bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet‐activating factor increases pH(i)in bovine neutrophils through the PI3K–ERK1/2 pathway
Authors: Hidalgo María A , Ojeda Flavio , Eyre Peter , LaBranche Timothy P , Smith Carlos , Hancke Juan L , Burgos Rafael A
Published: January 2004

Platelet‐activating factor (PAF) is known to stimulate a variety of neutrophil activities, including chemotaxis, phagocytosis, degranulation, reactive oxygen species production and intracellular pH increase. The purpose of this study was to investigate the effect of PAF on pH(i), specifically if these changes in pH are the result of phosphatidylinositol 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathway activation in bovine neutrophils.

PAF caused intracellular alkalinization in 2′,7′‐bis‐(2‐carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein acetoxymethyl ester‐loaded bovine neutrophils. This phenomenon seems to be mediated by amiloride‐sensitive Na+/H+exchange, and is inhibited by WEB2086 (a selective PAF receptor antagonist), genistein (a tyrosine kinase inhibitor), wortmannin and LY294002 (PI3K inhibitors), and PD98059 and UO126 (MEK inhibitors).

PAF 100 nMinduced an increase in tyrosine phosphorylation of proteins 62, 44 and 21 kDa with a maximum response at 2 min of incubation.

Unlike human neutrophils, bovine neutrophils are strongly stimulated by PAFviaphosphorylation of ERK1/2 (extracellular‐signal‐regulated protein kinase) with an EC50of 30 and 13 nM, respectively.

PAF MAPK activation was also inhibited by WEB2086, pertussis toxin (PTX), genistein, wortmannin, LY294002, PD98059 and UO126 in bovine neutrophils. The ERK1/2 activation is dependent on PI3K pathway, because protein kinase B was phosphorylated by PAF and inhibited by wortmannin and LY294002, but not by U0126.

Our results suggest that PAF induces intracellular alkalinizationviaPI3K–MAPK activation. This effect is upstream regulated by PAF receptor, PTX‐sensitive G protein, tyrosine kinase, PI3K and MEK1/2 in bovine neutrophils.

British Journal of Pharmacology(2004)141, 311–321. doi:10.1038/sj.bjp.0705590
The endothelin system in Morris hepatoma‐7777: an endothelin receptor antagonist inhibits growth in vitro and in vivo
Authors: Pfab Thiemo , Stoltenburg‐Didinger Gisela , Trautner Christoph , Godes Michael , Bauer Christian , Hocher Berthold
Published: January 2004

Plasma concentrations of endothelin are increased in patients with hepatocellular cancer as well as in patients with liver metastasis. However, the impact of these findings remains uncertain.

We thus analyzed the endothelin system in a rat hepatoma model (Morris hepatoma 7777) in vitro and in vivo.

Our study revealed that tissue concentrations of endothelin‐1 (ET‐1) and big‐ET‐1, the precursor of ET‐1, were significantly elevated in Morris hepatoma 7777 as compared to normal liver. The ETA receptor density was significantly elevated, whereas the density of the ETB receptor was decreased in Morris hepatoma 7777.

We could also demonstrate that hepatoma cells secrete ET‐1.

Exogenously added ET‐1 enhances hepatoma cell growth in a dose‐dependent manner. Endothelin receptor antagonists (ETA and combined ETA/ETB receptor antagonists) inhibit tumor cell growth in vitro. Since the combined ETA/ETB receptor antagonist was more effective in vitro, we used this compound also for in vivo studies and could demonstrate that a combined ETA/ETB receptor antagonist is able to reduce hepatoma growth in vivo.

In conclusion, the endothelin system is activated in Morris hepatoma 7777 and contributes to hepatoma growth. Since endothelin receptor antagonists are well‐tolerated upcoming clinically used drugs without major side effects, our data might provide a new pharmacological approach to reduce hepatoma growth in vivo.

British Journal of Pharmacology (2004) 141, 215–222. doi:10.1038/sj.bjp.0705601
Chronic treatment of male rats with daidzein and 17β‐oestradiol induces the contribution of EDHF to endothelium‐dependent relaxation
Authors: Woodman Owen L , Boujaoude Mirna
Published: January 2004

We investigated the effect of chronic (7 days) treatment of male rats with the isoflavone daidzein (0.2 mg kg−1 sc per day) or 17β‐oestradiol (0.1 mg kg−1 sc per day) on the contribution of nitric oxide (NO), prostaglandins and endothelium‐derived hyperpolarising factor (EDHF) to endothelium‐dependent relaxation of isolated aortic rings.

The sensitivity and maximum relaxation to acetylcholine (ACh) were significantly greater in aortic rings from rats treated with daidzein or 17β‐oestradiol, in comparison to vehicle‐treated rats. Inhibition of nitric oxide synthase with N‐nitro‐L‐arginine (L‐NOARG) abolished ACh‐induced relaxation in the aortae from vehicle‐treated rats, but only attenuated relaxation in aortae from daidzein or 17β‐oestradiol‐treated rats. The presence of haemoglobin in addition to L‐NOARG did not cause any further inhibition of relaxation.

The cyclooxygenase inhibitor indomethacin had no effect on endothelium‐dependent relaxation in aortae from any treatment group. Charybdotoxin (ChTX), which blocks large‐conductance calcium‐activated potassium channels (BKCa) and intermediate‐conductance calcium‐activated potassium channels (IKCa), plus apamin, which blocks small‐conductance calcium‐activated potassium channels (SKCa), but not iberiotoxin, which only blocks BKCa, attenuated endothelium‐dependent relaxation of aortae from daidzein or 17β‐oestradiol‐treated rats. Blockade of KCa channels had no effect on the responses to ACh in aortae from vehicle‐treated rats. In aortae from daidzein‐ or 17β‐oestradiol‐treated rats, endothelium‐dependent relaxation was also attenuated by inhibition of cytochrome P450 (CYP450) epoxygenase with 6‐(2‐propargylloxyphenyl)hexanoic acid (PPOH) or inhibition of KIR channels and Na+/K+‐ATPase with barium and oubain, respectively.

This study demonstrates that endothelium‐dependent relaxation of male rat aorta is normally entirely mediated by NO, whereas treatment with daidzein or 17β‐oestradiol stimulates a contribution from a non‐NO, nonprostaglandin factor acting through the opening of SKCa and IKCa channels, and involving activation of Na/K‐ATPase, KIR and CYP450 epoxygenase. This pattern of sensitivity to the tested inhibitors is consistent with the contribution of EDHF to relaxation. Thus, EDHF contributes to the enhanced endothelium‐dependent relaxation that is observed after chronic treatment with the phytoestrogen daidzein or with 17β‐oestradiol.

British Journal of Pharmacology (2004) 141, 322–328. doi:10.1038/sj.bjp.0705603
Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors
Authors: Leggett James D , Aspley S , Beckett S R G , D'Antona A M , Kendall D A , Kendall D A
Published: January 2004

The ability of the endogenous fatty acid amide, cis‐oleamide (ODA), to bind to and activate cannabinoid CB1 and CB2 receptors was investigated.

ODA competitively inhibited binding of the nonselective cannabinoid agonist [3H]CP55,940 and the selective CB1 antagonist [3H]SR141716A to rat whole‐brain membranes with Ki values of 1.14 μM (0.52–2.53 μM, Hill slope=0.80, n=6) and 2.63 μM (0.62–11.20 μM, Hill slope=0.92, n=4), respectively. AEA inhibited [3H]CP55,940 binding in rat whole‐brain membranes with a Ki of 428 nM (346–510 nM, Hill slope=−1.33, n=3).

ODA competitively inhibited [3H]CP55,940 binding in human CB1 (hCB1) cell membranes with a Ki value of 8.13 μM (4.97–13.32 μM, n=2). In human CB2 transfected (hCB2) HEK‐293T cell membranes, 100 μM ODA produced only a partial (42.5±7%) inhibition of [3H]CP55,940 binding.

ODA stimulated [35S]GTPγS binding in a concentration‐dependent manner (EC50=1.64 μM (0.29–9.32 μM), R2=0.99, n=4–9), with maximal stimulation of 188±9% of basal at 100 μM. AEA stimulated [35S]GTPγS binding with an EC50 of 10.43 μM (4.45–24.42 μM, R2=1.00, n=3, 195±4% of basal at 300 μM). Trans‐oleamide (trans‐ODA) failed to significantly stimulate [35S]GTPγS binding at concentrations up to 100 μM.

ODA (10 μM)‐stimulated [35S]GTPγS binding was reversed by the selective CB1 antagonist SR141716A (IC50=2.11 nM (0.32–13.77 nM), R2=1.00, n=6).

The anatomical distribution of ODA‐stimulated [35S]GTPγS binding in rat brain sections was indistinguishable from that of HU210. Increases of similar magnitude were observed due to both agonists in the striatum, cortex, hippocampus and cerebellum.

ODA (10 μM) significantly inhibited forskolin‐stimulated cyclic AMP (cAMP) accumulation in mouse neuroblastoma N1E 115 cells (P=0.02, n=11). ODA‐mediated inhibition was completely reversed by 1 μM SR141716A (P<0.001, n=11) and was also reversed by pretreatment with 300 ng ml−1 pertussis toxin (P<0.001, n=6).

These data demonstrate that ODA is a full cannabinoid CB1 receptor agonist. Therefore, in addition to allosteric modulation of other receptors and possible entourage effects due to fatty acid amide hydrolase inhibition, the effects of ODA may be mediated directly via the CB1 receptor.

British Journal of Pharmacology (2004) 141, 253–262. doi:10.1038/sj.bjp.0705607
Oleamide: a member of the endocannabinoid family?
Authors: Fowler Christopher J
Published: January 2004

The fatty acid amide class of compounds, which include the endocannabinoid anandamide and the sleep‐inducing compound oleamide, have been shown in vitro to have a multiplicity of actions upon different neurochemical systems. In the present issue of this journal, Leggett et al present data indicating that oleamide functionally activates CB1 cannabinoid receptors in vitro. The significance of their finding is discussed in this commentary.

British Journal of Pharmacology (2004) 141, 195–196. doi:10.1038/sj.bjp.0705608
Characterization of ERK1/2 signalling pathways induced by adenosine receptor subtypes in newborn rat cardiomyocytes
Authors: Germack Renée , Dickenson John M
Published: January 2004

Adenosine A1, A2A, and A3 receptors (ARs) and extracellular signal‐regulated kinase 1/2 (ERK1/2) play a major role in myocardium protection from ischaemic injury. In this study, we have characterized the adenosine receptor subtypes involved in ERK1/2 activation in newborn rat cardiomyocytes.

Adenosine (nonselective agonist), CPA (A1), CGS 21680 (A2A) or Cl‐IB‐MECA (A3), all increased ERK1/2 phosphorylation in a time‐ and dose‐dependent manner. The combined maximal response of the selective agonists was similar to adenosine alone. Theophylline (nonselective antagonist) inhibited completely adenosine‐mediated ERK1/2 activation, whereas a partial inhibition was obtained with DPCPX (A1), ZM 241385 (A2A), and MRS 1220 (A3).

PD 98059 (MEK1; ERK kinase inhibitor) abolished all agonist‐mediated ERK1/2 phosphorylation. Pertussis toxin (PTX, Gi/o blocker) inhibited completely CPA‐ and partially adenosine‐ and Cl‐IB‐MECA‐induced ERK1/2 activation. Genistein (tyrosine kinase inhibitor) and Ro 318220 (protein kinase C, PKC inhibitor) partially reduced adenosine, CPA and Cl‐IB‐MECA responses, without any effect on CGS 21680‐induced ERK1/2 phosphorylation. H89 (protein kinase A, PKA inhibitor) abolished completely CGS 21680 and partially adenosine and Cl‐IB‐MECA responses, without any effect on CPA response.

Cl‐IB‐MECA‐mediated increases in cAMP accumulation suggest that A3AR‐induced ERK1/2 phosphorylation involves adenylyl cyclase activation via phospholipase C (PLC) and PKC stimulation.

In summary, we have shown that ERK1/2 activation by adenosine in cardiomyocytes results from an additive stimulation of A1, A2A, and A3ARs, which involves Gi/o proteins, PKC, and tyrosine kinase for A1 and A3ARs, and Gs and PKA for A2AARs. Moreover, the A3AR response also involves a cAMP/PKA pathway via PKC activation.

British Journal of Pharmacology (2004) 141, 329–339. doi:10.1038/sj.bjp.0705614
Topiramate hyperpolarizes and modulates the slow poststimulus AHP of rat olfactory cortical neurones in vitro
Authors: Russo Emilio , Constanti Andrew
Published: January 2004

The effects of the novel antiepileptic drug topiramate (TPM) were investigated in rat olfactory cortex neurones in vitro using a current/voltage clamp technique.

In 80% of recorded cells, bath application of TPM (20 μM) reversibly hyperpolarized and inhibited neuronal repetitive firing by inducing a slow outward membrane current, accompanied by a conductance increase. The response was reproducible after washout, and was most likely carried largely by K+ ions, although other ionic conductances may also have contributed.

In 90% of cells, TPM (20 μM) also enhanced and prolonged the slow (Ca2+‐dependent) poststimulus afterhyperpolarization (sAHP) and underlying slow outward tail current (sIAHP). This effect was due to a selective enhancement/prolongation of an underlying L‐type Ca2+ current that was blocked by nifedipine (20 μM); the TPM response was unlikely to involve an interaction at PKA‐dependent phosphorylation sites.

The carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ, 20 μM) and the poorly membrane permeant inhibitor benzolamide (BZ, 50 μM) both mimicked the membrane effects of TPM, in generating a slow hyperpolarization (slow outward current under voltage clamp) and sAHP enhancement. ACTZ and BZ occluded the effects of TPM in generating the outward current response, but were additive in producing the sAHP modulatory effect, suggesting different underlying response mechanisms.

In bicarbonate/CO2‐free, HEPES‐buffered medium, all the membrane effects of TPM and ACTZ were reproducible, therefore not dependent on CA inhibition.

We propose that both novel effects of TPM and ACTZ exerted on cortical neurones may contribute towards their clinical effectiveness as anticonvulsants.

British Journal of Pharmacology (2004) 141, 285–301. doi:10.1038/sj.bjp.0705617
Identification of interstitial cells of Cajal in corporal tissues of the guinea‐pig penis
Authors: Hashitani Hikaru , Suzuki Hikaru
Published: January 2004

This study shows for the first time the presence of interstitial cells of Cajal (ICC) and their possible role in the initiation of spontaneous excitation in the corporal tissue of the guinea‐pig penis. ICC, which were identified by their c‐kit immunoreactivity, were abundantly distributed in the corporal smooth muscle meshwork. Spontaneous increases in the intracellular calcium concentration ([Ca2+]i; calcium transients) were visualized in preparations loaded with the fluorescent dye fura‐2. Ca transients originated from the boundary of muscle bundles and then spread throughout the meshwork (Ca waves). Ca waves were strongly suppressed by either CPA (10 μM), ryanodine (50 μM) or 2‐APB (10 μM), and their synchronicity was disrupted by 18β‐GA (30 μM). These results suggest that ICC in the corporal tissue may have a role as pacemakers to drive the bulk of smooth muscles, and that intracellular Ca2+ stores and gap junctions are critical for the generation of spontaneous excitation.

British Journal of Pharmacology (2004) 141, 199–204. doi:10.1038/sj.bjp.0705622
Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use
Authors: Martínez Carmen , Blanco Gerardo , Ladero José M , García‐Martín Elena , Taxonera Carlos , Gamito Francisco G , Diaz‐Rubio Manuel , Agúndez José A G
Published: January 2004

Impaired drug metabolism is a major cause of adverse drug reactions, and it is often caused by mutations at genes coding for drug‐metabolising enzymes. Two amino‐acid polymorphisms of cytochrome P4502C9 (CYP2C9), an enzyme involved in the metabolism of several nonsteroidal anti‐inflammatory drugs (NSAIDs), were studied in 94 individuals with acute bleeding after NSAIDs use and 124 individuals receiving NSAIDs with no adverse effects. The frequency of CYP2C9 variant alleles was increased in overall bleeding patients, with a significant trend to higher risk with increasing number of variant alleles (P=0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n=33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (P<0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.

British Journal of Pharmacology (2004) 141, 205–208. doi:10.1038/sj.bjp.0705623
Ouabain exerts biphasic effects on connexin functionality and expression in vascular smooth muscle cells
Authors: Martin Patricia E M , Hill Nathan S , Kristensen Bo , Errington Rachael J , Griffith Tudor M
Published: January 2004

Correction to: British Journal of Pharmacology (2003) 140, 1261–1271. doi:10.1038/sj.bjp.0705556

We have compared the effects of ouabain on the maintenance of gap junctional communication in rat aortic A7r5 smooth muscle cells, monkey COS‐1 fibroblasts and human HeLa epithelial cells.

Ouabain (1 mM) interrupted dye coupling between confluent A7r5 cells within ∼1 h, and high concentrations of ouabain were similarly required to reduce coupling between COS‐1 cells selected to express the rat α1 Na+/K+‐ATPase subunit, which is ouabain resistant. By contrast, low concentrations of ouabain (1–10 μM) attenuated dye transfer in wild‐type COS‐1 and HeLa cells, whose endogenous α1 subunits possess relatively high affinity for the glycoside (Ki∼0.3 vs ∼100 μM) Ouabain‐induced reductions in dye transfer therefore correlated with the ability of the glycoside to bind to the Na+/K+‐ATPase isoenzymes expressed in these different cell lines.

No consistent relationship between inhibition of intercellular dye transfer and secondary changes in [Ca2+]i or pHi could be identified following incubation with ouabain.

In separate experiments, the effects of ouabain on real‐time trafficking of connexin (Cx) protein were monitored by time‐lapse microscopy of A7r5 cells transfected to express a fluorescent Cx43‐green fluorescent protein (GFP) and the ability of the glycoside to modulate endogenous expression of Cx40 and Cx43 evaluated in A7r5 cells by immunochemical and Western blot analysis.

Ouabain (1 mM) depressed vesicular trafficking of Cx43‐GFP after ∼1 h, and caused a time‐dependent loss of endogenous Cx40 and Cx43 protein that was first evident at 2 h and almost complete after 4 h. These effects of ouabain on Cx expression were reversed ∼90 min following washout of the glycoside.

We conclude that ouabain exerts biphasic effects on intercellular communication that involve an initial decrease in gap junctional permeability followed by a global reduction in the expression of Cx protein. Further studies are necessary to establish to what extent these actions of ouabain reflect inversion of the normal [Na+]i/[K+]i ratio and/or conversion of the Na+/K+‐ATPase into a general signal transducer that regulates downstream protein synthesis.

British Journal of Pharmacology (2004) 141, 374–384. doi:10.1038/sj.bjp.0705671
Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference
Authors: Kong Xian Chu , Barzaghi Patrizia , Ruegg Markus A
Published: January 2004

The formation of the vertebrate neuromuscular junction (NMJ) requires the receptor tyrosine kinase MuSK and the adaptor molecule rapsyn. Here, we report that the phenotypes of mice deficient in these two molecules can be reproduced by RNA interference (RNAi) in rat muscle in vivo. Specifically, double‐stranded RNA (dsRNA) targeting MuSK and rapsyn inhibited the formation of the NMJ in rat muscle fibres in vivo, while dsRNA targeting nonessential proteins did not have any effect. Moreover, plasmids that trigger RNAi to MuSK induced the disassembly of existing NMJs. These results thus demonstrate for the first time the functionality of dsRNA in silencing endogenous genes in adult mammalian muscle in vivo. Moreover, they show that MuSK is also required for the maintenance of the NMJ, offering a mechanistic explanation for the myasthenia gravis caused by auto‐antibodies to MuSK.
Characterization of the interactions between mammalian PAZ PIWI domain proteins and Dicer
Authors: Tahbaz Nasser , Kolb Fabrice A , Zhang Haidi , Jaronczyk Katarzyna , Filipowicz Witold , Hobman Tom C
Published: January 2004

PAZ PIWI domain (PPD) proteins, together with the RNA cleavage products of Dicer, form ribonucleoprotein complexes called RNA‐induced silencing complexes (RISCs). RISCs mediate gene silencing through targeted messenger RNA cleavage and translational suppression. The PAZ domains of PPD and Dicer proteins were originally thought to mediate binding between PPD proteins and Dicer, although no evidence exists to support this theory. Here we show that PAZ domains are not required for PPD protein–Dicer interactions. Rather, a subregion of the PIWI domain in PPD proteins, the PIWI‐box, binds directly to the Dicer RNase III domain. Stable binding between PPD proteins and Dicer was dependent on the activity of Hsp90. Unexpectedly, binding of PPD proteins to Dicer inhibits the RNase activity of this enzyme in vitro. Lastly, we show that PPD proteins and Dicer are present in soluble and membrane‐associated fractions, indicating that interactions between these two types of proteins may occur in multiple compartments.
DJ‐1 has a role in antioxidative stress to prevent cell death
Authors: Taira Takahiro , Saito Yoshiro , Niki Takeshi , Iguchi‐Ariga Sanae M M , Takahashi Kazuhiko , Ariga Hiroyoshi
Published: January 2004

Deletion and point (L166P) mutations of DJ‐1 have recently been shown to be responsible for the onset of familial Parkinson's disease (PD, PARK7). The aim of this study was to determine the role of DJ‐1 in PD. We first found that DJ‐1 eliminated hydrogen peroxide in vitro by oxidizing itself. We then found that DJ‐1 knockdown by short interfering RNA rendered SH‐SY5Y neuroblastoma cells susceptible to hydrogen peroxide‐, MPP+‐ or 6‐hydroxydopamine‐induced cell death and that cells harbouring mutant forms of DJ‐1, including L166P, became susceptible to death in parallel with the loss of oxidized forms of DJ‐1. These results clearly showed that DJ‐1 has a role in the antioxidative stress reaction and that mutations of DJ‐1 lead to cell death, which is observed in PD.
Indole‐based analogs of melatonin: in vitro antioxidant and cytoprotective activities
Authors: Mor Marco , Silva Claudia , Vacondio Federica , Plazzi Pier Vincenzo , Bertoni Simona , Spadoni Gilberto , Diamantini Giuseppe , Bedini Annalida , Tarzia Giorgio , Zusso Morena , Franceschini Davide , Giusti Pietro
Published: January 2004

Abstract:  The known neuroprotective actions of melatonin could be due to its antioxidant or radical scavenging activity, or they could be due to specific interactions of the indole with its receptors. A study of structure–activity relationships may provide useful information when a validated macromolecular target has not been (or is not) identified. A set of indole derivatives, with changes in the 5‐methoxy and acylamino groups, the side chain position and the lipophilic/hydrophilic balance, were selected and tested for their in vitro antioxidant potency in the ABTS (2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid disodium salt) and thiobarbituric acid reactive substances (TBARS) assays and for their cytoprotective activity against kainate excitotoxicity on cerebellar cell cultures. No quantitative model was able to relate the potencies obtained in the two antioxidant assays, probably because they are related to different physico‐chemical properties. However, the lipophilicity of the compounds and the antioxidant potency in the TBARS assay were linearly correlated. This may be due to improved access to the lipidic substrate, where the antioxidant action occurs. In the cytoprotection assay, most compounds showed potencies comparable with or lower than melatonin. An exception was N‐[2‐(5‐methoxy‐1H‐indol‐2‐yl)ethyl]acetamide (12), yielding, at 50 μm, percentages of cell vitality higher than 75%, while melatonin EC50 was 333 μm. No correlation was observed between cytoprotective and antioxidant potencies, nor with MT1 or MT2 receptor affinity. Compound 12 is a low‐affinity antagonist at melatonin membrane receptors, and one of the most potent compounds in the antioxidant assays; its cytoprotective potency and the absence of agonist activity at melatonin membrane receptors make it a valid candidate for further investigations.
Melatonin and viral infections
Authors: Bonilla Ernesto , Valero Nereida , Chacín‐Bonilla Leonor , Medina‐Leendertz Shirley
Published: January 2004

Abstract:  The therapeutic effects of melatonin against viral infections, with emphasis on the Venezuelan equine encephalomyelitis (VEE), are reviewed. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also postpones the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus‐infected mice stressed by either isolation or dexamethasone injection. An increase in the host resistance to the virus via a peripheral immunostimulatory activity is considered responsible for these effects. It has also been demonstrated that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B‐ and T‐cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE‐infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. This protective effect seems to be due to the increase in the production of interleukin‐1β (IL‐1β), as 100% of the infected mice treated with melatonin die when IL‐1β is blocked with antimurine IL‐1β antibodies. Although melatonin administration raises serum levels of tumor necrosis factor‐alpha (TNF‐α) and interferon‐gamma (IFN‐γ), the mortality observed in neutralization experiments with the corresponding anticytokine antibodies, suggests that neither TNF‐α nor IFN‐γ are essential for the protective effect of melatonin on murine VEE virus infection. Melatonin treatment also enhances the efficiency of immunization against the VEE virus. Reactive oxygen species have been implicated in the dissemination of this virus, and their deleterious effects may be diminished by melatonin. This indole inhibits nitric oxide synthetase activity and it is a potent scavenger of nitric oxide, which also plays an important role in the spread of the VEE virus. In conclusion, the immunomodulatory, antioxidant, and neuroprotective effects of melatonin suggest that this indole must be considered as an additional therapeutic alternative to fight viral diseases.
Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP+ treatment in human astrocytoma U373MG cells
Authors: Chuang Jih‐Ing , Chen Tsung‐Hung
Published: January 2004

Abstract:  1‐Methyl‐4‐phenylpyridinium (MPP+) ion, a toxic metabolite of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine, is produced by monoamine oxidase B in astrocytes. MPP+ causes a selective dopaminergic neurodegeneration, the pathophysiologic hallmark of Parkinson disease. However, the toxic effect of MPP+ on astrocytes remains unclear. Here, we examined the effect of MPP+ on human astrocytoma U373MG cells, with particular attention to the temporal interaction of glutathione (GSH) and reactive oxygen species (ROS) (H2O2 and O). MPP+ induced astrocyte apoptosis in a dose‐dependent manner 48 hr after treatment. Distinctive early (<6 hr) and late (24–48 hr) responses were observed. ROS production and the oxidized GSH (GSSG)/GSH ratio, indicators of oxidative stress, rose dramatically after 24 hr of MPP+ exposure, whereas the H2O2 level transiently decreased at 6 hr. ROS overproduction and GSH dysfunction were concomitantly associated with caspase‐3 activation and finally led to cell apoptosis. Moreover, GSH depletion by diethyl maleate, but not buthionine sulfoximine, caused cells to die quickly and potentiated the cytotoxicity of MPP+. Co‐treatment with melatonin, a known antioxidant secreted by the pineal gland, significantly prevented cell apoptosis by inhibiting oxidative stress and caspase‐3 activation, but it did not affect that the early changes due to MPP+ treatment. Our results demonstrate that in astrocytes, GSH is involved in the early decrease and late increase in ROS levels induced by MPP+ treatment. Melatonin remedies the dysfunction of GSH system to block caspase‐3 activation and cell apoptosis induced by oxidative stress during the long‐term exposure of MPP+.
Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar
Authors: Fjelldal Per Gunnar , Grotmol Sindre , Kryvi Harald , Gjerdet Nils Roar , Taranger Geir Lasse , Hansen Tom , Porter Mark J. R. , Totland Geir K.
Published: January 2004

Abstract:  This study describes the long‐term effects of surgical ablation of the pineal gland on the spine of 3‐yr‐old Atlantic salmon (Salmo salar L.) with a mean weight of 3.2 kg. Radiographic examinations showed that 82% of the pinealectomized fish developed marked lateral (scoliosis) and dorso‐ventral spinal curvatures. The proportions of the individual vertebral bodies and their mechanical properties were also altered. The stiffness, yield limit and resilience of the vertebral bodies, as measured by compression in the cranio‐caudal direction, were significantly lower in the pinealectomized than in the sham‐pinealectomized group. Calcium, phosphorous and total mineral content of the vertebral bodies were also significantly lower in the pinealectomized fish, while these parameters were similar in scales in the two groups. Alterations of the spinal curve accompanied by changes in the proportions, mechanical strength and mineral content of the vertebral bodies of the pinealectomized salmon indicate that melatonin has several functions related to vertebral bone growth. As the lesions found in salmon are similar to the spinal malformations observed in avian species and mammals after pinealectomy, this study strengthens the hypothesis of a phylogenetically conserved function of the pineal gland related to skeletal development.
Impact of an oblique breaking wave on a wall
Authors: Shu Jian-Jun
Published: January 2004

The intention of this paper is to study impact force of an oblique-angled slamming wave acting on a rigid wall. In the present study the analytical approach is pursued based on a technique proposed by Shu (Proceedings of the International Conference on Applied Mathematics & Mathematical Physics, Sylhet, Bangladesh, 2000). A nonlinear theory in the context of potential flow is presented for determining accurately the free-surface profiles immediately after an oblique breaking wave impingement on the rigid vertical wall that suddenly starts from rest. The small-time expansion is taken as far as necessary to include the accelerating effect. The analytical solutions for the free-surface elevation are derived up to the third order. The results derived in this paper are of particular interest to the marine and offshore engineering industries, which will find the information useful for the design of ships, coastal and offshore.
Conductances between confined rough walls
Authors: Plouraboué F. , Geoffroy S. , Prat M.
Published: January 2004

Two- and three-dimensional creeping flows and diffusion transport through constricted and possibly rough surfaces are studied. Asymptotic expansions of conductances are derived as functions of the constriction local geometry. The validity range of the proposed theoretical approximations is explored through a comparison either with available exact results for specific two-dimensional aperture fields or with direct numerical computations for general three-dimensional geometries. The large validity range of the analytical expressions proposed for the hydraulic conductivity (and to a lesser extent for the electrical conductivity) opens up interesting perspectives for the simulation of flows in highly complicated geometries with a large number of constrictions.
HOLOGRAPHIC STEREOGRAM FROM SEQUENTIAL COMPONENT PHOTOGRAPHS
Authors: McCrickerd J. T. , George Nicholas
Published: January 2004

Holograms of naturally illuminated objects are synthesized in two steps. A stereoscopic camera technique is used to record the objects' parallax qualities in white light; this photographic information is transformed into a hologram with coherent light. The image quality is excellent, and the method seems practical for making full-color reconstructions using stereoscopic photographs taken with color film.
MODE INTERACTIONS IN AN ARGON ION LASER
Authors: Bass M. , deMars G. , Statz H.
Published: January 2004

We have observed that at certain levels of laser power, an argon ion laser oscillates in only two strong modes. The frequency difference between these two modes is an integer multiple of the cavity fundamental beat frequency and increases with the laser power. Analysis of this effect shows that pulses from such a laser are 0.3π rather than π pulses.
MODE-LOCKED QUIETING OF HE–NE AND ARGON LASERS
Authors: Targ Russell , Yarborough J. M.
Published: January 2004

We report the suppression of low-frequency noise in the He–Ne and argon lasers as a result of mode coupling by means of an internal phase modulator. Suppression of off-axis modes and 20 to 30 dB of low-frequency AM noise suppression have been obtained in both FM and phase-locked operation, with no loss of output power.
SECOND HARMONIC GENERATION FROM SHORT PULSES
Authors: Comly J. , Garmire E.
Published: January 2004

The second harmonic pulse shape generated from ultrashort pulses is calculated. In long dispersive crystals the pulse width may be much broader than the incident pulse and the power conversion ratio may saturate at a low value. These effects should be prominent in LiNbO3 with 4 × 10−13 sec pulses.
PHOSPHOROUS-ION-IMPLANTED CdS
Authors: Anderson W. W. , Mitchell J. T.
Published: January 2004

High energy phosphorous ions implanted into CdS have given evidence of conductivity type conversion after careful post-annealing. Thermal probe measurements consistently showed p-type conductivity on the implanted surface. Diodes fabricated from implanted material show good rectification characteristics, low voltage electroluminescence, and double-injection phenomena at room temperature.
ANOMALOUS BEHAVIOR OF THE COMPETITION BETWEEN THE LASERING TRANSITIONS OF THE ARGON ION LASER
Authors: Merkelo H. , Wright R. H. , Bialecke E. P. , Kaplafka J. P.
Published: January 2004

A wavelength-selective feedback modulation scheme was devised to study the competitive behavior of the lasering transitions in the argon ion laser and to determine the coupling relationships, radiative as well as collisional, between the inverted states of the ion. By means of monitoring cross modulation on lasering lines, spontaneous transitions, and discharge current, the interdependence of the lasering transitions was determined. Whereas lasering transitions which share common energy levels, upper or lower, are expected to compete adversely with each other, it was found that under certain conditions the contrary takes place.
POLARIZATION OF A SINGLE-MODE LASER IN A TRANSVERSE MAGNETIC FIELD
Authors: Settles R. A. , Heer C. V.
Published: January 2004

The polarization intensities Ix and Iy of a single-mode linear laser are measured as a function of the transverse magnetic field Bx and By. The experimental data are in excellent agreement with the recent analysis of Sargent, Lamb, and Fork.
CALCULATION OF THE NONLINEAR OPTICAL TENSOR COEFFICIENTS IN OXYGEN-OCTAHEDRA FERROELECTRICS
Authors: DiDomenico M. , Wemple S. H.
Published: January 2004

We show, using the concept of the polarization potential tensor β which relates energy band shifts to the crystal polarization, that the nonlinear optical (NLO) tensor coefficients δ in oxygen-octahedra ferroelectrics are proportional to the quantity βPs where Ps is the crystal spontaneous polarization. Because β is found to be nearly the same in all oxygen-octahedra ferroelectrics, we are able to calculate the δ coefficients from a knowledge of Ps. The polarization-induced energy band shifts are shown to be nearly the same for static polarizations (giving rise to the clamped electro-optic effect) and for optical-frequency electronic polarizations (giving rise to nonlinear optical effects).
THE GAUSSIAN MODE IN OPTICAL RESONATORS WITH A RADIAL GAIN PROFILE
Authors: Casperson Lee , Yariv Amnon
Published: January 2004

The dependence of the parameters of the Gaussian mode in laser resonators on the properties of the medium in the cavity is studied. Experimental verification of the theoretical results is presented. It is found that the modes in a high-gain laser may differ widely from the usual free space resonator results. Also, resonator configurations which in free space are unstable may, with a suitable medium, support low-loss Gaussian modes.
A WIDE-RANGE VARIABLE-FREQUENCY GUNN OSCILLATOR
Authors: Haydl William H.
Published: January 2004

By controlling the illumination intensity along a sample of photoconducting GaAs, the point of nucleation of the high field domain has been varied. When a very thin line shadow was projected on an illuminated sample, the oscillation frequency corresponded to the distance between the shadow and the anode and could be varied continuously over a range of about 5:1 by varying the position of the shadow along the sample.
NEW PERMANENT MAGNET MATERIALS
Authors: Nesbitt E. A. , Willens R. H. , Sherwood R. C. , Buehler E. , Wernick J. H.
Published: January 2004

New permanent magnet materials containing rare-earth elements (RE) have been discovered. For the most part, these alloys are based on the hexagonal intermetallic compounds, Co5RE. Replacement of cobalt with copper in some of these rare-earth compounds results in solid materials with substantial permanent magnet properties. Coercive forces as high as 28,700 Oe have been obtained in heat-treated samples of alloys in the Co5Sm–Cu5Sm system.
IMPROVED RESOLUTION AND SIGNAL-TO-NOISE RATIOS IN TOTAL INTERNAL REFLECTION HOLOGRAMS
Authors: Stetson Karl A.
Published: January 2004

This Letter reports improvements in resolution and signal-to-noise ratio for total internal reflection hologram reconstructions. It outlines the conditions employed to produce these results and indicates some of the relevant properties.
INTERNAL Q SWITCHING IN GaAs JUNCTION LASERS
Authors: Ripper J. E. , Dyment J. C.
Published: January 2004

Internally Q-switched light pulses have been obtained from junction lasers. Narrow bursts of light (<400 psec wide) were detected immediately after the termination of the injection current pulse. The effect persists for a wide variation in the length of the current pulse, from less than 2 nsec to several μsec. The internal absorption losses controlling Q switching are strongly dependent on both temperature and current. The effect is only seen in diodes with very low transition temperatures (Tt) between the regions of short and long stimulated emission delay times.
USE OF NEON AS A NONLINEAR ABSORBER FOR MODE LOCKING A He–Ne LASER
Authors: Fox A. G. , Schwarz S. E. , Smith P. W.
Published: January 2004

We find that a tube of pure Ne20, excited by a discharge and placed within the cavity of a He3–Ne20 laser operating at 6328 Å can cause a stable, continuous train of short optical pulses to be produced.
PARAMETRIC AMPLIFICATION OF ULTRASONIC WAVES IN CdS
Authors: Zemon S. , Zucker J. , Wasko J. H. , Conwell E. M. , Ganguly A. K.
Published: January 2004

Traveling-wave parametric amplification of 0.5-GHz acoustic shear waves has been observed in CdS at room temperature. Acoustoelectric coupling provides the nonlinear interaction. Observed gain was about 10 dB/mm, which is comparable to that of the conventional acoustic amplifier.
ANODIC-BORE ION LASER TUBE
Authors: McMahan William H.
Published: January 2004

Ion laser plasma tubes have been designed and tested in which the major cause of deterioration is eliminated and laser efficiency is improved. Ion bombardment of the walls of the discharge bore is eliminated by electrical means. The walls of the discharge bore are maintained at a positive potential with respect to the laser plasma.
RADIATION EFFECTS AND ELECTRICAL STABILITY OF METAL-NITRIDE-OXIDE-SILICON STRUCTURES
Authors: Perkins C. W. , Aubuchon K. G. , Dill H. G.
Published: January 2004

Radiation-induced threshold voltage shifts in MNOS structures are measured as a function of oxide layer thickness. The shifts for negative biases vanish at an oxide thickness near 125 Å and remain negligible for positive biases at this thickness. Electrical stability for this thickness is maintained for gate voltages from −40 to +35 V.
SPUTTERING OF OXIDE FILMS IN PLASMA ANODIZATION OF ALUMINUM
Authors: Locker L. D. , Skolnick L. P.
Published: January 2004

Oxide films on aluminum can be sputtered off in oxygen or in argon glow discharges, when a positive bias is applied to the specimen. It is shown that this phenomenon limits the thickness of films that can be grown by plasma anodization. The sputtering does not necessarily require negative ions, since these are absent in the argon discharge.
MAGNETIC AND OPTICAL PROPERTIES OF COBALT-SUBSTITUTED RbNiF3
Authors: Suits J. C. , McGuire T. R. , Shafer M. W.
Published: January 2004

When nickel is replaced by cobalt in RbNi1–xCoxF3, the hexagonal structure and the ferrimagnetic order are maintained; however, the easy axis of magnetization at 77°K rotates in a complex manner from perpendicular (x < .07) to parallel to the optic axis (x > .17). In the optical window region at 17,000 cm−1 the bulk absorption remains constant at 5 cm−1 and the Faraday rotation increases to 200 deg/cm at x = .25.
RADIANT SELF-STABILIZATION OF TEMPERATURE
Authors: Boyle W. S. , Verleur H. W.
Published: January 2004

The change in optical constants of VO2 associated with the semiconductor-to-metal transition at 340°K can be used to stabilize the temperature of a radiating body. Calculations based on a particular composite thin-film structure show that the temperature of a body remains fixed for an eightfold change in radiated power. Optical measurements over a limited range of the infrared confirm the calculations.
IGNITION OF A HOT PLASMA AT THE SECOND HARMONIC OF THE ELECTRON CYCLOTRON FREQUENCY
Authors: Lisitano G.
Published: January 2004

A plasma has been heated to electron temperatures of several hundred eV by concentrating rf power of 60 W, 3 Gc/sec in a plasma volume of 3 cm3. The heating of the plasma is most efficient at the second harmonic resonances of the electron cyclotron frequency.
LENGTH CHANGE OF COPPER AFTER ELECTRON IRRADIATION
Authors: Hanada R. , Kauffman J. W.
Published: January 2004

The length change of pure copper after 2.2 MeV electron irradiation was measured with a sensitivity of 3 × 10−8 at liquid-helium temperature. Subsequent isochronal annealing showed the existence of substructures in stage I. These substructures in length change are found to be similar with resistivity recovery results.
FIELD EMISSION SHADOW MICROSCOPY
Authors: Melmed Allan J.
Published: January 2004

An electron field emitter is used as an approximate point source of electrons to produce magnified shadows, or profile images, of small electrically conducting objects in ultrahigh vacuum. Some electrical and electron optical properties of this type of microscopy are described.
OBSERVATION OF SUPERRADIANT LASER ACTION IN SPARK DISCHARGES IN AIR AT ATMOSPHERIC PRESSURE
Authors: Svedberg A. , Högberg L. , Nilsson R.
Published: January 2004

Superradiant, stimulated emission at 3371 Å has been observed from spark discharges in air at atmospheric pressure. This emission corresponds to transitions in the second positive band system of molecular nitrogen. Duration of the emitted laser pulse is about 0.6 nsec and peak power output is about 2 W.
THIRD HARMONIC OF AN INITIALLY SINUSOIDAL ULTRASONIC WAVE IN COPPER
Authors: Peters R. D. , Breazeale M. A.
Published: January 2004

The amplitude of the third harmonic of an initially sinusoidal ultrasonic wave is measured in the [100] direction in copper, both directly and by a pulse overlap technique. The value of the third-order elastic constant C111=−16 × 1012 dyn/cm2 is obtained from measurements of third harmonic amplitudes of the order of 10−3 Å. The contribution of the fourth-order constant C1111 to these amplitudes appears to be negligible.
MEASUREMENT OF THE VELOCITY FIELD CHARACTERISTIC OF ELECTRONS IN GERMANIUM
Authors: Chang D. M. , Ruch J. G.
Published: January 2004

The velocity field characteristics of electrons in germanium were measured in a range of temperatures between 33°K and 130°K and the electric field along the 〈 100 〉 orientation of the crystal. At 33°K a negative differential mobility of 300 cm2/V-sec was observed with a threshold field of 1.5 kV/cm. The negative differential mobility decreases with increasing temperature. At 130°K there is definitely no negative differential mobility.
REPETITIVE PULSING OF THE CO2 LASER BY MEANS OF CO2 GAS AND OTHER ABSORBERS
Authors: Hanst Philip L. , Morreal John A. , Henson William J.
Published: January 2004

Repetitive pulsing of the CO2 laser has been obtained as a result of absorption by formic acid vapor, propylene gas, heated CO2 gas or heated CO2-propylene mixtures. Pulsing rates of close to 105 pulses per second have been obtained. Remarkable stability in the frequency and amplitude of the pulses has been observed. Any CO2 line can be pulsed without difficulty, and it is suggested that a proper match of absorber lines and laser lines should permit pulsing of other types of infrared lasers.
PHOTOEMISSION FROM GaAs THIN FILMS
Authors: Steinberg R. F.
Published: January 2004

A technique is described for obtaining atomically clean GaAs surfaces by evaporating epitaxially a GaAs layer on the bulk crystal under ultrahigh vacuum. Photoemission sensitivities of 220 μA/lumen have been obtained, with high quantum yields in the near-infrared region.
IMAGE CONVERSION FROM 1.6 μ TO THE VISIBLE IN LITHIUM NIOBATE
Authors: Midwinter J. E.
Published: January 2004

Image information at 1.6 μ has been converted to the green by mixing it with highly collimated ruby laser radiation in lithium niobate. About 50 lines resolution has been achieved, limited only by the laser beam quality. A tenfold increase on this should be attainable with a single transverse mode laser.
MAGNON SIDEBANDS AND LOCAL ORDER IN Co-DOPED MnF2
Authors: van der Ziel J. P.
Published: January 2004

A magnon sideband associated with an isolated Co single-ion optical transition is reported in Co-doped MnF2. Measurements of the temperature dependence of the absorption, after the subtraction of the thermal contribution to the line shift, indicates the presence of local order above the Néel temperature.
MODE LOCKING OF THE CO2 LASER
Authors: Caddes D. E. , Osterink L. M. , Targ Russell
Published: January 2004

Mode-locking a CO2 laser through the use of a GaAs intracavity acousto-optic loss modulator is reported. Also presented are the results of an analysis which includes the important effect of nonlinear saturation on the output power.
HETERODYNE DETECTION AT mm WAVELENGTHS USING A ROLLIN InSb BOLOMETER
Authors: Kinch M. A.
Published: January 2004

A Rollin free-carrier InSb bolometer has been operated in both video and heterodyne modes at 4 mm wave-lengths. Responsivities ∼1.75 × 103 V/W were obtained at 1.2°K with N.E.P.'s for (a) the video mode ∼10−13 W, and (b) the heterodyne mode ∼8 × 10−21 W, using an i.f. ∼ 2.6 kHz.
IMPROVED PERFORMANCE OF PULSED NOBLE GAS ION LASERS WITH AN AXIAL MAGNETIC FIELD
Authors: Birnbaum Milton
Published: January 2004

The output of pulsed argon ion lasers with an axial magnetic field was studied as a function of magnetic field, current, inside diameter, pressure, and oscillating wavelength. The increased output and efficiency obtained by use of an axial magnetic field clearly indicate its advantages. A simple method of providing the required magnetic field is described.