gebhart/patrepeval huggingface dataset:
Optimizing an Artificial Metabolic Pathway:  Engineering the Cofactor Specificity of Corynebacterium 2,5-Diketo-d-gluconic Acid Reductase for Use in Vitamin C Biosynthesis (2002)

The strict cofactor specificity of many enzymes can potentially become a liability when these enzymes are to be employed in an artificial metabolic pathway. The preference for NADPH over NADH exhibited by the Corynebacterium 2,5-diketo-D-gluconic acid (2,5-DKG) reductase may not be ideal for use in industrial scale vitamin C biosynthesis. We have previously reported making a number of site-directed mutations at five sites located in the cofactor-binding pocket that interact with the 2'-phosphate group of NADPH. These mutations conferred greater activity with NADH upon the Corynebacterium 2,5-DKG reductase [Banta, S., Swanson, B. A., Wu, S., Jarnagin, A., and Anderson, S. (2002) Protein Eng. 15, 131-140; (1)]. The best of these mutations have now been combined to see if further improvements can be obtained. In addition, several chimeric mutants have been produced that contain the same residues as are found in other members of the aldo-keto reductase superfamily that are naturally able to use NADH as a cofactor. The most active mutants obtained in this work were also combined with a previously reported substrate-binding pocket double mutant, F22Y/A272G. Mutant activity was assayed using activity-stained native polyacrylamide gels. Superior mutants were purified and subjected to a simplified kinetic analysis. The simplified kinetic analysis was extended for the most active mutants in order to obtain the kinetic parameters in the full-ordered bi bi rate equation in the absence of products, with both NADH and NADPH as cofactors. The best mutant 2,5-DKG reductase produced in this work was the F22Y/K232G/R238H/A272G quadruple mutant, which exhibits activity with NADH that is more than 2 orders of magnitude higher than that of the wild-type enzyme, and it retains a high level of activity with NADPH. This new 2,5-DKG reductase may be a valuable new catalyst for use in vitamin C biosynthesis.
Direct gene transfer to the liver with herpes simplex virus type 1 vectors: transient production of physiologically relevant levels of circulating factor IX. (1992)

We have used gene transfer vectors derived from a replication-defective mutant of herpes simplex virus type 1 (HSV-1) expressing the hepatitis B virus surface antigen (HBsAg), Escherichia coli beta-galactosidase (beta-gal), or canine factor IX (cFIX) from the immediate early promoter of human cytomegalovirus (hCMV) to infect mouse liver by direct injection or through the portal vein. By either route, high levels of transgene expression were demonstrated by the detection of immunoreactive HBsAg or cFIX in the circulation and by histochemical detection of beta-gal activity in situ. The results were striking in that the serum level of cFIX reached 10% of the normal murine levels. Although the level of transgene expression from the hCMV promoter was transient, a significant number of persistent vectors could be rescued from the livers of recipient mice up to 2 months after inoculation. Replacement of the hCMV promoter with the HSV-1 latency-associated transcript (LAT) promoter resulted in reduced but prolonged expression of both HBsAg and cFIX. The very high level of factor IX expression suggests that clinically useful gene transfer may eventually be feasible through direct vector delivery to the liver.
Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial (2020)

A projected dose and schedule to achieve the target C<sub>trough</sub> was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.
Autographa californica Nuclear Polyhedrosis Virus Efficiently Enters but Does Not Replicate in Poikilothermic Vertebrate Cells (1986)

The host range of the insect virus Autographa californica nuclear polyhedrosis virus (AcMNPV) was examined. AcMNPV could not initiate a productive infection in frog, turtle, trout, or codling moth cell lines. After exposure to AcMNPV, neither viral DNA nor RNA synthesis could be detected in these cell lines as assayed by nucleic acid probe hybridization. Entry of AcMNPV nucleocapsids into the cytoplasm and viral DNA into the nucleus, however, was as efficient in the nonpermissive cell lines as it was in a permissive insect cell line. The data suggest that the block in AcMNPV infection in these nonpermissive cell lines is at a stage subsequent to viral DNA entry into the nucleus.
A monoclonal antibody defining a lymphoma-associated antigen in man. (1980)

A monoclonal antibody (Ab 89) was developed against a lymphoma-associated antigen on the tumor cells of a patient (N.B.) with a B cell, poorly differentiated lymphocytic lymphoma (D-PDL). By indirect immunofluorescence, Ab 89 was shown to react only with N.B. lymphoma cells and was unreactive with normal N.B. lymphoid cells, normal fractionated peripheral blood cells, other normal lymphoid tissues, fetal tissues, and non-lymphoid malignant cells. In addition, Ab 89 was unreactive with conventional immunoglobulins, private and public HLA antigens, or Ia-like antigens. More importantly, Ab 89 was reactive with some B cell lymphoid malignancies. Of the 57 B cell lymphomas tested, it was found that Ab 89 reacted with approximately 10% of B cell D-PDL and B cell chronic lymphocytic leukemia (CLL). Of interest was the finding that N.B. serum contained a circulating antigen which could specifically block the reactivity of Ab 89. The data obtained suggests that Ab 89 defines a tumor-associated antigen shared by a unique subgroup of B cell lymphomas. The group of patients reactive with Ab 89 did not fall into any histopathologic classification system. These data support the notion that there is greater heterogeneity of B cell lymphomas than may have been previously recognized.
Enhancing long-term memory with stimulation tunes visual attention in one trial (2014)

Scientists have long proposed that memory representations control the mechanisms of attention that focus processing on the task-relevant objects in our visual field. Modern theories specifically propose that we rely on working memory to store the object representations that provide top-down control over attentional selection. Here, we show that the tuning of perceptual attention can be sharply accelerated after 20 min of noninvasive brain stimulation over medial-frontal cortex. Contrary to prevailing theories of attention, these improvements did not appear to be caused by changes in the nature of the working memory representations of the search targets. Instead, improvements in attentional tuning were accompanied by changes in an electrophysiological signal hypothesized to index long-term memory. We found that this pattern of effects was reliably observed when we stimulated medial-frontal cortex, but when we stimulated posterior parietal cortex, we found that stimulation directly affected the perceptual processing of the search array elements, not the memory representations providing top-down control. Our findings appear to challenge dominant theories of attention by demonstrating that changes in the storage of target representations in long-term memory may underlie rapid changes in the efficiency with which humans can find targets in arrays of objects.
Function minimization by conjugate gradients (1964)

A quadratically convergent gradient method for locating an unconstrained local minimum of a function of several variables is described. Particular advantages are its simplicity and its modest demands on storage, space for only three vectors being required. An ALGOL procedure is presented, and the paper includes a discussion of results obtained by its used on various test functions.
Hybridization of crop plants (1980)

Hybridization and self-pollination are important aspects of research for the genetic improvement of crop plants. Hybridization is used to develop new genotypes, evaluate their performance, or exploit hybrid vigor. Self-pollination is used to evaluate genotypes and develop pure lines for cultivar development or genetic research.
Improving Influence of Insulin on Cognitive Functions in Humans (2001)

Insulin receptors have been identified in limbic brain structures, but their functional relevance is still unclear. In order to characterize some of their effects, we evaluated auditory evoked brain potentials (AEP) in a vigilance task, behavioral measures of memory (recall of words) and selective attention (Stroop test) during infusion of insulin. The hormone was infused at two different rates (1.5 mU/kg x min, "low insulin", and 15 mU/kg x min, "high insulin"), inducing respectively serum levels of 543 +/- 34 and 24,029 +/- 1,595 pmol/l. This experimental design allowed to compare cognitive parameters under two conditions presenting markedly different insulin levels, but with minimal incidence on blood glucose concentrations since these were kept constant by glucose infusion. A "no insulin treatment" group was not included in order to avoid leaving patients infused with glucose without insulin treatment. Measures were taken during a baseline phase preceding insulin infusion and every 90 min during the 360 min of insulin infusion. Compared with "low insulin", "high insulin" induced a slow negative potential shift in the AEP over the frontal cortex (average amplitude, high insulin: 0.27 +/- 0.48 microV; low insulin: 1.87 +/- 0.48 microV, p < 0.005), which was paralleled by enhanced memory performance (words recalled, high insulin: 22.04 +/- 0.93; low insulin: 19.29 +/- 0.92, p < 0.05). Also, during "high insulin" subjects displayed enhanced performance on the Stroop test (p < 0.05) and expressed less difficulty in thinking than during "low insulin" (p < 0.03). Results indicate an improving effect of insulin on cognitive function, and may provide a frame for further investigations of neurobehavioral effects of insulin in patients with lowered or enhanced brain insulin, i.e., patients with Alzheimer's disease or diabetes mellitus.
Synthesis, cell-growth inhibition, and antitumor screening of 2-(p-n-butylanilino)purines and their nucleoside analogs (1987)

Derivatives of N2-(p-n-butylphenyl)guanine (BuPG) and 2-(p-n-butylanilino)adenine (BuAA) were synthesized and tested as inhibitors of mammalian DNA polymerase alpha, cell growth, and macromolecule synthesis. 2-(p-n-Butylanilino)-6-chloropurine (BuACl) served as a useful intermediate to prepare a series of 6-substituted analogues. BuACl, as its sodium salt, reacted with 2-deoxy-3,5-di-p-toluoyl-beta-D-ribofuranosyl chloride in acetonitrile to give 64% of the corresponding 9-beta nucleoside (blocked BuAdCl) and only 14% of the 7-beta isomer. Deblocking and substitution of chlorine in BuAdCl generated a series of 2-(p-n-butylanilino)-9-(2-deoxy-beta-D-ribofuranosyl)purine derivatives. Reaction of the sodium salt of BuACl with (2-acetoxyethoxy)methyl bromide also afforded, after deblocking and substitution of the 6-chloro group, a series of 2-(p-n-butylanilino)-9-[(2-hydroxyethoxy)methyl]purines. The bases synthesized were inhibitors of DNA polymerase alpha isolated from Chinese hamster ovary cells, the most potent compounds being 6-methoxy and 6-methylthio derivatives of 2-(p-n-butylanilino)purine. When tested for their ability to inhibit [3H]thymidine incorporation into DNA in HeLa cell cultures and the growth of exponentially growing HeLa cells, 9-(2-deoxy-beta-D-ribofuranosyl) derivatives had greater potency than their base counterparts, but "adenine" analogues, such as 2-(p-n-butylanilino)-2'-deoxyadenosine (BuAdA, IC50 = 1 microM), were considerably more potent than N2-(p-n-butylphenyl)-2'-deoxyguanosine (BuPdG, IC50 = 25 microM). Derivatives bearing the 9-[(2-hydroxyethoxy)methyl] group were nearly as potent inhibitors of [3H]thymidine incorporation in these experiments as the corresponding deoxyribonucleosides. Base and deoxynucleoside derivatives also inhibited cellular RNA synthesis, and several compounds, at high concentrations, inhibited protein synthesis. BuPG, BuAA, and four deoxyribonucleoside derivatives of 2-(p-n-butylanilino)purines were tested against P-388 lymphocytic leukemia in mice. None of the compounds increased the survival time of test animals, but two of them, BuAdA and its 6-desamino derivative BuAdP, were lethal at the highest concentration used (400 mg/kg).
Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities (2009)

Chagas disease is caused by a parasite, Trypanosoma cruzi, transmitted primarily by a triatomine insect and affects approximately 8 million people in Latin American countries. The principal aim of the management of the disease is to avoid the development of cardiomyopathy and transmission by blood transfusion, congenital and organ transplants. Currently, benznidazole is the only etiological treatment commercially available for the disease until new and better drugs can be developed and tested. Benznidazole has been used even though it does not have all the conditions of an ideal drug. The efficacy and tolerance of benznidazole is inversely related to the age of the patient, while its side effects are more frequent in elderly patients. The side effects are systematically evaluated only in controlled studies designed for that purpose. However, the true clinical impact of the side effects could be different, considering that the treatment is for a short duration (between 30 and 60 days) and only carried out once. In this article, we discuss the benefits and risks of the treatment with benznidazole from a clinical point of view to be considered for the management of the treatment of chronic adult Chagas disease patients in the current medical practice.
Predicting outcome in patients with sepsis: new biomarkers for old expectations (2014)

Early prediction of the outcome of patients with sepsis could be helpful in guiding therapies but remains challenging. Presepsin, a new sepsis biomarker whose elevation as early as day 1 is well correlated with 28-day mortality, could be considered to this end.
Wearable ECG Recognition and Monitor (2005)

ECG (electrocardiogram) recognition and monitor are inevitable to trace and determine heart diseases. As self-health being focused on and social medical grade being progressed, ECG monitors with features such as portable/wearable, wireless, use-friendly, low-cost and convenient at home, are more and more necessary. Unfortunately, such kind of equipments couldn't be got currently. Thus, wearable ECG recognition and monitor instrument is developed. Palm, mobile phone and PC could be acting as display and relay terminals, where ECG signals would be transmitted to service center (e.g. hospital) through GSM/GPRS/CDMA and Internet. After introducing system architecture, the paper describes software design, direct ECG recognition method with morphology parameters based on specialists' experiences. The first generation product includes wearable monitor and palm is ready now, which has huge market.
Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease (2014)

IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.
Significance of Vascular Dipeptidyl Peptidase-4 Inhibition on Vascular Protection in Zucker Diabetic Fatty Rats (2014)

To clarify the role of dipeptidyl peptidase-4 (DPP-4) inhibition in vascular tissues, we compared the effects of the poorly tissue-penetrative DPP-4 inhibitor sitagliptin to the highly tissue-penetrative DPP-4 inhibitor linagliptin in Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats were orally treated with placebo, sitagliptin (10 mg/kg), or linagliptin (3 mg/kg) for 4 weeks. Sitagliptin and linagliptin produced equivalent decreases in blood glucose concentrations and increased plasma insulin concentrations during oral glucose tolerance tests after the first and the last treatments. In isolated arteries, acetylcholine-induced vascular relaxation was significantly augmented by sitagliptin and linagliptin, with significantly stronger relaxation observed with linagliptin compared to sitagliptin. Vascular DPP-4 activity was attenuated by these drugs, with linagliptin producing significant greater attenuation than sitagliptin. Vascular malondialdehide levels were significantly lower with linagliptin compared to sitagliptin. Significantly greater attenuation of vascular gene expressions of p22(phox) and monocyte chemoattractant protein-1 by linagliptin, compared with sitagliptin, was also observed. In conclusion, the superior vascular protection by linagliptin compared with sitagliptin was unrelated to the regulation of circulating glucose and insulin levels, and the stronger vascular DPP-4 inhibition by linagliptin may contribute to the mechanism of vascular protection.
Antifungal Hydrolases in Pea Tissue (1988)

Chitinase and beta-1,3-glucanase purified from pea pods acted synergistically in the degradation of fungal cell walls. The antifungal potential of the two enzymes was studied directly by adding protein preparations to paper discs placed on agar plates containing germinated fungal spores. Protein extracts from pea pods infected with Fusarium solani f.sp. phaseoli, which contained high activities of chitinase and beta-1,3-glucanase, inhibited growth of 15 out of 18 fungi tested. Protein extracts from uninfected pea pods, which contained low activities of chitinase and beta-1,3-glucanase, did not inhibit fungal growth. Purified chitinase and beta-1,3-glucanase, tested individually, did not inhibit growth of most of the test fungi. Only Trichoderma viride was inhibited by chitinase alone, and only Fusarium solani f.sp. pisi was inhibited by beta-1,3-glucanase alone. However, combinations of purified chitinase and beta-1,3-glucanase inhibited all fungi tested as effectively as crude protein extracts containing the same enzyme activities. The pea pathogen, Fusarium solani f.sp. pisi, and the nonpathogen of peas, Fusarium solani f.sp. phaseoli, were similarly strongly inhibited by chitinase and beta-1,3-glucanase, indicating that the differential pathogenicity of the two fungi is not due to differential sensitivity to the pea enzymes. Inhibition of fungal growth was caused by the lysis of the hyphal tips.
Expression of CD64 as a potential marker of neonatal sepsis (2002)

The aim of this study was to identify a novel immunological indicator useful for the early diagnosis (through a rapid and single determination) of neonatal sepsis (NS). Peripheral blood samples were taken from 63 neonates, who were classified into four groups: proven NS (n = 17); clinical NS (n = 14); disease without infection (n = 17); and healthy newborns (n = 15). Neutrophil expression of CD64, CD43, CD44, CD50, CD62L and Mac-1, and plasma levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha) and soluble L-selectin (sCD62L), were determined. Expression of CD64 was significantly enhanced in the group with proven sepsis and clinical NS compared to newborns without infection (p < 0.05). Eight newborns with proven or clinical sepsis, but only one with disease without infection, showed an increased percentage of CD64+ cells (diagnostic specificity = 96.8%). No significant differences were found in the expression of the other leucocyte differentiation antigens studied. As previously described, TNF-alpha and IL-6 levels were significantly elevated in newborns with proven or clinical sepsis compared to neonates without infection (p < 0.05). Our results suggest that, through a single determination, the enhanced expression of CD64 is a highly specific indicator of NS, although its diagnostic sensitivity is low (25.8%). In contrast, we found that plasma levels of IL-1beta and sCD62L, as well as the expression of Mac-1, CD43, CD44, CD50, and CD62L, do not appear to be useful for the diagnosis of NS.
Bleomycin-induced strand-scission of DNA. Mechanism of deoxyribose cleavage. (1981)

The bleomycins, a family of glycopeptides with antineoplastic activity, bind to DNA and cause strand-scission in a reaction requiring Fe(I1) and oxygen.Strandscission is accompanied by the simultaneous release of free bases and four low molecular weight compounds that react with 2-thiobarbituric acid to form chromophores absorbing maximally at 532 nm.The structure of these four products was elucidated as follows: formic acid hydrolysis released thymine, cytosine, adenine, and guanine, respectively; treatment of each compound with phenylhydrazine yielded 1-phenylpyrazole.The adenine-containing compound was reduced with sodium borohydride and the trimethylsilyl derivative was prepared.High resolution mass spectrometry of this derivative revealed silylated 3-(adenin-B'-y1)-2-propen-1-01, consistent with formulation of the original compound as 3-(adenin-9'-~1)-2-propenal.The reaction product containing thymine was similarly shown to be 3-(thymin-l'-yl)-2-propenal.The 3-substituted propenal structures proposed were confirmed by chemical synthesis.Oligonucleotides, produced by bleomycin-induced strand-scission, were found to contain glycolic acid residues esterified through the hydroxyl group to the 3'-phosphate termini.We conclude that the primary reaction products resulting from bleomycin-induced strand-scission of DNA have a common structure: Base-CH=CH-CHO.These observations are consistent with a reaction mechanism initiated by free radical abstraction of the C-4' proton of deoxyribose and leading to oxidative cleavage of the (C-3')-(C-43 bond.DNA, isolated from bleomycin-treated cells, is known to be degraded (1-7), an effect which is presumed to be responsible for the chemotherapeutic properties of this family of antibiotics.Bleomycin creates single-and double-stranded breaks in purified preparations of DNA (1, 3-6, 8-19), strand-scission occurring preferentially at guanine-pyrimidine (5' + 3') base sequences (20,21).Products of the reaction between bleomycin and DNA include free bases, oligonucleotides, and several compounds which form chromophores with TBA' (9-11, 18,
Synthesis of multifunctionalized phosphonic acid esters via opening of oxiranes and azetidinium salts with phosphoryl-substituted carbanions (2001)

Ring-opening of N,N-diethyl-3-benzyloxyazetidinium salt 1b and N,N-dibenzyl-2,3-epoxypropylamine 6 by phosphoryl-substituted carbanions generated from phosphonates 2a–e furnishes the multifunctional phosphonates 3a–e and 7a, 7b, 7e bearing the same carbon skeleton. The reaction of the heterocyclic electrophiles 1b and 6 with the P-allyl anion generated from 2f demonstrates the strong dependence of the α/γ-regioselectivity on the reaction conditions. Depending on the character of the electrophile and/or the reaction medium the regioselective synthesis of both α- and γ-regioisomers is realized.