gebhart/patrepeval huggingface dataset:
Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products. (1988)

Four steroid 21-hydroxylase B [P-450(C21)B] genes (designated P.7, P.10-1, P.10-2, and P.3) from three P-450(C21)-deficient patients were isolated to analyze their structures and functions. Several base changes were observed in the sequences of the four P-450(C21)B genes as compared to that of the functional B gene. Many of these base changes were identical to those of the P-450(C21)A pseudogene. The three DNAs (P.10-1, P.10-2, and P.3) produced no P-450(C21) activity in a functional assay for P-450(C21) by the COS cell expression system, while the P.7 DNA expressed the activity. The P.10-1 and P.10-2 DNAs were shown to have a point mutation in the second intron, causing aberrant splicing. The P.3 DNA carried three clustered missense mutations in the sixth exon, which impaired P-450(C21) activity. All these critical mutations could be seen in the corresponding site of the P-450(C21)A pseudogene. These data strongly suggest the involvement of gene conversion in this genetic disease.
Copolymers from benzodithiophene and benzotriazole: synthesis and photovoltaic applications (2010)

Two new alternating low bandgap copolymers from benzodithiophene and benzotriazole units, namely poly{4,8-bis(2-ethylhexyloxy)benzo[1,2-b; 3,4-b]dithiophene-2,6-diyl-alt-2-octyl-4,7-di(thiophen-2-yl)-2H-benzo[d][1,2,3]triazole-5′,5′′-diyl} (PBDTDTBTz) and poly{4,8-bis(2-ethylhexyloxy)benzo[1,2-b;3,4-b]dithiophene-2,6-diyl-alt-2-dodecylbenzotriazole-4,7-diyl} (PBDTBTz), were designed and synthesized by a typical Stille coupling polymerization method. The copolymers were characterized by thermogravimetric analysis, UV-vis absorption and cyclic voltammetry. PBDTDTBTz and PBDTBTz possess moderate molecular weights and excellent thermal properties with a 5% weight loss temperatures (Td) around 300 °C. They exhibited good optical absorption, with peaks at 527 nm and 562 nm in the film state, respectively. Photovoltaic properties of the copolymers blended with [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) or [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as electron acceptors, were investigated. The photovoltaic device with the PBDTDTBTz/PC71BM shows a power conversion efficiency of 1.7% with a short circuit current density of 4.5 mA cm−2 and a good fill factor of 0.62, while PBDTBTz demonstrated a moderate power conversion efficiency of up to 1.4%, under the illumination of AM 1.5, 100 mW cm−2 with a device structure of ITO/PEDOT: PSS/polymer: PC71BM (1 : 4)/Ca/Al. All the above information highlighted that this kind of the copolymers is promising for the application of polymer solar cells.
Noninvasive intracranial compliance and pressure based on dynamic magnetic resonance imaging of blood flow and cerebrospinal fluid flow: review of principles, implementation, and other noninvasive approaches (2003)

Current techniques for intracranial pressure (ICP) measurement are invasive. All require a surgical procedure for placement of a pressure probe in the central nervous system and, as such, are associated with risk and morbidity. These considerations have driven investigators to develop noninvasive techniques for pressure estimation. A recently developed magnetic resonance (MR) imaging-based method to measure intracranial compliance and pressure is described. In this method the small changes in intracranial volume and ICP that occur naturally with each cardiac cycle are considered. The pressure change during the cardiac cycle is derived from the cerebrospinal fluid (CSF) pressure gradient waveform calculated from the CSF velocities. The intracranial volume change is determined by the instantaneous differences between arterial blood inflow, venous blood outflow, and CSF volumetric flow rates into and out of the cranial vault. Elastance (the inverse of compliance) is derived from the ratio of the measured pressure and volume changes. A mean ICP value is then derived based on a linear relationship that exists between intracranial elastance and ICP. The method has been validated in baboons, flow phantoms, and computer simulations. To date studies in humans demonstrate good measurement reproducibility and reliability. Several other noninvasive approaches for ICP measurement, mostly nonimaging based, are also reviewed. Magnetic resonance imaging-based ICP measurement may prove valuable in the diagnosis and serial evaluation of patients with a variety of disorders associated with alterations in ICP.
Transcriptional Regulation of Human Prostaglandin-endoperoxide Synthase-2 Gene by Lipopolysaccharide and Phorbol Ester in Vascular Endothelial Cells (1995)

There exist two distinct isozymes of prostaglandin-endoperoxide synthase (PES). PES-2 mRNA is synergistically induced by lipopolysaccharide (LPS) and 12-O-tetradecanoylphorbol-13-acetate (TPA) in bovine arterial endothelial cells. On the other hand, PES-1 mRNA is constitutively expressed under these conditions. Therefore, the promoter activities of the human genes for PES-1 and -2 in bovine arterial endothelial cells were examined. The 5'-flanking region of the human PES-2 gene (nucleotides -327 to +59) showed promoter activity inducible by LPS and TPA using transient transfection analysis, whereas that of the PES-1 gene (nucleotides -1010 to +69) showed constitutive promoter activity. Destruction of both consensus sequences for the nuclear factor responsible for the interleukin-6 expression (NF-IL6) site (nucleotides -132 to -124) and the cyclic AMP response element (CRE) (nucleotides -59 to -53) of the human PES-2 gene markedly reduced the promoter activity (25%) of the PES-2 gene after combined treatment with LPS and TPA, although single destruction of the NF-IL6 site or the CRE slightly reduced the promoter activity (60 or 90%, respectively). Moreover, cotransfection experiments showed that a trans-acting factor, CCAAT enhancer binding protein delta (C/EBP delta), which binds to both the NF-IL6 site and the CRE, increased the promoter activity of the PES-2 gene mainly through the CRE. C/EBP delta mRNA was rapidly induced by LPS. Collectively, these results suggest that transcription of the PES-2 gene in vascular endothelial cells is regulated through combination of the NF-IL6 site and the CRE and that C/EBP delta functions as one of the trans-acting factors.
CRISPRmap: an automated classification of repeat conservation in prokaryotic adaptive immune systems (2013)

Central to Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas systems are repeated RNA sequences that serve as Cas-protein-binding templates. Classification is based on the architectural composition of associated Cas proteins, considering repeat evolution is essential to complete the picture. We compiled the largest data set of CRISPRs to date, performed comprehensive, independent clustering analyses and identified a novel set of 40 conserved sequence families and 33 potential structure motifs for Cas-endoribonucleases with some distinct conservation patterns. Evolutionary relationships are presented as a hierarchical map of sequence and structure similarities for both a quick and detailed insight into the diversity of CRISPR-Cas systems. In a comparison with Cas-subtypes, I-C, I-E, I-F and type II were strongly coupled and the remaining type I and type III subtypes were loosely coupled to repeat and Cas1 evolution, respectively. Subtypes with a strong link to CRISPR evolution were almost exclusive to bacteria; nevertheless, we identified rare examples of potential horizontal transfer of I-C and I-E systems into archaeal organisms. Our easy-to-use web server provides an automated assignment of newly sequenced CRISPRs to our classification system and enables more informed choices on future hypotheses in CRISPR-Cas research: http://rna.informatik.uni-freiburg.de/CRISPRmap.
Silicon Photonic Microring Resonators for Quantitative Cytokine Detection and T-Cell Secretion Analysis (2010)

The ability to perform multiple simultaneous protein biomarker measurements in complex media with picomolar sensitivity presents a large challenge to disease diagnostics and fundamental biological studies. Silicon photonic microring resonators represent a promising platform for real-time detection of biomolecules on account of their spectral sensitivity toward surface binding events between a target and antibody-modified microrings. For all refractive index-based sensing schemes, the mass of bound analytes, in combination with other factors such as antibody affinity and surface density, contributes to the observed signal and measurement sensitivity. Therefore, proteins that are simultaneously low in abundance and have a lower molecular weight are often challenging to detect. By employing a more massive secondary antibody to amplify the signal arising from the initial binding event, it is possible to improve both the sensitivity and the specificity of protein assays, allowing for quantitative sensing in complex sample matrices. Herein, a sandwich assay is used to detect the 15.5 kDa human cytokine interleukin-2 (IL-2) at concentrations down to 100 pg/mL (6.5 pM) and to quantitate unknown solution concentrations over a dynamic range spanning 2.5 orders of magnitude. This same sandwich assay is then used to monitor the temporal secretion profile of IL-2 from Jurkat T lymphocytes in serum-containing cell culture media in the presence of the entire Jurkat secretome. The same temporal secretion analysis is performed in parallel using a commercial ELISA, revealing similar IL-2 concentration profiles but superior precision for the microring resonator sensing platform. Furthermore, we demonstrate the generality of the sandwich assay methodology on the microring resonator platform for the analysis of any biomolecular target for which two high-affinity antibodies exist by detecting the approximately 8 kDa cytokine interleukin-8 (IL-8) with a limit of detection and dynamic range similar to that of IL-2. This work demonstrates the first application of silicon photonic microring resonators for detecting cellular secretion of cytokines and represents an important advance for the detection of protein biomarkers on an emerging analytical platform.
Role of inflammation in the mechanism of acetaminophen-induced hepatotoxicity (2005)

Acetaminophen (AAP) overdose and the resulting hepatotoxicity is an important clinical problem. In addition, AAP is widely used as a prototype hepatotoxin to study mechanisms of chemical-induced cell injury and to test the hepatoprotective potential of new drugs and herbal medicines. Because of its importance, the mechanisms of AAP-induced liver cell injury have been extensively investigated and controversially discussed for > 30 years. This review highlights recent new insight into intracellular events critical for liver cell death. In addition, the relevance of the inflammatory response is addressed, including cytotoxic and inflammatory mediators generated by activated inflammatory cells, that is, resident macrophages and lymphocytes as well as newly recruited blood-derived leukocytes. Inflammation is a critical component of the overall pathophysiology, not only as a potential factor that may aggravate cell damage, but more importantly as a vital response to limit cell injury, remove cell debris and promote regeneration.
Cocaine-Induced Cerebral Vasoconstriction Detected in Humans With Magnetic Resonance Angiography (1998)

Cocaine administration induced dose-related cerebral vasoconstriction on magnetic resonance angiograms. These changes occurred at low cocaine doses and in the absence of other risk factors, including polydrug abuse, hypertension, or cerebrovascular disease. Outcome stratification by prior cocaine use statistically strengthened the relationship between cocaine administration and vasoconstriction, suggesting that cocaine may have a cumulative residual effect in promoting cerebrovascular dysfunction.
Novel mass spectrometric immunoassays for the rapid structural characterization of plasma apolipoproteins (2003)

Novel mass spectrometric immunoassays (MSIAs) for the isolation and structural characterization of plasma apolipoprotein A-I (apoA-I), apoA-II, and apoE have been developed. The assays combine selective isolation of apolipoprotein species via affinity capture with mass-specific detection using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In application, plasma (from 50 microl of whole blood drawn from individuals, using finger lancet) was addressed with affinity pipette tips derivatized with antibodies toward the specific apolipoprotein. The time required for each assay was approximately 15 min, less if assays on multiple individuals were performed in parallel. In a brief study of five individuals, several recently reported apoA-II variants were identified and observed consistently in all individuals. Additionally, the apoE phenotype of E3/E3 was observed in three of the individuals, and E2/E3 and E3/E4 observed in the remaining two individuals, the latter of whom suffers from Alzheimer's disease. Overall, the MSIA approach offers a rapid, sensitive, and highly accurate means of profiling apolipoproteins from small volumes of plasma.
Increased serum hepcidin and alterations in blood iron parameters associated with asymptomatic P. falciparum and P. vivax malaria (2010)

Asymptomatic malarial parasitemia is associated with increased hepcidin concentrations and anemia, in the absence of a manifest acute phase response. Prolonged iron maldistribution may be an underestimated cause of anemia. Screening for parasitemia should be performed before starting iron supplementation, as iron therapy may be less effective and even hazardous in these circumstances.
Development of a Pressure Swing Adsorption Cycle for Producing High Purity CO2 from Dilute Feed Streams. Part I: Feasibility Study (2018)

Simulations of a 3-bed 9-step pressure swing adsorption (PSA) cycle were carried out to study the enrichment and recovery of 0.4 vol % CO2 from dry air using 13X zeolite with the feed pressure and flow rate fixed at 1 atm and 570 SLPM. The goal was to produce 97 vol % CO2 at greater than 62% CO2 recovery, less than 1 kW vacuum pump power, and small volume. The PSA cycle step sequence consisted of feed (F), idle (I), heavy reflux (HR), cocurrent equalization down (EqD), forced cocurrent depressurization (CoD), countercurrent depressurization (CnD), light reflux (LR), countercurrent equalization up (EqU), and light product pressurization (LPP). A parametric study revealed the following effects on the PSA process performance. Increases in the HR = LR = F step time (thus cycle time) caused significant increases in the CO2 purity and vacuum pump power, while the CO2 recovery exhibited a modest maximum. Increases in the LR ratio caused significant increases in both the CO2 recovery and power but only a modest increase in the CO2 purity. Increases in the CnD end pressure caused only slight changes in all three parameters, with the CO2 purity increasing and CO2 recovery and power decreasing. Increases in the LR pressure caused significant decreases in both the CO2 recovery and power, with only a slight decrease in CO2 purity. Increases in the CoD end pressure caused a significant decrease in the CO2 purity, a modest increase in the CO2 recovery, and only a slight decrease in power. The best PSA process performance produced a CO2 purity of 96.3 vol % at a CO2 recovery of 87.8% and a feed throughput of 1264 L(STP)/h/kg, while consuming 572 W. This new PSA cycle was very effective at concentrating CO2 (over 242 times) because of a forced CoD step and a very long HR = LR step time relative to the other cycle steps, where the source of the HR was exclusively from the LR step. The LR step dominated the power requirement, so much that the power required by the CnD step and especially the forced CoD step were both insignificant in comparison.
Amination of Ketones by Employing Two New (S)‐Selective ω‐Transaminases and the His‐Tagged ω‐TA from Vibrio fluvialis (2011)

Abstract Two recently identified ( S )‐selective ω‐transaminases (ω‐TAs) that originate from Paracoccus denitrificans (Strep‐PD‐ωTA, cloned with an N ‐terminal Strep ‐tag II) and Pseudomonas fluorescens (PF‐ωTA) were employed for the asymmetric amination of selected prochiral ketones. The substrates tested were transformed into optically pure amines (&gt;99 % ee ) with high conversion (up to &gt;99 %). The ω‐TAs led to higher conversion in the absence of dimethyl sulfoxide as a cosolvent than in its presence (15 %, v/v). Additionally, it was shown that a His‐tagged recombinant transaminase from Vibrio fluvialis (His‐VF‐ωTA, cloned with an N ‐terminal His 6 ‐tag) showed for a single substrate, ethyl acetoacetate, significantly higher stereoselectivity for the amination compared to the corresponding commercial enzyme preparation (&gt;99 vs. 50 %).
5-Aminoimidazole-4-Carboxamide Ribonucleoside. A Specific Method for Activating AMP-Activated Protein Kinase in Intact Cells? (1995)

The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidazole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.
Preparation and evaluation of carborane-derived inhibitors of prostate specific membrane antigen (PSMA) (2014)

A series of C-hydroxy carborane derivatives of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)-pentanedioic acid were prepared as a new class of boron rich inhibitors of prostate specific membrane antigen (PSMA), which is overexpressed on prostate cancer tumours and metastases. Closo-, nido- and iodo-carborane conjugates were prepared and screened in vitro where the water soluble iodinated cluster had the highest affinity with an IC50 value (73.2 nM) that was comparable to a known PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (PMPA, 63.9 nM). The radiolabeled analogue was prepared using (123)I and the biodistribution determined in a prostate cancer model derived from a PSMA positive cell line (LNCaP) at 1, 2, 4, 6 and 24 h post injection (n = 4 per time point). The results showed good initial tumour uptake of 4.17% at 1 h, which remained at that level only decreasing somewhat at 6 h (3.59%). At the latter time point tumour-to-blood and tumour-to-muscle ratios peaked at 3.47 at 25.52 respectively. There was significant off-target binding particularly in the liver and gall bladder and a surprising amount of deiodination in vivo. Notwithstanding, this work demonstrates that carboranes can be used to prepare potent ligands for PSMA creating the opportunity to develop a new class of BNCT agents for prostate cancer.
Randomized Trial of Doxorubicin, Bisantrene, and Miltoxantrone in Advanced Breast Cancer: A Southwest Oncology Group Study (1991)

Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients), 320 mg/m2 bisantrene (146 patients), or 14 mg/m2 mitoxantrone (135 patients). The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity. To be eligible, patients must have had one previous chemotherapy regimen, and patients who were estrogen receptor positive must have failed endocrine therapy. There were 365 patients assessable for response and 399 assessable for toxic effects. The median age was 57 years; 18% were premenopausal or perimenopausal. Visceral dominant disease was present in 66% of the patients. Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year. The response rate was 28% with doxorubicin, 13% with bisantrene, and 14% with mitoxantrone (P = .004). Median time to treatment failure was 133 days with doxorubicin, 66 days with bisantrene, and 68 days with mitoxantrone (logrank P = .06). The median survival was 315 days for doxorubicin, 290 days for bisantrene, and 177 days for mitoxantrone (logrank P = .04), although survival at 2 years was similar for all three agents. There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene (39 patients) or mitoxantrone (63 patients). Toxicity leading to discontinuance of therapy was more common with doxorubicin, and discontinuance of therapy was due primarily to patient's request or cardiotoxicity. The major dose-limiting toxic effect for all three agents was leukopenia. Nausea and vomiting, mucositis, and alopecia were more severe with doxorubicin. Congestive heart failure developed in nine patients treated with doxorubicin, zero patients treated with bisantrene, and two patients treated with mitoxantrone. A decrease in the left ventricular ejection fraction, as defined by moderate to severe Alexander grade changes, was more common in patients treated with doxorubicin (doxorubicin-treated patients = 20%, bisantrene-treated patients = 5%, and mitoxantrone-treated patients = 10%). This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma. The activity of doxorubicin is greater than that of the other two agents, but at a cost of increased toxicity.
Current concepts related to hypertrophic scarring in burn injuries (2016)

ABSTRACT Scarring following burn injury and its accompanying aesthetic and functional sequelae still pose major challenges. Hypertrophic scarring (HTS) can greatly impact patients' quality of life related to appearance, pain, pruritus and even loss of function of the injured body region. The identification of molecular events occurring in the evolution of the burn scar has increased our knowledge; however, this information has not yet translated into effective treatment modalities. Although many of the pathophysiologic pathways that bring about exaggerated scarring have been identified, certain nuances in burn scar formation are starting to be recognized. These include the effects of neurogenic inflammation, mechanotransduction, and the unique interactions of burn wound fluid with fat tissue in the deeper dermal layers, all of which may influence scarring outcome. Tension on the healing scar, pruritus, and pain all induce signaling pathways that ultimately result in increased collagen formation and myofibroblast phenotypic changes. Exposure of the fat domes in the deep dermis is associated with increased HTS, possibly on the basis of altered interaction of adipose‐derived stem cells and the deep burn exudate. These pathophysiologic patterns related to stem cell‐cytokine interactions, mechanotransduction, and neurogenic inflammation can provide new avenues of exploration for possible therapeutic interventions.