gebhart/patrepeval huggingface dataset:
The Neurotoxic Effects of Amitriptyline Are Mediated by Apoptosis and are Effectively Blocked by Inhibition of Caspase Activity (2006)

Oral tricyclic antidepressants, widely used as adjuncts in the treatment of chronic pain, block sodium channels in vitro and nerve conduction in vivo. However, toxicity of amitriptyline has been observed after neural application. We therefore investigated the mechanism and possible prevention of amitriptyline neurotoxicity. To assess dose-dependent neurotoxicity of amitriptyline, we incubated neuron cultures from adult rat dorsal root ganglia with amitriptyline and quantified neuronal survival. Additionally, we investigated accepted markers of apoptosis (mitochondrial membrane potential, cytosolic cytochrome c, and activated caspase-3) and co-incubated amitriptyline with an inhibitor of caspase activity, z-vad-fmk, to assess the effect on cell survival. We found a dose-dependent neurotoxic effect of amitriptyline. Neurons incubated with amitriptyline exhibited loss of mitochondrial membrane potential, release of cytochrome c into the cytoplasm, and activation of caspase-3. Co-incubation with z-vad-fmk substantially improved neuronal survival in culture. In conclusion, amitriptyline-induced neurotoxicity is mediated by apoptosis and is attenuated by inhibition of caspase activity, suggesting that inhibition of apoptotic pathways may be efficient at alleviating local anesthetic-induced neurotoxicity. In vivo studies will have to corroborate whether the co-injection of anti-apoptotic drugs with local anesthetics decreases neurotoxic side effects.
Wnt/beta-Catenin Signaling and Small Molecule Inhibitors (2012)

Wnt/β-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/β-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, β-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where β-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where β-catenin levels are regulated and the nucleus where β-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of β-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular β- catenin levels. However, β-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/β-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of β-catenin at its various locations provides alternative points for therapeutic interventions.
Targeting of Tumor Cells by Cell Surface Urokinase Plasminogen Activator-dependent Anthrax Toxin (2001)

Urokinase plasminogen activator receptor (uPAR) binds pro-urokinase plasminogen activator (pro-uPA) and thereby localizes it near plasminogen, causing the generation of active uPA and plasmin on the cell surface. uPAR and uPA are overexpressed in a variety of human tumors and tumor cell lines, and expression of uPAR and uPA is highly correlated to tumor invasion and metastasis. To exploit these characteristics in the design of tumor cell-selective cytotoxins, we constructed mutated anthrax toxin-protective antigen (PrAg) proteins in which the furin cleavage site is replaced by sequences cleaved specifically by uPA. These uPA-targeted PrAg proteins were activated selectively on the surface of uPAR-expressing tumor cells in the presence of pro-uPA and plasminogen. The activated PrAg proteins caused internalization of a recombinant cytotoxin, FP59, consisting of anthrax toxin lethal factor residues 1-254 fused to the ADP-ribosylation domain of Pseudomonas exotoxin A, thereby killing the uPAR-expressing tumor cells. The activation and cytotoxicity of these uPA-targeted PrAg proteins were strictly dependent on the integrity of the tumor cell surface-associated plasminogen activation system. We also constructed a mutated PrAg protein that selectively killed tissue plasminogen activator-expressing cells. These mutated PrAg proteins may be useful as new therapeutic agents for cancer treatment.
Structure-function analysis of the Bcl-2 oncoprotein. Addition of a heterologous transmembrane domain to portions of the Bcl-2 beta protein restores function as a regulator of cell survival (1993)

The bcl-2 gene can potentially encode 26- and 22-kDa proteins that differ only in their carboxyl tails because of an alternative splicing mechanism. The larger of these proteins contains a hydrophobic transmembrane domain within its carboxyl terminus, resides (at least in part) in mitochondrial membranes and has been shown to prolong cell survival by blocking programmed cell death (also termed "apoptosis"). To explore the function of the shorter 22-kDa Bcl-2 protein that lacks a transmembrane domain, DNAs encoding p26-Bcl-2-alpha or p22-Bcl-2-beta were expressed in an interleukin-3 (IL-3)-dependent hematopoietic cell line 32D. In contrast to p26-Bcl-2 alpha that markedly prolonged cell survival, p22-Bcl-2-beta did not extend the survival of 32D cells when cultured in the absence of IL-3. Expression in 32D cells of a chimeric DNA that fused portions of the open reading frame common to Bcl-2-alpha and Bcl-2-beta (amino-acids 1-195) with sequences encoding the transmembrane and cytosolic domains of the IL-2 receptor-alpha protein resulted in production of a Bcl-2/IL-2R fusion protein that was capable of prolonging 32D cell survival in the setting of IL-3 withdrawal. Based on fractionation of cells to produce crude heavy membrane, light membrane, nuclei, and cytosolic preparations, much of the p22-Bcl-2-beta protein appeared to reside in the cytosol, whereas Bcl-2-alpha and the Bcl-2/IL-2R chimeric proteins were found exclusively in fractions that also contained the inner mitochondrial membrane protein F1-beta-ATPase. Taken together, these findings demonstrate the importance of membrane association for the function and intracellular targeting of the apoptosis-blocking Bcl-2 protein. Furthermore, despite the strong evolutionary conservation of the carboxyl regions of Bcl-2-alpha proteins observed previously for mammalian and avian species, these data suggest that a heterologous transmembrane domain can be substituted without loss of function.
Lentivirus-derived antimicrobial peptides: increased potency by sequence engineering and dimerization (1999)

We have previously described a family of cationic amphipathic peptides derived from lentivirus envelope proteins that have properties similar to those of naturally occurring antimicrobial peptides. Here, we explored the effects of amino acid truncations and substitutions on the antimicrobial potency and selectivity of the prototype peptide, LLP1. Removal of seven residues from the C-terminus of LLP1 had little effect on potency, but abrogated haemolytic activity. Replacement of the two glutamic acid residues of LLP1 with arginine resulted in a peptide with greater bactericidal activity. We discovered that the cysteine-containing peptides spontaneously formed disulphide-linked dimers, which were 16-fold more bactericidal to Staphylococcus aureus. Monomeric and dimeric LLP1 possessed similar alpha helical contents, indicating that disulphide formation did not alter the peptide's secondary structure. The dimerization strategy was applied to magainin 2, enhancing its bactericidal activity eight-fold. By optimizing all three properties of LLP1, a highly potent and selective peptide, named TL-1, was produced. This peptide is significantly more potent than LLP1 against gram-positive bacteria while maintaining high activity against gram-negative organisms and low activity against eukaryotic cells. In addition to new antimicrobial peptides, these studies contribute useful information on which further peptide engineering efforts can be based.
Inducible regulation of human brain natriuretic peptide promoter in transgenic mice (2001)

Studies have shown that brain natriuretic peptide (BNP) gene expression is rapidly induced in the infarcted heart and that plasma BNP levels reflect the degree of left ventricular dysfunction. Our previous in vitro work using transiently transfected neonatal rat cardiac myocytes has shown that the human BNP (hBNP) promoter, in particular a region extending from -127 to -40 relative to the start site of transcription, is more active in cardiac myocytes than in fibroblasts. To study tissue-specific and transcriptional regulation of the hBNP gene in vivo, we generated transgenic mice containing the proximal hBNP promoter (-408 to +100) coupled to a luciferase reporter gene. In four lines of transgenic mice, luciferase activity was approximately 33- to 100-fold higher in the heart than in other tissues, including the whole brain. To test whether the transgene responded to a pathophysiological stimulus, we induced infarction by coronary artery ligation. Luciferase activity was fivefold higher in the infarcted region of the left ventricle at 48 h than in sham-operated animals and remained elevated for 4 wk. Endogenous BNP mRNA was similarly increased in the infarcted hearts of a separate group of mice. We conclude that 1) the proximal 408-bp region of the hBNP promoter confers cardiac-specific expression and 2) myocardial infarction activates the proximal hBNP promoter in vivo. These data suggest that we have a valid model for the study of basal and inducible regulation of the hBNP gene in vivo.
Restoration of vision in blind individuals using bionic devices: A review with a focus on cortical visual prostheses (2014)

The field of neurobionics offers hope to patients with sensory and motor impairment. Blindness is a common cause of major sensory loss, with an estimated 39 million people worldwide suffering from total blindness in 2010. Potential treatment options include bionic devices employing electrical stimulation of the visual pathways. Retinal stimulation can restore limited visual perception to patients with retinitis pigmentosa, however loss of retinal ganglion cells precludes this approach. The optic nerve, lateral geniculate nucleus and visual cortex provide alternative stimulation targets, with several research groups actively pursuing a cortically-based device capable of driving several hundred stimulating electrodes. While great progress has been made since the earliest works of Brindley and Dobelle in the 1960s and 1970s, significant clinical, surgical, psychophysical, neurophysiological, and engineering challenges remain to be overcome before a commercially-available cortical implant will be realized. Selection of candidate implant recipients will require assessment of their general, psychological and mental health, and likely responses to visual cortex stimulation. Implant functionality, longevity and safety may be enhanced by careful electrode insertion, optimization of electrical stimulation parameters and modification of immune responses to minimize or prevent the host response to the implanted electrodes. Psychophysical assessment will include mapping the positions of potentially several hundred phosphenes, which may require repetition if electrode performance deteriorates over time. Therefore, techniques for rapid psychophysical assessment are required, as are methods for objectively assessing the quality of life improvements obtained from the implant. These measures must take into account individual differences in image processing, phosphene distribution and rehabilitation programs that may be required to optimize implant functionality. In this review, we detail these and other challenges facing developers of cortical visual prostheses in addition to briefly outlining the epidemiology of blindness, and the history of cortical electrical stimulation in the context of visual prosthetics.
The Effect of Partial Dissolution-Precipitation Treatment on Calcium Phosphate Ceramics in the Release of BMP-2 and Osteoinduction (2012)

Biomimetic calcium phosphate ceramics with excellent bio-absorption and osteoinduction were designed by the partial dissolution-precipitation (PDP) treatment. Beta-tricalcium phosphate (β-TCP) ceramics with single phase were transformed into monetite, hydroxyapatite (HAp) and β-TCP phases by the PDP treatment. The PDP-β-TCP ceramics had a specific surface area of 22.5 m2/g and porosities of 60-80 %. Changes in microstructure of the ceramics before and after PDP treatment influenced body fluid permeation, release characteristics of bone morphogenetic protein-2 (BMP-2) and osteoinduction. 125I-labeled BMP-2 was loaded on the four different ceramics, such as spongy-derived bulk of HAp (b-HAp), functionally graded HAp (fg-HAp), β-TCP, and PDP-β-TCP. The four kinds of ceramics were implanted into the back region of subcutaneous tissue in rats and the analyses of the release of BMP-2 and BMP-2 dose-response of bone formation were investigated. In the fg-HAp/BMP-2 and PDP-β-TCP/BMP-2 ceramics, the release time corresponding to the half amount (t 1/2) of BMP-2 were prolonged about 14 and 7 times respectively compared to the ceramics before PDP treatment. BMP-2 dose-response of bone formation study showed the areas of bone tissues were significant higher in the fg-HAp/BMP-2 (5.0μg) and PDP-β-TCP/BMP-2 (0.5μg) ceramics compared to the ceramics before PDP treatment. These results indicated the PDP treatment enhanced BMP-2 release and osteoinduction.
Multinuclear NMR Studies of Single Lipid Bilayers Supported in Cylindrical Aluminum Oxide Nanopores (2004)

Lipid bilayers were deposited inside the 0.2 μm pores of anodic aluminum oxide (AAO) filters by extrusion of multilamellar liposomes and their properties studied by 2H, 31P, and 1H solid-state NMR. Only the first bilayer adhered strongly to the inner surface of the pores. Additional layers were washed out easily by a flow of water as demonstrated by 1H magic angle spinning NMR experiments with addition of Pr3+ ions to shift accessible lipid headgroup resonances. A 13 mm diameter Anopore filter of 60 μm thickness oriented approximately 2.5 × 10-7 mol of lipid as a single bilayer, corresponding to a total membrane area of about 500 cm2. The 2H NMR spectra of chain deuterated POPC are consistent with adsorption of wavy, tubular bilayers to the inner pore surface. By NMR diffusion experiments, we determined the average length of those lipid tubules to be approximately 0.4 μm. There is evidence for a thick water layer between lipid tubules and the pore surface. The ends of tubules are well sealed against the pore such that Pr3+ ions cannot penetrate into the water underneath the bilayers. We successfully trapped poly(ethylene glycol) (PEG) with a molecular weight of 8000 in this water layer. From the quantity of trapped PEG, we calculated an average water layer thickness of 3 nm. Lipid order parameters and motional properties are unperturbed by the solid support, in agreement with existence of a water layer. Such unperturbed, solid supported membranes are ideal for incorporation of membrane-spanning proteins with large intra- and extracellular domains. The experiments suggest the promise of such porous filters as membrane support in biosensors.
Development of Process Chemistry for the Removal of Cesium from Acidic Nuclear Waste by Calix[4]arene-crown-6 Ethers (2000)

A solvent suitable for extracting cesium from acidic nitrate media, such as that stored at the U.S. Department of Energy's Idaho National Engineering and Environmental Laboratory (INEEL), has been developed. The solvent possesses good chemical stability, displays excellent cesium selectivity, and provides good extraction and stripping performance with satisfactory phase-coalescence behavior. The calix[4]arene-crown-6 ether used in this solvent (1,3-alt-bis-n-octyloxycalix[4]arene-benzo-crown-6) was selected from a series of mono- and bis-crown-6 derivatives of 1,3-alternate calix[4]arenes that were shown to possess good stability to a simulant of INEEL's Sodium Bearing Waste (SBW). Calixarene-benzo crown ethers possessing an alkyl substituent at the 4-position of the benzocrown, such as calix[4]arene-bis-tert-octylbenzo-crown-6, were shown to be much more susceptible to nitration by the SBW simulant or by 4 M nitric acid than calixarene-benzo crown ethers without the alkyl substituent. The cesium distribution behavior for a solvent comprised of l,3-alt-bis-n-octyloxy-calix[4]arene-benzo-crown-6 at 0.01 M in an aliphatic diluent modified with a fluorine-containing alcohol was shown to be stable over the course of a 60 day continuous contact with the SBW simulant at 25 °C. Toward process development, cesium distribution ratios on extraction (SBW simulant), scrubbing (50 mM nitric acid), and stripping (1 mM nitric acid) operations demonstrated a functional solvent cycle using a solvent of this composition augmented by 0.001 M trioctylamine (TOA). Without this lipophilic amine, stripping is inefficient. The presence of TOA in the solvent had no adverse effect on the Cs distribution behavior during extraction and scrubbing operations, nor did TOA negatively impact the Cs/Na and Cs/K selectivity ratios.
Inductance Calculations in a Complex Integrated Circuit Environment (1972)

This paper describes a method for calculating multiloop inductances formed by complicated interconnection conductors. Knowledge of these inductances leads to useful information concerning the design of such systems. In the approach pursued here, the conductor loops are divided into segments for which so-called partial inductances are calculated. The partial inductances are then appropriately added to yield the desired loop inductance.
High-resolution electron microscopy of a microporous carbon (2000)

The structure of a microporous carbon prepared by the carbonization of sucrose was examined using high-resolution electron microscopy. It was found to be disordered and isotropic and primarily made up of tightly curved individual carbon layers, enclosing pores typically about 1nm in size. Completely closed carbon particles were also present. These observations suggest that the carbon may have a fullerene-related structure, in which pentagons and heptagons are distributed randomly throughout a hexagonal network, producing continuous curvature.
DNA methylation-associated inactivation of TGFβ-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers (2005)

The transforming growth factor beta (TGFbeta)-signalling pathway is deregulated in many cancers. We examined the role of gene silencing via aberrant methylation of DRM/Gremlin and HPP1, which inhibit TGFbeta signalling, and RUNX3, which facilitates TGFbeta-signalling, of all genes that are thought to be tumour suppressors, are aberrantly expressed, and are thus thought to have important role in human cancers. We examined DRM/Gremlin mRNA expression in 44 cell lines and the promoter methylation status of DRM/Gremlin, HPP1, and RUNX3 in 44 cell lines and 511 primary tumours. The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13). Methylation percentages of the three genes ranged from 0-83% in adult tumours and 0-50% in paediatric tumours. Methylation of DRM/Gremlin was more frequent in lung tumours in smokers, and methylation of all three genes was inversely correlated with prognosis in patients with bladder or prostate cancer. Our results provide strong evidence that these TGFbeta-related genes are frequently deregulated through aberrant methylation in many human malignancies.
β-cell regeneration and differentiation: how close are we to the ‘holy grail’? (2014)

Diabetes can be managed by careful monitoring of blood glucose and timely delivery of exogenous insulin. However, even with fastidious compliance, people with diabetes can suffer from numerous complications including atherosclerosis, retinopathy, neuropathy, and kidney disease. This is because delivery of exogenous insulin coupled with glucose monitoring cannot provide the fine level of glucose control normally provided by endogenous β-cells in the context of intact islets. Moreover, a subset of people with diabetes lack awareness of hypoglycemic events; a status that can have grave consequences. Therefore, much effort has been focused on replacing lost or dysfunctional β-cells with cells derived from other sources. The advent of stem cell biology and cellular reprogramming strategies have provided impetus to this work and raised hopes that a β-cell replacement therapy is on the horizon. In this review, we look at two components that will be required for successful β-cell replacement therapy: a reliable and safe source of β-cells and a mechanism by which such cells can be delivered and protected from host immune destruction. Particular attention is paid to insulin-producing cells derived from pluripotent stem cells because this platform addresses the issue of scale, one of the more significant hurdles associated with potential cell-based therapies. We also review methods for encapsulating transplanted cells, a technique that allows grafts to evade immune attack and survive for a long term in the absence of ongoing immunosuppression. In surveying the literature, we conclude that there are still several substantial hurdles that need to be cleared before a stem cell-based β-cell replacement therapy for diabetes becomes a reality.
Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes1 (2001)

Culture of preimplantation mammalian embryos and cells can influence their subsequent growth and differentiation. Previously, we reported that culture of mouse embryonic stem cells is associated with deregulation of genomic imprinting and affects the potential for these cells to develop into normal fetuses. The purpose of our current study was to determine whether culture of preimplantation mouse embryos in a chemically defined medium (M16) with or without fetal calf serum (FCS) can affect their subsequent development and imprinted gene expression. Only one third of the blastocysts that had been cultured from two-cell embryos in M16 medium complemented with FCS developed into viable Day 14 fetuses after transfer into recipients. These M16 + FCS fetuses were reduced in weight as compared with controls and M16 fetuses and had decreased expression of the imprinted H19 and insulin-like growth factor 2 genes associated with a gain of DNA methylation at an imprinting control region upstream of H19. They also displayed increased expression of the imprinted gene Grb10. The growth factor receptor binding gene Grb7, in contrast, was strongly reduced in its expression in most of the M16 + FCS fetuses. No alterations were detected for the imprinted gene MEST: Preimplantation culture in the presence of serum can influence the regulation of multiple growth-related imprinted genes, thus leading to aberrant fetal growth and development.
Current dosage and schedule issues in the development of paclitaxel (Taxol). (1993)

Basic questions regarding optimal dose and schedule of anticancer drug administration frequently persist long after regulatory approval and commercial availability of a drug. For paclitaxel (TAXOL), these questions were considered early in drug development. This paper reviews the available preclinical studies that assessed different drug concentrations and durations of drug exposure. The current status of clinical trials designed to help resolve these issues is also reviewed.