gebhart/patrepeval huggingface dataset:
Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo (2004)

Many human diseases are caused by inactivating mutations in specific G-protein-coupled receptors (GPCRs). In about 10% of these cases, a premature stop codon leads to the generation of a truncated, functionally inactive receptor protein. In this study, we tested the hypothesis that such GPCR mutations can be functionally rescued in vitro and in vivo by treatment with aminoglycoside antibiotics, which are known for their ability to suppress premature termination codons. As a model system, we studied a mutant V2 vasopressin receptor (AVPR2) containing the inactivating E242X nonsense mutation which mimics human X-linked nephrogenic diabetes insipidus (XNDI) when introduced into mice via gene targeting techniques. Studies with cultured mammalian cells expressing the E242X mutant receptor showed that G418 (geneticin) was by far the most potent aminoglycoside antibiotic capable of suppressing the E242X nonsense codon. Strikingly, G418 treatment increased AVP-mediated cAMP responses in cultured kidney collecting duct cells prepared from E242X mutant mice in vitro, and significantly improved the urine-concentrating ability of E242X mutant mice in vivo. This is the first study demonstrating that G418 (aminoglycosides) can ameliorate the clinical symptoms of a disease-causing premature stop codon in a member of the GPCR superfamily.
Estimation of the intracellular free ADP concentration by fluorine-19 NMR studies of fluorine-labeled yeast phosphoglycerate kinase in vivo (1993)

Yeast phosphoglycerate kinase was selectively fluorine-labeled in vivo by inducing enzyme synthesis in stationary phase cells in the presence of 5-fluorotryptophan. Inducible expression was obtained using a galactose-inducible expression vector containing the yeast phosphoglycerate kinase coding sequence. 19F NMR measurements on intact cells showed two resolved resonances, from the two tryptophan residues in the protein, which underwent reversible changes in chemical shift under different metabolic conditions. Measurements in vitro showed that the difference in the chemical shifts of these two resonances was dependent on the adenine nucleotide concentration, in particular the MgADP concentration. A comparison of the spectra obtained in vitro with those obtained from the intact cell indicated that in glucose-fed cells the cytosolic free MgADP concentration was less than 50 microM, which is significantly lower than the concentrations measured in whole-cell extracts.
Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects (2009)

High cereal fibre intake is associated with reduced risk for type 2 diabetes, but wheat fibre had little or no effect on glycaemic control or oral glucose tolerance in clinical trials lasting 4-12 weeks. To explain this discrepancy, we hypothesised that colonic adaptation to increased wheat fibre intake takes many months but eventually results in increased SCFA production and glucagon-like peptide-1 (GLP-1) secretion. Thus, the primary objective was to determine the time-course of the effects of increased wheat fibre intake on plasma acetate, butyrate and GLP-1 concentrations in hyperinsulinaemic human subjects over 1 year. Subjects with fasting plasma insulin >or= 40 pmol/l were randomly assigned by computer to receive either a high-wheat fibre cereal (fibre group; 24 g fibre/d; twenty assigned; six dropped out, fourteen included) or a low-fibre cereal (control group; twenty assigned; six dropped-out, fourteen included) daily for 1 year. Acetate, butyrate and GLP-1 were measured during 8 h metabolic profiles performed every 3 months. There were no differences in body weight in the fibre group compared with the control group. After 9 months baseline-adjusted mean 8 h acetate and butyrate concentrations were higher on the high-fibre than the control cereal (P < 0.05). After 12 months on the high-fibre cereal, baseline-adjusted mean plasma GLP-1 was 1.3 (95 % CI 0.4, 2.2) pmol/l (P < 0.05) higher than at baseline (about 25 % increase) and 1.4 (95 % CI 0.1, 2.7) pmol/l (P < 0.05) higher than after 12 months on control. It is concluded that wheat fibre increased SCFA production and GLP-1 secretion in hyperinsulinaemic humans, but these effects took 9-12 months to develop. Since GLP-1 may increase insulin sensitivity and secretion, these results may provide a mechanism for the epidemiological association between high cereal fibre intake and reduced risk for diabetes.
Nutritional Modulation of the Inflammatory Bowel Response (2011)

Crohn's disease and ulcerative colitis represent distinct phenotypic forms of inflammatory bowel disease and continue to be a common cause of morbidity. The corticosteroids and the immunomodulatory drugs, which are the basis of treatment for the inflammatory bowel diseases, do not assure always satisfactory outcomes. Nutrition has been used in order to modify the inflammatory response of various chronic inflammatory diseases, including Crohn's disease and ulcerative colitis. In the pathogenesis of inflammatory bowel diseases, the intestinal microflora and the intestinal mucosal disorders play a crucial role. Also, the release of reactive oxygen species is a significant factor of initiation and preservation of the inflammatory reaction in these diseases. The advantages of the nutritional treatment derive from the sequestration of intraluminal agents which may promote the inflammatory bowel response or, alternatively, nutrition is able to modify the immune response, reducing the uncontrolled inflammatory reaction. Furthermore, nutrition can enhance the mucosal barrier function and consists a significant source of antioxidants. This review focuses on certain nutritional components that modulate the inflammatory response of the bowel and aims to present a rational thesis regarding the use of nutritional agents in the management of inflammatory bowel diseases.
RP-1776, a Novel Cyclic Peptide Produced by Streptomyces sp., Inhibits the Binding of PDGF to the Extracellular Domain of Its Receptor. (2001)

RP-1776, a novel cyclic peptide, was isolated from the culture broth of Streptomyces sp. KY11784. RP-1776 selectively inhibited the binding of PDGF BB to the extracellular domain of the PDGF beta-receptor with an IC50 value of 11 +/- 6 microM. Detailed binding experiments suggested that RP-1776 directly interacts with PDGF BB. RP-1776 inhibited the phosphorylation of the PDGF beta-receptor induced by PDGF BB. These results suggested that RP-1776 antagonizes the signaling of PDGF BB probably through the inhibition of PDGF BB binding to the PDGF beta-receptor.
Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/- mice. (1999)

Recent studies have shown that genetic deficiency of the adipocyte fatty acid-binding protein (aP2) results in minor alterations of plasma lipids and adipocyte development but provides significant protection from dietary obesity-induced hyperinsulinemia and insulin resistance. To identify potential mechanisms responsible for this phenotype, we examined lipolysis and insulin secretion in aP2-/- mice. Beta-adrenergic stimulation resulted in a blunted rise of blood glycerol levels in aP2-/- compared with aP2+/+ mice, suggesting diminished lipolysis in aP2-/- adipocytes. Confirming this, primary adipocytes isolated from aP2-/- mice showed attenuated glycerol and free fatty acid (FFA) release in response to dibutyryl cAMP. The decreased lipolytic response seen in the aP2-/- mice was not associated with altered expression levels of hormone-sensitive lipase or perilipin. The acute insulin secretory response to beta-adrenergic stimulation was also profoundly suppressed in aP2-/- mice despite comparable total concentrations and only minor changes in the composition of systemic FFAs. To address whether levels of specific fatty acids are different in aP2-/- mice, the plasma FFA profile after beta-adrenergic stimulation was determined. Significant reduction in both stearic and cis-11-eicoseneic acids and an increase in palmitoleic acid were observed. The response of aP2-/- mice to other insulin secretagogues such as arginine and glyburide was similar to that of aP2+/+ mice, arguing against generally impaired function of pancreatic beta-cells. Finally, no aP2 expression was detected in isolated pancreatic islet cells. These results provide support for the existence of an adipo-pancreatic axis, the proper action of which relies on the presence of aP2. Consequently, aP2's role in the pathogenesis of type 2 diabetes might involve regulation of both hyperinsulinemia and insulin resistance through its impact on both lipolysis and insulin secretion.
The Sequential Role of Lymphotoxin and B Cells in the Development of Splenic Follicles (1998)

The transfer of lymphocytes into severe combined immunodeficiency (SCID) mice induces a series of histological changes in the spleen, including the appearance of mature follicular dendritic cells (FDCs). Studies were undertaken to clarify the role of lymphotoxin (LT) in this process. The results show that SCID mice have a small and partially differentiated white pulp containing marginal zone and interdigitating dendritic cells, but lacking FDCs. Transferred spleen cells can segregate into T and B cell areas shortly after their injection to SCID mice. This ability is dependent on signaling through LT-beta receptor (LT-betaR), since blocking ligand-receptor interaction in recipient SCID mice ablates the capacity of the transferred cells to segregate. A week after lymphocyte transfer, host-derived FDCs appeared in the reconstituted SCID mice. This induction of FDCs is dependent on LT-betaR signaling by B cells since LT-alpha-/- B cells are incapable of inducing development of FDCs in SCID mice, even after cotransfer of LT-alpha+/+ T cells. Therefore, LT plays at least two discrete roles in splenic organization. First, it appears that LT induces the differentiation of the white pulp to create sites for lymphocyte segregation. Second, LT expression by B cells drives the maturation of FDCs and the organization of B cell follicles.
A Link between Blood Coagulation and Prophenol Oxidase Activation in Arthropod Host Defense (2000)

Phenol oxidase, a copper-containing enzyme, is widely distributed not only in animals but also in plants and fungi, which is responsible for initiating the biosynthesis of melanin. Activation of prophenol oxidase in arthropods is important in host defense. However, the prophenol oxidase-activating system remains poorly understood at the molecular level. Here we show that the coagulation cascade of the horseshoe crab Tachypleus tridentatus is linked to prophenol oxidase activation, with the oxygen carrier hemocyanin functioning as a substitute for prophenol oxidase. Tachypleus clotting enzyme functionally transforms hemocyanin to phenol oxidase, and the conversion reaches a plateau at 1:1 stoichiometry without proteolytic cleavage. The active site-masked clotting enzyme also has the same effect, suggesting that complex formation of the clotting enzyme with hemocyanin is critical for the conversion. The two systems of blood coagulation and prophenol oxidase activation may have evolved from a common ancestral protease cascade.
Total Synthesis of (+)‐Cortistatin A (2008)

Marine engineering: A modular strategy featuring an intramolecular 1,4-addition/aldol/dehydration cascade sequence (see scheme; TBS=tert-butyldimethylsilyl) has enabled the total synthesis of cortistatin A, a potent anti-angiogenic marine natural product. This flexible route offers access to other members of the cortistatin family, both natural and designed.
Cellular neural networks: applications (1988)

The theory of a novel class of information-processing systems, called cellular neural networks, which are capable of high-speed parallel signal processing, was presented in a previous paper (see ibid., vol.35, no.10, p.1257-72, 1988). A dynamic route approach for analyzing the local dynamics of this class of neural circuits is used to steer the system trajectories into various stable equilibrium configurations which map onto binary patterns to be recognized. Some applications of cellular neural networks to such areas as image processing and pattern recognition are demonstrated, albeit with only a crude circuit. In particular, examples of cellular neural networks which can be designed to recognize the key features of Chinese characters are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Factors influencing the survival of rat brain tumor cells after in vitro treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea. (1975)

The shape of dose-response curves obtained for asynchronous, exponentially growing 9L rat brain tumor cells treated in vitro with 1,3-bis(2-chloroethyl)-1-nitrosourea changed as a function of the drug exposure time. For short treatment times (less than 1 hr), the dose-response curves had shoulders, indicating that the cells may accumulate sublethal damage; however, after longer treatments (greater than 1 hr), little if any shoulder was apparent. The slope of the exponential portion of the dose-response curve increased progressively with treatment periods from 15 min to 2 hr. Longer exposure times (up to 24 hr) produced no further changes in the cell-kill kinetics. Cell survival was directly related to the BCNU exposure dose [o integral t Co(t)dt] and to the amount of bound BCNU per cell. Extrapolation of the curves for these two variables indicated that some BCNU damage accumulates before death occurs. The amount of serum and cell products available in the medium to bind BCNU affected the level of survival; however, there was no evidence that extracellular spontaneous breakdown products or chemical transformation products were involved in the cell-killing mechanism.
γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease (2009)

The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.
Solution Structure of the Glucocorticoid Receptor DNA-Binding Domain (1990)

The three-dimensional structure of the DNA-binding domain (DBD) of the glucocorticoid receptor has been determined by nuclear magnetic resonance spectroscopy and distance geometry. The structure of a 71-residue protein fragment containing two "zinc finger" domains is based on a large set of proton-proton distances derived from nuclear Overhauser enhancement spectra, hydrogen bonds in previously identified secondary structure elements, and coordination of two zinc atoms by conserved cysteine residues. The DBD is found to consist of a globular body from which the finger regions extend. A model of the dimeric complex between the DBD and the glucocorticoid response element is proposed. The model is consistent with previous results indicating that specific amino acid residues of the DBD are involved in protein-DNA and protein-protein interactions.
Noradrenergic and serotonergic modulation to treat vasomotor symptoms (2006)

Hot flushes are a major clinical problem for many menopausal women. Their aetiology is unknown. Centrally acting neurotransmitters are involved, but this involvement is yet to be fully characterized. In clinical trials with optimal patient selection and compliance, estrogen can reduce the frequency of hot flushes by 70-80%, and placebo by 20-40%. For some women, however, there are contraindications to the use of estrogen, and others are unwilling to use it. Furthermore, hot flushes may persist in spite of adequate estrogen replacement, and to improve symptoms physicians then have either to add another drug to the regimen or find an alternative to estrogen. The most commonly used non-hormonal alternatives for climacteric symptoms are neurotransmitter modulators such as the selective serotonin reuptake inhibitors. These reduce the frequency of hot flushes by 60%. The mechanism of this effect appears to differ from that underlying their effect on mood. They are generally well tolerated and rates of adverse events are far lower than those reported in studies of the use of these agents for depression. The limited efficacy of clonidine suggests that adrenergic mechanisms may be involved and data are awaited for more specific selective noradrenaline reuptake inhibitors. Thus, non-hormonal treatments are not as effective as estrogens in relieving hot flushes but may have a place as an alternative.
Mutation identification DNA analysis system (MIDAS) for detection of known mutations (1999)

We introduce a novel experimental strategy for DNA mutation detection named the Mismatch Identification DNA Analysis System (MIDAS) [1, 2], which has an associated isothermal probe amplification step to increase target DNA detection sensitivity to attomole levels. MIDAS exploits DNA glycosylases to remove the sugar moiety on one strand (the probe strand) at a DNA base pair mismatch. The resulting apyrimidinic/ apurinic (AP) site is cleaved by AP endonucleases/lyases either associated with the DNA glycosylase or externally added to the reaction mixture. MIDAS utilizes 32p- or FITC-labeled oligonucleotides as mutation probes. Generally between 20-50 nucleotides in length, the probe hybridizes to the target sequence at the reaction temperature. Mismatch repair enzymes (MREs) then cut the probe at the point of mismatch. Once the probe is cleaved, the fragments become thermally unstable and fall off the target, thereby allowing another full-length probe to hybridize. This oscillating process amplifies the signal (cleaved probe). Cleavage products can be detected by electrophoretic separation followed by autoradiography, or by laser-induced fluorescence-capillary electrophoresis (LIF-CE) of fluorophore-labeled probes in two minutes using a novel CE matrix. In the present experiments, we employed the mesophilic Escherichia coli enzyme deoxyinosine 3'-endonuclease (Endo V), and a novel thermostable T/G DNA glycosylase, TDG mismatch repair enzyme (TDG-MRE). MIDAS differentiated between a clinical sample BRCA 1 wild-type sequence and a BRCA1 185delAG mutation without the need for polymerase chain reaction (PCR). The combination of MIDAS with LIF-CE should make detection of known point mutations, deletions, and insertions a rapid and cost-effective technique well suited for automation.
The cytokine IL‐1β transiently enhances P2X7 receptor expression and function in human astrocytes (2004)

Extracellular nucleotide di- and triphosphates such as ATP and ADP mediate their effects through purinergic P2 receptors belonging to either the metabotropic P2Y or the ionotropic P2X receptor family. The P2X7R is a unique member of the P2X family, which forms a pore in response to ligand stimulation, regulating cell permeability, cytokine release, and/or apoptosis. This receptor is also unique in that its affinity for the ligand benzoyl-benzoyl ATP (BzATP) is at least 10-fold greater than that of ATP. Primary human fetal astrocytes in culture express low-levels of P2X7R mRNA and protein, and BzATP induces only a slight influx in intracellular calcium [Ca2+]i, with little demonstrable effect on gene expression or pore formation in these cells. We now show that, following treatment with the proinflammatory cytokine IL-1beta, BzATP induces a robust rise in [Ca2+]i with agonist and antagonist profiles indicative of the P2X7R. IL-1beta also induced the formation of membrane pores as evidenced by the uptake of YO-PRO-1 (375 Da). Quantitative real-time PCR demonstrated transient upregulation of P2X7R mRNA in IL-1beta-treated cells, while FACS analysis indicated a similar upregulation of P2X7R protein at the cell membrane. In multiple sclerosis lesions, immunoreactivity for the P2X7R was demonstrated on reactive astrocytes in autopsy brain tissues. In turn, P2X7R stimulation increased the production of IL-1-induced nitric oxide synthase activity by astrocytes in culture. These studies suggest that signaling via the P2X7R may modulate the astrocytic response to inflammation in the human central nervous system.
From the future Si technology perspective: Challenges and opportunities (2010)

As silicon technology enters sub-20nm nodes, new materials, structures and processes are being introduced in order to continue with the advantages of dimensional scaling, e.g, 3D NAND, ReRAM, EUVL, etc. Beyond 10 nm, Si CMOS technology will remain as the mainstream. In this paper, key drivers for silicon-based nano-electronics as well as research directions will be reviewed from viewpoints of system, memory, logic and emerging Si technologies.
Interactive Effects of Stress and Aging on Structural Plasticity in the Prefrontal Cortex (2010)

Neuronal networks in the prefrontal cortex mediate the highest levels of cognitive processing and decision making, and the capacity to perform these functions is among the cognitive features most vulnerable to aging. Despite much research, the neurobiological basis of age-related compromised prefrontal function remains elusive. Many investigators have hypothesized that exposure to stress may accelerate cognitive aging, though few studies have directly tested this hypothesis and even fewer have investigated a neuronal basis for such effects. It is known that in young animals, stress causes morphological remodeling of prefrontal pyramidal neurons that is reversible. The present studies sought to determine whether age influences the reversibility of stress-induced morphological plasticity in rat prefrontal neurons. We hypothesized that neocortical structural resilience is compromised in normal aging. To directly test this hypothesis we used a well characterized chronic restraint stress paradigm, with an additional group allowed to recover from the stress paradigm, in 3-, 12-, and 20-month-old male rats. In young animals, stress induced reductions of apical dendritic length and branch number, which were reversed with recovery; in contrast, middle-aged and aged rats failed to show reversible morphological remodeling when subjected to the same stress and recovery paradigm. The data presented here provide evidence that aging is accompanied by selective impairments in long-term neocortical morphological plasticity.
A physically supported gel polymer for low pressure, continuous flow solid phase reactions. Application to solid phase peptide synthesis (1981)

Copolymerisation of dimethylacrylamide, ethylene bisacrylamide, and acryloylsarcosine methyl ester within the pores of rigid macroporous inorganic particles provides supports suitable for continuous flow solid phase peptide synthesis and for other applications.