographic procedures. The purified toxin had a molecular weight of 112,000 to 158,000 and an apparent isoelectric point of 4.65 to 4.8. The toxin precipitated at pH near its isoelectric point. Electrofocusing-electrophoresis titration curves of the purified toxin preparation showed it consisted of 2 similar proteins which varied in their capabilities to stain with Coomassie brilliant blue. The proteins precipitated together near their apparent isoelectric point and interacted at pH 9.7.
Mechanisms of Pain in Arthritis (2002)

Inflammation in the joint causes peripheral sensitization (increase of sensitivity of nociceptive primary afferent neurons) and central sensitization (hyperexcitability of nociceptive neurons in the central nervous system). The processes of sensitization are thought to be the basis of arthritic pain that appears as spontaneous pain (joints at rest) and hyperalgesia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Sensitization also facilitates efferent neuronal processes through which the nervous system influences the inflammatory process. Peripheral sensitization is produced by the action of inflammatory mediators such as bradykinin, prostaglandins, neuropeptides, and cytokines which activate corresponding receptors in proportions of nerve fibers. In addition, the expression of receptors, for example, bradykinin and neurokinin 1 receptors, is upregulated during inflammation. The development of hyperexcitability of spinal cord neurons is produced by various transmitter/receptor systems that constitute and modulate synaptic activation of the neurons. The key transmitter is glutamate that activates N-methyl-d-aspartate (NMDA) and non-NMDA receptors on spinal cord neurons. Blockade of these receptors prevents and reduces central sensitization. Excitatory neuropeptides (substance P and calcitonin gene-related peptide) further central sensitization. Central sensitization also is facilitated by mediators that have complex actions (e.g., prostaglandin E(2)). Spinal PGE(2) binds to receptors at presynaptic endings of primary afferent neurons (thus influencing synaptic release) and to receptors on postsynaptic spinal cord neurons. The administration of PGE(2) to the spinal cord surface produces changes of responsiveness of spinal neurons similar to peripheral inflammation, and spinal indomethacin to the spinal cord attenuates development of hyperexcitability significantly.
Identification and characterization of a high-affinity zinc uptake system in Neisseria gonorrhoeae (2001)

A search of the gonococcal genome database using the known zinc-binding protein (znuA) sequences from Escherichia coli and Haemophilus influenzae identified an open reading frame encoding a putative gonococcal ZnuA. The consensus amino acid sequence of this open reading frame possessed a characteristic 30-amino acid histidine-rich metal-binding motif (repetitive HDH sequence) containing 43% histidine and 37% aspartic acid and glutamic acid. Subsequently, two adjacent open reading frames with homology to E. coli and H. influenzae znuB and znuC were located upstream of znuA. When partially purified from sonicated cell-free supernatants by CM-Sepharose chromatography, the mature gonococcal ZnuA had an estimated molecular mass of 38 kDa by SDS–PAGE. The presence of a DNA sequence encoding a 19-amino acid signal peptide and the solubility of the mature ZnuA suggested that this protein was located in the periplasm. Inactivation of the Neisseria gonorrhoeae F62 znuA by insertional mutagenesis resulted in a mutant that had a growth rate lower than that of the wild-type parent strain and that required high concentrations of ZnCl2 (≥200 μM) for optimal growth. Using a chemically defined agar medium, the gonococcal ZnuA mutant grew only in the presence of Zn2+, whereas Mg2+, Ca2+, Ni2+, Fe2+, Cu2+, Mn2+ and Cd2+ had either no effect or were growth inhibitory.
Drug delivery to lymphatic tissue. (1996)

Efficient diagnosis and therapy of diseases affecting lymph nodes rely on the availability of drugs that are retained by lymph nodes. Intralymphatically or interstitially administered macromolecular carriers accumulate efficiently in draining lymph nodes. However, because of the high variability of lymphatic networks and drainage routes, systemic administration of lymphotropic carriers would be preferable and currently represents a major focus in lymphotropic drug design. This review focuses on advances in the development of intravenous drug carriers and briefly discusses agents used for local delivery.
Integrating virtual and physical context to support knowledge workers (2002)

The Kimura system augments and integrates independent tools into a pervasive computing system that monitors a user's interactions with the computer, an electronic whiteboard, and a variety of networked peripheral devices and data sources.