gebhart/patrepeval huggingface dataset:
Efficient Chemoenzymatic Dynamic Kinetic Resolution of 1-Heteroaryl Ethanols (2009)

The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80 degrees C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.
PREDICT: a method for inferring novel drug indications with application to personalized medicine (2011)

Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large-scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug-drug and disease-disease similarity measures for the prediction task. On cross-validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue-specific expression information on the drug targets. We further show that disease-specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease-specific signatures.
Desilication of agro based black liquor and green liquor using jet loop reactor (2007)

Non-wood fibers represent the largest resource of fibrous materials for many developing countries in the world. Attention is now being focused on cellulose bearing agricultural residues, which can be used as raw materials for production of paper. Though chemical pulping of these raw materials poses no problem, major difficulty arises in the recovery of heat and chemicals from the spent cooking chemical (black liquor). The presence of silica in black liquor obtained from agro based pulp and paper mill causes serious problems at filtration, washing, evaporation, burning, recausticizing and clarification levels of chemical recovery. It is, therefore, necessary to remove silica before the black liquor is concentrated to high solid content. The success of the desilication process by carbonation lies in accurate pH control otherwise lignin co-precipitation occurs during desilication. In the present work, a high mass transfer efficient, compact Jet Loop Reactors (JLR) or some times called as Highty Compact Reactor (HCR) is used for desilication to obtain exact pH control. The experiments were carried out in a 15 L reactor at room temperature as well as at higher temperatures. The results obtained in JLR are compared with those obtained by Bubble Column Reactor (BCR). Desilication of green liquor in both the reactors at different temperatures is also studied. The results show that desilication in JLR is more efficient at higher temperatures.
Sorafenib (2006)

In this review, we will discuss the clinical development of sorafenib and its role in the treatment of renal cancer. Additionally, we will highlight critical methods of clinical trial design and biomarker development that contribute to the development of sorafenib.
Umbilical cord blood–derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect (2015)

We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB)-derived regulatory T cells (Tregs) that expanded in cultures stimulated with K562 cells modified to express the high-affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3-100 × 10(6) Treg/kg. The median proportion of CD4(+)FoxP3(+)CD127(-) in the infused product was 87% (range, 78%-95%), and we observed no dose-limiting infusional adverse events. Clinical outcomes were compared with contemporary controls (n = 22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-versus-host disease (GVHD) at 100 days was 9% (95% confidence interval [CI], 0-25) vs 45% (95% CI, 24-67) in controls (P = .05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, nonrelapse mortality, relapse, and disease-free survival were similar in the Treg recipients and controls. KT64/86-expanded UCB Tregs were safe and resulted in low risk of acute GVHD.
Shear stress in atherosclerosis, and vascular remodelling. (1998)

Shear stress plays a role in lipid accumulation in primary atherosclerosis and vascular remodelling. We will present applications of a new technique, which enables to quantify shear stress in 3D vessel reconstructions. The method is based on 3D IVUS reconstructions of blood vessels either obtained by IVUS pull back (external iliac artery) or by a combination of angiography and IVUS (curved coronary artery). Distribution of wall thickness of a curved human right coronary artery was such that low wall thickness occurred where shear stress was high, and wall thickness was high where shear stress was low. Consequently, an inverse relationship between shear stress and wall thickness was detected. Although vascular remodelling after PTA in external iliac arteries of atherosclerotic Yucatan pigs was predicted both by acute gain and decrements in shear stress, the decrement in shear stress appeared a better predictor. In conclusion, shear stress appears to play a role in primary atherosclerosis and vascular remodelling after PTA.
Long‐term outcome results of the first tandem autotransplant trial for multiple myeloma (2006)

Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow-up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0.002), postenrolment (P < 0.001) and at relapse (P = 0.004); elevations of serum C-reactive protein (CRP) (P = 0.003) and lactate dehydrogenase (P = 0.029), anaemia (P = 0.029) and they more often completed two transplants within 12 months (P = 0.019). Postenrolment overall survival (OS) and event-free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0.001 and 0.037 respectively) and in the presence of low CRP at baseline (P = 0.001 and 0.017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0.001), IgA isotype (P = 0.002), International Staging System stage 3 (P = 0.014), and when patients had two protocol transplants prior to relapse (P = 0.038). Ten-year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high-dose melphalan, were applied together upfront for the management of myeloma.
Construction of an Artificial Receptor Protein (“Anticalin”) Based on the Human Apolipoprotein D (2004)

Human apolipoprotein D (ApoD) is a prominent member of the lipocalin family of proteins and transports arachidonic acid and progesterone in various body fluids. Lipocalins share a structurally conserved beta barrel as their central folding unit, which supports a set of four hypervariable loops that form the entrance to the ligand pocket. Based on this structural pattern ApoD was employed as a scaffold for the combinatorial design of artificial receptor proteins termed anticalins. After randomization of 24 amino acids located within the loop region, several ApoD variants were selected against hemoglobin, a biochemically well-characterized model target, by using bacterial phagemid display and colony screening. One variant, dubbed HbgA, was further investigated by surface plasmon resonance interaction analysis and found to complex hemoglobin specifically and with a dissociation constant of about 2 microM. While our previous work on the structurally related insect bilin-binding protein was focused on the generation of binding activity towards low-molecular-weight ligands, this study demonstrates for the first time that a lipocalin can also be tailored to recognize a protein target. The fact that even a human member of this protein family has now been successfully recruited for anticalin construction opens the possibility for future application of such engineered lipocalins as target-recognition vehicles in medical therapy.
Induction of Nitric Oxide Synthase Activity by Cytokines in Ventricular Myocytes Is Necessary but Not Sufficient to Decrease Contractile Responsiveness to β-Adrenergic Agonists (1995)

Recent evidence has documented that increased activity of an inducible nitric oxide synthase (iNOS; type 2 NO synthase) in primary isolates of adult rat ventricular myocytes after exposure to soluble mediators in medium conditioned by lipopolysaccharide-activated macrophages is associated with a decrease in their contractile responsiveness to beta-adrenergic agonists. It remained unclear which specific inflammatory cytokines in this medium contribute to the induction of iNOS activity in myocytes and whether induction of iNOS would result in an obligatory decline in contractile function. Interleukin (IL)-1 beta and tumor necrosis factor-alpha (TNF-alpha) were both present in the lipopolysaccharide-activated macrophage-conditioned medium. However, only IL-1 receptor antagonist and not an anti-rat TNF-alpha antiserum diminished the extent of iNOS induction in myocytes exposed to this medium and prevented a decline in contractile responsiveness to isoproterenol. When recombinant cytokines were used, IL-1 beta, TNF-alpha, and IFN-gamma each induced iNOS activity in cardiac myocytes at 24 hours. However, only the combination of IL-1 beta and IFN-gamma reproducibly caused contractile dysfunction in cardiac myocytes. Among the constituents of the defined medium routinely used for maintenance of adult rat ventricular myocytes in primary culture, it was noted that insulin (10(-7) mol/L) was required for NO production, as detected by nitrite release in cytokine-pretreated myocytes, although insulin had no effect on the extent of induction of iNOS mRNA or maximal enzyme activity in myocyte cell lysates.(ABSTRACT TRUNCATED AT 250 WORDS)
Oxidative Degradation of 4-Hydroxyacetophenone inArthrobactersp. TGJ4 (2012)

The 4-hydroxyacetophenone assimilating bacterium Arthrobacter sp. TGJ4 was isolated from a soil sample. The resting cell reaction suggested that the strain cleaved 4-hydroxyacetophenone and its 3-methoxy derivative to the corresponding carboxylic acids and formaldehyde. Some properties of the enzyme catalyzing the cleavage reaction were examined.
A femtomolar-acting neuroprotective peptide. (1996)

A novel 14-amino acid peptide, with stress-protein-like sequences, exhibiting neuroprotection at unprecedented concentrations, is revealed. This peptide prevented neuronal cell death associated with the envelope protein (GP 120) from HIV, with excitotoxicity (N-methyl d-aspartate), with the beta amyloid peptide (putative cytotoxin in Alzheimer's disease), and with tetrodotoxin (electrical blockade). The peptide was designed to contain a sequence derived from a new neuroprotective protein secreted by astroglial cells in the presence of vasoactive intestinal peptide. The neurotrophic protein was isolated by sequential chromatographic methods combining ion exchange, size separation, and hydrophobic interaction. The protein (mol mass, 14 kD and pI, 8.3 +/- 0.25) was named activity-dependent neurotrophic factor, as it protected neurons from death associated with electrical blockade. Peptide sequencing led to the synthesis of the novel 14-amino acid peptide that was homologous, but not identical, to an intracellular stress protein, heat shock protein 60. Neutralizing antiserum to heat shock protein 60 produced neuronal cell death that could be prevented by cotreatment with the novel protein, suggesting the existence of extracellular stress-like proteins with neuroprotective properties. These studies identify a potent neuroprotective glial protein and an active peptide that provide a basis for developing treatments of currently intractable neurodegenerative diseases.
Glycerolation and Thawing Effects on Bull Spermatozoa Frozen in Detergent-Treated Egg Yolk and Whole Egg Extenders (1987)

Bull sperm in Experiment 1 were added to a standard egg yolk-Tris extender containing 0, .25, .5, 1.0, 1.5, and 2.0% (vol/vol) of the detergent mixture, sodium and triethanolamine lauryl sulfate. Glycerol was added in one step to the initial extender or in three steps after cooling semen to 4 degrees C. The extended semen was packaged in .5-ml French straws and frozen over static nitrogen vapor. Thawing was at 4, 30, and 60 degrees C. There was little difference due to the method of adding glycerol provided detergent was present. Percentages of motile sperm after freezing in the six concentrations of detergent, in ascending order, were 31, 45, 52, 51, 48, and 36. Percentages of motile sperm following thawing at 4, 30, and 60 degrees C were 36.5, 46.0, and 48.6. Acrosome retention also was better preserved with the higher thaw temperatures. A second experiment, similar in design to the first one, was conducted with whole egg-Tris extender. The best results were in whole egg-Tris containing .125% detergent where post-thaw motile sperm of 70.4% greatly exceeded 30.7% without sodium and triethanolamine lauryl sulfate. Fertility of sperm frozen in yolk-Tris-detergent was equivalent to whole milk used as a control.
Lessons Learned from Three Decades of Experience with Cap and Trade (2016)

This article presents an overview of the design and performance of seven major emissions trading programs that have been implemented over the past 30 years and identifies a number of important lessons for future applications of this important environmental policy instrument. A brief discussion of several other proposed or implemented emissions trading programs is also included.
Cellular and behavioural effects of the adenosine A2a receptor antagonist KW‐6002 in a rat model of l‐DOPA‐induced dyskinesia (2003)

We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with L-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with L-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did L-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.
Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. (1985)

The Philadelphia chromosome (Ph1), observed in greater than 90% of chronic myelogenous leukemia (CML) patients, results from a specific chromosomal translocation involving the c-abl gene. The translocation breakpoint occurs near c-abl and correlates with the production of an altered c-abl mRNA. In the CML-derived cell line K562, Ph1 is accompanied by a structurally altered c-abl protein (P210c-abl) with in vitro tyrosine kinase activity not detected with the normal c-abl protein (P145c-abl). We have examined c-abl proteins in other Ph1-positive CML cell lines and found that they all express P210c-abl. P210c-abl was also detected in bone marrow cells from CML patients with Ph1 in the accelerated and blast crisis phases of the disease. Comparison of the [35S]methionine-labeled tryptic peptides generated from the normal P145c-abl and P210c-abl showed that they have closely related structures, but additional polypeptide sequences are present in P210c-abl. Based on these results we propose that translocation of c-abl in Ph1-positive CML results in the creation of a chimeric gene leading to the production of a structurally altered c-abl protein with activated tyrosine kinase activity. The altered P210 c-abl protein is strongly implicated in the pathogenesis of CML.
Localization of specific erythropoietin binding sites in defined areas of the mouse brain. (1995)

The main physiological regulator of erythropoiesis is the hematopoietic growth factor erythropoietin (EPO), which is induced in response to hypoxia. Binding of EPO to the EPO receptor (EPO-R), a member of the cytokine receptor superfamily, controls the terminal maturation of red blood cells. So far, EPO has been reported to act mainly on erythroid precursor cells. However, we have detected mRNA encoding both EPO and EPO-R in mouse brain by reverse transcription-PCR. Exposure to 0.1% carbon monoxide, a procedure that causes functional anemia, resulted in a 20-fold increase of EPO mRNA in mouse brain as quantified by competitive reverse transcription-PCR, whereas the EPO-R mRNA level was not influenced by hypoxia. Binding studies on mouse brain sections revealed defined binding sites for radioiodinated EPO in distinct brain areas. The specificity of EPO binding was assessed by homologous competition with an excess of unlabeled EPO and by using two monoclonal antibodies against human EPO, one inhibitory and the other noninhibitory for binding of EPO to EPO-R. Major EPO binding sites were observed in the hippocampus, capsula interna, cortex, and midbrain areas. Functional expression of the EPO-R and hypoxic upregulation of EPO suggest a role of EPO in the brain.
Recombinant Respiratory Syncytial Virus Bearing a Deletion of either the NS2 or SH Gene Is Attenuated in Chimpanzees (1999)

The NS2 and SH genes of respiratory syncytial virus (RSV) have been separately deleted from a recombinant wild-type RSV strain, A2 (M. N. Teng and P. L. Collins, J. Virol. 73:466-473, 1998; A. Bukreyev et al., J. Virol. 71:8973-8982, 1997; and this study). The resulting viruses, designated rA2DeltaNS2 and rA2DeltaSH, were administered to chimpanzees to evaluate their levels of attenuation and immunogenicity. Recombinant virus rA2DeltaNS2 replicated to moderate levels in the upper respiratory tract, was highly attenuated in the lower respiratory tract, and induced significant resistance to challenge with wild-type RSV. The replication of rA2DeltaSH virus was only moderately reduced in the lower, but not the upper, respiratory tract. However, chimpanzees infected with either virus developed significantly less rhinorrhea than those infected with wild-type RSV. These findings demonstrate that a recombinant RSV mutant lacking either the NS2 or SH gene is attenuated and indicate that these deletions may be useful as attenuating mutations in new, live recombinant RSV vaccine candidates for both pediatric and elderly populations. The DeltaSH mutation was incorporated into a recombinant form of the cpts248/404 vaccine candidate, was evaluated for safety in seronegative chimpanzees, and can now be evaluated as a vaccine for humans.
Transplantation of Hepatocytes for Treatment of Surgically Induced Acute Hepatic Failure in the Rat (1984)

Efficacy of transplanted hepatocytes was evaluated in rats with a surgically induced acute hepatic failure. After 75% liver resection and portacaval shunt, the intrasplenic or intraperitoneal injection of 20 million isolated fresh hepatocytes was shown to significantly reduce the mortality rate. These results confirm that the transplantation of isolated hepatocytes may prevent death in rats with acute hepatic failure, and suggest that hepatocyte transplantation acts by a mechanism of hepatic support.
Insecticidal Activity of Monoterpenoids to Western Corn Rootworm (Coleoptera: Chrysomelidae), Twospotted Spider Mite (Acari: Tetranychidae), and House Fly (Diptera: Muscidae) (1997)

Acute toxicities of 34 naturally occurring monoterpenoids were evaluated against 3 important arthropod pest species; the larva of the western corn rootworm, Diabrotica virgifera virgifera LeConte; the adult of the twospotted spider mite. Tetranychus urticae Koch; and the adult house fly. Musca domestica L. Potential larvicidal or acaricidal activities of each monoterpenoid were determined by topical application, leaf-dip method, soil bioassay, and greenhouse pot tests. Phytotoxicity was also tested on a corn plant. Citronellic acid and thymol were the most topically toxic against the house fly, and citronellol and thujone were the most effective on the western corn rootworm. Most of the monoterpenoids were lethal to the twospotted spider mite at high concentrations; carvomenthenol and terpinen-4-ol were especially effective. A wide range of monoterpenoids showed some larvicidal activity against the western corn rootworm in the soil bioassay. Perillaldehyde, the most toxic (LC50 = 3 micrograms/g) in soil, was only 1/3 as toxic as carbofuran, a commercial soil insecticide (LC50 = 1 microgram/g). Selected monoterpenoids also effectively protected corn roots from attack by the western corn rootworm larvae under greenhouse conditions. alpha-Terpineol was the best monoterpenoid in the greenhouse pot test. The acute toxicity of monoterpenoids was low relative to conventional insecticides. Some monoterpenoids were phytotoxic to corn roots and leaves. l-Carvone was the most phytotoxic, whereas pulegone was the safest. The results with thymyl ethyl ether, one of the synthetic derivatives of thymol, showed a potential of derivatization to reduce monoterpenoid phytotoxicity.