gebhart/patrepeval huggingface dataset:
Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis (2005)

The base excision repair DNA glycosylase MutY homolog (MYH) is responsible for removing adenines misincorporated into DNA opposite guanine or 7,8-dihydro-8-oxo-guanine (8-oxoG), thereby preventing G:C to T:A mutations. Biallelic germline mutations in the human MYH gene predispose individuals to multiple colorectal adenomas and carcinoma. We have recently demonstrated that hMYH interacts with the mismatch repair protein hMSH6, and that the hMSH2/hMSH6 (hMutSalpha) heterodimer stimulates hMYH activity. Here, we characterize the functional effect of two missense mutations (R227W and V232F) associated with hMYH polyposis that lie within, or adjacent to, the putative hMSH6 binding domain. Neither missense mutation affects the physical interaction between hMYH and hMSH6. However, hMYH(R227W) has a severe defect in A/8-oxoG binding and glycosylase activities, while hMYH(V232F) has reduced A/8-oxoG binding and glycosylase activities. The glycosylase activity of the V232F mutant can be partially stimulated by hMutSalpha but cannot be restored to the wild-type level. Both mutants also fail to complement mutY-deficiency in Escherichia coli. These data define the pathogenic mechanisms underlying two further hMYH polyposis-associated mutations.
Making a frothy shampoo or beer (2010)

Both beer and shampoo have polar molecules that accumulate at a liquid-gas interface, but the mechanisms that prevent bubble collapse in soap foams or pilsner heads are fundamentally different.
Electronic and steric effects on the rate of the traceless Staudinger ligation (2008)

Interplay between electronic effects imparted by phosphinothiol substituents and steric effects imposed by amino-acid reactants affects the rate of the traceless Staudinger ligation of peptides in a predictable manner.
Conversion of glycerol to pyruvate by Escherichia coli using acetate- and acetate/glucose-limited fed-batch processes (2009)

We report the conversion of glycerol to pyruvate by E. coli ALS929 containing knockouts in the genes encoding for phosphoenolpyruvate synthase, lactate dehydrogenase, pyruvate formate lyase, the pyruvate dehydrogenase complex, and pyruvate oxidase. As a result of these knockouts, ALS929 has a growth requirement of acetate for the generation of acetyl CoA. In steady-state chemostat experiments using excess glycerol and limited by acetate, lower growth rates favored the formation of pyruvate from glycerol (0.60 g/g at 0.10 h(-1) versus 0.44 g/g at 0.25 h(-1)), while higher growth rates resulted in the maximum specific glycerol consumption rate (0.85 g/g h at 0.25 h(-1) versus 0.59 g/g h at 0.10 h(-1)). The presence of glucose significantly improved pyruvate productivity and yield from glycerol (0.72 g/g at 0.10 h(-1)). In fed-batch studies using exponential acetate/glucose-limited feeding at a constant growth rate of 0.10 h(-1), the final pyruvate concentration achieved was about 40 g/L in 36 h. A derivative of ALS929 which additionally knocked out methylglyoxal synthase did not further increase pyruvate productivity or yield, indicating that pyruvate formation was not limited by accumulation of methylglyoxal.
Advanced Eccentricity Fault Recognition in Permanent Magnet Synchronous Motors Using Stator Current Signature Analysis (2013)

In this paper, a novel index is introduced for static and dynamic eccentricity fault diagnosis in permanent magnet synchronous motors (PMSMs). The proposed index is a linear combination of the energy, shape factor, peak, head angle of the peak, area below the peak, gradient of the peak of the detail signals in wavelet decomposition, and coefficients of the autoregressive model, which are extracted from the stator current signature analysis. Principal component analysis is applied to the features as the linear transform for dimension reduction and elimination of linear dependence between the features. In order to demonstrate the capability of these indexes to estimate eccentricity type and degree, the fuzzy support vector machine is employed as a classifier. Classification of the results indicates that the nominated index can be utilized to detect eccentricity occurrence, recognize its type, and determine its degree precisely. Since extraction of efficient indexes closely depends on precise computation of necessary signals, the time-stepping finite element method is utilized to model the PMSM under eccentricity fault and calculate the stator currents as a proper signal for processing. Simulation results are verified by the experimental results.
Prostatic acid phosphatase levels (enzymatic method) from completely sectioned, clinically benign, whole prostates (1996)

Clinically benign, whole, untrimmed prostates were obtained from 104 patients at autopsy, completely sectioned, and examined microscopically. The histological and gross findings of the prostate were correlated with premortem prostatic acid phosphatase levels (PAP, enzymatic method, ACA, Dupont Co.) to determine how often carcinoma of the prostate (CAP) affected PAP levels and to identify other findings within the prostate associated with elevated PAP levels. Sixty (58%) prostates did not have CAP, 34 (33%) had CAP smaller than 1 ml in volume, and 10 (10%) had CAP larger than 1 ml in volume. PAP levels were elevated (greater than 1 U/L) in 8 of the 60 (13%) prostates without CAP, in 2 of the 34 (6%) prostates with CAP smaller than 1 ml, and in 1 of the 10 (10%) prostates with CAP larger than 1 ml. These differences were not statistically significant. Likewise, a statistically significant correlation between PAP levels and patient age, patient race, severe inflammation, or high grade prostatic intraepithelial neoplasia (PIN) was not found. However, there was a statistically significant correlation between PAP levels and prostate weight (P < 0.0001). This study suggests that PAP cannot distinguish between patients with clinically undetected CAP and patients without CAP. Furthermore, elevated PAP levels are often not due to metastatic CAP and additional evidence should be present, even in patients with known CAP, before an elevated PAP level is considered to be conclusive evidence of metastatic CAP. © 1996 Wiley-Liss, Inc.
Assembled systems [X‐azolopyridine][quinoline]. Bases and salts (1992)

Abstract A series of bases containing X‐azolopyridines (X = O, NH) and methylquinolines, assembled in different ways, was prepared by reaction of methylquinolinecarboxylic acids (or carboxamides) with diamino (or hydroxyamino) pyridines. The bases were quaternized with methyl iodide. The physical and spectroscopic data of both the bases and the salts were correlated and compared with those of [X‐azolopyridine][pyridine] systems previously studied. The structure of the salts was markedly influenced by a balance of basicity‐hindrance factors in the heteroaromatic substrates.
Control of meningococcal meningitis with meningococcal vaccines. (1975)

The development of effective meinigococcal vaccines was based upon the finding that immunity to the meningococcus was directly correlated with serum bactericidal antibodies. Purified high molecular weight capsular polysaccharides of serogroups A and C meningococci stimulated the production of humoral antibodies which had group specific bactericidal activity. In controlled field trials in Army recruits, group C polysaccharide vaccines were highly effective in preventing group C disease. Following its use as a routine immunization in recruits in October 1971 group C meningococcal disease has been almost completely eliminated from Army training centers. Group A vaccine has been field tested in Egyptian school children with great success. Group B polysaccharide has failed to induce bactericidal antibodies in humans and, therefore, new research is underway to attempt to develop a cell wall protein antigen as a vaccine against group B disease.
Quantitative Characterization of the Activation Steps of Mannan-binding Lectin (MBL)-associated Serine Proteases (MASPs) Points to the Central Role of MASP-1 in the Initiation of the Complement Lectin Pathway (2013)

Mannan-binding lectin (MBL)-associated serine proteases, MASP-1 and MASP-2, have been thought to autoactivate when MBL/ficolin·MASP complexes bind to pathogens triggering the complement lectin pathway. Autoactivation of MASPs occurs in two steps: 1) zymogen autoactivation, when one proenzyme cleaves another proenzyme molecule of the same protease, and 2) autocatalytic activation, when the activated protease cleaves its own zymogen. Using recombinant catalytic fragments, we demonstrated that a stable proenzyme MASP-1 variant (R448Q) cleaved the inactive, catalytic site Ser-to-Ala variant (S646A). The autoactivation steps of MASP-1 were separately quantified using these mutants and the wild type enzyme. Analogous mutants were made for MASP-2, and rate constants of the autoactivation steps as well as the possible cross-activation steps between MASP-1 and MASP-2 were determined. Based on the rate constants, a kinetic model of lectin pathway activation was outlined. The zymogen autoactivation rate of MASP-1 is ∼3000-fold higher, and the autocatalytic activation of MASP-1 is about 140-fold faster than those of MASP-2. Moreover, both activated and proenzyme MASP-1 can effectively cleave proenzyme MASP-2. MASP-3, which does not autoactivate, is also cleaved by MASP-1 quite efficiently. The structure of the catalytic region of proenzyme MASP-1 R448Q was solved at 2.5 Å. Proenzyme MASP-1 R448Q readily cleaves synthetic substrates, and it is inhibited by a specific canonical inhibitor developed against active MASP-1, indicating that zymogen MASP-1 fluctuates between an inactive and an active-like conformation. The determined structure provides a feasible explanation for this phenomenon. In summary, autoactivation of MASP-1 is crucial for the activation of MBL/ficolin·MASP complexes, and in the proenzymic phase zymogen MASP-1 controls the process.
Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. (1995)

Acid aspiration lung injury may be mediated primarily by neutrophils recruited to the lung by acid-induced cytokines. We hypothesized that a major acid-induced cytokine was IL-8 and that a neutralizing anti-rabbit-IL-8 monoclonal antibody (ARIL8.2) would attenuate acid-induced lung injury in rabbits. Hydrochloric acid (pH = 1.5 in 1/3 normal saline) or 1/3 normal saline (4 ml/kg) was instilled into the lungs of ventilated, anesthetized rabbits. The rabbits were studied for 6 or 24 h. In acid-instilled rabbits without the anti-IL-8 monoclonal antibody, severe lung injury developed in the first 6 h; in the long-term experiments, all rabbits died with lung injury between 12 and 14 h. In acid-instilled rabbits given the anti-IL-8 monoclonal antibody (2 mg/kg, intravenously) either as pretreatment (5 min before the acid) or as treatment (1 h after the acid), acid-induced abnormalities in oxygenation and extravascular lung water were prevented and extravascular protein accumulation was reduced by 70%; in the long-term experiments, anti-IL-8 treatment similarly protected lung function throughout the 24-h period. The anti-IL-8 monoclonal antibody also significantly reduced air space neutrophil counts and IL-8 concentrations. This study establishes IL-8 as a critical cytokine for the development of acid-induced lung injury. Neutralization of IL-8 may provide the first useful therapy for this clinically important form of acute lung injury.
Mlh1 is unique among mismatch repair proteins in its ability to promote crossing-over during meiosis. (1997)

In eukaryotes, homologs of the bacterial MutS and MutL proteins function in DNA mismatch repair and recombination pathways. The mutL homolog MLH1 is required for nuclear mismatch repair. Previously, cytological analysis of MLH1-deficient mice has implied a role for Mlh1 in crossing-over during meiosis. Here we demonstrate that Saccharomyces cerevisiae diploids containing a deletion of MLH1 have reduced crossing-over in addition to a deficiency in the repair of mismatched DNA during meiosis. Absence of either of the meiosis-specific mutS homologs Msh4 or Msh5 results in a similar reduction in crossing-over. Analysis of an mlh1 msh4 double mutant suggests that both genes act in the same pathway to promote crossing-over. All genetic markers analyzed in mlh1 mutants display elevated frequencies of non-Mendelian segregation. Most of these events are postmeiotic segregations that represent unrepaired heteroduplex. These data suggest that either restorational repair is frequent or heteroduplex tracts are shorter in wild-type cells. Comparison of mlh1 segregation data with that of pms1, msh2, msh3, and msh6 mutants show that the ability to promote crossing-over is unique to MLH1. Taken together these observations indicate that both crossing-over and gene conversion require MutS and MutL functions and that Mlh1 represents an overlap between these two pathways. Models of Mlh1 function are discussed.
Chemopreventive effects of NSAIDs against colorectal cancer: regulation of apoptosis and mitosis by COX-1 and COX-2. (1998)

There is a wealth of evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent colorectal cancer. In this article the role of cyclooxygenase 1 and 2, the principle target of NSAIDs, in the development of colorectal cancer is reviewed. Cyclooxygenase is constitutively expressed in normal colonic epithelium and surrounding stroma and could catalyse the generation of malondialdehyde which is a known mutagen and could initiate colorectal carcinogenesis. Mutation of APC which is an early genetic event leads to the expression of cyclooxygenase 2 which may prevents the appropriate apoptosis of mutant adenoma cells. Other proneoplastic effects of cyclooxygenase include changing the action of Transforming Growth Factor beta from anti-proliferative to pro-proliferative, reducing adherence to extracellular matrix, promotes metastasis and angiogenesis. These properties of cyclooxygenases suggest that inhibition of both isoforms may have important protective effects against colorectal cancer.
Identification of a second neutrophil-chemoattractant cytokine generated during an inflammatory reaction in the rabbit peritoneal cavity in vivo. Purification, partial amino acid sequence and structural relationship to melanoma-growth-stimulatory activity (1991)

The intraperitoneal injection of zymosan in the rabbit results in the generation of an inflammatory exudate containing oedema-forming and chemoattractant activities. Previous studies demonstrated the early appearance of the complement fragment C5a, followed by the generation of two mediators related to the cytokine interleukin-8 that were separable by cation-exchange h.p.l.c. N-Terminal amino acid sequencing identified one of these mediators as rabbit interleukin-8. This paper describes the purification of the second cytokine by cation-exchange, gel-filtration and reversed-phase h.p.l.c. The purified material had both oedema-forming and chemoattractant activity when assayed in rabbit skin in vivo. On SDS/PAGE a single 6-8 kDa band was observed and N-terminal amino acid sequencing of the reduced and alkylated protein positively identified 36 amino acids. This sequence revealed the rabbit homologue of melanoma-growth-stimulatory activity. The identification of these two cytokines in vivo will provide an opportunity to investigate the importance of their co-release in the inflammatory process.
Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate:  Structural Bases of Dehydrogenation and Decarboxylation Reactions , (2004)

Acyl-CoA dehydrogenases (ACDs) are a family of flavoenzymes that metabolize fatty acids and some amino acids. Of nine known ACDs, glutaryl-CoA dehydrogenase (GCD) is unique: in addition to the alpha,beta-dehydrogenation reaction, common to all ACDs, GCD catalyzes decarboxylation of glutaryl-CoA to produce CO(2) and crotonyl-CoA. Crystal structures of GCD and its complex with 4-nitrobutyryl-CoA have been determined to 2.1 and 2.6 A, respectively. The overall polypeptide folds are the same and similar to the structures of other family members. The active site of the unliganded structure is filled with water molecules that are displaced when enzyme binds the substrate. The structure strongly suggests that the mechanism of dehydrogenation is the same as in other ACDs. The substrate binds at the re side of the FAD ring. Glu370 abstracts the C2 pro-R proton, which is acidified by the polarization of the thiolester carbonyl oxygen through hydrogen bonding to the 2'-OH of FAD and the amide nitrogen of Glu370. The C3 pro-R proton is transferred to the N(5) atom of FAD. The structures indicate a plausible mechanism for the decarboxylation reaction. The carbonyl polarization initiates decarboxylation, and Arg94 stabilizes the transient crotonyl-CoA anion. Protonation of the crotonyl-CoA anion occurs by a 1,3-prototropic shift catalyzed by the conjugated acid of the general base, Glu370. A tight hydrogen-bonding network involving gamma-carboxylate of the enzyme-bound glutaconyl-CoA, with Tyr369, Glu87, Arg94, Ser95, and Thr170, optimizes orientation of the gamma-carboxylate for decarboxylation. Some pathogenic mutations are explained by the structure. The mutations affect protein folding, stability, and/or substrate binding, resulting in inefficient/inactive enzyme.
The appropriateness of early discharge of hospitalized children with suspected sepsis. (1997)

Although our study data suggest that culture-negative children hospitalized for suspected sepsis who meet the criteria for normal clinical assessment can be safely discharged at 48 hours, a stronger statistical validation of this approach can be made if a larger sample size is studied.
The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease (2018)

Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification.
Electrochemical Studies of Chromium in Molten LiF ‐ NaF ‐  KF  (FLINAK) (1984)

The mechanism of the reduction of Cr(III) in molten FLINAK was studied using cyclic voltammetry and chronopotentiometry over a temperature range of 612°–983°C and a Cr(III) concentration of 0.07 to 0.13 mol/l. Two reduction and two oxidation steps were observed, but extensive differences in the electrochemistry were seen over the measured temperature range. Cr(III) is reduced to Cr(II) followed by a two‐electron reduction of Cr(II) to Cr metal and both reduction processes are quasi‐reversible. The product of the first reduction process is soluble at 983°C, but is insoluble at lower temperatures.
Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb (1969)

Abstract The properties and fate of the cells of the subependymal layer of the anterior lateral ventricle and its rostral extension into the olfactory bulb were examined. In one experiment, histological analysis was made of this structure in a large group of rats, ranging in age from newborn to adults. It was established that the ventricular subependymal layer and its rostral extension are present as proliferative and migratory matrices throughout the period studied, with relatively little reduction in size from birth to adulthood. In another, autoradiographic study, the proliferation and migration of cells of this system, and their destination and mode of differentiation, were studied in rats that were injected with thymidine‐H 3 at 30 days of age and killed at intervals ranging from 1 hour to 180 days. There was a declining gradient in cell proliferation in a caudorostral direction from a high level near the lateral ventricle to the absence of cell proliferation in the olfactory bulb. The labeled cells that were present in high proportion near the lateral ventricle in the rats killed 1–24 hours after injection had further multiplied and moved to the middle portion of the “rostral migratory stream” by the third day, and were located in the subependymal layer of the olfactory bulb by the sixth day after injection. By the twentieth day the labeled cells disappeared from the subependymal layer of the olfactory bulb and were distributed throughout the internal granular layer. The differentiated cells were tentatively identified as granular nerve cells and neuroglia cells. These results established that the major target structure of cell production in the subependymal layer of the lateral ventricle in young‐adult rats is the olfactory bulb, with only moderate contribution made to the anterior neocortex and basal ganglia. It was postulated that the function of cell migration to the olfactory bulb is the renewal of its cell population.
Targeting DLL4 in Tumors Shows Preclinical Activity But Potentially Significant Toxicity (2010)

Evaluation of: Yan M, Callahan CA, Beyer JC et al.: Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6-E7 (2010). Delta-like ligand 4 (DLL4) is a Notch ligand that is critical in the formation of a functional vascular network in tumors. Blockade of DLL4-mediated Notch signaling strikingly increases nonproductive angiogenesis, but significantly inhibits tumor growth in preclinical mouse models. Thus, DLL4 has emerged as an attractive target for cancer therapy. Anti-DLL4 antibodies have recently entered clinical trials. However, the potential toxic effects of anti-DLL4 are poorly understood. In this article, Yan et al. reported that chronic DLL4 blockade abnormally activates endothelial cells, causes pathological changes of multiple organs and induces vascular neoplasms. The findings need confirmation in further studies using different tumor-bearing animals but, nevertheless, raise important safety concerns regarding the use of anti-DLL4 agents and warrant monitoring for these effects in clinical trials for targeting DLL4.