gebhart/patrepeval huggingface dataset:
Of circles and spirals: Bridging the gap between the leading circle and spiral wave concepts of cardiac reentry (2005)

The "leading circle model" was the first detailed attempt at understanding the mechanisms of functional reentry, and remains a widely-used notion in cardiac electrophysiology. The "spiral wave" concept was developed more recently as a result of modern theoretical analysis and is the basis for consideration of reentry mechanisms in present biophysical theory. The goal of this paper is to present these models in a way that is comprehensible to both the biophysical and electrophysiology communities, with the idea of helping clinical and experimental electrophysiologists to understand better the spiral wave concept and of helping biophysicists to understand why the leading circle concept is so attractive and widely used by electrophysiologists. To this end, the main properties of the leading circle and spiral wave models of reentry are presented. Their basic assumptions and determinants are discussed and the predictions of the two concepts with respect to pharmacological responses of arrhythmias are reviewed. A major difference between them lies in the predicted responses to Na(+)-channel blockade, for which the spiral wave paradigm appears more closely to correspond to the results of clinical and experimental observations. The basis of this difference is explored in the context of the fundamental properties of the models.
Human SR proteins and isolation of a cDNA encoding SRp75. (1993)

SR proteins are a family of proteins that have a common epitope recognized by a monoclonal antibody (MAb104) that binds active sites of polymerase II transcription. Four of the SR family members have been shown to restore activity to an otherwise splicing-deficient extract (S100 extract). Here we show that two untested SR proteins, SRp20 and SRp75, can also complement the splicing-deficient extract. We isolated a cDNA encoding SRp75 and found that this protein, like other SR proteins, contains an N-terminal RNA recognition motif (RRM), a glycine-rich region, an internal region homologous to the RRM, and a long (315-amino-acid) C-terminal domain composed predominantly of alternating serine and arginine residues. The apparent molecular mass of dephosphorylated SRp75 is 57 kDa, the size predicted from the cDNA clone. We also detected mobility shifts after dephosphorylating SRp55, SRp40, SRp30a, and SRp30b; the sizes of the shifts are proportional to the length of the SR domain, suggesting that serines in this domain are phosphorylated.
Nanostructure-Initiator Mass Spectrometry Metabolite Analysis and Imaging (2010)

Nanostructure-Initiator Mass Spectrometry (NIMS) is a matrix-free desorption/ionization approach that is particularly well-suited for unbiased (untargeted) metabolomics. An overview of the NIMS technology and its application in the detection of biofluid and tissue metabolites are presented. (To listen to a podcast about this feature, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html .).
Spinal Cord Stimulation for Chronic Pain Management (2004)

This article reviews the current knowledge and clinical applications of spinal cord stimulation for chronic pain management. It also covers basic neurophysiology, implantation techniques, indications, and complications.
β‐Amyloid inhibits NOS activity by subtracting NADPH availability (2002)

The amyloid peptides Abeta1-42 and Abeta25-35 strongly inhibited the activity of constitutive neuronal and endothelial nitric oxide synthases (i.e., NOS-I and NOS-III, respectively) in cell-free assays. The molecular mechanism of NOS inhibition by Ab fragments was studied in detail with Abeta25-35. The inhibitory ability was mostly NADPH-dependent and specific for the soluble form of Abeta25-35. Optical, fluorescence, and NMR spectroscopy showed that the soluble, but not aggregated, Abeta25-35 interacted with NADPH, thus suggesting that a direct recruitment of NADPH may result in diminished availability of the redox cofactor for NOS functioning. To assess the physiological relevance of our findings, rat neuronal-like PC12 and glioma C6 cell lines were used as cellular models. After Abeta25-35 internalization into cells was verified, the activity of constitutive NOS was measured using the DAF-2DA detection system and found to be severely impaired upon Abeta25-35 uptake. Consistent with previous results on the molecular cross-talk between NOS isoforms, repression of constitutive NOS by Abeta25-35 resulted in enhanced expression of inducible NOS (NOS-II) mRNA in C6 cells. Our results represent the first evidence that amyloid fragments impair constitutive NOS activity in cell-free and cellular systems, providing a possible molecular mechanism for the onset and/or maintenance of Alzheimer's disease.
Corticosteroids and Pediatric Septic Shock Outcomes: A Risk Stratified Analysis (2014)

Risk stratified analysis failed to demonstrate any benefit from corticosteroids in this pediatric septic shock cohort.
Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation (2004)

Radial glial cells derive from neuroepithelial cells, and both cell types are identified as neural stem cells. Neural stem cells are known to change their competency over time during development: they initially undergo self-renewal only and then give rise to neurons first and glial cells later. Maintenance of neural stem cells until late stages is thus believed to be essential for generation of cells in correct numbers and diverse types, but little is known about how the timing of cell differentiation is regulated and how its deregulation influences brain organogenesis. Here, we report that inactivation of Hes1 and Hes5, known Notch effectors, and additional inactivation of Hes3 extensively accelerate cell differentiation and cause a wide range of defects in brain formation. In Hes-deficient embryos, initially formed neuroepithelial cells are not properly maintained, and radial glial cells are prematurely differentiated into neurons and depleted without generation of late-born cells. Furthermore, loss of radial glia disrupts the inner and outer barriers of the neural tube, disorganizing the histogenesis. In addition, the forebrain lacks the optic vesicles and the ganglionic eminences. Thus, Hes genes are essential for generation of brain structures of appropriate size, shape and cell arrangement by controlling the timing of cell differentiation. Our data also indicate that embryonic neural stem cells change their characters over time in the following order: Hes-independent neuroepithelial cells, transitory Hes-dependent neuroepithelial cells and Hes-dependent radial glial cells.
Anti-DLL4, a cancer therapeutic with multiple mechanisms of action (2011)

DLL4 is a ligand for the Notch family of receptors. DLL4 has many important functions in normal development and tissue homeostasis, including roles in the immune system, the gastro-intestinal tract, and in vascular development. Because of the importance of Notch signaling in stem cell biology, DLL4 has been investigated for its role in the maintenance and proliferation of cancer stem cells (CSC). In addition, its important role in angiogenesis has been investigated for utility as an anti-angiogenic agent. Preclinical studies have highlighted that both anti-CSC and anti-angiogenic activities contribute to its anti-tumor efficacy, and have supported the clinical development of anti-DLL4 antibody for the treatment of cancer.
A phase IIa study of a sequential regimen using azacitidine to reverse platinum resistance to carboplatin in patients with platinum resistant or refractory epithelial ovarian cancer (2008)

3500 Background: Our preclinical model established the rationale for using azacitidine to reverse platinum resistance. Sequential azacitidine and carboplatin treatment conferred an effect against platinum resistant ovarian cancer cells that was greater than from each agent alone (synergistic interaction). Based on a well tolerated phase I regimen of azacitidine 75 mg/m2/day for 5 days plus carboplatin AUC 5 on day 2 once every 28 days, we initiated a phase IIa trial to evaluate efficacy. Methods: Patients with pathologically confirmed epithelial ovarian cancer who progressed within 6 months after a platinum-based regimen (resistant, Plat-RS, n=18) or on a platinum- based regimen (refractory, Plat-RF, n=12), were eligible to receive sequential azacitidine and carboplatin. All patients had measurable disease. Results: Thirty patients received a total of 159 cycles of treatment and 2 patients are still being actively treated at the cycle 14 and 19, respectively. Side effects include neutropenia, anemia, fatigue, nausea, and pain/irritation at the injection sites. All patients were followed for more than 12 months or until death. Remarkably, our regimen resulted in 1 CR, 3 PR (RR: 14%) and 10 SD in 29 evaluable patients, which is in stark contrast to no responses to a carboplatin-based regimen in a similar cohort of patients in the same institution. The median duration of response was 7.5 months. OS at 1-yr was 53%. Patients classified as having Plat-RS disease had an objective response of 22% and one-year OS of 67% compared to 0% and 33% in Plat-RF patients, respectively. Conclusions: To the best of our knowledge, this is the first phase II trial in epithelial ovarian cancer patients that demonstrates the ability of a hypomethylating agent to reverse platinum resistance. Based on these data, a randomized phase III trial in patients with platinum-resistant epithelial ovarian cancer is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion, Inc Pharmion, Inc. Pharmion, Inc
Structural Basis for Shikimate-Binding Specificity ofHelicobacter pyloriShikimate Kinase (2005)

Shikimate kinase (EC 2.7.1.71) catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid in the presence of ATP. As the fifth key step in the shikimate pathway for aromatic amino acid biosynthesis in bacteria, fungi, and plants, but not mammals, shikimate kinase represents an attractive target for the development of new antimicrobial agents, herbicides, and antiparasitic agents. Here, we report the 1.8-Angstroms crystal structure of Helicobacter pylori shikimate kinase (HpSK). The crystal structure shows a three-layer alpha/beta fold consisting of a central sheet of five parallel beta-strands flanked by seven alpha-helices. An HpSK-shikimate-PO(4) complex was also determined and refined to 2.3 Angstroms, revealing induced-fit movement from an open to a closed form on substrate binding. Shikimate is located above a short 3(10) helix formed by a strictly conserved motif (GGGXV) after beta(3). Moreover, several highly conserved charged residues including Asp33 (in a conserved DT/SD motif), Arg57, and Arg132 (interacting with shikimate) are identified, guiding the development of novel inhibitors of shikimate kinase.
New Approaches in the Treatment of Hypertension (2015)

Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na(+)/H(+) exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1-7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.
Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. (1986)

Transforming growth factor type beta (TGF-beta), when injected subcutaneously in newborn mice, causes formation of granulation tissue (induction of angiogenesis and activation of fibroblasts to produce collagen) at the site of injection. These effects occur within 2-3 days at dose levels than 1 microgram. Parallel in vitro studies show that TGF-beta causes marked increase of either proline or leucine incorporation into collagen in either an NRK rat fibroblast cell line or early passage human dermal fibroblasts. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) do not cause these same in vivo and in vitro effects; in both rat and human fibroblast cultures, EGF antagonizes the effects of TGF-beta on collagen formation. We have obtained further data to support a role for TGF-beta as an intrinsic mediator of collagen formation: conditioned media obtained from activated human tonsillar T lymphocytes contain greatly elevated levels of TGF-beta compared to media obtained from unactivated lymphocytes. These activated media markedly stimulate proline incorporation into collagen in NRK cells; this effect is blocked by a specific antibody to TGF-beta. The data are all compatible with the hypothesis that TGF-beta is an important mediator of tissue repair.
THE DEPTH-OF-FOCUS OF THE HUMAN EYE FOR SNELLEN LETTERS (1975)

Snellen acuity is determined as a function of refractive error for two subjects under cyploplegia, using randomised test charts, constant test chart luminance and a series of artificial pupils. These results allow determination of the depth-of-focus of the eye for Snellen targets, and it is shown that both optical and retinal factors influence the depth-of-focus achieved. Depth-of-focus is found to increase with decreasing pupil diameter and visual acuity. The clinical significance of these results, particularly with respect to the precision with which refractive error may be determined, is discussed.
COMPLEXATION OF STRONTIUM IN THE SYNERGISTIC EXTRACTION SYSTEM DICYCLOHEXANO-18-CROWN-6, VERSATIC ACID, CARBON TETRACHLORIDE (1986)

ABSTRACT The synergism in the extraction of Sr⊃ +⊃ from 0.5M Sr(NO⊂3⊂) ⊂2⊂ by 0.05M dicyclohexano-18-crown-6 (DC18C6) + 0.1M Versatic 1519 (abbreviated v-acid or RCOOH, a neo carboxylic acid) in CCl⊂4⊂ has been found to stem from a strong 1:1 interaction between DC18C6 and Sr⊃2+ ⊃ However, both nitrate and carboxylate can function as the anion for the (DC18C6)Sr⊃2+⊃ moiety. At aqueous conditions corresponding to less than complete loading (i.e., [Sr⊃2+⊃[ org < 0.05M for pH < 11.7), (DC18C6)Sr(NO⊂3;)⊂2⊂ precipitates as a solid. As the pH is raised in the interval 7 < pH < 11.7 to deprotonate the V-acid, the precipitate (DC18C6)Sr(NO⊂3⊂) ⊂2⊂ becomes solubilized first with probable formation of a mixed-anion complex and finally with quantitative (0.05M) formation of the monoraeric complex (DC18C6)Sr(OOCR) ⊂2⊂ H⊂2⊂O at pH = 11.7 as confirmed by viscometric titration of 0.05M DC18C6 in wet CCl⊂4⊂ with Sr(OOCR) ⊂2⊂, Karl-Fischer titrations, vapor-phase osmometry, and IR spectrophotometry.
Basonuclin, a zinc finger protein of keratinocytes and reproductive germ cells, binds to the rRNA gene promoter (1999)

Basonuclin is a protein containing three pairs of C(2)H(2) zinc fingers. The protein has been found in the basal (germinal) cell layer of stratified squamous epithelia, such as the epidermis, and in germ cells of the testis and ovary. We show here that the human protein has specific affinity for a segment of the promoter of the gene for rRNA. Basonuclin interacts with two separate parts of the promoter, each possessing dyad symmetry. The upstream part, but not the downstream part, is known to bind UBF1, a transcription factor for rDNA. Basonuclin is likely to be a cell-type-specific regulatory protein for rDNA transcription.
Serotonin receptor gene (HTR2A) T102C polymorphism modulates individuals’ perspective taking ability and autistic-like traits (2015)

Previous studies have indicated that empathic traits, such as perspective taking, are associated with the levels of serotonin in the brain and with autism spectrum conditions. Inspired by the finding that the serotonin receptor 2A gene (HTR2A) modulates the availability of serotonin, this study investigated to what extent HTR2A modulates individuals' perspective taking ability and autistic-like traits. To examine the associations of the functional HTR2A polymorphism T102C (rs6313) with individuals' perspective taking abilities and autistic-like traits, we differentiated individuals according to this polymorphism and measured empathic and autistic-like traits with Interpersonal Reactivity Index (IRI) and Autism-Spectrum Quotient (AQ) scale in 523 Chinese people. The results indicated that this polymorphism was significantly associated with the scores on Perspective Taking and Personal Distress subscales of IRI, and Communication subscale of AQ. Individuals with a greater number of the C alleles were less likely to spontaneously adopt the point of view of others, more likely to be anxious when observing the pain endured by others, and more likely to have communication problems. Moreover, the genotype effect on communication problems was mediated by individuals' perspective taking ability. These findings provide evidence that the HTR2A T102C polymorphism is a predictor of individual differences in empathic and autistic-like traits and highlight the role of the gene in the connection between perspective taking and autistic-like traits.
CRISPR-Pass: Gene Rescue of Nonsense Mutations Using Adenine Base Editors (2019)

A nonsense mutation is a substitutive mutation in a DNA sequence that causes a premature termination during translation and produces stalled proteins, resulting in dysfunction of a gene. Although it usually induces severe genetic disorders, there are no definite methods for inducing read through of premature termination codons (PTCs). Here, we present a targeted tool for bypassing PTCs, named CRISPR-pass, that uses CRISPR-mediated adenine base editors. CRISPR-pass, which should be applicable to 95.5% of clinically significant nonsense mutations in the ClinVar database, rescues protein synthesis in patient-derived fibroblasts, suggesting potential clinical utility.
Rapid characterization and quality control of complex cell culture media solutions using raman spectroscopy and chemometrics (2010)

The use of Raman spectroscopy coupled with chemometrics for the rapid identification, characterization, and quality assessment of complex cell culture media components used for industrial mammalian cell culture was investigated. Raman spectroscopy offers significant advantages for the analysis of complex, aqueous-based materials used in biotechnology because there is no need for sample preparation and water is a weak Raman scatterer. We demonstrate the efficacy of the method for the routine analysis of dilute aqueous solution of five different chemically defined (CD) commercial media components used in a Chinese Hamster Ovary (CHO) cell manufacturing process for recombinant proteins.The chemometric processing of the Raman spectral data is the key factor in developing robust methods. Here, we discuss the optimum methods for eliminating baseline drift, background fluctuations, and other instrumentation artifacts to generate reproducible spectral data. Principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) were then employed in the development of a robust routine for both identification and quality evaluation of the five different media components. These methods have the potential to be extremely useful in an industrial context for "in-house" sample handling, tracking, and quality control.
Dual aromatase–sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity (2007)

The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of aromatase inhibitory pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed SN2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC50 3.5 nM), comparable with that of Anastrozole (IC50 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase.
Neurotensin Analog NT69L Induces Rapid and Prolonged Hypothermia after Hypoxic Ischemia (2001)

NT69L induced rapid and prolonged mild brain hypothermia after ACA in this rat model and reduced neurological deficits.
NVN1000, a novel nitric oxide-releasing compound, inhibits HPV-18 virus production by interfering with E6 and E7 oncoprotein functions (2019)

• Six daily 1 h topical applications of 2 mg/ml NVN1000, a NO-releasing polymer, abrogated HPV-18 progeny virus production. • NVN1000 inhibits terminal squamous differentiation of both infected and uninfected PHK raft cultures. • NVN1000 reduces HPV-18 E6 and E7 proteins and activities. • NVN1000 impairs S-phase progression and induces DNA damage in infected cultures. • NVN1000 is a promising candidate for sustained inhibition of HPV DNA replication and progeny virus production.