gebhart/patrepeval huggingface dataset:
Epigenetic therapy using the histone deacetylase inhibitor for increasing therapeutic gain in oral cancer: prevention of radiation-induced oral mucositis and inhibition of chemical-induced oral carcinogenesis (2009)

In addition to genetic changes, epigenetic aberrations also play important roles in radiation- and chemical-induced disorders and carcinogenesis. The present study investigated whether epigenetic therapy with a histone deacetylase (HDAC) inhibitor has dual benefits for radiation-induced oral mucositis and chemical-induced oral carcinogenesis, which should be treated at the same time. The HDAC inhibitor phenylbutyrate was first tested to determine if it influences DNA damage repair and survival in irradiated normal cells in vitro by investigating the patterns and dynamics of phospho-gammaH2AX foci, Rad51 foci and phospho-gammaH2AX/Rad51 colocalization and using the comet and clonogenic assays. Oral mucositis or carcinogenesis was induced in hamsters using radiation or 7,12-dimethylbenz[a]anthracene (DMBA) irritation to the cheek pouch. The ability of phenylbutyrate formed in proper carriers to prevent radiation-induced oral mucositis and inhibit chemical-induced oral carcinogenesis was assessed. The treated or untreated irradiated or DMBA-irritated oral tissues or mucosal epithelia were subjected to the studies of histology, immunohistochemistry, gene expression, comet assay, HDAC activity or oxidative stress. We found that phenylbutyrate promoted DNA repair and survival in normal cells after radiation. Compared with blank or vehicle-treated hamsters, the irradiated mucosa treated with phenylbutyrate had significantly lower oxidative stress and tumor necrosis factor-alpha expression and less severe oral mucositis of a shorter duration. A reduction of the oral tumor incidence, burden and progression by phenylbutyrate correlated with the suppression of oncomiRs and Rad51 overexpression, the upregulation of differentiation markers and the decrease of intracellular HDAC activity and oxidative stress during DMBA-induced oral carcinogenesis. Thus, epigenetic therapy using the HDAC inhibitor as an adjuvant to radiotherapy for chemical-induced oral cancer may provide a promising strategy combining the prevention of radiation-induced oral mucositis and the inhibition of oral carcinogenesis.
Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies. (1998)

Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles.
Modification of Cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles (1993)

Abstract Strong bases (lithium diisopropylamide (LDA) or BuLi) convert cyclosporin A (CS) to hexalithio derivative containing a Li alkoxide, four Li azaenolate, and one Li enolate units. The Li 6 compound is solubilized in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reactions with electrophiles (alkyl halides, aldehydes, ClCO 2 R, CO 2 , (RS) 2 , D 2 O) at low temperatures give products containing new side chains in amino‐acid residue 3 of the cyclic undecapeptide (see 1 – 13 , Schemes 1 , and 2 , and Figs. 1 and 2 ) in moderate to high yields and, with Re ‐ or Si ‐selectivities, depending upon the conditions of lithiation of up to 7:1, Pure CS derivatives ( Scheme 2, Table 1 in the Exper. Part ) can be isolated by column chromatography. N ‐Alkylations or cleavage of the peptide backbone by carbonyl addition occur only at higher temperatures and/or with prolonged reaction times (see 14 and 15 in Scheme 4 ). Very little or no epimerization of stereogenic centers occurs under the conditions employed. Possible reasons for the feasibility of these surprizing conversions of CS are discussed ( Schemes 4 and 5 and Fig. 3 ). For comparision, [MeAla 3 ]CS ( 2b ) and [ D ‐MeAla 3 ]CS ( 2a ) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7) . Their 1 H‐ and 13 C‐NMR spectra are compared with those of CS ( Table 2 in the Exper. Part ).
HyperSQL: web-based query interfaces for biological databases (2002)

HyperSQL is an interoperability layer that enables database administrators to rapidly construct browser-based query interfaces to remote Sybase databases. Current browsers (i.e., Netscape, Mosaic, Internet Explorer) do not easily interoperate with databases without extensive CGI (Common Gateway Interface) programming. HyperSQL can be used to create forms and hypertext-based database interfaces for non-computer experts (e.g., scientists, business users). Such interfaces permit the user to query databases by filling out query forms selected from menus. No knowledge of SQL is required because the interface automatically composes SQL from user input. Database results are automatically formatted as graphics and hypertext, including clickable links which can issue additional queries for browsing through related data, bring up other Web pages, or access remote search engines. Query interfaces are constructed by inserting a small set of HyperSQL descriptors and HTML formatting into text files. No compilation is necessary because commands are interpreted and carried out by the special gateway, positioned between the remote databases and the Web browser. Feedback from developers who have used the initial release of HyperSQL has been encouraging. At present, query interfaces have been successfully implemented for three major NSF-sponsored biological databases: Microbial Germplasm Database, Mycological Types Collection, and Vascular Plants Types Collection.
Evaluation of the DNA fingerprinting method AFLP as a new tool in bacterial taxonomy (1996)

We investigated the usefulness of a novel DNA fingerprinting technique, AFLP, which is based on the selective amplification of genomic restriction fragments by PCR, to differentiate bacterial strains at the subgeneric level. In totals, 147 bacterial strains were subjected to AFLP fingerprinting: 36 Xanthomonas strains, including 23 pathovars of Xanthomonas axonopodis and six pathovars of Xanthomonas vasicola, one strain of Stenotrophomonas, 90 genotypically characterized strains comprising all 14 hybridization groups currently described in the genus Aeromonas, and four strains of each of the genera Clostridium, Bacillus, Acinetobacter, Pseudomonas and Vibrio. Depending on the genus, total genomic DNA of each bacterium was digested with a particular combination of two restriction endonucleases and the resulting fragments were ligated to restriction halfsite-specific adaptors. These adaptors served as primer-binding sites allowing the fragments to be amplified by selective PCR primers that extend beyond the adaptor and restriction site sequences. Following electrophoretic separation on 5% (w/v) polyacrylamide/8.3 M urea, amplified products could be visualized by autoradiography because one of the selective primers was radioactively labelled. The resulting banding patterns, containing approximately 30-50 visualized PCR products in the size range 80-550 bp, were captured by a high-resolution densitoscanner and further processed for computer-assisted analysis to determine band-based similarity coefficients. This study reveals extensive evidence for the applicability of AFLP in bacterial taxonomy through comparison of the newly obtained data with results previously obtained by well-established genotypic and chemotaxonomic methods such as DNA-DNA hybridization and cellular fatty acid analysis. In addition, this study clearly demonstrates the superior discriminative power of AFLP towards the differentiation of highly related bacterial strains that belong to the same species or even biovar (i.e. to characterize strains at the infrasubspecific level), highlighting the potential of this novel fingerprinting method in epidemiological and evolutionary studies.
Which diagnostic tests are most useful in a chest pain unit protocol? (2005)

Serial ECG/ST monitoring, as used in our protocol, adds little diagnostic or prognostic value in patients with a normal or non-diagnostic initial ECG. CK-MB(mass) can rule out ACS with clinical myocardial infarction but not myocyte necrosis(defined as a troponin elevation without myocardial infarction). Using a low threshold for positivity for troponin T improves sensitivity of this test for myocardial infarction and myocardial necrosis. Exercise treadmill testing predicts subsequent adverse cardiac events.
Green infrared-pumped erbium upconversion laser (1987)

An upconversion pumping scheme was used to produce cw laser action at 0.55 μm in YAlO3:Er3+ at temperatures up to 77 K on the 4S3/2→4I15/2 transition. Two infrared dye lasers at 792.1 and 839.8 nm were used as the pump sources for stepwise two-photon excitation of the 4S3/2 upper laser level at 18 406 cm−1. The laser operates in the fundamental TEM00 mode, and a cw output power of ∼1 mW was achieved with ∼200 mW pump power from each infrared dye laser.
The molecular mechanism of erythropoietin action (1992)

Erythropoietin (EPO) is the glycoprotein hormone which controls the production of erythrocytes in mammals. Erythrocytes contain hemoglobin which delivers oxygen from the lungs to other tissues throughout the body. The amount of oxygen delivered to the tissues is controlled by the number of erythrocytes in the bloodstream. Erythrocytes have a finite life span, and, therefore, maintenance of normal oxygen delivery requires continuous replacement of those aged erythrocytes normally lost from the circulation. Adjustments in this basal rate of erythrocyte production are made when tissue oxygenation becomes either decreased or increased compared to the normal level. Development of anemia due to blood loss or inspiration of decreased atmospheric oxygen at high altitude results in decreased oxygen delivery to the tissues.
The hydrophobic moment detects periodicity in protein hydrophobicity. (1984)

Periodicities in the polar/apolar character of the amino acid sequence of a protein can be examined by assigning to each residue a numerical hydrophobicity and searching for periodicity in the resulting one-dimensional function. The strength of each periodic component is the quantity that has been termed the hydrophobic moment. When proteins of known three-dimensional structure are examined, it is found that sequences that form alpha helices tend to have, on average, a strong periodicity in the hydrophobicity of 3.6 residues, the period of the alpha helix. Similarly, many sequences that form strands of beta sheets tend to have a periodicity in their hydrophobicity of about 2.3 residues, the period typical of beta structure. Also, the few sequences known to form 3(10) helices display a periodicity of about 2.5 residues, not far from the period of 3 for an ideal 3(10) helix. This means that many protein sequences tend to form the periodic structure that maximizes their amphiphilicity. This observation suggests that the periodicity of the hydrophobicity of the protein primary structure is a factor in the formation of secondary structures. Moreover, the observation that many protein sequences tend to form segments of maximum amphiphilicity suggests that segments of secondary structure fold at a hydrophobic surface, probably formed from other parts of the folding protein.
Estimation of pKa for organic oxyacids using calculated atomic charges (1993)

Abstract A method for the estimation of p K a from empirically calculated atomic charges has been developed and tested on a diverse set of organic oxyacids. The approach involves a comparison of the atomic charges calculated for both the acid and the negative ion that is formed after loss of the acidic proton. These charges have been used in conjunction with the familiar concepts of induction and resonance to develop an accurate formula to predict p K a . Results for a set of 135 compounds, including alcohols, phenols, and carboxylic acids, yielded a fit of p K a with r = 0.993 and an rms error of 0.455. © John Wiley &amp; Sons, Inc.
Recruitment of factors linking transcription and processing of pre-rRNA to NOR chromatin is UBF-dependent and occurs independent of transcription in human cells (2007)

Efficient ribosome biogenesis requires coordination of a highly complex series of events. Early events include pre-RNA transcription, processing, and modification. Analysis in yeast has demonstrated that t-UTPs, components of the U3 snoRNA-containing pre-rRNA processing complex, are required for efficient transcription of ribosomal genes (rDNA) by RNA polymerase I (pol I). Here, we characterize human t-UTPs and establish that their ability to link transcription and pre-rRNA processing is evolutionarily conserved. The pol I transcription factor UBF binds extensively across rDNA throughout the cell cycle, resulting in a specialized form of chromatin that is the hallmark of active nucleolar organizer regions (NORs). Transcriptionally silent pseudo-NORs are ectopic, chromosomally integrated, artificial arrays that mimic this specialized chromatin structure. Pseudo-NORs sequester t-UTPs and factors linking transcription with pre-rRNA modification (Nopp140 and Treacle). Recruitment is independent of transcription, the underlying DNA sequence, and location within the nucleolus. Previously, we have demonstrated that pseudo-NORs sequester every component of the pol I transcription machinery. Taken together, these results highlight the importance of the specialized chromatin structure at active NORs in coordinating early events in ribosome biogenesis and nucleolar formation.
Resonance Light Scattering: A New Technique for Studying Chromophore Aggregation (1995)

Light scattering experiments are usually performed at wavelengths away from absorption bands, but for species that aggregate, enhancements in light scattering of several orders of magnitude can be observed at wavelengths characteristic of these species. Resonance light scattering is shown to be a sensitive and selective method for studying electronically coupled chromophore arrays. The approach is illustrated with several examples drawn from porphyrin and chlorin chemistry. The physical principles underlying resonance light scattering are discussed, and the advantages and limitations of the technique are reviewed.
Automatic speech based emotion recognition using paralinguistics features (2019)

Affective computing studies and develops systems capable of detecting humans affects. The search for universal well-performing features for speech-based emotion recognition is ongoing. In this paper, a small set of features with support vector machines as the classifier is evaluated on Surrey Audio-Visual Expressed Emotion database, Berlin Database of Emotional Speech, Polish Emotional Speech database and Serbian emotional speech database. It is shown that a set of 87 features can offer results on-par with state-of-the-art, yielding 80.21, 88.6, 75.42 and 93.41% average emotion recognition rate, respectively. In addition, an experiment is conducted to explore the significance of gender in emotion recognition using random forests. Two models, trained on the first and second database, respectively, and four speakers were used to determine the effects. It is seen that the feature set used in this work performs well for both male and female speakers, yielding approximately 27% average emotion recognition in both models. In addition, the emotions for female speakers were recognized 18% of the time in the first model and 29% in the second. A similar effect is seen with male speakers: the first model yields 36%, the second 28% a verage emotion recognition rate. This illustrates the relationship between the constitution of training data and emotion recognition accuracy.
34Efficacy and safety of various doses of the new dual endothelin receptor antagonist aprocitentan in the treatment of hypertension (2019)

Abstract Background Endothelin Receptor Antagonists (ERAs) have been investigated for the treatment of a variety of cardiovascular conditions because of their potent vasodilating properties. However, until now, ERAs have only been registered for the treatment of pulmonary arterial hypertension and scleroderma-induced digital ulcers. This class of drugs may also be useful in the treatment of difficult to control hypertension with a medical need. Purpose To investigate the efficacy and safety of various doses of the new dual ERA, aprocitentan, in the treatment of hypertension in order to determine the most appropriate dose(s) for further clinical development using an unattended, automated office BP (AOBP) device (BpTRU). This Phase 2 trial was registered at ClinicalTrials.gov [NCT02603809]. Methods Eligible patients with hypertension (mean sitting systolic/diastolic BP 149.7/97.6 mmHg) received aprocitentan 5, 10, 25 or 50 mg, matching placebo or lisinopril 20 mg as a positive control, once daily for 8 weeks using a randomised, double-blind, parallel-group study design. AOBP was assessed at baseline and weeks 2, 4, 8, and 10 (withdrawal) by recording multiple BP readings with the patient resting quietly. Additionally, 24 h ambulatory BP monitoring was performed at baseline and week 8. Results A total of 490 eligible patients were randomised to the double-blind phase with 430 subjects successfully completing 8 weeks of treatment. Decreases in sitting systolic/diastolic AOBP, from baseline to week 8 were 10.3/6.3, 15.0/9.9, 18.5/12.0 and 15.1/10.0 mmHg for aprocitentan 5, 10, 25, and 50 mg, respectively vs. 7.7/4.9 mmHg for placebo and 12.8/8.4 mmHg for lisinopril. No changes in heart rate or body weight were observed for any dose of aprocitentan. Modelling the dose-response suggested that the maximal effect of aprocitentan is achieved at a dose of approximately 25 mg and that 70% of this effect is already observed at a dose of 10 mg. Aprocitentan treatment was associated with decreases in haemoglobin, haematocrit, and albumin which exhibited a monotonic dose-response relationship, in line with its known vasodilating effects. Estimated increases in plasma volume were 3.0%, 5.1%, 6.9%, and 9.5% for aprocitentan 5, 10, 25, and 50 mg, respectively, vs. 1.6% for lisinopril and a decrease of 0.3% for placebo. All these values are below the accepted pathophysiological threshold of 10%. The overall incidence of adverse events observed in the aprocitentan groups (ranging from 22.0% to 40.2%) was similar to that seen in the placebo group (36.6%). Overall, the most common events were hypertension, headache, and nasopharyngitis. Conclusions These findings support the use of aprocitentan at doses between 10 and 25 mg for further investigation as a potential treatment for hypertension. Acknowledgement/Funding Actelion conducted study. Drug discovery &amp; early clinical pipeline demerged during Johnson &amp; Johnson acquisition. Idorsia supported abstract.
Non-contiguous finished genome sequence and description of Megasphaera massiliensis sp. nov. (2013)

Megasphaera massiliensis strain NP3(T) sp. nov. is the type strain of Megasphaera massiliensis sp. nov., a new species within the genus Megasphaera. This strain, whose genome is described here, was isolated from the fecal flora of an HIV-infected patient. M. massiliensis is a Gram-negative, obligate anaerobic coccobacillus. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 2,661,757 bp long genome (1 chromosome but no plasmid) contains 2,577 protein-coding and 61 RNA genes, including 5 rRNA genes.
The two largest chloroplast genome‐encoded open reading frames of higher plants are essential genes (2000)

The chloroplast genomes of most higher plants contain two giant open reading frames designated ycf1 and ycf2. In tobacco, ycf1 potentially specifies a protein of 1901 amino acids. The putative gene product of the ycf2 reading frame is a protein of 2280 amino acids. In an attempt to determine the functions of ycf1 and ycf2, we have constructed several mutant alleles for targeted disruption and/or deletion of these two reading frames. The mutant alleles were introduced into the tobacco plastid genome by biolistic chloroplast transformation to replace the corresponding wild-type alleles by homologous recombination. Chloroplast transformants were obtained for all constructs and tested for their homoplastomic state. We report here that all transformed lines remained heteroplastomic even after repeated cycles of regeneration under high selective pressure. A balanced selection was observed in the presence of the antibiotic spectinomycin, resulting in maintenance of a fairly constant ratio of wild-type versus transformed genome copies. Upon removal of the antibiotic and therewith release of the selective pressure, sorting out towards the wild-type plastid genome occurred in all transplastomic lines. These findings suggest that ycf1 and ycf2 are functional genes and encode products that are essential for cell survival. The two reading frames are thus the first higher plant chloroplast genes identified as being indispensable.
Diacylglycerol Kinases in T Cell Tolerance and Effector Function (2016)

Diacylglycerol kinases (DGKs) are a family of enzymes that regulate the relative levels of diacylglycerol (DAG) and phosphatidic acid (PA) in cells by phosphorylating DAG to produce PA. Both DAG and PA are important second messengers cascading T cell receptor (TCR) signal by recruiting multiple effector molecules, such as RasGRP1, PKCθ, and mTOR. Studies have revealed important physiological functions of DGKs in the regulation of receptor signaling and the development and activation of immune cells. In this review, we will focus on recent progresses in our understanding of two DGK isoforms, α and ζ, in CD8 T effector and memory cell differentiation, regulatory T cell development and function, and invariant NKT cell development and effector lineage differentiation.