gebhart/patrepeval huggingface dataset:
Über tertiäre und quartäre Salze von Hexahydro‐pyrimidinen (1969)

Abstract Aus 1.3‐Dialkyl‐hexahydro‐pyrimidinen und Chlorwasserstoff sind in geeigneten Lösungsmitteln die mono‐sowie bis‐tertiären Salze 7, 11, 12 zu gewinnen. – Die monoquartären Salze 8 – 10 entstehen aus 1.3‐Dialkyl‐hexahydro‐pyrimidinen und Alkylhalogeniden in Äther. Die bis‐quartären Salze 5, 6 und 13 – 17 sind durch Alkylierung von 1.3‐Dialkyl‐hexahydropyrimidinen mit Methylbromid oder ‐jodid sowie Trialkyl‐oxoniumfluoroboraten in polaren, aprotischen Lösungsmitteln oder durch Umsetzung α‐halogenierter Amine mit γ‐Chlorpropylaminen zugänglich.
Neovascularization produced by angiotensin II. (1985)

Following vascular occlusion, development of collateral circulation occurs in at least two time-related phases: (1) the fast enhancement of the function of preexisting channels and (2) the slow formation of new vessels. Inasmuch as the renin-angiotensin system can act as a protective mechanism against local ischemia by activating preexisting collateral vessels, it is of interest to establish whether angiotensin II also produces stimulation of new vessel formation. Angiotensin II or cholecystokinin, an unrelated peptide, was incorporated in a slow-release formulation polyacrylamide gel and implanted in a pocket made in the rabbit cornea. Periodic examinations revealed that angiotensin II significantly stimulates new vessel formation; maximum values were attained in approximately 2 to 3 weeks. In contrast, cholecystokinin or polyacrylamide gel alone failed to stimulate any significant new vessel formation. Positive neovascularization was present in 85% of the total number of corneas implanted with angiotensin II, whereas 14% and 8% positive results were seen in the corneas implanted with either cholecystokinin or polyacrylamide gel alone, respectively. It is concluded that angiotensin II not only facilitates the activation of preexisting collateral vascular pathways but also has angiogenic properties and therefore could play an active role not only in the fast but also in the slow phase of the development of collateral circulation.
Lethal thalassemia after insertional disruption of the mouse major adult beta-globin gene. (1993)

Thalassemias are hereditary anemias caused by mutations that disturb the normal 1:1 balance of alpha- and beta-globin chains that form hemoglobin. We have disrupted the major adult beta-globin gene (b1) in mouse embryonic stem cells by using homologous recombination to insert selectable sequences into the gene. Mice homozygous for this insertional disruption of the b1 gene (Hbbth-2/Hbbth-2) are severely anemic and die perinatally. In contrast, approximately 60% of mice homozygous for deletion of the same gene (Hbbth-1/Hbbth-1) survive to adulthood and are much less anemic [Skow, L. C., Burkhart, B. A., Johnson, F. M., Popp, R. A., Goldberg, S. Z., Anderson, W. F., Barnett, L. B. & Lewis, S. E. (1983) Cell 34, 1043-1052]. These different phenotypes have implications for the control of beta-globin gene expression.
In situ assessment of the role of the β1, β2‐ and β3‐adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue (1996)

1. The involvement of beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow was investigated in abdominal subcutaneous adipose tissue of healthy young adults by use of an in situ microdialysis technique. 2. Dialysis probes were infused either with isoprenaline (non-selective beta-adrenoceptor agonist), CGP 12,177 (selective beta 3-adrenoceptor agonist having beta 1-/beta 2-antagonist properties), dobutamine (selective beta 1-adrenoceptor agonist) or terbutaline (selective beta 2-adrenoceptor agonist). The recovery of each probe used for perfusion was calculated by an in vivo calibration method. The local blood flow was estimated through the measurement of the escape of ethanol infused simultaneously with the drugs included in the probe. 3. Isoprenaline infusion at 0.01 microM had a weak effect while higher concentrations of isoprenaline (0.1 and 1 microM) caused a rapid, sustained and concentration-dependent increase of glycerol outflow; the maximum increase was 306 +/- 34% with 1 microM. Isoprenaline also increased the nutritive blood flow in adipose tissue; a significant effect appeared at 0.1 microM isoprenaline and was greater at 1 microM. 4. CGP 12,177 (10 and 100 microM) increased the glycerol concentration in the dialysate (128 +/- 8 and 149 +/- 12%, respectively) and nutritive blood flow. Terbutaline and dobutamine (100 microM) both provoked rapid and similar increases in glycerol outflow (252 +/- 18 and 249 +/- 18%, respectively). Both, terbutaline and dobutamine increased nutritive blood flow. 5. It is concluded that beta 1- and beta 2-adrenoceptor subtypes are both mainly involved in the mobilization of lipids and in the control of nutritive blood flow. beta 3-Adrenoceptors play a weaker role in the control of lipolysis and nutritive blood flow in human subcutaneous abdominal adipose tissue.
Oxidative modification of glutamine synthetase. I. Inactivation is due to loss of one histidine residue. (1983)

Intracellular proteolytic degradation of glutamine synthetase occurs in two distinct steps in Escherichia coli (Levine, R. L., Oliver, C. N., Fulks, R. M., and Stadtman, E. R. (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 2120-2124). In the first step, a mixed function oxidation modifies the glutamine synthetase. The modified enzyme, which is catalytically inactive, becomes susceptible to proteolytic attack. In the second step, a protease specific for the modified enzyme catalyzes the actual proteolytic degradation. The oxidatively modified glutamine synthetase was studied to determine the chemical differences between it and the native enzyme. Only a single alteration was found; one of sixteen histidine residues/subunit was altered by the oxidative modification. The modification introduced a carbonyl group into the protein, permitting isolation of a stable dinitrophenylhydrazone. No other differences were detected between the native and modified proteins. Specifically, the cysteine, methionine, phenylalanine, tyrosine, and tryptophan contents were not altered. A number of other prokaryotic and eukaryotic enzymes are also susceptible to oxidative modification. This covalent modification may be important in intracellular proteolysis, in mammalian host defense systems, in prevention of autolysis, in aging processes, and in oxygen toxicity.
Security by Negotiation (1984)

The negotiations about arms control and disarmament, that now occupy so prominent a place on the agenda of international politics, have as their chief purported objective the advancement of our security. There is, however, a great deal of scepticism today as to whether our security can in fact be advanced in this way. On the political right in Western countries — especially in the United States — there has occurred a resurgence of belief that our security rests chiefly on measures of defence to strengthen the West’s position relative to that of the Soviet Union, that arms control negotiations are the impediments to this and that serious negotiations about them should be postponed until the West’s defences are stronger. But on the political left also, the movement for unilateral disarmament expresses a lack of confidence in negotiated measures, a search for security independent of the reciprocation of measures we take by other parties.
The challenge of standoff explosives detection (2005)

While there currently are a number of effective technologies and methodologies for explosive screening when close proximity to the person, package, or vehicle being screened is feasible, the problem of detecting explosives at significant standoff distances remains one of the most difficult - and most important - challenges confronting physical security specialists. Among the major detection techniques, trace detection suffers from the fact that available vapor plumes are normally too dilute for detection at appreciable standoff under all but the most favorable conditions, and probing bulk techniques suffer from an intrinsic 1/r/sup 4/ fall-off of the signal intensity with distance. Research into potential means of standoff detection is necessary to try to address this important problem. This paper presents an overview of detection technologies that could prove useful in certain standoff detection applications, along with comments on future research needs. A distinction is made between remote detection, in which the personnel searching for explosives maintain a safe standoff distance from the object being screened but where a sampling and/or detection unit may approach the object closely, and true standoff detection, where both the personnel and the sampling/detection equipment maintain a large standoff distance.
Membrane association of functional vesicular stomatitis virus matrix protein in vivo (1993)

The matrix (M) protein of vesicular stomatitis virus (VSV) is a major structural component of the virion which is generally believed to bridge between the membrane envelope and the ribonucleocapsid (RNP) core. To investigate the interaction of M protein with cellular membranes in the absence of other VSV proteins, we examined its distribution by subcellular fractionation after expression in HeLa cells. Approximately 90% of M protein, expressed without other viral proteins, was soluble, whereas the remaining 10% was tightly associated with membranes. A similar distribution in VSV-infected cells has been observed previously. Conditions known to release peripherally associated membrane proteins did not detach M protein from isolated membranes. Membrane-associated M protein was soluble in the detergent Triton X-114, whereas soluble M protein was not, suggesting a chemical or conformational difference between the two forms. Membranes containing associated M protein were able to bind RNP cores, whereas membranes lacking M protein were not. We suggest that this membrane-bound M fraction constitutes a functional subset of M protein molecules required for the attachment of RNP cores to membranes during normal virus budding.
ADR1-mediated regulation of ADH2 requires an inverted repeat sequence. (1986)

DNA sequence analysis of wild-type and mutant ADH2 loci suggested that two unusual features 5' of the promoter, a 22-base-pair perfect dyad sequence and a (dA)20 tract, were important for regulation of this gene (D. W. Russell, M. Smith, D. Cox, V. M. Williamson, and E. T. Young, Nature [London] 304:652-654, 1983). Oligonucleotide-directed mutagenesis was used to construct ADH2 genes lacking the 22-base-pair dyad or the (dA)20 tract (V.-L. Chan and M. Smith, Nucleic Acids Res. 12:2407-2419, 1984). These mutant genes and other ADH2 deletions constructed by BAL 31 endonuclease digestion were studied after replacing the wild-type chromosomal locus with the altered alleles by the technique of gene transplacement (T. L. Orr-Weaver, J. W. Szostak, and R. S. Rothstein, Proc. Natl. Acad. Sci. USA 78:6354-6358, 1981), using canavanine resistance as the selectable marker. Deletions lacking the dyad failed to derepress normally and did not respond to mutations at the ADR1 locus, which encodes a protein necessary to activate ADH2. Deletions of the (dA)20 tract did not have a detectable phenotype. A small deletion located just 3' to the (dA)20 tract (between positions -164 and -146) had a low amount of ADR1-dependent transcription during repressed growth conditions, indicating that the regulatory protein encoded by ADR1 is present in a potentially active form during repression and that alterations of a DNA sequence in the promoter region can unmask its latent activity.
The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease (2012)

A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38 MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
Sequencing and analysis of the Methylococcus capsulatus (Bath) soluble methane monooxygenase genes (2000)

The soluble methane monooxygenase (sMMO) hydroxylase is a prototypical member of the class of proteins with non-heme carboxylate-bridged diiron sites. The sMMO subclass of enzyme systems has several distinguishing characteristics, including the ability to catalyze hydroxylation or epoxidation chemistry, a multisubunit hydroxylase containing diiron centers in its alpha subunits, and the requirement of a coupling protein for optimal activity. Sequence homology alignment of known members of the sMMO family was performed in an effort to identify protein regions giving rise to these unique features. DNA sequencing of the Methylococcus capsulatus (Bath) sMMO genes confirmed previously identified sequencing errors and corrected two additional errors, each of which was confirmed by at least one independent method. Alignments of homologous proteins from sMMO, phenol hydroxylase, toluene 2-, 3-, and 4-monooxygenases, and alkene monooxygenase systems revealed an interesting set of absolutely conserved amino-acid residues, including previously unidentified residues located outside the diiron active site of the hydroxylase. By mapping these residues on to the M. capsulatus (Bath) sMMO hydroxylase crystal structure, functional and structural roles were proposed for the conserved regions. Analysis of the active site showed a highly conserved hydrogen-bonding network on one side of the diiron cluster but little homology on the opposite side, where substrates are presumed to bind. It is suggested that conserved residues on the hydroxylase surface may be important for protein-protein interactions with the reductase and coupling ancillary proteins and/or serve as part of an electron-transfer pathway. A possible way by which binding of the coupling protein at the surface of the hydroxylase might transfer information to the diiron active site at the interior is proposed.
Need for Analgesics/drugs of Abuse: A Comparison Between Headache Patients and Addicts by the Leeds Dependence Questionnaire (LDQ) (2005)

Our aim was to compare the need for analgesics/drugs of abuse between headache patients--chronic and episodic headache sufferers--and addicts, by the Leeds Dependence Questionnaire (LDQ). This is a self-completion 10-item instrument to measure dependence upon a variety of substances. We administered the LDQ questionnaire to 122 chronic daily headache (CDH) sufferers who had been taking one dose of analgesic drug every day for at least 1 year; 71 subjects suffering from episodic headache (EH) using analgesics only occasionally; 115 consecutive drug addicts (DA) with a diagnosis of substance dependence. The mean LDQ total score was similar in the CDH (11.58+/-6.35) and DA (10.37+/-6.51) groups, and for both it was significantly higher than the score in the EH (5.61+/-3.00) group (P<0.001). The CDH group had the highest scores, and higher scores than the DA group (Z=-8.18, P<0.001) in item 8, assessing the primacy of effect over the kind of analgesic used, and in item 10 (Z=-5.03, P<0.001), asking if it is difficult to live without the analgesic; the DA group had the highest scores, and higher scores than the CDH group, in item 9 (Z=-5.07, P<0.001) addressing the need for the continued administration of the drug to maintain well-being, and in item 3 (Z=-2.39, P<0.05), exploring compulsion to start the use of the drug. The EH group had lower scores in all items (P<0.05) except for item 9, where there was no difference from CDH group; the EH group had also lower scores (P<0.001) than the DA group, except for item 8, where, instead, the score was higher than in the DA group (Z=-5.33, P<0.001). A strong link develops between chronic headache patients and the analgesics they use. This sort of 'dependence' appears to be a consequence of headache, originating from the necessity for the analgesic to cope with everyday life.
Rapid glucose sensing by protein kinase A for insulin exocytosis in mouse pancreatic islets (2005)

The role of protein kinase A (PKA) in insulin exocytosis was investigated with the use of two-photon excitation imaging of mouse islets of Langerhans. Inhibitors of PKA selectively reduced the number of exocytic events during the initial period (< 250 s) of the first phase of glucose-induced exocytosis (GIE), without affecting the second phase, in intact islets or small clusters of islet cells. The PKA inhibitors did not reduce the extent of the glucose-induced increase in [Ca(2+)](i). The actions of glucose and PKA in Ca(2+)-induced insulin exocytosis (CIE) triggered by photolysis of a caged-Ca(2+) compound, which resulted in large increases in [Ca(2+)](i) and thereby bypassed the ATP-sensitive K(+) channel-dependent mechanism of glucose sensing, were therefore studied. A high concentration (20 mM) of glucose potentiated CIE within 1 min, and this effect was blocked by inhibitors of PKA. This PKA-dependent action of glucose required glucose metabolism, given that increasing the intracellular concentration of cAMP by treatment with forskolin potentiated CIE only at the high glucose concentration. Finally, PKA appeared to reduce the frequency of 'kiss-and-run' exocytic events and to promote full-fusion events during GIE. These data indicate that a PKA-dependent mechanism of glucose sensing, which is operative even at the basal level of PKA activity, plays an important role specifically in the first phase of GIE, and they suggest that the action of PKA is mediated at the level of the fusion reaction.
Multipurpose Internet Mail Extensions (MIME) Part Four: Registration Procedures (2005)

STD 11, RFC 822, defines a message representation protocol specifying considerable detail about US-ASCII message headers, and leaves the message content, or message body, as flat US-ASCII text. This set of documents, collectively called the Multipurpose Internet Mail Extensions, or MIME, redefines the format of messages to allow for
A Combination of Two Antioxidants (An SOD Mimic and Ascorbate) Produces a Pro-Oxidative Effect Forcing Escherichia coli to Adapt Via Induction of oxyR Regulon (2011)

Cationic Mn(III) N-alkylpyridyl (MnTalkyl-2(or 3)-PyP(5+)) and N, N'-dialkylimidazolylporphyrins (MnTDalkyl-2-ImP(5+)) have been regarded as the most powerful SOD mimics/peroxynitrite scavengers - i. e. antioxidants. The ethyl-, MnTE-2-PyP(5+) (AEOL10113), and hexylpyridyl-, MnTnHex-2-PyP(5+) and diethylimidazolylporphyrin, MnTDE-2-ImP(5+) (AEOL10150) have been mostly studied in vitro and in vivo. Given the in vivo abundance of cellular reductants, MnPs can couple with them in removing superoxide. Thus, they could be readily reduced from Mn(III)P to Mn(II)P with ascorbate and glutathione, and in a subsequent step reduce either O(2)(.-) (while acting as superoxide reductase) or oxygen (while exerting pro-oxidative action). Moreover, MnPs can catalyze ascorbate oxidation and in turn hydrogen peroxide production. The in vivo type of MnP action (anti- or pro-oxidative) will depend upon the cellular levels of reactive species, endogenous antioxidants, availability of oxygen, ratio of O(2)(.-)- to peroxide-removing systems, redox ability of MnPs and their cellular localization/bioavailibility. To exemplify the switch from an anti- to pro-oxidative action we have explored a very simple and straightforward system - the superoxide-specific aerobic growth of SOD-deficient E. coli. In such a system, cationic MnPs, ortho and meta MnTE-2-(or 3)-PyP(5+) act as powerful SOD mimics. Yet, in the presence of exogenous ascorbate, the SOD mimics catalyze the H(2)O(2) production, causing oxidative damage to both wild and SOD-deficient strains and inhibiting their growth. Catalase added to the medium reversed the effect indicating that H(2)O(2) is a major damaging/signaling species involved in cell growth suppression. The experiments with oxyR- and soxRS-deficient E. coli were conducted to show that E. coli responds to increased oxidative stress exerted by MnP/ascorbate system by induction of oxyR regulon and thus upregulation of antioxidative defenses such as catalases and peroxidases. As anticipated, when catalase was added into medium to remove H(2)O(2), E. coli did not respond with upregulation of its own antioxidant systems.
Olfactory Absorption of Insulin to the Brain (1997)

A vast number of potent neuropharmaceuticals, many of which are peptides, are excluded from entry into the brain because of the highly selective blood-brain barrier. The fact that a number of drugs have been shown to be transported directly to the central nervous system following application to the olfactory region of the nose is therefore of major interest. In the present study, the feasibility of delivering peptides to the brain via the olfactory route was assessed using insulin as a model peptide. Systemic hyperinsulinemia induced by subcutaneous injection did not significantly reduce the amount of 125I-insulin transported from the nose to the brain in vivo, which suggests that the impact of systemic absorption on drug transport is minimal. A linear relationship was seen between insulin accumulation in the brain and the dose applied, without any relevant saturation. Contrary to what was expected, both systemic and olfactory absorption of insulin was enhanced when the pH of the medium was near the isoelectric point. The amount absorbed to the brain was found to be linearly related to the net charge of the molecule (r = -0.61; n = 20). It was concluded that insulin gains access to the central nervous system from the olfactory region of the nose by a nonspecific pathway. The olfactory route may therefore become an important means to deliver peptides to the brain.
Adenine-Aptamer Complexes (2002)

RNA aptamers that are able to complex free adenine have been isolated by a SELEX (systematic evolution of ligands by exponential enrichment) procedure. The adenine binding site was revealed by sequence alignment for a prevalent cluster of aptamers, and its structure and interactions with adenine were probed by RNase digestion studies, lead cleavage, boundary determination experiments, and truncated sequences studies. A new purine binding motif was functionally and structurally characterized and compared with other RNAs specific to purine or adenylated compounds. The affinity for adenine and the specificity for other related targets were quantified. This work suggests that the adenine binding site is composed of two independent secondary structure elements forming a bipartite binding site that interacts with adenine in a new mode of purine recognition. Such binding is of great interest because the imidazole moiety is not trapped in the binding site, and would easily be available for catalytic activity.