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Patrick McDonnell is an Irish actor and comedian. He has starred in the RTÉ hidden camera comedy show Naked Camera and the sketch show Stew. However he is probably best remembered at home and abroad for his role as Eoin McLove in the Channel 4 sitcom Father Ted.

Patrick McDonnell is a native of Dromiskin, County Louth.  He studied in Dundalk CBS and St Patrick's College, Maynooth holding a master's degree in Irish history.

He has played various roles in hit Irish comedy show The Savage Eye, which is written and also co-stars David McSavage. He also is the co-host of the podcast "Talking Ted" from the HeadStuff Podcast Network".

Career
 Stephanie Knows Who (1994) (Short)
 Father Ted (TV series) (1998)
 Don't Feed the Gondolas (TV series)
 Separation Anxiety (2002)
 Stew (TV series) (Various Roles) (2004)
 Naked Camera (TV series) (Producer) (2005–2007)
 Comedy Showcase (TV series) (2007)
 The Savage Eye (Various Roles) (2009–Present)
 Val Falvey TD (TV series) (2009)
 Small, Far Away: The World of Father Ted (TV documentary) (2011)
 Moone Boy
 The Young Offenders (1 episode) (Guard) (2020)

References

Living people
Alumni of St Patrick's College, Maynooth
Irish male television actors
Irish male comedians
Irish stand-up comedians
People from County Louth
1967 births

redpajama_set_name: RedPajamaWikipedia


New York and Rome-based artist C. Finley debuts Same Bed, Different Dreams, a cycle of large scale paintings in dialogue with the universal nature of dreaming and the human desire to understand and order the meaning of dreams. Each canvas is proportional to a mattress set-single, full, queen, or king with corresponding pillows-and responds to the progression of the zodiac, using the elements of each sign to guide the composition. On their multicolored surfaces, various systems of symbols converge and are woven together, echoing the seemingly esoteric and illusory montage of our dreams. Shifted vertically onto the wall, the shape of each canvas bed becomes a supernatural portal to the mystical visions embodied in dreams.
Each night we fall asleep, setting out on similar journeys, crossing thresholds and inhabiting distinct worlds as numerous and unique as we are. As Eleanor Roosevelt said, "The future belongs to those who believe in the beauty of their dreams." These vibrant works by C. Finley explore the exquisite nature of dreams, and guide us from the realm of sleep into a collective, ecstatic awakening.
Opening Reception: Saturday, October 15th, 6-8 PM. Finley is introducing 12 different food parings for each of her paintings created by chef Patricia Clark of All Five Senses who describes her inspiration as "Dream-state instincts combine with ethereal flavors and textures."
Coco Karol / C. Finley performance: Tuesday, October 18th, 7 PM.
Suddenly Every Wednesday: October 26th 7 PM. Literary night – please bring original writing or something that inspires you to read aloud. This is a sister event to Rome based Suddenly Every Wednesday founded by Jahan Genet.
Dusty Shoulders Storytelling: November 2nd, 7:30 PM.
Through the Veil: Thursday, November 3rd, 7PM | Natalie Lomonte of Chiron Dance presents 'Through the Veil' a dance performance, creating a collective effervescence, embodying the nature of dreams as they swim through her subconscious.
Founded in 1984, La MaMa La Galleria is a nonprofit gallery committed to nurturing artistic experimentation. La Galleria serves its neighborhood as a venue that encourages an active dialogue between the visual arts, new media, performance, curatorial and educational projects. Its focus is to offer programming that reaches beyond the expectations of traditional gallery and institutional exhibition-making, to a diverse and intergenerational audience. And as a non-profit, La Galleria is able to provide artists and curators with unique exhibition opportunities that are largely out of reach in a commercial gallery setting.
Find out more about La MaMa Galleria!


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«Грузинский виноград» — грузинская короткометражная эротическая комедия 2001 года режиссёра Георгия Шенгелая с Ией Парулава в главной роли.

Сюжет
Скучно течёт жизнь Лии среди виноградников сельской грузинской деревушки. Ей красота в расцвете, но это не замечает даже её муж Сандро, автомеханик, стены автомастерской которого увешаны плакатами с красотками. Но как-то в этом глухом краю ломается машина кинозвезды Меги, будто сошедшей с этих плакатов. Лия видит, что муж вьётся перед кинозвездой, ей всё это надоедает и она собирается уехать к родителям. Но вдруг Меги предлагает подвезти Лию… она, как фея в своей тыкве-БМВ, кое-что приготовила для этой сельской «Золушки»…

В ролях
 Ия Парулава — Лия
 Заза Папуашвили — Сандро
 Селина Вейджореки — Меги
 Михаил Гомиашвили — Георг
 Тристан Саларидзе — ''водитель такси

О фильме
Фильм из серии короткометражек «Эротические истории от Регины Циглер» немецкого продюсера Регины Циглер.

«Грузинский виноград» следует в режиссёрской линии популярных фольклорных сказок — «Мелодии Верийского квартала» (1973), «Приди в долину винограда» (1976), «Путешествие молодого композитора» (1984), — которые отражают повседневную жизнь, юмор «давай и бери», спокойное буколическое существование его народа. Сравните городское с сельским, добавьте непринужденный диалог, приправьте его ритмичным музыкальным мотивом и осенней пасторальной обстановкой — и у вас получится очаровательная грузинская сказка.

Фильм позиционируется как как первый грузинский фильм, в котором было показано обнаженное женское тело, однако это не первый фильм, где Ия Парулава обнажается, до этого ещё при СССР она снялась в фильме 1990 года «Роковой выстрел».

Примечания

Источники
 Georgian Grapes (1999) // ziegler-film.com
  სიყვარული ვენახში (2000) // Georgian Cinema
 სიყვარული ვენახში // Национальная фильмография Грузии
 Эротические истории. Том № 5: Грузинский виноград; Можно я буду твоей сосиской?; Кимоно // Министерство культуры России

Фильмы Грузии 2001 года
Кинокомедии Грузии
Фильмы-мелодрамы Грузии
Романтические кинокомедии Грузии
Короткометражные фильмы Грузии
Эротические фильмы 2000-х годов
Эротические комедии
Короткометражные фильмы 2000-х годов


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Samizdat: Bringing fresh meat to The Pool
By Peter Guy on	 14th October 2008 All Talk, News
Ever wondered why there's been so many rad bands playing Liverpool over the last 18 months? Promoters Samizdat are the answer. Getintothis talks to Samizdat chief Andrew Ellis prior to their Los Campesinos!/No Age/New Times Viking tripple-header, on emerging talent, knife crime and why they had to escape the Death House.
Getintothis: Hey Andrew, so who and what is Samizdat? Are you all Liverpudlians?
Ellis: Samizdat is myself with the help of a bunch of good friends, in particular Hari Ashurst and Paul Rafferty along with alot of collaboration with Darren Roper (of Meshuggy fame). My roots are up here but I was born in the cesspool that is Romford, Essex.
Getintothis: It seems kind of silly interviewing a promoter, however, it is quite a while since Liverpool attracted such a wealth of ultra-hip breaking new bands that you've brought here in such a short space of time – how did you get involved? Give us a bit of a potted history.
Ellis: Having picked up a number of instruments in my teens and realised that I was completely talentless in the creation of music I decided once I moved up here in 2005 to put my hand to putting on shows. With good advice from the likes of Engine and Class A Audio and a gig offer from some friends down south I put my plans into practice and the results were decent so I kept going from there.
From then on I just progressed a bit further; every show getting lucky enough to book some of my favourite acts. The ethos has pretty much stayed the same, if I like the band and I think I can cover my costs then I'll do the show. It's a shame there wasn't a bottomless pit of money because I'd definitely do a lot more shows but this way the quality of the acts is never compromised and hopefully everyone has as awesome a time as I do.
Getintothis: Any shows particularly stand out?
Ellis: I have a tendency to say after every show, 'That was the best show so far,' so every show stands out to an extent.
The moments that stand out the most were probably totally packing out Korova with The Mae Shi while working with Evol and Meshuggy. The atmosphere was fantastic.
Then there was Liars and Deerhunter at the Kazimier, i wouldn't have dreamed of putting on a line-up like that when i started out.
Getintothis: You've hosted nights at new, uber-hip club the Kazimier – are you part of the set up there?
We heard about strange goings on at the opening night involving horses tied to ceilings and Victorian freakshows. Sounds kinda funky…
Ellis: I'm not involved in the running of the place but I'm more than happy to bring shows to the Kazimier. It's a great change from the standard venues in Liverpool, a change of location is always refreshing.
I can't wait to have Oxes on there later this month, rowdy Americans with wireless guitars + 2001 A Space Odyssey re-enactions (Check youtube) + The Kazmier = rad times.
Oxes: Thus Spoke Zarathustra (2001: A Space Odyessy) at SXSW.
Getintothis: It says on your myspace, that you're based at the Life Hostel – what goes down here? Is it a den of iniquity or just a dull office?
Ellis: For the two years prior to this summer I lived in Kenny (Kensington), the first house had a huge metal door, metal grids on all of the windows and was a serious dive, that was Death-House I.
The next year we move down the road which wasn't quite as bad but wasn't exactly palatial, that was Death-House II.
Then at the beginning of summer me and 11 friends moved into a big old ex-nursing home/rehab clinic by Sefton Park. Being the antithesis of the Death-houses we thought Life-Hostel would be a fitting name. Current residents form parts of Indica Ritual, Balloons, a.P.A.t.T., Hackney Carriages and a multitude of other projects, it's the perfect place to run Samizdat from.
Getintothis: As well as No Age, Times New Viking and Oxes on the horizon, you've the buzz band of the moment Abe Vigoda on in December, you must be pleased to bring bands of this calibre to town… Who are you most looking forward to, and anyone in the future we can expect/you'd like to put on?
Ellis: I'm incredibly excited to bring No Age and Times New Viking back to Liverpool, I think No Age have slightly outgrown the Everyman Bistro by now.
Abe Vigoda have been a firm favourite of mine for a year or so and I've been pestering them about a tour for ages now. It seems everything that comes out of the Smell (LA post-punk(ish) venue) is gold at the moment and I'm more than happy to bring those bands over here.
As far as future bookings I'm all booked up until the end of the year including maybe a house-show or two and hopefully the new year will bring some new opportunities.
I'd love to do shows with Avey Tare (Animal Collective) and Kria Brekken (Mum), their collaboration album is phenomenal, as well as Barr and Foot Village who'll both i'm sure be touring next year, so give them a listen.
Getintothis: Having endured the Cosmic Scouse lull of a few years ago, Liverpool's local band live scene appears to be on the up again, any particular favourites stand out with the Samizdat?
Ellis: I may well have missed the lull or simply not noticed it, however, of course I champion Indica Ritual and Balloons who definitely deserve to get a lot more attention outside of Liverpool than they do. a.P.A.t.T. and Stig Noise Soundsystem, despite having been playing for a good while now, still deserve a great deal of credit.
I've always been a big fan of Red Panda and arms at last (especially ATP chalet shows). Then there's Monobrow, they're playing a free Samizdat with the almighty Neptune on November 6, I'm not going to say anything other than, get down to it.
Getintothis: Knife crime. Media exaggeration or cause for concern?
Ellis: Violence is of course a cause for concern, this said, the media, particularly the tabloid press hasn't helped the situation with endless scaremongering.
There has been street crime, knife or otherwise for decades particularly surrounding certain teenage subcultures but never before have teenagers been so poorly publicized, I don't think this generations youth has been fairly judged by the media and i'd say to some extent makes people live up to the stereotypes which have been thrust upon them.
Getintothis: Have you endured any nightmare gig scenarios?
Ellis: One of my favourite US bands (Death Sentence: Panda!) came over to play, eight people turned up, two hundred quid out of pocket – I can't listen to them any more – haha!
Getintothis: Promoters have a pretty bad reputation for being cash-cows, without going too much into the mechanics of how your night runs, how do you ensure your future. Is Samizdat your full-time focus now?
Ellis: There are many people who succeed financially from promoting, many by the old method of making bands sell tickets, by running battle of the bands or by cashing in on hype bands, these are the main reasons why promoters get a bad name, very very rarely however will you find a decent DIY promoter or for that matter anyone genuinely interested in music that employs those schemes.
While Samizdat does take up a lot of my time, it's not financially viable.
Over the years I'm probably about breaking even. If you put hours to income I probably make about 5p an hour or something ridiculous from running Samizdat, it really is a labour of love. I do odd bits and bobs to pay my rent and got a new job on Friday so I can pay the bills.
Getintothis: Capital Culture, what's your take on it thus far?
Ellis: I mean it's nice to see investment in my adopted city but to be fair the areas of 'culture' that are being pushed don't represent the people of Liverpool accurately.
There are so many subcultures in Liverpool that are grossly under-represented by the board behind Liverpool 08, it's fair enough if you are some middle class thirty something with an interest in Edwardian architecture who enjoys seeing money for investment in their city being spent on novelty animal-fruits which could have been spent alot more wisely in the areas that need it the most.
But what about everyone else? I for one thank the culture company for totally missing the point on what 'culture' is really about.
Getintothis: It's October, the students are back, and the City genuinely has a buzz about it, what excites you about Liverpool at present?
Ellis: I'm really glad to have rowdy students being sick on themselves outside the Raz (Blue Angel) back in Liverpool. In all seriousness, the students are essential for Samizdat, the population rise brings alot to the city and everyone I've talked to about it agrees.
I know what you mean about the buzz, I put alot of it down to alot of fresh minds coming into the city, it's refreshing, the city centre is pretty vibrant and hopefully this will reflect itself on Liverpool shows!
Getintothis: Your posters are great, who designs them?
Ellis: They're all designed by different people, some by Paul, some by a guy called A.J. and occasionally the odd one or two by Sean Wars and Ben Wisset. If anyone wants any posters or flyers doing by any of the guys, drop us a mail and I'll put you in contact. (They're all dotted about in here with artist credit)
Getintothis: You've got 71 fans on Facebook, that's kind of pitiful – but also shows you're at the under-exposed, cool-end of things waiting to break when all the hip cats get on it (say mid-October), are you ready for blaggers, bust-ups and messy nights in The Pool?
Ellis: Since you sent this we're up to 108 which is nice! We've got a pretty loyal crowd of awesome people and I hope that continues and stays the same, anyones welcome to come down and we like to keep things as non-exclusive as possible.
As long as these hip-cats don't act like pricks they can come back any time. As far as blaggers, we operate a guestlist policy which goes along the lines of 'if you help out the night, do us a poster, play some records, then you can come in for free' if i just let everyone in for free i'd be out of pocket, it's the only fair way to look at guestlists.
Getintothis: American bands are ridiculously in vogue; we can lay this squarely at the feet of the Libertines – vacuous London journo's over-hyping them and the subsequent death of Brit-rock due to the rise of their shit offspring The Pigeon Detectives, The Holloways, The View et al. Right?
Ellis: I never really got into that much modern British music that popped up into the mainstream, I think you've got it in one though, that whole scene was fairly vacuous, songs to get pissed to and get nostalgic about.
I can see why people got into the likes of the Libertines but it just wasn't for me. America being the size that it is churns out thousands of bands every year so comparably there's going to be alot more promise from US acts based purely on the volume of artists.
Getintothis: What'd be your advice to people starting to host their own nights?
Ellis: Don't rush into things, start off small and running smoothly, testing the water is always important. Treat people well and when they're on the up they might return the favour.
Promotion is key, internet flyering isn't enough, get out there with flyers (good flyers are always a plus too, i'll take the time to read a decent flyer). Logistically it's not all that difficult though it is a stressful business, keep a firm head on yourself and try to keep relaxed and you'll be fine.
Getintothis: Football, who do you support?
Ellis: West Ham, fifth in the league currently somehow, it won't last I'm sure. (since time of writing the happy Hammers are sixth).
Getintothis: What are your records of the year?
Ellis: Abe Vigoda: Skeleton
Pocahaunted: Mirror Mics
Indian Jewelry: Free Gold!
Gang Gang Dance: Saint Dymphna
Getintothis: Fantasy gig time, who would be your three bands dead or alive you'd dream of putting on?
Ellis: This Heat, Scholastic Deth and Pavement (and Arab on Radar and The Nation of Ulysses)
Totally impossible question!
Getintothis: Anything else to declare?
Ellis: See you at the front. Check out the website for details and mail we_are_samizdat@hotmail.com for info and booking.
Upcoming Samizdat shows in Liverpool:
15/10 – Los Campesinos!, No Age, Times New Viking: Academy 2
24/10 – Indian Jewelry: Barfly
27/10 – Oxes, Bilge Pump, Pulled Apart by Horses, Honey Ride Me A Goat: Kazimier
6/11 – Neptune, Monobrow: Korova (free show)
21/11 – Jay Reatard, Lovvers: Korova
30/11 – Anavan, Hackney Carriages: Korova
4/12 – Abe Vigoda, Lovvers: Korova
Los Campesinos!: Death To Los Campesinos!
Previous ArticleHoliday fun with Grails
Next Article Los Campesinos!, No Age, Times New Viking: Carling Academy, Liverpool
Milk:Presents: Fresh produce shaking up the pool Spectres of Spectacle: AND Festival Forest Swords, Samizdat and the persistence of memory – part two Spectres of Spectacle: AND Festival Forest Swords, Samizdat and the persistence of memory – part one Liverpool Sound City Jump in the Pool Leon Bridges bringing vintage soul to Liverpool Beak> guru Geoff Barrow: I'm bringing Portishead to Liverpool The Magnet – bringing Las Vegas glamour back to Liverpool Earth Wind & Fire bringing The Funk to the Echo Arena

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Journal of Pharmacological Sciences
Journal of Pharmacological Sci ...
Volume Vol 126 Vol 125 Vol 124 Vol 123 Vol 122 Vol 121 Vol 120 Vol 119 Vol 118 Vol 117 Vol 116 Vol 115 Vol 114 Vol 113 Vol 112 Vol 111 Vol 110 Vol 109 Vol 108 Vol 107 Vol 106 Vol 105 Vol 104 Vol 103 Vol 102 Vol 101 Vol 100 Vol 99 Vol 98 Vol 97 Vol 96 Vol 95 Vol 94 Vol 93 Vol 92 Vol 91
Issue Issue 4 Issue 3 Issue 2 Issue 1
The Japanese Journal of Pharmacology
Forum Minireview
Optical Bioimaging: From Living Tissue to a Single Molecule: Preface
Hikaru Tanaka, Takeshi Nakamura
Subject area: Infomation Science
DOIhttps://doi.org/10.1254/jphs.93.225
Download PDF (89K)
Optical Bioimaging: From Living Tissue to a Single Molecule: Imaging and Functional Analysis of Blood Flow in Organic Microcirculation
Haruyuki Minamitani, Kosuke Tsukada, Eiichi Sekizuka, Chikara Oshio
Activity of blood cells, erythrocytes, leucocytes, and platelets, in microcirculation was observed by using an intravital microscope and confocal laser scanning microscope connected with an image processing system including fluorescence and phosphorescence emission methods. Dynamic functions of the blood flow were mainly observed in mesentery, brain, and liver tissues of rats. The results are summarized as follows: Deformability of diabetic erythrocytes was significantly lower than that of healthy controls, particularly at high shear rate. The spring constant and Young's modulus of diabetic erythrocytes obviously stiffened, making them hard to deform in the capillary. During hemorrhagic shock and thrombosis, flow velocity and oxygen partial pressure of blood decreased in the brain and liver tissues that can be visualized by using FITC stained erythrocytes and Pd-porphyrin derivative as a pO2 probe. Platelet adhesion and thrombus formation in the micro-vessels accelerated under the photodynamic reaction; diabetic platelets showed augmented adhesion and aggregation on the vessel wall which was followed by acute thromboembolism. Active oxygen radicals take part in thrombus formation, accompanied with adhesion of the activated leucocytes. Fluorescent dye probes, rhodamine G and acridine orange, are quite useful for visualization of the flow behavior of platelets and leucocytes, respectively.
Optical Bioimaging: From Living Tissue to a Single Molecule: Optical Detection of Synaptically Induced Glutamate Transporter Activity in Hippocampal Slices
Takeshi Nakamura, Yoshinobu Kawamura, Hiroyoshi Miyakawa
Since voltage-sensitive dyes (VSDs) change their optical properties in response to membrane potential changes, non-invasive optical measurements of membrane excitation using VSDs have been applied to various types of excitable tissue. This article deals with the authors' recent work using this technique in addition to basic and technical information about VSD imaging. By applying this technology to hippocampal brain slices, we have found that astrocytes play indispensable roles in sequestering glutamate, maintenance of synaptic transmission, and neuronal survival. Finally, the potential of VSD imaging for drug development was discussed.
Optical Bioimaging: From Living Tissue to a Single Molecule: Calcium Imaging in Blood Vessel In Situ Employing Two-Photon Excitation Fluorescence Microscopy
Hisayuki Ohata, Hideyuki Yamada, Takeharu Niioka, Masayuki Yamamoto, K ...
Recent developments in optoelectronics permit real-time Ca2+ imaging of thin planes within cells utilizing laser scanning confocal microscopy (LSCM). However, a major complication associated with this imaging system involves increased phototoxicity with improved spatiotemporal resolution. Two-photon excitation microscopy (TPEM) helps to minimize phototoxicity due to the restriction of this technique to the volume proximal to the geometric focus of the light. In this study, the capability of Ca2+ imaging was investigated employing recently developed real-time TPEM, RTS2000MP (Bio-Rad, Tokyo) with a mode-locked Ti-sapphire laser. Z-axis resolution of RTS2000MP with high NA objectives defined as full-width at half maximum (FWHM) with a 0.5-μm fluorescent bead provided values nearly identical to those obtained with LSCM at a small pinhole (0.2 mm) (approximately 0.6 μm). When serial sectioning of 21 sequential images at 0.3-μm intervals in cultured endothelial cells loaded with calcein and tetramethyl-rhodamine methylester were performed with TPEM, the z-axis resolution was higher than that observed with LSCM; moreover, the photobleaching rate was significantly lower than that obtained with LSCM. Maximum fluorescence intensities were detected at 780 nm in excitation spectra of fluo-3 and fluo-4 Ca2+-sensitive probes with TPEM. Fluorescence images in mouse arterial endothelial cells loaded with fluo-4 could be clearly visualized by TPEM in situ. Application of acetylcholine caused oscillatory increase in [Ca2+]i of endothelial cells; subsequently, relaxation along the major axis of smooth muscle cells was evident. Furthermore, consecutive long-lasting experiments could be repeated with identical response in the same microscopic field. In conclusion, fluorescence imaging employing TPEM is useful for Ca2+ imaging in blood vessels in situ.
Optical Bioimaging: From Living Tissue to a Single Molecule: Atrio-Ventricular Difference in Myocardial Excitation-Contraction Coupling — Sequential Versus Simultaneous Activation of SR Ca2+ Release Units —
Hikaru Tanaka, Toru Kawanishi, Koki Shigenobu
Rapid-scanning cofocal microscopy has been applied to the analysis of early phase Ca2+ transients in ventricular and atrial cardiomyocytes. On electrical stimulation of ventricular myocytes, Ca2+ concentration begins to rise earliest at the Z-line level and becames uniform throughout the cytoplasm within about 10 ms after the onset of the action potential; transsarcolemmal Ca2+ influx triggers Ca2+ release from release sites on the junctional sarcoplasmic reticulum (SR) coupled to T-tubules at the Z-line throughout the cytoplasm. In atrial myocytes lacking the T-tubular network, transsarcolemmal Ca2+ influx during an action potential triggers SR Ca2+ release only at subsarcolemmal region. SR Ca2+ release then spreads towards the central region of the cell thourgh a propagated Ca2+-induced-Ca2+ release mechanism. The atrio-ventricular difference in excitation-contraction coupling mechanisms underlies some of the atrio-ventricular difference in response to physiological and pharmacological stimuli.
Optical Bioimaging: From Living Tissue to a Single Molecule: Single-Molecule Visualization of Cell Signaling Processes of Epidermal Growth Factor Receptor
Yasushi Sako, Junya Ichinose, Miki Morimatsu, Kosuke Ohta, Takeshi Uye ...
Single-molecule imaging is an ideal technology to study molecular mechanisms of biological reactions in vitro. Recently, this technology has been extended to real-time observation of fluorescent dye-labeled molecules in living cells. Total internal reflection fluorescence microscopy is the major technique for this purpose. Using this technique, we have studied the process of early signal transduction of epidermal growth factor (EGF) in single molecules: binding of EGF to its receptor (EGFR) on the cell surface, dimerization of EGFR induced by binding of EGF, fluctuation of the structure of EGFR clusters, activation of EGFR through tyrosine phosphorylations on its cytoplasmic domain, and recognition of activated EGFR by a cytoplasmic adaptor protein, Grb2. EGF induces intracellular calcium response, sometimes caused by less than one hundred EGF molecules. Single-molecule studies suggested that this highly sensitive response to EGF was due to the amplification of the EGFR signal using dynamic clustering, reorganization of the dimers, and lateral mobility of EGFR on the cell surface. Through these studies, single-molecule analysis has proven to be a powerful technology to analyze intracellular protein systems.
Full Papers
Modulation of 8-OH-DPAT-Induced Hypothermia by Imipramine in Rats
Yoshihisa Kitamura, Hiroaki Araki, Kazuhiko Shibata, Yutaka Gomita, Yo ...
The effects of imipramine on 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the 5-hydroxytryptamine (5-HT)1A-receptor full agonist, -induced hypothermia was examined in rats. Single administration of imipramine (30 mg/kg, i.p.) attenuated 8-OH-DPAT-induced hypothermia. This effect of imipramine was blocked by the 5-HT2A-receptor antagonist ketanserin. 8-OH-DPAT-induced hypothermia was not altered 24 h after repeated administration of imipramine (1 – 10 mg/kg per day) for 14 days. However, 8-OH-DPAT-induced hypothermia was significantly enhanced in repeated imipramine (10 mg/kg per day)-treated rats that received 8-OH-DPAT plus imipramine 24 h after the final imipramine administration for 14 days. The 5-HT2A-receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((±)-DOI) attenuated the 8-OH-DPAT-induced hypothermia in drug naive rats. The inhibitory effect of (±)-DOI (0.3 mg/kg, s.c.) on 8-OH-DPAT-induced hypothermia was attenuated by repeated administration of imipramine (10 mg/kg per day) for 14 days. These findings suggest that enhancement of the 5-HT1A receptors by repeated administration of imipramine may be due to reduction of the inhibitory effects from the 5-HT2A receptors to the 5-HT1A receptors.
cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells
Hiroaki Shiraishi, Taiya Kato, Koji Atsuta, Chiho Sumi-Ichinose, Masat ...
Tetrahydrobiopterin (BH4) acts as an essential cofactor for the enzymatic activity of nitric oxide (NO) synthases. Biosynthesis of the cofactor BH4 starts from GTP and requires 3 enzymatic steps, which include GTP cyclohydrolase I (GCH I) catalysis of the first and rate-limiting step. In this study we examined the effects of cGMP on GCH I activity in human umbilical vein endothelial cells under inflammatory conditions. Exogenous application of the cGMP analogue 8-bromo-cGMP markedly inhibited GCH I activity in the short term, whereas an cAMP analogue had no effect on GCH I activity under the same condition. NO donors, NOR3 and sodium nitroprusside, elevated the intracellular cGMP level and reduced GCH I activity in the short term. This inhibition of GCH I activity was obliterated in the presence of an NO trapper carboxy-PTIO. NO donors had no effect on GCH I mRNA expression in the short term. Moreover, cycloheximide did not alter the inhibition by NO donors of GCH I activity. These findings suggest that stimulation of the cGMP signaling cascade down-regulates GCH I activity through post translational modification of the GCH I enzyme.
Amyloid β Peptide Specifically Promotes Phosphorylation and Nuclear Translocation of the Extracellular Signal-Regulated Kinase in Cultured Rat Cortical Astrocytes
Kazuho Abe, Rie Hisatomi, Miwa Misawa
To explore cellular signaling molecules that respond to amyloid β protein (Aβ), we investigated the effect of Aβ on tyrosine phosphorylation of cellular proteins in cultured rat cortical astrocytes. Western blotting with the phosphotyrosine-specific monoclonal antibody 4G10 demonstrated that exposure of cultured rat cortical astrocytes to 20 μM Aβ1 – 40 or Aβ25 – 35 for 24 h resulted in a prominent increase in the phosphotyrosine content of 44-kDa protein. The Aβ-induced increase in tyrosine phosphorylation of 44-kDa protein was blocked by U0126, a specific inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK. Western blotting with anti-phospho-ERK1/2 antibody and anti-ERK1/2 antibody demonstrated that Aβ1 – 40 or Aβ25 – 35 induced an increase in the dually (tyrosine and threonine) phosphorylated form of ERK1 and ERK2, with no change in total ERK1/2 level. In addition, immunofluorescent staining with anti-ERK1/2 antibody revealed that Aβ induced a significant increase in the number of cells expressing ERK1/2 mainly in the nucleus. These results suggest that Aβ specifically promotes tyrosine phosphorylation and nuclear translocation of ERK in astrocytes.
Ca2+-Releasing Effect of Cerivastatin on the Sarcoplasmic Reticulum of Mouse and Rat Skeletal Muscle Fibers
Ryotaku Inoue, Mitsuo Tanabe, Keita Kono, Kei Maruyama, Takaaki Ikemot ...
We analyzed the effect of HMG-CoA reductase inhibitors on Ca2+ release from the sarcoplasmic reticulum (SR) using chemically skinned skeletal muscle fibers from the mouse and the rat. Cerivastatin (>20 μM) released Ca2+ from the SR, while pravastatin showed only a little effect. The rates of Ca2+ release were increased by cerivastatin at all Ca2+ concentrations tested. Cerivastatin-induced Ca2+ release in the presence of Ca2+ was affected by adenosine monophosphate, Mg2+, and procaine in essentially the same way as for caffeine-induced Ca2+ release. The Ca2+-uptake capacity of the SR was reduced after co-treatment with ryanodine and cerivastatin at pCa 6.0 to a much greater extent than with ryanodine alone. Thus, cerivastatin-induced Ca2+ release in the presence of Ca2+ must be a result of the activation of the Ca2+-induced Ca2+ release (CICR) mechanism of the ryanodine receptor. However, even when CICR was maximally inhibited by Mg2+ and procaine, or in the practical absence of Ca2+ (pCa >8), cerivastatin still caused Ca2+ release. These results indicate that cerivastatin causes Ca2+ release also by activating some other mechanism(s) in addition to the activation of CICR. Either or both of these effects might be related to its adverse effect, rhabdomyolysis.
Effects of KRN4884, a Novel K+ Channel Opener, on Ionic Currents in Rabbit Femoral Arterial Myocytes
Katsuhiko Muraki, Akiko Sasaoka, Susumu Ohya, Minoru Watanabe, Yuji Im ...
Effects of KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine), a novel K+ channel opener, on ionic currents were examined in rabbit femoral arterial myocytes (RFAMs). Under whole-cell clamp conditions where cells were superfused with 5.9 mM K+ bathing solution, KRN4884 elicited an outward current at −30 mV. KRN4884-induced current had a reversal potential of −78 mV and was abolished by application of glibenclamide (glib). KRN4884 was approximately 43 times more potent than levcromakalim in activating an ATP-sensitive K+ current (IK-ATP). On the other hand, KRN4884 affected neither voltage-dependent Ca2+ nor delayed rectifier K+ channel currents. In the inside-out patch clamp configuration where cells were superfused with the symmetrical 140 mM K+ solution, KRN4884 activated 47 pS K+ channels in the presence of adenosine diphosphate. Similar 47 pS K+ channels, which were reversibly inhibited by glib, were recorded under outside-out patch conditions. Using RT-PCR analysis, we found that inward rectifier K channel 6.1 (Kir6.1) and sulfonylurea 2B (SUR2B) transcripts were predominantly expressed in rabbit femoral artery. These results indicate that KRN4884 potently activates IK-ATP in RFAMs. The KRN4884-sensitive 47 pS K+ channel activity underlying IK-ATP is a vascular type KATP channel consisting of Kir6.1 and SUR2B and has similar characteristics to those of ATP-sensitive K+ channels activated by K+ channel openers in other types of smooth muscles.
Intrathecal Treatment With 6-Hydroxydopamine or 5,7-Dihydroxytryptamine Blocks the Antinociception Induced by Endomorphin-1 and Endomorphin-2 Given Intracerebroventricularly in the Mouse
Kuei-chun Hung, Hsiang-en Wu, Hirokazu Mizoguchi, Randy Leitermann, Le ...
The involvement of spinopetal noradrenergic and serotonergic systems in antinociception induced by endomorphin-1 (EM-1) and endomorphin-2 (EM-2) given supraspinally or spinally were investigated in male CD-1 mice. Groups of mice were pretreated intrathecally (i.t.) with 6-hydroxydopamine (6-OHDA, 20 μg) or 5,7-dihydroxytryptamine (5,7-DHT, 50 μg) for 3 days before intracerebroventricular (i.c.v.) or i.t. injection of different doses of EM-1 or EM-2, and the tail-flick response was measured for antinociceptive effects. I.t. pretreatment with 6-OHDA for 3 days, which markedly depleted noradrenaline (NA) contents by more than 90%, but not serotonin (5-HT) in the spinal cord, completely abolished the antinociception induced by i.c.v.-administered EM-1 or EM-2. Intrathecal pretreatment with 5,7-DHT for 3 days, which markedly reduced 5-HT contents by more than 92%, but only reduced NA by 14 – 25% in the spinal cord, also markedly attenuated the antinociception induced by i.c.v.-administered EM-1 or EM-2. However, the antinociception induced by i.t.-administered EM-1 or EM-2 was not affected in either 6-OHDA or 5,7-DHT pretreated mice. It is concluded that NA and 5-HT in the spinal cord are involved in the antinociception induced by supraspinally, but not spinally administered EM-1 and EM-2.
Bulgarian Propolis Induces Analgesic and Anti-inflammatory Effects in Mice and Inhibits In Vitro Contraction of Airway Smooth Muscle
Niraldo Paulino, Andreia Pires Dantas, Vassya Bankova, Daniela Tagglia ...
Propolis is a bee product, which has long been used in folk medicine for the management of different diseases. In this study we evaluated the analgesic and anti-inflammatory effects of a standard ethanolic extract of Bulgarian propolis (Et-Blg) in mice and its in vitro effect on airway smooth muscle. Et-Blg inhibited acetic acid-induced abdominal contortions with an ID50 = 7.4 ± 0.7 mg · kg−1. In the formalin test, the extract caused a significant reduction in pain in mice treated with 100 mg · kg−1 Et-Blg during the neurogenic phase and for the inflammatory phase with all doses of the extract, with an ID50 = 2.5 ± 0.4 mg · kg−1. Et-Blg inhibited also the capsaicin-induced ear edema in mice; however, this extract was ineffective when assessed in the tail-flick and hot-plate thermal assays. The analgesic effect of Et-Blg was associated with the inhibition of inflammatory responses and not to a simple irritation of nervous terminals. In vitro, this extract inhibited the contraction of trachea smooth muscle induced by histamine (IC50 = 50 ± 5 μg · mL−1), capsaicin (IC50 = 26.8 ± 3 μg · mL−1), 80 mM KCl (IC50 = 27.8 ± 3 μg · mL−1), and carbachol (IC50 = 54 ± 2 μg · mL−1).
Irsogladine Prevents Monochloramine-Induced Gastric Mucosal Lesions by Improving the Decrease in Mucosal Blood Flow Due to the Disturbance of Nitric Oxide Synthesis in Rats
Takashi Kyoi, Michiko Oka, Kumiko Noda, Yojiro Ukai
The inhibitory effect of an anti-ulcer drug irsogladine [2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate] on monochloramine (NH2Cl)-induced gastric mucosal lesions and its mechanisms of action were clarified in rats. Irsogladine dose-dependently prevented the formation of gastric mucosal lesions induced by 60 mM NH2Cl. The mucosal protective effect of irsogladine was not influenced by capsaicin-sensitive sensory defunctionalization. On the other hand, its protective effect was diminished by the inhibitor of nitric oxide synthase NG-nitro-L-arginine methylester (L-NAME), but not by the inducible nitric oxide synthase selective inhibitor aminoguanidine. Irsogladine restored the NH2Cl-induced decrease in the gastric cGMP formation as an index of nitric oxide synthesis, while it alone had no influence on the cGMP formation in intact tissues. Pretreatment with L-NAME abolished the recovery of cGMP by irsogladine. Furthermore, irsogladine ameliorated the NH2Cl-induced decrease in gastric mucosal blood flow, which was also reversed by pretreatment with L-NAME. These findings suggest that the improvement of the decrease in mucosal blood flow subsequent to the disturbance of gastric nitric oxide synthesis is involved in the protective effect of irsogladine on gastric mucosal lesions caused by NH2Cl.
Roxatidine- and Cimetidine-Induced Angiogenesis Inhibition Suppresses Growth of Colon Cancer Implants in Syngeneic Mice
Kazuyoshi Tomita, Kazuki Izumi, Susumu Okabe
Cimetidine is known to suppress the growth of several tumors, including gastrointestinal cancer, in humans and animals. Nonetheless, whether other histamine H2-receptor antagonists exert such tumor suppressive effects remains unclear. The effect of roxatidine acetate hydrochloride (roxatidine), an H2-receptor antagonist, on the growth of colon cancer implanted in mice was examined and compared with that of cimetidine. Drugs were orally delivered for 26 – 29 days beginning before or after implantation of syngeneic colon cancer (Colon 38) in C57BL/6 mice. Tumor volume was determined throughout and histochemical analysis was also performed. Tumor tissue and serum vascular endothelial growth factor (VEGF) levels were measured. In vitro cell growth was assessed by the MTT assay. Both roxatidine and cimetidine significantly suppressed the growth of Colon 38 tumor implants. Histologic analysis revealed that such antagonists markedly increased necrotic areas and decreased the density of microvessels in tumor tissue. Both H2-receptor antagonists suppressed VEGF levels in tumor tissue and significantly decreased serum VEGF levels in Colon 38-bearing mice. Such drugs, however, failed to suppress in vitro growth of the cell line. In conclusion, both roxatidine and cimetidine were found to exert suppressive effects on the growth of colon cancer implants in mice by inhibiting angiogenesis via reducing VEGF expression.
Protective Effects of Kakkalide From Flos Puerariae on Ethanol-Induced Lethality and Hepatic Injury Are Dependent on Its Biotransformation by Human Intestinal Microflora
Yeo-Ok Han, Myung Joo Han, Sung-Hwan Park, Dong-Hyun Kim
When kakkalide, which was isolated from Flos Puerariae, was incubated with human fecal bacteria, kakkalide was metabolized to irisolidone via kakkalidone. When kakkalide (250 mg/kg) was orally administered to rats, irisolidone, but not kakkalide, was detected in the blood. The mortality associated with ethanol treatment was slightly reduced when the mice were intraperitoneally treated with kakkalide. Intraperitoneally administered kakkalide and kakkalidone did not reduce alcohol toxicity. However, orally administered kakkalide and intraperitoneally administered irisolidone significantly reduced the mortality. Orally administered kakkalide and intraperitoneally injected irisolidone greatly reduced serum alanine aminotransferase and aspartate aminotransferase activities in ethanol-intoxified mice. Orally administered kakkalide and intraperitoneally administered irisolidone significantly lowered the level of blood ethanol. The results indicate that kakkalide is a prodrug of irisolidone in protecting against ethanol-induced lethality and hepatic injury.
Protective Effect of Teprenone Against Acute Gastric Mucosal Lesions Induced by Compound 48/80, a Mast Cell Degranulator, in Rats
Yoshiji Ohta, Takashi Kobayashi, Kazuo Inui, Junji Yoshino, Saburo Nak ...
The protective effect of teprenone, an anti-ulcer drug, against acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Teprenone (50, 100, or 200 mg/kg) was orally administered 0.5 h before compound 48/80 treatment. Administered teprenone prevented gastric mucosal lesion development found at 3 h after compound 48/80 treatment dose-dependently, although no dose of teprenone affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the tresatment. Increases in the activities of myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase and the content of thiobarbituric acid reactive substances (an index of lipid peroxidation) and decreases in the contents of hexosamine (a marker of gastric mucus) and adherent mucus occurred in gastric mucosal tissues at 3 h after compound 48/80 treatment. Administered teprenone dose-dependently attenuated all these changes found at 3 h after compound 48/80 treatment. These results indicate that orally administered teprenone protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its stimulatory action on gastric mucus synthesis and secretion and its inhibitory action on neutrophil infiltration and enhanced lipid peroxidation in the gastric mucosal tissue.
Evaluation of Human Peroxisome Proliferator-Activated Receptor (PPAR) Subtype Selectivity of a Variety of Anti-inflammatory Drugs Based on a Novel Assay for PPARδ(β)
Hitoshi Kojo, Masao Fukagawa, Kaoru Tajima, Akiko Suzuki, Takao Fujimu ...
The nuclear receptor PPAR (peroxisome proliferator-activated receptor) has three subtypes named α, δ(β), and γ that may act as receptors for a range of compounds including antihyperglycaemic drugs, insulin sensitizers, and non-steroidal anti-inflammatory drugs (NSAIDs). Although profiling of the subtype selectivity of the compounds for PPAR is indispensable to elucidate their pharmacological action, the absence of an appropriate transactivation assay for PPARδ led us to develop a sensitive and reproducible method. We found that co-expression of PPARδ, retinoid X receptor (RXR) α, and coactivators such as CBP and SRC-1 enhanced basal and agonist-dependent activation of PPAR responsive element (PPRE)-driven transcription by PPARδ, rendering a PPRE-driven reporter assay reliable and sensitive. Utilizing this assay for PPARδ, we re-evaluated the subtype selectivity of a variety of anti-inflammatory drugs for human PPAR. The PPAR agonists tested included two leukotriene (LT) D4 antagonist, seven NSAIDs, and two anti-rheumatoid drugs. We found that a novel LTD4 antagonist, FK011 ([2-(((2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl)oxy)methyl)phenyl]acetic acid), showed marked agonistic activity for PPARγ. NSAIDs were classified into the following three groups: those showing no activity for all subtypes, those that were selective for PPAR γ such as indomethacin and diclofenac, and those showing agonistic activity for the δ and γ subtypes such as ibuprofen. These results will be important to studies on the molecular mechanisms of pharmacological actions of LTD4 antagonists and NSAIDs.
Comparative Pharmacological Studies on the A2 Adenosine Receptor Agonist 5'-n-Ethyl-carboxamidoadenosine and Its F19 Isotope Labelled Derivative
Bálint Rubovszky, A. József Szentmiklósi, Ter&eac ...
Adenosine receptors are expressed in various mammalian tissues where they mediate the effects of adenosine on cellular functions through a number of signalling mechanisms. 18F-NECA is the positron-emitting derivative of the A2-receptor agonist NECA (5'-n-ethyl-carboxamidoadenosine) and is a radioligand for PET imaging of adenosine receptors. Contractility and relaxation studies were performed on guinea pig atrial myocardium, pulmonary artery, and thoracic aorta to compare the pharmacological effects of NECA and F-NECA (a non-emitting derivative) on tissues. Furthermore, the effect of NECA and F-NECA on the potassium conductance was investigated in DDT1 MF-2 smooth muscle cells with the patch-clamp technique. Both NECA and F-NECA reduced the contractile force in atrial myocardium and evoked phasic contraction in pulmonary artery (A1 adenosine-receptor-mediated actions) in a dose dependent manner; however, the apparent affinity was lower for F-NECA. No difference was found in relaxation induced by these compounds in 1 μM noradrenaline-precontracted aorta and pulmonary artery (in the presence of DPCPX, an A1 adenosine receptor antagonist, tissue containing A2B adenosine receptors). NECA (5 μM) and F-NECA (5 μM) also decreased the peak current and accelerated activation and inactivation properties of the potassium channels, but F-NECA was less effective. These results suggest that while NECA and F-NECA are equivalent agonists of vascular A2B receptors, they mediate different changes of some parameters. When evaluating the data obtained by the use of radiolabelled ligands, one has to take into consideration the possible physiological effects of the ligands besides its binding properties to tissues.
Effect of a Novel Potential Atypical Antipsychotic Drug, Y-931, in Producing Dystonia in Cebus Monkeys
Yasuyuki Shiigi, Jun-ichi Maeda, Hiroshi Yasumatsu, Hiroshi Tanaka, Da ...
The effect of Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine maleate), a novel potential atypical antipsychotic candidate, in producing dystonia in Cebus monkeys was investigated. Y-931 induced relatively weak dystonia in several observation periods at doses greater than 0.1 mg/kg, i.m. Although Y-931 significantly increased total dystonia scores (the sum of 15 to 360 min after injection) at doses greater than 0.5 mg/kg, i.m., the scores did not exceed 20, up to a dose of 1.0 mg/kg, i.m. and lacked a dose-response relationship. The present result suggests that Y-931 is predicted to have a low risk of extrapyramidal side effects.
Harpagophytum procumbens Suppresses Lipopolysaccharide-Stimulated Expressions of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in Fibroblast Cell Line L929
Mi-Hyeon Jang, Sabina Lim, Seung-Moo Han, Hi-Joon Park, Insop Shin, Ji ...
Harpagophytum procumbens (Pedaliaceae) has been used for the treatment of pain and arthritis. The effect of Harpagophytum procumbens against lipopolysaccharide-induced inflammation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, reverse transcription-polymerase chain reaction, prostaglandin E2 (PGE2) immunoassay, and nitric oxide detection on mouse fibroblast cell line L929. The aqueous extract of Harpagophytum procumbens was shown to suppress PGE2 synthesis and nitric oxide production by inhibiting lipopolysaccharide-stimulated enhancement of the cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) mRNAs expressions in L929 cells. These results suggest that Harpagophytum procumbens exerts anti-inflammatory and analgesic effects probably by suppressing cyclooxygenase-2 and iNOS expressions.
Nonspecific Effects of the Selective κ-Opioid Receptor Agonist U-50,488H on Dopamine Uptake and Release in PC12 Cells
Nuannoi Chudapongse, Seong-Youl Kim, Robert E. Kramer, Ing K. Ho
κ-Opioid receptor agonists decrease the levels of extracellular dopamine in vivo and in vitro. However, the mechanism(s) underlying these actions are unclear. The objective of this study was to distinguish between an effect of the selective κ-opioid receptor agonist U-50,488H ((trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate) on secretion and reuptake of dopamine by PC12 cells. The data show that U-50,488H has both a modest effect to increase dopamine release and a more pronounced effect to inhibit dopamine uptake. Neither effect was sensitive to nor-binaltorphimine or naloxone, suggesting that they are not mediated through an opioid receptor.
Platonin, a Cyanine Photosensitizing Dye, Inhibits Pyrogen Release and Results in Antipyresis
Jie-Jen Lee, Wu-Tein Huang, Dong-Zi Shao, Jyh-Fei Liao, Mao-Tsun Lin
Intravenous injection of the supernatant fluids from human peripheral blood mononuclear cells (PBMC) incubated with lipopolysaccharide (LPS) caused fever in rabbits. The fever was in parallel with the levels of either interleukin-1β (IL-1β), IL-6, or tumor necrosis factor-α (TNF-α) in supernatant fluids. When incubating the platonin with the LPS-human PBMC, both the levels of IL-1β, IL-6, or TNF-α in supernatant fluids and the pyrogenicity of supernatant fluids were significantly suppressed. The febrile response to supernatant fluids from the LPS-stimulated PBMC was attenuated almost completely by adding anti-IL-1β, but not anti-IL-6 or anti-TNF-α, monoclonal antibody to supernatant fluids. In addition, both the fever and the increased levels of either IL-1β, IL-6, or TNF-α in rabbit serum following an intravenous administration of LPS were significantly attenuated by pretreatment with an intravenous dose of platonin. Furthermore, the fever induced by intravenous injection of IL-1β was reduced by pretreatment of rabbits with intravenous injection of platonin. The data indicate that platonin inhibits production of pyrogenic cytokines (in particular, IL-1β) from PBMC and results in antipyresis.
Edited and published by : The Japanese Pharmacological Society
Produced and listed by : Nakanishi Printing Co., Ltd.


Thomas LECKEY (Tom) Passed away 7th February 2019 peacefully in hospital. Much loved husband of Dorothy. Loving father of Jonathan, Ruth, and Esther. Will be sadly missed and fondly remembered by the entire family circle.
Thomas LECKEY (Tom) funeral service will be held in Brae Hill, Baptist Church, 2-4, Brae Hill Park, Belfast. BT14 8FP on Wednesday 13th February 2019 at 11 am. Followed by committal in Carmoney Main Cemetery at 2 pm.
Family flowers only, please. Donations in lieu if desired to Friends Of The Cancer Care Centre, Belfast City Hospital, Lisburn Road. BT9 7AB.
Absent from the body present with the Lord.


The author comments on what Father Marcos Aziz Khalil of the Hanging Church stated in the magazine about the beliefs of the Adventist Church.
Pope Shenouda III says that religions call for peace, tolerance and the acceptance of the other. He adds that all forms of religious extremism are rejected. He again criticizes the Adventist Church and businessman Galal Dos.
The public relations manager of the Coptic Adventist Denomination in Egypt and three Orthodox fathers sent letters to Rose El-Youssef commenting on its articles on the Adventist Church.
Interview with Galal Dos whom Pope Shenouda accuses of being the leader of the Adventist group in Egypt. He wonders why the pope attacks him and asks for a proof that his teachings are against the Holy Bible.
A center for the Adventists has been inaugurated in Bur-Fou´ad city. The Coptic Orthodox Church is dissatisfied at this, as the Adventists try to attract Orthodox youths with their publications that are not in accordance with the Orthodox faith.
Pope Shenouda warns against the activities of the Adventist Church and accuses a businessman called Gamal Dos of being its leader. Father Marcos Aziz Khalil of the Hanging Church gives a brief historical background about the group and its beliefs.
The RNSAW sent the summary of Akher Saa to the Seventh-day Adventist Church and received a response of the chairman of the Seventh-day Adventist Church in Egypt.
17. Seizing an extremist Christian group in Heliopolis!
Some background is given of Osama Bin Laden, the Saudi dissident, whom Washington describes as one of the greatest protectors of terrorism in the world.


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Index > Library > Articles > Decline > English > E-text
Decline of the English Murder
It is Sunday afternoon, preferably before the war. The wife is already asleep in the armchair, and the children have been sent out for a nice long walk. You put your feet up on the sofa, settle your spectacles on your nose, and open the News of the World. Roast beef and Yorkshire, or roast pork and apple sauce, followed up by suet pudding and driven home, as it were, by a cup of mahogany-brown tea, have put you in just the right mood. Your pipe is drawing sweetly, the sofa cushions are soft underneath you, the fire is well alight, the air is warm and stagnant. In these blissful circumstances, what is it that you want to read about?
Naturally, about a murder. But what kind of murder? If one examines the murders which have given the greatest amount of pleasure to the British public, the murders whose story is known in its general outline to almost everyone and which have been made into novels and re-hashed over and over again by the Sunday papers, one finds a fairly strong family resemblance running through the greater number of them. Our great period in murder, our Elizabethan period, so to speak, seems to have been between roughly 1850 and 1925, and the murderers whose reputation has stood the test of time are the following: Dr. Palmer of Rugely, Jack the Ripper, Neill Cream, Mrs. Maybrick, Dr. Crippen, Seddon, Joseph Smith, Armstrong, and Bywaters and Thompson. In addition, in 1919 or thereabouts, there was another very celebrated case which fits into the general pattern but which I had better not mention by name, because the accused man was acquitted.
Of the above-mentioned nine cases, at least four have had successful novels based on them, one has been made into a popular melodrama, and the amount of literature surrounding them, in the form of newspaper write-ups, criminological treatises and reminiscences by lawyers and police officers, would make a considerable library. It is difficult to believe that any recent English crime will be remembered so long and so intimately, and not only because the violence of external events has made murder seem unimportant, but because the prevalent type of crime seems to be changing. The principal cause célèbre of the war years was the so-called Cleft Chin Murder, which has now been written up in a popular booklet(1); the verbatim account of the trial was published some time last year by Messrs. Jarrolds with an introduction by Mr. Bechhofer Roberts. Before returning to this pitiful and sordid case, which is only interesting from a sociological and perhaps a legal point of view, let me try to define what it is that the readers of Sunday papers mean when they say fretfully that 'you never seem to get a good murder nowadays'.
In considering the nine murders I named above, one can start by excluding the Jack the Ripper case, which is in a class by itself. Of the other eight, six were poisoning cases, and eight of the ten criminals belonged to the middle class. In one way or another, sex was a powerful motive in all but two cases, and in at least four cases respectability — the desire to gain a secure position in life, or not to forfeit one's social position by some scandal such as a divorce — was one of the main reasons for committing murder. In more than half the cases, the object was to get hold of a certain known sum of money such as a legacy or an insurance policy, but the amount involved was nearly always small. In most of the cases the crime only came to light slowly, as the result of careful investigations which started off with the suspicions of neighbours or relatives; and in nearly every case there was some dramatic coincidence, in which the finger of Providence could be clearly seen, or one of those episodes that no novelist would dare to make up, such as Crippen's flight across the Atlantic with his mistress dressed as a boy, or Joseph Smith playing 'Nearer, my God, to Thee' on the harmonium while one of his wives was drowning in the next room. The background of all these crimes, except Neill Cream's, was essentially domestic; of twelve victims, seven were either wife or husband of the murderer.
With all this in mind one can construct what would be, from a News of the World reader's point of view, the 'perfect' murder. The murderer should be a little man of the professional class — a dentist or a solicitor, say — living an intensely respectable life somewhere in the suburbs, and preferably in a semi-detached house, which will allow the neighbours to hear suspicious sounds through the wall. He should be either chairman of the local Conservative Party branch, or a leading Nonconformist and strong Temperance advocate. He should go astray through cherishing a guilty passion for his secretary or the wife of a rival professional man, and should only bring himself to the point of murder after long and terrible wrestles with his conscience. Having decided on murder, he should plan it all with the utmost cunning, and only slip up over some tiny unforeseeable detail. The means chosen should, of course, be poison. In the last analysis he should commit murder because this seems to him less disgraceful, and less damaging to his career, than being detected in adultery. With this kind of background, a crime can have dramatic and even tragic qualities which make it memorable and excite pity for both victim and murderer. Most of the crimes mentioned above have a touch of this atmosphere, and in three cases, including the one I referred to but did not name, the story approximates to the one I have outlined.
Now compare the Cleft Chin Murder. There is no depth of feeling in it. It was almost chance that the two people concerned committed that particular murder, and it was only by good luck that they did not commit several others. The background was not domesticity, but the anonymous life of the dance-halls and the false values of the American film. The two culprits were an eighteen-year-old ex-waitress named Elizabeth Jones, and an American army deserter, posing as an officer, named Karl Hulten. They were only together for six days, and it seems doubtful whether, until they were arrested, they even learned one another's true names. They met casually in a teashop, and that night went out for a ride in a stolen army truck. Jones described herself as a strip-tease artist, which was not strictly true (she had given one unsuccessful performance in this line); and declared that she wanted to do something dangerous, 'like being a gun-moll'. Hulten described himself as a big-time Chicago gangster, which was also untrue. They met a girl bicycling along the road, and to show how tough he was Hulten ran over her with his truck, after which the pair robbed her of the few shillings that were on her. On another occasion they knocked out a girl to whom they had offered a lift, took her coat and handbag and threw her into a river. Finally, in the most wanton way, they murdered a taxi-driver who happened to have £8 in his pocket. Soon afterwards they parted. Hulten was caught because he had foolishly kept the dead man's car, and Jones made spontaneous confessions to the police. In court each prisoner incriminated the other. In between crimes, both of them seem to have behaved with the utmost callousness: they spent the dead taxi-driver's £8 at the dog races.
Judging from her letters, the girl's case has a certain amount of psychological interest, but this murder probably captured the headlines because it provided distraction amid the doodle-bugs and the anxieties of the Battle of France. Jones and Hulten committed their murder to the tune of V1, and were convicted to the tune of V2. There was also considerable excitement because — as has become usual in England — the man was sentenced to death and the girl to imprisonment. According to Mr. Raymond, the reprieving of Jones caused widespread indignation and streams of telegrams to the Home Secretary: in her native town, 'SHE SHOULD HANG' was chalked on the walls beside pictures of a figure dangling from a gallows. Considering that only ten women have been hanged in Britain this century, and that the practice has gone out largely because of popular feeling against it, it is difficult not to feel that this clamour to hang an eighteen-year-old girl was due partly to the brutalizing effects of war. Indeed, the whole meaningless story, with its atmosphere of dance-halls, movie-palaces, cheap perfume, false names and stolen cars, belongs essentially to a war period.
Perhaps it is significant that the most talked-of English murder of recent years should have been committed by an American and an English girl who had become partly Americanized. But it is difficult to believe that this case will be so long remembered as the old domestic poisoning dramas, product of a stable society where the all-prevailing hypocrisy did at least ensure that crimes as serious as murder should have strong emotions behind them.
1) The Cleft Chin Murder, by R. Alwyn Raymond (Claude Morris IS. 6D.) [back]
____BD____
George Orwell: 'Decline of the English Murder'
First published: Tribune. — GB, London. — February 15, 1946.
Reprinted:
— 'Shooting an Elephant and Other Essays'. — 1950.
— 'The Orwell Reader, Fiction, Essays, and Reportage' — 1956.
— 'Decline of the English Murder and Other Essays'. — 1965.
— 'The Collected Essays, Journalism and Letters of George Orwell'. — 1968.
Machine-readable version: O. Dag
Last modified on: 2015-09-24
'Decline of the English Murder and Other Essays'
© 1965 Penguin Books & Secker and Warburg
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FEATURE 19/05/2013
A Golden Age of Print
The independent magazine scene is thriving. It is a corner of the magazine market where passion pays. Peter Houston looks at what lessons we can learn from the vibrant Indie scene.
By Peter Houston
So many of the biggest stories in the magazine industry today centre on "Burning the Boats" strategies where wounded print gets abandoned by publishers running off to a brighter digital future.
I don't think any publisher should automatically abandon print, in many cases a complimentary crossmedia offering is a stronger proposition for both readers and advertisers. But I recently presented InPublishing's first webinar under the banner of "A Golden Age of Print". A Golden Age? Really? Try telling that to the guys at Newsweek.
No one is going to argue that everything in the print garden is rosy, but there are corners where print appears to be blooming.
I can't take the credit, or the blame, for the "Golden Age of Print" tagline. I stole it from the catalogue for Mag Dossier, a magazine exhibition held earlier this year in Cyprus. In turn, the exhibition organiser, Peter Eramian, credits Jeremy Leslie of the magCulture blog for coining the phrase.
Jeremy says he first used the term in this context at an independent magazine exhibition he curated in Edinburgh, using it to counter what he calls "the usual negative narrative" about print. "Too many commentators wear rose-tinted glasses and look back at 'Golden Ages' and compare today unfavourably with the past", he explains; "I also wanted to highlight the many magazines doing strong creative work today."
It's this interest in quality work that is driving the independent magazine scene, complete with exhibitions, meetups, mainstream media coverage, and weekly slots on the Stack internet radio show presented on Monocle.com by leading print propagandist Tyler Brûlé.
What makes the magazines celebrated by this scene so different from those caught up in the "death of print" stories we hear elsewhere, and what can we learn from them?
Not about the money
First a disclaimer. Commercial concerns are not generally top of the independent publisher's list. And it goes without saying, it's much more difficult to run a print title with a hefty mainstream circulation and make a solid return than it is to publish a short-run niche magazine where breaking even is sometimes looked upon as a bonus.
So if you're reading this to find the magazine market's latest million-dollar formula, sorry. That's not what these guys are about. What they are about is passion, a word used by every single person I contacted about this feature. It's the energy, enthusiasm and entrepreneurship with which independent publishers approach their craft that we can learn from.
And for the independents, it is a craft. They put huge emphasis on production values – design and paper stock are paramount. Dan Rowden is the web-developer founder of Magpile.com, an online magazine community where independent titles feature heavily. He says working in small teams, or even as individuals, gives smaller publishers a lot more freedom on what the output is and, "nearly all the time in the independent magazine market, the output is extremely high quality."
The principle at work appears to be that "Value Adds Value"; high production values and unique content build the audience and the audience pays it forward by creating awareness of the brand.
Stand-out production quality also allows publishers to put a clear value on their products. They celebrate the top-notch production values of attractive well-made publications and make no apologies for the fact that this comes at a price. While much of the mainstream publishing market has been in a race to the bottom, slashing subscription rates to boost circulation figures for ad sales, the independents have been charging real money for subs and single copies. Cover prices up to £15 are not uncommon.
The price tags are justified by the 'Object of Desire' aura that attaches itself to many of these publications – the best become collectables. The current issue of cycling magazine Rouleur will cost you £10, but a quick search on Ebay will turn up back issues selling for five times that. A set of the first 13 issues and three Rouleur annuals went for £400 mid-April. Readers – fans - really value these publications.
There is also an incredibly singular focus apparent in the way independent magazine publishers approach their subject matter. Kid's magazine Anorak will be seven in November and founder Cathy Olmedillas says it was perseverance and single-mindedness that got it there. She points to the current crop of independent food magazines to illustrate her point. "All deal with one universal subject, food, but in many different and interesting ways. Not one looks like the other", she says. "That's because they all are quite personal to the people who make them."
Dan Rowden agrees, "These magazines are more often than not personal projects and therefore the publishers put a lot of their time and effort into them."
The online dimension
Cathy says the internet and blogging has a lot to do with this trend. "One thing that the internet has done for the Indie scene is that it has helped demystify the process of making a magazine. It has allowed bloggers, editors, artists, art directors, designers and photographers to find a captive audience which they can take with them when they create something physical. Magazines are now very personal, they are as much about the people who make them as they are about subjects", she says.
The Indie scene didn't just appear overnight. According to Jeremy Leslie, "it's been growing for a decade at least. My 2003 book magCulture notes the growth of the 'microzine', small Indies playing with the traditional magazine form. Since then there have been ever-increasing numbers of launches." Jeremy says new launches arrive at magCulture at the rate of between five and 10 a month.
"There are no more independent magazines now than there were, say, 20 years ago", says Cathy. "I remember walking into Borders 10 years ago and being overwhelmed with the amount of Indie mags available." But she does think the community of independent magazine makers is more visible than ever before. "Since the introduction of social networks, it feels like there are so many of us now."
There is a certain irony in the idea that digital technology is at the very heart of this print Golden Age, but it plays a huge role in both magazine creation and distribution.
"Anyone with a decent computer has the basic wherewithal to publish a magazine", says Jeremy Leslie. "The internet has also helped hugely with distribution and discoverability – hiring a distributor from the get-go is no longer a must. Post some spreads of your mag and see if it sells", he says.
Independent publishers, despite their obsession for print, have tuned into the fact that the followers of the Indie magazine scene live online. They use the networks to draw readers and potential readers deep inside the publishing process and make them part of the magazine making experience.
Twitter is a huge part of the mix, from sharing feedback, asking readers to contribute interview questions, seeking out new talent, trailing upcoming issues, supporting retailers, even talking about where the publication is in the printing process.
Cathy Olmedillas tweets pictures of magazine stockists and Vine videos of the magazine on the presses. "Social media has been hugely important to Anorak's growth. When you run a small business with limited resources but bags of ambition, these social networks are a godsend. I joined Twitter about four years ago and I am still hooked. It has been instrumental in Anorak reaching an international audience as well as making contacts with journalists and stockists."
Few Indie magazines make it to the newsstand so ecommerce is also an important enabler. Visit any of their websites and you can't miss the sales pitch, not just for single copies and subscriptions; back issues, bundles and collection binders are almost ubiquitous.
Besides selling directly themselves, publishers are taking advantage of a growing number of alternative channels, from specialist distributors, subscription services like Stack which delivers subscribers a regular magazine lucky bag; bricks and mortar stores like Magma in London and Manchester; to ecommerce sites like Anikibo.com. Magpile, which started out as a community site where people simply documented their collection has recently launched an online store.
The Magpile Store was created to help readers get their hands on the magazines they discovered on Magpile and the feature seems to be popular with publishers. "It was the obvious next step - once a magazine has added their details to the site, what better way is there to sell an issue than by providing a "buy" button on the same page", says Dan Rowden.
The ad sales opportunity
Revenue is not all about single copy sales and subscriptions; even with smaller distribution numbers, advertising has its place. Jane Grylls is publisher at the Royal Academy of Arts. She and her team sell advertising in the RA magazine and for a small portfolio of independent titles including Hot Rum Cow, Oh Comely and Eye. "We only work with publishers whose standards and excellence in their fields reflect ours at the Royal Academy", she says.
Jane doesn't think that limited circulation is a negative. "It's an advantage, delivering targeted readership and lower unit page cost. We are not just selling numbers we are selling smaller magazines with loyal interested readerships."
The Trojan Horse strategy
Broader business development goals are also a factor for independents, with many publishers starting magazines to showcase what they can do. The most celebrated example of this is the Church of London leveraging the work they did on movie magazine Little White Lies into a contract to produce the Think Quarterly for Google – 2,000 beautifully crafted publications delivered to the world's top CEOs.
Fraser Allen, MD at White Light Media in Edinburgh describes his own title, the brilliantly named Hot Rum Cow as something of a Trojan Horse to get his design agency inside the consumer magazine market. Previously focused on financial services, the drinks and drinking magazine Hot Rum Cow was an entrée to new business. "We pitched for the whisky association magazine and didn't get it because we were perceived as too corporate. We now get business in the food and drink market."
Fraser thinks the biggest thing established publishing houses can learn from their smaller independent cousins is entrepreneurship. "There's a new generation of publishers, not necessarily with any real experience in the magazine market, but with a love of good magazines. It shows in the product. Some are a labour of love and an indulgence, but many are entrepreneurial and looking for revenue from other sources", he says.
Golden Age or not, there is certainly a refreshing passion for print in this corner of the magazine market. "There remains something universally exciting about the concrete reality of a printed thing as opposed to a web page", says Jeremy Leslie. "That's not to say one wins over the other, just that both have a place."
Jane Gryll confirms this duality, describing a business model that relies on publishing magazines less frequently - two or three times a year - backed by a lively, constantly updated website. But she makes a point to restate that these magazines have very high production values and are "kept and treasured".
It's this "Treasured Title" status that defines the whole Indie magazine ethos, for the publishers as well as the audiences. "Despite all the hype about e-books or digital magazines, nothing comes as close to the pleasures of creating your own magazine or book", says Cathy Olmedillas. "Magazines are pretty things (well most of them anyway) that make you feel good about yourself. So the passion for making them will always be there."
And there's that word passion again. Maybe the big lesson to be learned from the Indie magazine scene is to pay a little less attention to the numbers, bottom lines and reader scores, and a little more to the enthusiasm readers have for the subjects we cover.
"You have to love what you're doing, share the passion of your readers, get out and meet them and know them", concludes Jeremy Leslie. "You can no longer publish and laugh your way to the bank."
A recording of Peter's webinar can be viewed here.
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When Karl Lagerfeld teams up with one of the world's most innovative makeup creators, nothing less than a "miracle of color and beauty" can be expected. Born of a longtime mutual admiration, The Karl Lagerfeld for Shu Uemura collection is fashion meets art in a colorful juxtaposition of classic edge. This is basically wearable art for your face (just take a look at those lashes!).


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Home»NFC North Odds: Packers Remain Big Favorites
NFC North Odds: Packers Remain Big Favorites
Odds Shark Staff | Fri, Nov 26 2021, 8:19am
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The Green Bay Packers have won the NFC North in 11 of the division's 19 years in existence. The Pack won it easily in each of the last two seasons with a 13-3 record both years. 11 weeks into this season, the Packers are sitting at 8-3 and two and a half games up in the division. Oddsmakers have them as the heavy -1200 favorite to win for the NFC North third year in a row.
According to the latest odds at Bovada, the Green Bay Packers (-1200) are the favorites to claim the division this season. The Minnesota Vikings (+600), and the Chicago Bears (+10000) round out the rest of the teams that are mathematically alive to win the division.
Odds Shark is your one-stop-shop for the best NFL betting content on the web. Keep up to date on the likeliest teams to win the championship by visiting our Super Bowl odds article. For a full list of the top places to bet on football, head over to our best NFL betting sites page.
Packers Lead Latest NFC North Odds
Odds To win the NFC North In 2021-22
Current Odds
Green Bay Packers -1200
Minnesota Vikings +600
Chicago Bears +10000
Odds as of November 26 at Bovada
NFC North Odds: Green Bay Packers (-1200)
With questions surrounding the team's quarterback situation swirling for much of the offseason, there were legitimate questions about the Packers' outlook for the 2021 season.
Aaron Rodger has been at the forefront of a lot of controversy this season, but when he is on the field, nobody can question his greatness. Rodgers has led the Packers to an 8-2 record in his 10 starts this season, and has been a legitimate MVP candidate 11 weeks in.
Add another NFL sportsbook today
It doesn't hurt that the Pack has a top-notch offensive line, one of the best receivers in the league, and one of the best running backs in football. They certainly do not struggle to score points, but a lot of their success depends on there that has been solid for the most part this season.
The team added cornerback Eric Stokes in the first round of the NFL draft to add to a group of defensive backs that now includes three recent first-round picks (Jaire Alexander and Darnell Savage Jr. being the others).
This team is the heavy favorite to close out these last six weeks of the season with another NFC North crown. Although, for betting purposes, it is a steep price at -1200.
NFC North Odds: Minnesota Vikings (+600)
The Minnesota Vikings were an interesting case at the beginning of the season. The team returned key defensive starters Danielle Hunter, Anthony Barr, Eric Kendricks, and Michael Pierce, who have all been a huge help to a unit that struggled last season.
The team also added veterans Dalvin Tomlinson, Bashaud Breeland, and Patrick Peterson to the mix on defense. All in all, this will be a completely different defense from last season – one that has kept the Vikings in a lot of games.
The problem they have had is closing out games. All five of the Vikings' losses this season have been within one touchdown. Not to mention, the team blew multiple double-digit leads early on in the season.
Now, the Vikings are starting to close games and beat some good teams, including this past week against their NFC North rival, Green Bay Packers. The Vikings are now winners of two straight games and find themselves right in the thick of the playoff race.
A playoff berth is certainly not out of the picture, but a division title appears to be somewhat out of reach. However, the Vikings still have two more games against the Bears, and one more against the Lions. Chances are slim, but at +600, it may be worth a flyer.
NFC North Odds: Chicago Bears (+10000)
The team drafted Ohio State star Justin Fields with the 11th overall pick to be their quarterback of the future, and Fields has shown flashes. But all rookie quarterbacks experience growing pains, and we have definitely seen that early on with Fields.
The Bears actually got off to a good start to begin the season, starting 3-2 through the first five weeks. They even beat some pretty good teams in the Bengals and Raiders in that stretch. But after that red-hot start, the Bears have lost five of their last six and just squeaked out a Thanksgiving win over the Lions just one day ago.
Place your NFL bets now!
The offensive line has been a mess for Chicago. They let a couple of key players walk in free agency and have now sustained some injuries to the replacements.
The defense has been fine as they have talented players at all levels, but the team's ranking as third in NFC North odds feels warranted until Fields gains more experience, and can prove that he can be a good quarterback at the NFL level.
How To Understand NFC North Odds
When you take a trip to any NFL sportsbook to make a futures bet – more on that later – you'll notice the odds laid out the same way they are in the above table. Teams with a minus sign (-) preceding their odds are favorites. The rest are underdogs, which you can see because of the plus sign (+). However, when divisions are tight or there are no clear front-runners, the team with the lowest odds is considered the fave.
At -1200 you may like Green Bay and decide to throw $100 on them. If they did win the NFC North, you'd get a payout of $108.33 – your original $100 is returned along with your prize of $8.33. On the other hand, you could believe that the Vikings at +600 are going to rise to the top. That same $100 on them would give you a payout of $700 – you get your $100 back coupled with your winnings of $600.
Visit our most trusted NFL betting sites
To see how much you'd win based on the amount bet and the odds offered, check out our Odds Calculator.
When oddsmakers set the lines they look at everything from past performances to roster moves to schedule. If a team is a +3500 underdog, it's probably because they deserve to be. Don't bet blindly on dogs without doing your research.
What Is A Futures Bet For Football?
This is a bet you'd make weeks or even months in advance on which team you think has the best odds of winning the NFC North. Future betting lines are available early and if you see odds you like, it's best to jump on them. The odds will shift as the season progresses, players succumb to injuries, trades happen, and teams climb or fall in the standings.
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text:
Q: Using selenium for testing multiple file upload and download I have a web application which I need to test whether it can simulate user behavior for many users logged in at the same time and perform multiple file uploads and downloads. There are multiple entry points for the uploads as well as downloads. I went ahead with using Selenium for imitating user behavior. Integrated Java, Selenium, TestNG, AutoIT and also using Selenium Grid to connect to various VMs for browser compatibility testing. Browsers supported are Chrome, Firefox, IE 8,9,10,11. Everything works fine except the handling of windows dialogs in parallel. Any tool that I came across which handles windows dialogs requires the window to be in the front. This is not possible when I am running say 100 instances. Please suggest.
I am adding the code snippets. They wont run because they are configured for Selenium Grid.
Here is my java class:

public class Test {

   RemoteWebDriver driver;

  @Test
  public void testDownload() {

   driver.findElement(By.id("Download")).click();

  Runtime.getRuntime().exec("C:\\IE11.exe");

  }

  @BeforeTest
  @Parameters({"browser","version","environment","username","password"})
  public void launchBrowserAndLogin(String browser, String version, String environment, String username, String password) throws MalformedURLException, InterruptedException {

   DesiredCapabilities caps = new DesiredCapabilities();

   if(browser.equalsIgnoreCase("chrome")){
    System.setProperty("webdriver.chrome.driver", "C://chromedriver.exe");
    caps = DesiredCapabilities.chrome();
   }

   if(browser.equalsIgnoreCase("ie")){
    System.setProperty("webdriver.ie.driver", "C://IEDriverServer.exe");
    caps = DesiredCapabilities.internetExplorer();
    caps.setVersion(version);
   }

   switch(environment){
    case "trunk" : baseURL = "http://trunk-url"; break;
    case "prod" : baseURL = "https://prod-url"; break;
    default : baseURL = ""; break;
   }

   driver = new RemoteWebDriver(new URL("http://localhost/wd/hub"), caps);
   driver.navigate().to(baseURL); //go to selected URL
   driver.manage().window().maximize(); //maximize window
   Thread.sleep(7000);
   driver.findElement(By.xpath(".//*[@id='username']")).sendKeys(username); //enter Username
   driver.findElement(By.xpath(".//*[@id='password']")).sendKeys(password); //enter Password
   driver.findElement(By.xpath(".//*[@id='login']")).click(); //click on Login
   Thread.sleep(7000);
   Assert.assertEquals(driver.getTitle(), "Order History");

  }

  @AfterTest
  public void logoutAndTerminateBrowser() throws InterruptedException {

   driver.findElement(By.xpath(".//*[@id='login-menu']/a")).click(); //click on Logout
   Thread.sleep(7000);
   driver.quit();

  }

}

As you can see, the
Runtime.getRuntime().exec("C:\IE11.exe");
runs the AutoIt script. The AutoIt script simply contains:
Send("!s")
This just sends Alt+S (command to save in IE download pop up bar). And this is the area where parallel execution fails.
Here is my TestNG xml:

<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE suite SYSTEM "http://testng.org/testng-1.0.dtd">
<suite name="TestSuite" verbose="2" parallel="tests" thread-count="2">

<test name="IE11_1">
  <parameter name="browser" value="ie"/> <parameter name="version" value="11"/> <parameter name="environment" value="trunk"/> <parameter name="username" value="User1"/> <parameter name="password" value="Pass1"/>
  <classes><class name="Test"/></classes>
</test>

<test name="IE11_2">
  <parameter name="browser" value="ie"/> <parameter name="version" value="11"/> <parameter name="environment" value="trunk"/> <parameter name="username" value="User2"/> <parameter name="password" value="Pass2"/>
  <classes><class name="Test"/></classes>
</test>

A: I would just circumvent the windows dialogs altogether and simulate the network traffic on the backend using HTTP Requests.
Use something like Fiddler2 to capture the exact traffic, parameterize it, and voila.
I have an example of it on another post, one sec:
Copied from previous answer on question here:
Selenium Webdriver doesn't really support this.  Interacting with non-browser windows (such as native file upload dialogs and basic auth dialogs) has been a topic of much discussion on the WebDriver discussion board, but there has been little to no progress on the subject.
I have, in the past, been able to work around this by capturing the underlying request with a tool such as Fiddler2, and then just sending the request with the specified file attached as a byte blob.
If you need cookies from an authenticated session, WebDriver.magage().getCookies() should help you in that aspect.
edit: I have code for this somewhere that worked, I'll see if I can get ahold of something that you can use.
public RosterPage UploadRosterFile(String filePath){
        Face().Log("Importing Roster...");

        LoginRequest login = new LoginRequest();
        login.username = Prefs.EmailLogin;
        login.password = Prefs.PasswordLogin;
        login.rememberMe = false;
        login.forward = "";
        login.schoolId = "";

        //Set up request data
        String url = "http://www.foo.bar.com" + "/ManageRoster/UploadRoster";
        String javaScript = "return $('#seasons li.selected') .attr('data-season-id');";
        String seasonId = (String)((IJavaScriptExecutor)Driver().GetBaseDriver()).ExecuteScript(javaScript);
        javaScript = "return Foo.Bar.data.selectedTeamId;";
        String teamId = (String)((IJavaScriptExecutor)Driver().GetBaseDriver()).ExecuteScript(javaScript);

        //Send Request and parse the response into the new Driver URL
        MultipartForm form = new MultipartForm(url);
        form.SetField("teamId", teamId);
        form.SetField("seasonId", seasonId);
        form.SendFile(filePath,LoginRequest.sendLoginRequest(login));
        String response = form.ResponseText.ToString();
        String newURL = StaticBaseTestObjs.RemoveStringSubString("http://www.foo.bar.com" + response.Split('"')[1].Split('"')[0],"amp;");

        Face().Log("Navigating to URL: "+ newURL);
        Driver().GoTo(new Uri(newURL));

        return this;
    }

Where MultiPartForm is:
    MultiPartForm
And LoginRequest/Response:
    LoginRequest
LoginResponse
The code above is in C#, but there are equivalent base classes in Java that will do what you need them to do to mimic this functionality.
The most important part of all of that code is the MultiPartForm.SendFile method, which is where the magic happens.

A: After trying a hell lot of things, I have come to the conclusion that the parallel execution is possible through selenium grid, and the file upload and download works fine if I run my tests only on Chrome or Firefox. Selenium is not for performance testing, and other tools (like JMeter) might be more helpful.

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