When you're doing something which is so different to everyone else. Having a mentor or following the herd is kind of the opposite of what you're doing….
I'm a big believer in being self-taught, learning yourself, trial-and-error. Nobody can tell you how to do it. People can point you in the right direction and you can do lots of research but you've gotta apply it yourself.
But after listening to the interview back, I think that I was wrong. While I do 100% believe you need to forge your own path and do something different, I also think you should learn as much as possible. Learning and building on what others have done before.
I've written a lot about the need to continue learning and the importance of investing in your own development. Why shouldn't that extend to online business as well?
So I started to research, looking for the best course on online business. I ended up investing in quite a few. Once I got past the sales pitches and exaggerated promises to the meat of the material, I was actually quite impressed.
I began with the biggest marketplace for online courses, Udemy.
Anyone can create a course on Udemy, and sometimes it feels like everyone does. Whether you are looking for a course on online business or a course on bodybuilding, Udemy will have hundreds to choose from. But in my mind, that is a good thing. There is a review system that seems to work. And as there are so many competing courses on each topic the cream rises to the top.
I purchased a few different courses. One on general writing, one on copywriting, one on marketing through Facebook adverts, one on PR and one on WordPress software development.
A pretty eclectic bunch, but I wasn't looking for anything in particular, just browsing. If I found a course that sounded interesting and had a high rating I purchased it. None of them really blew me away, but they were all pretty good. And for just £19 each they were well worth the money. I learnt and applied something from each one.
I also purchased a few courses on starting an Amazon FBA business. I've long been telling people not to bother paying loads for a course and that my article on Amazon FBA has everything they need to know to get started in it. So I thought I should actually see if that claim backs up.
I purchased "Amazon – FBA – Private Label Products – A step-by-step guide" and "Private Label Products: Create Brands & Sell with Amazon FBA", the two highest rated courses. The first was my favourite and even contained some information that hadn't really thought through before. It doesn't tell you everything, but well worth the £19 I spent.
The section on importing filled in a few gaps my article was missing.
The low cost of courses on Udemy also meant that I didn't feel the need to watch every video or read every lecture. I could pick and choose the stuff that suited me, and fast forward the stuff that didn't. Because I'm quite impatient I also found myself watching the videos at 1.5x or 2x speed which helped blitz through lots of material while I was looking for the gems.
It's cheap. At the moment all courses are under £20. Compared to some other places where the courses can run into the thousands, that is a bargain.
It's peer-reviewed. You can tell how good a course is without relying on a sales pitch and hand-picked customer testimonials.
There's lots of competition so the quality of the highest rated courses are generally very good.
The course creators don't make much money per customer, so it is in their interest to make the course as broad and wide appealing as possible.
There is a lot of choice. I got very trigger happy and purchased more courses than I really should.
The courses with the most ratings can sometimes be out of date. In the fast moving world of online business, a course on Facebook ads from two years ago might not be that useful.
Lynda at first glance looks pretty similar to Udemy. But whereas Udemy is like blockbusters where you pay per course, Lynda It is more like Netflix, a monthly fee and then all you can eat courses. Currently, it costs about £20 a month for the standard subscription paid on a monthly basis.
There are thousands of courses put together by Lynda's 'experts'. But I found there really wasn't the depth that I wanted. A search on Udemy for 'Amazon FBA' returned 5 pages of different courses with some really in-depth walkthroughs. On Lynda, there was just one course and to be honest it was pretty poor. More 'how to use the site' rather than a 'how to create a business'.
Lynda does have lessons on loads and loads of topics, but while it's quite cool that there are 131 different courses on illustration, I don't really have any interest at the moment in learning illustration. It's like how at first glance Netflix is great with hundreds of shows, but when you go browsing you realise you don't really want to watch any of them.
I must at admit though that the layout and ease of use is pretty awesome. It took me about 2 minutes from signing up to stumble across a 'pathway' of courses that apparently would teach me how to become a digital marketer.
Ok great, I thought. I'm interested in digital marketing. But when I started I quickly found the courses on the 'digital marketer pathway' were all either too basic or on a subject I had very little interest in.
Whereas with Udemy I found myself purchasing too many courses, I was left a bit underwhelmed by Lynda.
Don't get me wrong. It's a great site, great value for money and from the browsing I did the courses seemed pretty well done. I just preferred Udemy.
It's even cheaper than Udemy provided you do more than one course a month.
The website is very easy to use and the courses run smoothly.
The all-you-can-eat education meant I found myself wanting to get my money's worth and learn as much as possible.
There are no peer reviews of the courses so you need to actually start watching to decide if they are worthwhile.
The people who create the courses are 'experts' in the most traditional way. Lots of degrees and academia, but I felt like they aren't quite on the cutting edge of online business.
What about Those Really Expensive Super-Hyped Courses?
Lynda and Udemy are both marketplaces of courses. But even with their huge libraries they barely scratch the surface of what is available. Most courses are sold on dedicated websites or on really spammy looking sales pages.
I started my research into these by looking at which courses the bloggers and podcasters I follow are promoting. And boy did the prices range. Everything from a few dollars to many thousands. I couldn't believe it, how good could a course on online business possibly be to be worth $4,000?
No idea. I couldn't bring myself to pay that much for one. But I did sign up for one of the cheaper ones.
Affilorama popped up quite a few times. It is a course and community that teaches you all there is to know about affiliate marketing… or so they promise.
There are a lot of paid-for services that you can buy from Affilorama. From educational material to one-to-one coaching for $5,000 a year.
I signed up for the premium monthly membership. It cost $1 for the first 30-days and from then on it is $67 a month.
To be fair, I think that's pretty good value. It comes with hosting for the websites, all the educational material, a customer support helpline and a community of people all trying to do the same thing as you.
The community aspect is something that is really missing from Udemy and Lynda. Online business can be a really lonely road. Most people in the real world don't understand what you're trying to do and think you're wasting your time. It can be really encouraging to have other people who are all in the same boat.
But it wasn't for me. I already have hosting and affiliate marketing isn't the type of online business I am most interested in. Plus I get plenty of community from this blog and the friends I have made from it. So I looked through all the educational material, took which parts I liked the most and then unsubscribed before the month was up. What a bargain for just $1.
Affilorama also has a separate course on online business you can pay $197 for. I didn't buy it and am not entirely sure whether it's worth it or not. If anyone out there has taken it, how was it? Worth the money?
By joining Affilorama you also join a community. Online business can be lonely and an active community is great.
You can start from scratch and launch a successful site using only the tools on Affilorama. No need to find separate hosting or themes.
There is a customer support service who you can contact at any time for help.
The education is pretty specific to do with affiliate marketing. There is no education on other forms of online business, even those that can tie in well with affiliate marketing.
You are limited only to what the creators of the site think is important. There isn't the constant competition that keeps the Udemy course top quality and relevant.
The way the site is laid out gave me the impression they are always trying to upsell something. It grated on me a bit.
So, Should You Invest In a Course On Online Business?
So after buying all these courses and spending many hours 'studying', what did I get out of it all?
And none of them lived up to those claims. Not even close.
But actually, I got a lot more from them than I expected. Particularly from Udemy. From every course, I took something useful away and ended up learning a lot. I think the money and time I spent was well worth it.
I also really liked buying lots of different courses and mixing and matching. It made me feel like I was building an overaching course that was unique to me. I wasn't just following one guru and trying to copy his methods like every other person out there.
Which leads me to reiterate what I said at the beginning. A course on online business can teach you specific skills, or help point you in the right direction. But to succeed you need to go beyond that, build on what you have learnt and forge your own path.
Personally, I have kept my membership at Lynda and am currently working through some more courses on Udemy. But I don't think I am going to be forking out thousands of dollars for a course on online business anytime soon.


text:
Professor William Philpott
Professor of the History of Warfare
Co-director, SSS research theme in military and political history.
Research subject areas
Conflict and security
william.philpott@kcl.ac.uk
William Philpott joined the department of War Studies as a lecturer in September 2001, becoming Professor of the History of Warfare in 2011. He was previously a member of the Department in 1991–2, as a postdoctoral research fellow working for a collaborative research project investigating British civil–military relations, 'Government and the Armed forces in Britain, 1856–1990'.
Professor Philpott is President of the British Commission for Military History. He has been a councillor of the National Army Museum and is a member of its Collections and Research Committee and its advisory panel; Honorary Secretary of the Army Records Society; and chair of the University of London's Military Education Committee.
He convenes the Institute of Historical Research's military history research seminar. He is on the editorial board of the British Commission for Military History's British Journal for Military History, and series editor of the Palgrave monograph series, Studies in Military and Strategic History.
He leads a First World War Operations Research Group (known locally as the Coal Hole Club), in which academics, current and former research students share their interests in aspects of tactical and operational theory and practice on the western front in the First World War.
Professor Philpott researches the military and international history of the early twentieth century. His current research interests lie in the field of First World War military history at the strategic, operational and tactical levels: in particular, the role of France and the French army in the First World War; the legacy wars that spread through Europe
4SSW1003 The Experience of War
6SSW3025 War and Peace: The Changing International Order in the Early Twentieth Century (c1900–1925)
7SSWM005 The Entente at War, 1914–1918
He can offer research supervision in these areas:
The strategic and operational history of the Western Front in the First World War, including command, tactics and logistics: British, French and transnational comparative perspectives
The First World War – strategy, operations and tactics, with particular focus on the French and British armies
The legacy of the First World War, political, military and cultural
First World War era military, naval, political and international history
The military history of France in the nineteenth and twentieth centuries
Anglo-French military and international relations in the twentieth century
The history and historiography of battle
Military operations and change in the twentieth century
International political and defence co-operation
Joshua Bilton: The military identities of British conscripts serving on the Western Front, 1916–19.
Julie Marionneau: Lawfare and its relationship with UK national security strategy in the 21st century.
Yusuf Ozkan: British military, naval, and diplomatic intelligence before and during the Gallipoli (Dardanelles) Campaign.
Alexander Pickering: The British Admiralty and Strategy in the First World War
Charles Fair: The professionalisation of the selection and training of junior 'temporary officers' and its impact on the operational effectiveness of the BEF during the Great War
Completed PhD students
Laura Rowe (2008): At the Sign of the Foul Anchor: Discipline and Morale in the Royal Navy During the First World War
Jonathan Boff (2010): British Third Army, the Application of Modern War, and the Defeat of the Germany Army, August–November 1918
Tim Gale (2011): La Salamandre: The French Army's Artillerie Speciale in the First World War
Jonathan Krause (2011): The Second Battle of Artois, May 1915
Simon House (2012): The Battle of the Ardennes, 22 August 1914: An Operational Study
Paul Harris (2013): The British Army's General Staff in the First World War
Martin Farrar (2015): The Illusory Threat: Enemy Aliens in Britain during the Great War
Catherine Boylan (2015): The North Russia Relief Force: A Study of Military Morale and Motivation in the Post-First World War World
Tony Vines (2015): The Heroic Manager: An Assessment of Sir Douglas Haig's Role as a Military Manager on the Western Front
Alice Pannier (2016): Franco-British Defence Cooperation under the Lancaster House Treaties (co-tutelle with Sciences Po, Paris)
Brett Van Ess (2018): Wartime Tactical Adaptation and Operational Success: British and Japanese Armies in Burma and India, 1941–45
Christopher Newton (2018): British Third Army and the Battles of the Scarpe, April–June 1917
Bryon Smith (2018): The 'Auspicious Entrance' of June 1918: Managing the Early French–US Relationship in the First World War.
Attrition: Fighting the First World War (Little, Brown, 2014), a military and international history of the conflict. The US edition, War of Attrition, Overlook 2014), was nominated as a Wall St Journal book of the year 2014
Bloody Victory: The Sacrifice on the Somme and the Making of the Twentieth Century (Little, Brown, 2009): US edition, Three Armies on the Somme, (Knopf, 2010). Winner of the 2009 Society for Army Historical Research Templer Medal and the US Western Front Association's Norman B. Tomlinson Jr book prize
Anglo-French Relations and Strategy on the Western Front, 1914–1918 (Macmillan, 1996)
Anglo-French Defence Relations between the Wars, edited with Professor Martin (Palgrave Macmillan, Studies in Military and Strategic History, 2002)
Palgrave Advances in Modern Military History, edited with Mathew Hughes, Brunel University (Palgrave Macmillan, 2006)
'The Making of the Military Entente, 1904–1914: France, the British Army, and the Prospect of War', The English Historical Review CXXVII (2013), pp. 1155–85.
'France's Forgotten Victory', review article, Journal of Strategic Studies, 34/6 (2011), pp. 901–18.
'The French and the British Field Force: Moral Support or Material Contribution?' (With Prof M.S.Alexander), The Journal of Military History, 71 (2007), pp. 743–72. Society for Military History Moncado prize winner.
'The Anglo-French Victory on the Somme', Diplomacy and Statecraft special edition, 'Anglo-French Relations from the late 18th to the late 20th Century', 17, (2006), pp. 731–51.
'Squaring the Circle: The Co-ordination of the Entente in the Winter of 1915/16', English Historical Review, September 1999, pp. 875–98.
'Kitchener and the 29th Division; A Study in Anglo-French Strategic Relations, 1914–1915', The Journal of Strategic Studies, September 1993, pp. 375–407.
Recent Book Chapters
'Oh, What an Ambiguous War! The Contested Memory of the First World War in Britain', in One Hundred Years After: The Memory of the first World War, ed. Elli Lemonidou (École français d'Athènes, 2018), pp. 59–75.
'Albert I, King of the Belgians: A 'Neutral' Sovereign and Commander', in Monarchies and the Great War, ed. Matthew Glencross and Judith Rowbotham (Palgrave Macmillan, 2018)
'France Leads the Way to Victory', in Britain and Victory in the Great War, ed. P. Liddle (Pen & Sword, 2018,), pp. 185–203.
'Never over by Christmas: Meeting the Challenges of Interminable War', in Turning Point 1917: The British Empire at War, ed. D. Delaney & N. Gardner (University of British Columbia Press, 2017)
'The Trauma of Attrition: Verdun and the Somme', in Britain and the Widening War, 1915–1916: From Gallipoli to the Somme: The Central Years of the Great War, ed. P. Liddle (Barnsley: Pen & Sword, 2016), pp. 48–63.
'The rise of the "continentalists": the British Army Prepares for War in Coalition with France', in 1914 – La guerre avant la guerre. Regards sur un conflit à venir, ed. François Cochet (Riveneuve, 2015)
'Attrition: How the War was Fought and Won', in The Greater War: Other Combatants and Other Fronts, 1914–1918, ed. Jonathan Krause (Palgrave Macmillan, 2014), pp. 235–54.
'Unequal Sacrifice? Two Armies, Two Wars?' in Britain and France in Two World Wars: Truth, Myth and Memory, ed. R. Tombs & E. Chabal (Bloomsbury, 2013), pp. 47–61.
Professor William Philpott PURE Profile
Strand Campus, Strand, London, WC2R 2LS
Room K7.29
Office hours: Thursday 11.15-12.15
War Studies
Sir Michael Howard Centre for the History of War

redpajama_set_name: RedPajamaCommonCrawl


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In honor of the nuclear deal struck between Iran and the world powers, I've made my eArticle Rope Diplomacy: On the Steeps in Iran FREE for the next five days.
In the summer of 2011, I traveled to Iran with National Geographic photographer Stephen Alvarez and spent a jaw-dropping month climbing some of the highest mountains in the Islamic Republic of Iran and doing some excellent rock climbing. We were members of a goodwill exchange between the American Alpine Club and the Alpine Club of Iran intended to improve the strained relations between our two peoples. Besides having wild adventures in gorgeous mountains, we built excellent relationships with our Persian hosts, gained a better appreciation of the ancient culture of Iran, and experienced some of the tensions inherent in life in modern Iran, all at a time when the two captured American hikers were still languishing in a Tehran prison.
Stephen's website is gorgeous: Alvarezphotography.com, and full of gobsmacking images and stories.
I've made a number of posts about Iran, with some of my own photographs. They're available through the "Iran" category of this website.


text:
Vesti News outdoes US propagandists by its own scare tactics [Video]
by Seraphim Hanisch February 26, 2019 18.9k Views 6 Comments
The Russian news program Vesti Nedeliy launched a propaganda nuke at the Russian nation and at the West on 25 February with a broadcast narrated by Dmitry Kiselyov about the capabilities of Russia's new hypersonic Zircon missile. The report made waves with its bellicose graphic and discussion of the missile being used against specific US targets. The video segment is shown here below:
Naturally, the Western media went into an uproar, castigating the Russian President as a warmonger, while at the same time conveniently ignoring the fact that the Russian President's statements were in response to the US withdrawal from the Intermediate-range Nuclear Forces Treaty.
President Trump announced the US' plan to withdraw from this treaty, and the American government cites Russia as being in violation of the treaty, though the truth is that the Americans have at the very least also, and perhaps unilaterally violated the treaty as well.
However, there are multiple problems with VESTI as a news service that this report exposes. In discussions with people in Moscow, we were able to get some perspective on this network and what it does.
Vesti is a state-run propaganda arm of the news media, and of the most virulent type.
Vesti is to the Russian people something like a mix of "You Are All Going to Die Now News" plus the National Enquirer in the US. The network regularly operates its broadcasts as incendiary propaganda, so much so that the aggregate of Russian citizens view the network as conservative Americans view CNN – a bunch of nonsense, putting it politely (and it ought to be said here that Russians do not put things politely – they relish calling things what they are. We just cannot print that language here.)
The anchors of Vesti, like Dmitry Kiselyov, know they are disseminating nonsense.
How do we know this? By looking at the people themselves and examining what is known about them. Dmitry Kiselyov is actually highly notorious in this regard. He is often referred to as the "Russian Goebbels" after the infamous Nazi propagandist who is famous for the line "if you keep telling the same lie often enough, it becomes accepted as the truth."
Kiselyov makes his paycheck doing his rather morbid entertainment TV, but his talk about threats of nuclear war actually go against his own personal interests. He as well as others among some of the wealthy Russian elites, have properties in Europe, and in the United States. They have children attending schools in these places. They have money kept in accounts outside Russia.
This was alluded to, actually on another Vesti program, in an interview with the LDPR firebrand Vladimir Zhirinovsky who said as much. We can see this here:
Our source maintains that Mr. Kiselyov is one of this number.
The Russian people themselves do not buy it.
So, what about the report itself? How is this received by the Russian people?
In almost – if not every – situation in which Vesti has arisen for discussion with various people in Moscow, Vesti is considered "extremely fake news." However, it does have a strong sensationalist aspect that can be used to frighten the Russian people. Since the network is slick in its production values, it easily gets attention, both in Russia and outside the country, and it is easy to look like it represents the thought of the government and the people of Russia.
This is not usually so. It appears that Russian people have had their fill of state run news, so they do not carry the tendency to trust the news media the way Americans seem to. In order for a Russian person to really understand what is going on, he or she watches these things, and then reads or watches other broadcasts to "read between the lines."
The notion of news networks in the country being trustworthy seems to be heartily and constantly denied, at least in those we spoke with.
What does this mean about this report?
Perhaps about one year ago, Glenn Beck reported in the US that in Moscow, the city was absolutely quiet because everyone was afraid of war breaking out. This was around the time that the US, France and Great Britain launched the missile strike against mostly empty buildings in Syria as a show of strength against what appears to have been a false-flag attack. Nevertheless at that time, according to Beck, the war drums were beating in Russia. How did he know this?
He watched or was made aware of a Vesti broadcast in which the network was telling anyone who cared to listen how to store food against the probability of a nuclear conflict. We did a quick bit of communication with contacts in Russia with the question "is there a panic going on there? Is there a war scare going on right now? That is what the news here in the States is saying."
The response, from an American living in Moscow, was, "no, everything is normal. One person talked about seeing this Vesti report on TV a little bit, but everyone is fine."
And that is how it is in Russia now. Vesti conducted its business and got some attention, but no one in Russia, including its president, is looking for or is eager for war. And although President Putin spoke strongly about the INF situation and Russia's exceptionally astute program of weapons development, the charge Mr. Putin laid was that the Americans are acting unpredictably and Russia must protect itself. However, no one wants war, and there is no threat of it, but rather a wish that the foreign policy wonks in the US would come to their senses.
The upshot of this latest media kerfluffle is that some people in Russia and in the West probably collected their paychecks for the week.
There is nothing to see here, but there are plenty of real events far more deserving of attention by the press.
The problem here is the press, not the governments
In the United States, the issue of falsified news has dominated the conversation of conservative America. We see more and more crazy examples of pure and deliberate dishonesty in reporting by the day. We have seen that the same practice is happening in Russia and presumably many other countries.
More and more the press is trying to become the driver of policy in the United States. In Russia the role of the press is as yet unclear, though speculation abounds that it is trying to distract people from their own problems by scapegoating other places and people. This is true everywhere.
But one of the key factors stoking this may be the presence of the 24-hour news cycle, the ease of access to the Internet, and the fact that most of the time in the world there is very little happening that is of interest to the whole world. If you do not have a story, why not embellish one to make it sensational, and draw some views or clicks? This appears to be the model that many networks and providers are following.
However, it is damaging. Vesti appears to have overstepped its bounds by speculating on the things President Putin spoke about and taking his words way out of context. This kind of thing can be very dangerous, especially when there is a warmongering faction in the West that would love an excuse to call Russia an aggressor nation.
President Putin is not an agressor. But Dmitry Kiselyov is certainly playing this very role.
RussiapropagandaAmericaeliteVestinuclear warfake newshypersonic missilesensationalismDmitry KiselyovKiselyov
Thomas Malthaus
I watch excerpts from Vesti's YouTube channel and I mostly ignore the political discussions. Otherwise, I like some of their in-depth discussions or reportage of Russia's manufacturing, tourism, and environment.
President Putin has said in past interviews with journalists that, and I'm paraphrasing, they don't get it. One particular interview can be found on YouTube for those searching to confirm my account.
Mr Hanisch doesn't appear to have watched this particular broadcast by Vesti News, or he would have realized that it was no more than a more visual explanation of what Putin said in his state of the union speech: a warning that the US should do the math first, before withdrawing unilaterally from the INF. Precisely because Russia will for its own security have to respond if the US installs intermediate range nukes on Russia's border. What Vesti News explained graphically is what Putin said, that they would hit not only the missile installations, but the command centers. And yes,… Read more »
he was pointing out that the russians know that the orders to launch the missiles would come from the US and that would not go unpunished
Tom Welsh
Is Herr Hanisch another CIA asset, then? I have watched the video clip carefully and all the presenter did was to illustrate graphically what Mr Putin said in his speech.
Which is worse, pray? For the US government secretly to plot a first strike against Russia – which would inevitably lead to the deaths of all human beings, everywhere – or for the Russian government and media openly to explain, as one would to a very young child, exactly what the consequences would be?
Vesti Nedeli is a very bad and boring programme of Russian news. Mr. Kisselev is the wrong man at the wrong place: a sensationalist, very biased, and not all too well informed about what is generally going on in the world. I stopped watching this stupid show a long time ago. Thankfully, it is only once a week, on Sunday night, to be avoided!
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text:
It's about one-five-hundred-fiftieth as fast as a Knuckleball (baseball)
In other words, 324.160 centimeters per minute is 0.002 times the speed of a Knuckleball (baseball), and the speed of a Knuckleball (baseball) is 560 times that amount.
(a.k.a. knuckler, a.k.a. floater, a.k.a. dancer, a.k.a. butterfly ball) (major league average)
The average speed of major league knuckleball pitch is 180,000 centimeters per minute. Eddie Cicotte, who was later implicated in the 1919 Black Sox scandal, is credited with developing the pitch ca. 1906.
It's about one-five-hundred-fiftieth as fast as a Cheetah
In other words, 324.160 centimeters per minute is 0.0018 times the speed of a Cheetah, and the speed of a Cheetah is 568.2 times that amount.
(Acinonyx jubatus)
The cheetah can reach speeds of up to 184,200 centimeters per minute in short bursts. From a crouching position, the cheetah can attain these speeds in just 2.25 seconds.
It's about one-six-hundredth as fast as a Hurricane
In other words, 324.160 centimeters per minute is 0.0016 times the speed of a Hurricane, and the speed of a Hurricane is 613 times that amount.
(formally: Topical cyclone; a.k.a. typhoon)
A hurricane is defined by the US National Hurricane Center as a Northern Hemisphere tropical storm having one-minute average wind-speeds of at least 198,000 centimeters per minute. Typhoons Tip (October, 1979) and Keith (October, 1997) and Hurricanes Camille (August, 1969) and Allen (August, 1980) jointly hold the record for highest tropical storm wind speeds at 517,000 centimeters per minute.
It's about one-six-hundred-fiftieth as fast as a Curveball (baseball)
In other words, 324.160 centimeters per minute is 0.002 times the speed of a Curveball (baseball), and the speed of a Curveball (baseball) is 630 times that amount.
(a.k.a. hook, a.k.a. hammer, a.k.a. yakker) (major league average)
The average speed of major league curveball pitch is 200,000 centimeters per minute. In the 1940's, debate over whether there really was a curve in the curveball pitch was settled with the conclusion that the ball does curve; however, an optical illusion caused by the spin of the ball and the batter's perception of motion exaggerates the extent of the curve.
It's about one-seven-hundred-fiftieth as fast as a Fastball (baseball)
In other words, 324.160 centimeters per minute is 0.001 times the speed of a Fastball (baseball), and the speed of a Fastball (baseball) is 770 times that amount.
(a.k.a. rising fastball, a.k.a. cross-seam fastball, a.k.a. heater, a.k.a. hummer, a.k.a. smoker; for four-seam grip) (major league average)
The average speed of major league fastball pitch is 250,000 centimeters per minute. When up against the quickest professional fastball pitchers, a batter may have less than 0.4 seconds to react to a pitched ball.
It's about one-one-thousandth as fast as a Skydiver (belly-to-earth)
In other words, 324.160 centimeters per minute is 0.00 times the speed of a Skydiver (belly-to-earth), and the speed of a Skydiver (belly-to-earth) is 1,000 times that amount.
(Belly-to-Earth orientation, average conditions, terminal velocity)
A belly-to-Earth oriented skydiver's terminal velocity is about 320,000 centimeters per minute. In a typical jump from 3,900 m (13,000 ft), a diver in this orientation will be in freefall for 60 seconds.
It's about one-one-thousandth as fast as a Tornado
In other words, 324.160 centimeters per minute is 0.000978577 times the speed of a Tornado, and the speed of a Tornado is 1,021.892 times that amount.
(EF2) (wind speed range average)
According to the Enhanced Fujita scale implemented by the US National Oceanographic and Atmospheric Administration, a "significant" tornado has an Enhanced Funjita scale classification of EF2 and is characterized by wind gust speeds between 295,046.40 centimeters per minute and 367,466.90 centimeters per minute. The largest recorded tornado — an F4 event occurring in Nebraska in May, 2004 — was almost 4.02 km (2.5 mi) across.


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United States aviation news
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Elaine z Astolat – postać jednej z legend arturiańskich.

Córka Bernarda z Astolat, znana też jako Pani z Shalott. Rzucono na nią śmiertelne przekleństwo, które na zawsze miało ją uwięzić na wyspie Shalott – gdyby ją opuściła, miała ją czekać niechybna śmierć. Spędzała całe dnie w zamku, tkając gobelin, jednak pewnego dnia spostrzegła przez okno pięknego rycerza w lśniącej zbroi. Był to sir Lancelot, w którym zakochała się od pierwszego wejrzenia. Porzuciła pracę, opuściła zamek i – nie bacząc na klątwę – popłynęła łodzią do Camelotu. Po drodze słabła coraz bardziej, ale nie zawróciła. Gdy wpłynęła do Camelotu, umarła. Rycerze i mieszczanie zebrali się nad rzeką, aby podziwiać jej urodę. Lancelot powiedział, że nigdy nie widział nikogo piękniejszego i prosił o litość dla niej u Boga.

Poemat Pani z Shalott Alfreda Tennysona inspirowany był legendą Elaine z Astolat.

Zobacz też

 Elaine z Corbenic
 Elaine z Garlot

Przypisy

Mitologia celtycka
Postacie z legend arturiańskich
Postacie z angielskich utworów literackich

redpajama_set_name: RedPajamaWikipedia


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Biphasic Kinetics of Quaternary Ammonium Glucuronide Formation from Amitriptyline and Diphenhydramine in Human Liver Microsomes
Ursula Breyer-Pfaff, Dorothee Fischer and Dietrich Winne
Drug Metabolism and Disposition March 1997, 25 (3) 340-345;
Ursula Breyer-Pfaff
Dorothee Fischer
Dietrich Winne
The tricyclic antidepressant amitriptyline and the H1-receptor antagonist diphenhydramine are conjugated in human liver microsomes fortified with UDP-glucuronic acid at their tertiary amino groups with the formation of quaternary ammonium glucuronides. The kinetics of the reactions were found to be biphasic with apparentKM1 andKM2 values of 1.4 μM and 311 μM for amitriptyline and 2.6 μM and 1180 μM for diphenhydramine in four liver samples.Vmax1 values varied between 2 and 17 pmol·mg protein−1·min−1for the two substrates and Vmax2 values between 80 and 740 pmol·mg protein−1·min−1. A close correlation existed between amitriptyline and diphenhydramine glucuronidation rates in microsomes from seven livers at concentrations corresponding to 10–40% ofKM2. At low concentrations, diphenhydramine competitively inhibited the glucuronidation of amitriptyline.Vmax/KMvalues of the high-affinity UDP-glucuronosyltransferase(s) (UGTs) exceed those of the low-affinity enzyme(s) severalfold, such that the former should make the major contribution toN-glucuronidation of the drugs at therapeutic concentrations in vivo.
Attachment of a glucuronosyl residue to an aliphatic tertiary amino group is a biotransformation reaction common to many basic amphiphilic drugs. The resultant quaternary ammonium glucuronides have been detected as in vivo metabolites of H1-antagonists (1-3), tricyclic antidepressants (4-11) and neuroleptics (6, 11, 12), and structurally related drugs (13-15) in humans (1-15) and nonhuman primates (14,15). Their formation in vitro can be demonstrated using liver microsomes from man (16-20) or rabbit (6, 18, 19). Various experimental approaches have been used in order to elucidate which one of the individual isozymes belonging to two UDP-glucuronosyltransferase (UGT) families (21) catalyse the N-glucuronidation reaction in human liver. The involvement of a specific UGT isozyme was indicated by the lack of a correlation between the glucuronidation rates of imipramine and those of 1-naphthol or steroid substrates (19). While purification of an N-glucuronidating enzyme from human liver has hitherto not been achieved, human UGT1.4 expressed in human embryonic kidney cells proved able to glucuronidate a number of tertiary amine drugs in addition to primary and secondary aromatic amines (22) and numerous hydroxylated endo- and xenobiotics (23).
The present investigation aimed at elucidating, in more detail, the kinetics of conjugation of two drugs, amitriptyline and diphenhydramine, in human liver microsomes to their quaternary ammonium glucuronides (fig. 1). The tricyclic antidepressant amitriptyline is the only drug with tertiary amino group for which urinary N-glucuronide excretion has been measured in larger groups of patients and volunteers (5, 7-9), with the results varying between 2.5 and 21% of the dose (7, 8) or between 3.4 and 58% of total metabolites recovered (5, 9). Amitriptyline conjugation can be performed by expressed UGT1.4 (22, 23), and its rate in liver microsomes exhibited considerable variation among samples from different donors (17). Ingestion of the H1-antagonist diphenhydramine by two volunteers led to the recovery of 2.9 and 5%, respectively, of the dose in urine as the N-glucuronide (3). It is formed by expressed UGT1.4 at a rate similar to amitriptylineN-glucuronide (23), but its production in liver microsomes has apparently not been studied.
Structures of the N-glucuronides of amitriptyline and diphenhydramine.
Substances.
Amitriptyline hydrochloride was a gift from Troponwerke (Köln, Germany), and diphenhydramine hydrochloride was purchased from Sigma (Deisenhofen, Germany). Their N-glucuronides were synthesized as described previously (24) by a modification of the procedure of Luo et al. (25). UDP-glucuronic acid was purchased from Boehringer Mannheim (Mannheim, Germany), cation exchanger SCX 500-mg cartridges from Analytichem International (Harbor City, CA), Triton X-100 and nonanoyl-N-methylglucamide from Sigma and organic solvents from E. Merck (Darmstadt, Germany).
Human Liver Microsomes.
Human liver (HL)1 samples were obtained from organ donors or as excess material on partial hepatectomy (26). Pieces 5–10 g in size were stored at −80°C until microsomes were prepared in tris-buffered isotonic sucrose containing 2 mM EDTA (26). Pellets of washed microsomes were stored at −80°C for up to 6 months. Before use they were suspended in 0.25 M tris-HCl buffer, pH 8.0, to a concentration of about 10 mg protein/ml (1 ml buffer per gram of liver). Protein was measured (27) using bovine serum albumin as the standard.
Incubation and N-glucuronide Isolation.
The standard incubation mixture of 1 or 2 ml contained 57 mM tris-HCl, pH 8.0, 5 mM MgCl2, 2 mM UDP-glucuronic acid, 1.2–1000 μM substrate, 0.5 mg/ml microsomal protein, and 0.2 mg/ml Triton X-100. Amitriptyline concentrations did not exceed 700 μM because samples started to be turbid at 700 μM and, in some cases, reaction rates were lower than at 500 μM. After a standard incubation time of 30 min at 37°C, the reaction was stopped by two extractions with 1 mltert-butyl methyl ether, which removed excess substrate. The aqueous phase was washed with 1 ml n-hexane, and the protein interphase was removed together with the organic phase. Eighty per cent of the aqueous phase was processed to purify theN-glucuronide by solid-phase extraction on a SCX cartridge essentially as described previously (24). Briefly, after sample application, the cartridge was washed with 3 ml water and 3 ml methanol and eluted with 6 ml acetonitrile/methanol/0.2 M ammonium acetate (8:2:1, v/v/v) that was evaporated under a stream of nitrogen at 40°C. Regeneration of the cartridge required washing with 3 ml methanol, 3 ml water, and 8 ml 1 M acetic acid.N-glucuronide recoveries on SCX cartridge extraction were determined in duplicate in each series of incubations and found to vary between 75% and 100% for added quantities of 3 and 4 nmol amitriptyline N-glucuronide and between 63% and 98% for 3 and 4 nmol diphenhydramine N-glucuronide. The recoveries decreased on repeated use of the cartridges (12 to 15 times); within series, they showed coefficients of variation of 6% (N= 19) and 5% (N = 15), respectively. Quantities of 0.5–2 nmol were recovered by 54–65%. Values measured in incubations were corrected for recoveries in the same series.
HPLC.
Extract residues were dissolved in 150–600 μl water, and 100 μl was injected directly for HPLC on a 4.6 × 250 mm C18-silica column; the solvent was 10 mM perchloric acid adjusted to pH 2.5/acetonitrile (70:30, v/v, for amitriptylineN-glucuronide, 71:29 for diphenhydramineN-glucuronide) (24). Quantification was based on peak heights measured at 254 nm (amitriptyline N-glucuronide) or 220 nm (diphenhydramine N-glucuronide) relative to those of external standards.
To verify the identity of the products, one sample each with 9 μM or 250 μM amitriptyline or diphenhydramine was divided before extraction, and a 50% aliquot was incubated at pH 6.8 with β-glucuronidase from Escherichia coli for 16 hr at 37°C (24). The hydrolyzed samples then were processed in parallel with the unhydrolyzed aliquots.
Calculations.
Kinetic data were plotted according to Eadie and Hofstee to obtain first estimates of kinetic parameters. Since the plots were suggestive of the involvement of two enzymes with Michaelis-Menten kinetics, the respective equation was fitted to the experimental data after logarithmic transformation (to stabilize the variance) (28, p. 237). Nonlinear regression analysis (28, p. 458) started from the first estimates and used the substrate concentration S as the independent variable and the reaction velocity V as the dependent variable. The unknown variables were common high- and low-affinity Michaelis-Menten constantsKM1 andKM2 and individual maximal reaction velocities Vmax1 andVmax2 for each liver. The goodness-of-fit is expressed by the multiple correlation coefficientr2 = 1 - (residual sum of squares/total sum of squares) (28, p. 90).
Microsomes from all seven liver samples conjugated amitriptyline and diphenhydramine at measurable rates. The identity of the products was confirmed by hydrolysis of incubated samples with β-glucuronidase before extraction that led to complete disappearance of theN-glucuronide peaks in HPLC.
The rate of amitriptyline N-glucuronidation in human liver microsomes increased with increasing pH. Relative to the rate at pH 7.4, it was 125–150% at pH 7.7 and 158–167% at pH 8.0. This pH was chosen as the standard condition.
Activation of latent enzyme was examined at pH 8.0 with Triton X-100 and nonanoyl-N-methylglucamide. Whereas the latter at 0.1 and 0.2 mg/ml stimulated the N-glucuronidation of amitriptyline and diphenhydramine by less than 30%, Triton produced a concentration-dependent increase of the conjugation rates. At 9 and 250 μM amitriptyline, maximal rates of 240 and 180% of basal rates, respectively, were achieved with 0.2 mg/ml Triton corresponding to 0.4 mg/mg protein. The conjugation of 9 and 250 μM diphenhydramine was enhanced to 150 and 130%, respectively. No or only minimal further stimulation was produced with 0.3 mg/ml Triton.
Under standard conditions, N-glucuronide formation from both substrates was linear with time up to 60 min (r = 0.99,N = 6, p < 0.001). Variation of the concentration of UDP-glucuronic acid revealed KMvalues of 0.57 mM in the conjugation of 9 and 250 μM amitriptyline and 0.46 mM with 250 μM diphenhydramine as substrate. Standard incubations were carried out with 2 mM cosubstrate.
The dependence of N-glucuronidation rates on protein concentration was investigated in incubations with Triton concentrations of 0.4 mg/mg protein, but not below 0.2 mg/ml when amitriptyline was the substrate. With 9 and 250 μM amitriptyline, theN-glucuronide formation rate increased linearly with the protein concentration up to 0.5 mg/ml, whereas the increase was clearly less between 0.5 and 1.5 mg/ml (fig. 2). In contrast, the diphenhydramine N-glucuronidation rate was proportional to the protein concentration up to 1 mg/ml at 9 μM of substrate and up to 2 mg/ml at 250 μM (fig. 2).
Dependence of the glucuronidation rates of amitriptyline (solid lines) and diphenhydramine (dashed lines) on the protein concentration in microsomes from HL 17.
Substrate concentrations were 9 μM (A) or 250 μM (B).
Microsomes from HL 15, 16, 17, and 19 were incubated in duplicate or triplicate with 10 to 13 different concentrations of amitriptyline and diphenhydramine and the data subjected to model analysis for two-enzyme Michaelis-Menten kinetics. With the assumption of common apparentKM values and differentVmax values for the four livers, the kinetic parameters listed in table 1 were obtained (goodness-of-fit:r2 = 0.995 with amitriptyline as substrate and 0.989 with diphenhydramine). Regression lines calculated from the kinetic parameters for Eadie-Hofstee plots fitted the experimental data very well (figs. 3 and 4).
Apparent kinetic parameters for the N-glucuronidation of amitriptyline and diphenhydramine in microsomes from four human liver samples (mean ± SD)
Eadie-Hofstee plots for the kinetics of amitriptyline N-glucuronidation in microsomes from four human liver samples.
The lines were calculated from the kinetic parameters listed in Table1.
Eadie-Hofstee plots for the kinetics of diphenhydramine N-glucuronidation in microsomes from four human liver samples.
The high-affinity component exhibited higherVmax/KM values than the low-affinity enzyme(s) in all cases (table 1), and its contribution to totalVmax/KM ranged between 72 and 97%. Calculated glucuronidation rates by the high-affinity enzyme exceeded those by the low-affinity enzyme at amitriptyline concentrations below 3 μM (HL 15)to 27 μM (HL 19) and at diphenhydramine concentrations below 4 μM (HL 15) to 36 μM (HL 17).
A significant correlation (r = 0.95, p= 0.05) between the Vmax2 values for amitriptyline and diphenhydramine across the four liver samples pointed to conjugation of the two substrates by the same enzyme. Measurements including three additional liver samples (HL 18, 20, and 21) at substrate concentrations of 31–500 μM were in accordance with this conclusion, because at equal fractions of theirKM2 values, the two substrates exhibited close correlations of their reaction rates. Since theKM2 value of diphenhydramine was 4-fold that of amitriptyline, correlations were calculated betweenN-glucuronidation rates in the seven liver samples for the following substrate concentrations (corresponding to 10%, 20%, or 40% of KM2): amitriptyline 31 μMvs. diphenhydramine 125 μM (r = 0.99,p < 0.001), 62.5 μM vs. 250 μM (r = 0.98, p < 0.001, fig.5), and 125 μM vs. 500 μM (r = 0.94, p < 0.002).
Correlation of the N-glucuronidation rates of 62.5 μM amitriptyline and 250 μM diphenhydramine in microsomes from seven human liver samples (r = 0.98, p < 0.001).
Although the Vmax1 values for amitriptyline listed in table 1 failed to correlate with those for diphenhydramine, cross-inhibition of N-glucuronidation took place when both substrates were present at low concentrations. Since the Dixon plot for the inhibition of amitriptyline conjugation by diphenhydramine in HL 19 microsomes (fig. 6) was suggestive of competitive inhibition, the data were tentatively analyzed by a two-enzyme model with competitive inhibition using the parametersKM2 and Vmax2of HL 19 (table 1) for the low-affinity enzyme. Calculated values wereKi1 6.3 ± 1.2 μM,KM1 3.7 ± 0.7 μM, andVmax1 13.4 ± 0.9 pmol·mg protein−1·min−1.
Dixon plot showing the inhibition of amitriptyline glucuronidation by diphenhydramine in microsomes from HL 19.
In accordance with previous investigations (16-20),N-glucuronidation activity toward tertiary amine drugs was detected in microsomes from each one of the seven human liver samples examined. Some discrepancies became apparent with regard to published kinetic data for amitriptyline glucuronidation. Whereas a constant reaction rate up to 60 min incubation (17) could be confirmed now, the rate measured at pH 8.0 was linear neither with protein concentration beyond 0.5 mg/ml nor with substrate concentration up to 1 mM as has been reported for experiments at pH 8.4 (17). The present findings on optimal incubation conditions are in accordance with those for imipramine glucuronidation (18). Marked variations in amitriptyline conjugation rates among liver samples can be seen in fig.5 and from theVmax values in table 1. They are in accordance with a previous investigation (17) and correspond to pronounced interindividual differences in amitriptyline N-glucuronide excretion in patients with reported minimal and maximal values of 2.5% (7) and 21% of the dose (8).
The only KM value reported for amitriptylineN-glucuronide formation in human liver microsomes is 800 μM (20) and thus is even higher than the KMvalue of the low-affinity enzyme determined now. Biphasic kinetics have, to our knowledge, been described for ketotifen only that in incubations without Triton X-100 activation wasN-glucuronidated with apparent KMvalues of 12.5 and 100 μM, whereas in the presence of Triton a singleKM of 42 μM was measured (16). In the present series, data conforming to two-enzyme kinetics for amitriptyline and diphenhydramine N-glucuronidation were obtained in the presence of Triton. This points to the participation of more than one UGT isozyme in the conjugation of tertiary amine drugs. The high-affinity component has not been noticed in most of the previous investigations because of the use of high substrate concentrations (17,18, 20). According to the present data, this component can be expected to participate in drug conjugation, with higher efficacy at the low therapeutic concentrations prevailing in vivo. Thus, unbound amitriptyline and imipramine concentrations in plasma of patients receiving conventional doses hardly exceed 100 nM (29, 30), and these are assumed to reflect unbound concentrations in organs. The need to carry out drug metabolism studies in vitro at concentrations similar to those occurring in vivo to obtain valid information about the enzymes involved has been stressed recently by Kato and Yamazoe (31).
Whether the UGT isozymes conjugating amitriptyline and diphenhydramine are identical cannot be decided unambiguously on the basis of the present data. A common low-affinity enzyme is suggested by the significant correlation of Vmax2 values across four liver samples and by the close correlations of reaction rates at concentrations corresponding to equal fractions ofKM2. On the other hand, the reaction rate increased linearly with the protein concentration up to 2 mg/ml with diphenhydramine, but only up to 0.5 mg/ml with amitriptyline. In addition, Triton X-100 stimulated amitriptyline glucuronidation markedly more than that of diphenhydramine. This also applied to substrate concentrations of 9 μM for which the calculated contributions of the high-affinity enzyme are 66% in amitriptyline and 76% in diphenhydramine conjugation. The competitive inhibition of amitriptyline conjugation by diphenhydramine would, however, be in favor of the involvement of a common high-affinity enzyme.
One of the enzymes conjugating the two drugs is probably identical with UGT1.4, but the available data does not indicate which one. The expressed UGT1.4 conjugated imipramine, chlorpromazine, clozapine, and loxapine at their tertiary amino groups with apparentKM values of 310, 93 (22), 98, and 27 μM (23), respectively, the first three values being compatible with a low affinity towards tertiary amine drugs. Among such drugs, trifluoperazine was conjugated at the highest rate (23), whereas noN-glucuronide could be detected in urine from three patients under treatment with this drug (11). A possible explanation is that trifluoperazine is a substrate of the low-affinity UGT only that does not contribute measurably to in vivo metabolism. A remarkable feature is the strong inhibition that detergents, and particularly Triton X-100, exerted on the activity of expressed UGT1.4. The arrangement of the expressed enzyme in the membranes of the cultured cells may be different from that of native UGTs in human liver cells. Purification of active N-glucuronidating enzymes and/or expression of further isozymes will help to clarify these questions. To obtain knowledge on the UGTs relevant forN-glucuronide formation in vivo, emphasis should be placed on investigations at low substrate concentrations.
We are indebted to Prof. Dr. K.W. Bock and Prof. Dr. H. Bisswanger for valuable discussions and to Prof. Dr. W. Lauchart, Department of Surgery, University of Tübingen, for providing liver samples. Thanks are due to Mr. K. Nill for expert help with analytical techniques.
Send reprint requests to: Dr. Ursula Breyer-Pfaff, Department of Toxicology, University of Tübingen,Wilhelmstrasse 56, D-72074 Tübingen, Germany.
Abbreviations used are::
human liver
UDP-glucuronosyltransferase
Received August 2, 1996.
Accepted November 25, 1996.
The American Society for Pharmacology and Experimental Therapeutics
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(1995) Specificity of human UDP-glucuronosyltransferases and xenobiotic glucuronidation. Life Sci. 57:1819–1831.
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(1995) Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides. Drug Metab. Dispos. 23:299–302.
(1996) Glucuronidation of amines and hydroxylated xenobiotics and endobiotics catalyzed by expressed human UGT1.4 protein. Drug Metab. Dispos. 24:356–363.
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(1995) Comparison of procedures for measuring the quaternary N-glucuronides of amitriptyline and diphenhydramine in human urine with and without hydrolysis. J. Pharm. Pharmacol. 47:534–538.
(1992) Synthesis and characterization of quaternary ammonium-linked glucuronide metabolites of drugs with an aliphatic tertiary amine group. J. Pharm. Sci. 81:1079–1083.
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(1995) Stereoselective reversible ketone formation from 10-hydroxylated nortriptyline metabolites in human liver. Xenobiotica 25:1311–1325.
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New Genetic Technique Could Help Identify Potential Drug Targets for Malaria
Demonstration of new approach reveals a possible target for prophylactic treatment.
Scientists have developed a new technique for investigating the effects of gene deletion at later stages in the life cycle of a parasite that causes malaria in rodents. The novel approach, developed by Upeksha Rathnapala and colleagues at the University of Melbourne, Australia, could enhance research into potential drug targets for malaria treatment.
New treatments are needed for malaria because of increasing drug resistance in the single-celled Plasmodium parasites that cause it. Metabolic processes in Plasmodium that are essential for its development could serve as potential new drug targets. However, the Plasmodium life cycle, which occurs in both mosquitos and host animals, makes it difficult to identify and study such processes.
In the new study, the researchers demonstrate their novel technique by focusing on an important metabolic process in Plasmodium berghei, which causes malaria in rodents and is commonly used in mouse studies of malaria. This metabolic process requires a gene known as the ferrochelatase (FC) gene, and it allows P. berghei to produce a chemical compound known as heme.
Heme synthesis is known to be essential for P. berghei development in mosquitos that transmit the parasite between rodent hosts, but it is not essential during a later stage in the host bloodstream. However, between these two stages, P. berghei undergoes a developmental phase in the host liver, and it has been unclear whether heme synthesis is essential at this stage.
Rathnapala and colleagues produced P. berghei parasites that are capable of expressing the FC gene and developing properly in mosquitos, but produce a mix of FC-expressing and FC-deficient parasites once they infect mouse liver cells. The scientists genetically engineered the parasites so that FC-deficient individuals would express fluorescent markers, allowing for easy identification.
The researchers found that FC-deficient parasites were unable to complete their liver development phase. This suggests that disrupting the heme synthesis pathway could be an effective way to target Plasmodium parasites in the liver. Such an approach would be prophylactic, since symptoms aren't apparent until the parasite leaves the liver and begins its bloodstream phase.
This same novel approach involving fluorescent markers could be adapted for other genes, allowing scientists to identify additional metabolic processes that are essential for Plasmodium development in host animals.
"The idea of tagging mutant genes with fluorescent proteins is a simple one but it allowed us to follow mutant parasites throughout the malaria life cycle and dissect their phenotypes in the liver stage, something that hasn't been easy to do for mutations that block mosquito development," the author explain. "Our analysis of heme biosynthesis shows the power of this simple method but it's a technique that can be easily applied to other genes and other malaria parasite species, greatly expanding the scope for investigating this immunologically important stage in the malaria parasite's life cycle."
Illustration: Mosquito stage parasites generated by a genetic cross of parasites expressing either red or green fluorescence from the same location in the genome. Green and red parasites are the product of self-fertilization, so express only one fluorescent proteins. Orange parasites represent a cross of two parasites and express both fluorophores during development in the mosquito. Credit: Christopher D Goodman CC-BY
Abstract (PLoS Pathology; 2017.)


text:
/**
 * @file twic_util_macro.h
 * @brief a source file for TZ10xx TWiC for Bluetooth 4.0 Smart
 * @version V1.0.0.FS (Free Sample - The information in this code is
 * subject to change without notice and should not be construed as a
 * commitment by TOSHIBA CORPORATION SEMICONDUCTOR & STORAGE PRODUCTS
 * COMPANY.
 * @note TZ1EM provides the automatic low energy consumption. The low
 * energy consumption of interal BLE Processor and UART2 is managed by
 * the part of TWIC BLE CE (BLE Controller Extension). Please refer to
 * the twicIfLeCe API group. TZ1EM combines the HOST Core low energy
 * consumption with the BLE CE and the other peripheral modules.
 */

/*
 * COPYRIGHT (C) 2015
 * TOSHIBA CORPORATION SEMICONDUCTOR & STORAGE PRODUCTS COMPANY
 * ALL RIGHTS RESERVED.
 *
 * THE SOURCE CODE AND ITS RELATED DOCUMENTATION IS PROVIDED "AS
 * IS". TOSHIBA CORPORATION MAKES NO OTHER WARRANTY OF ANY KIND,
 * WHETHER EXPRESS, IMPLIED OR, STATUTORY AND DISCLAIMS ANY AND ALL
 * IMPLIED WARRANTIES OF MERCHANTABILITY, SATISFACTORY QUALITY, NON
 * INFRINGEMENT AND FITNESS FOR A PARTICULAR PURPOSE.
 *
 * THE SOURCE CODE AND DOCUMENTATION MAY INCLUDE ERRORS. TOSHIBA
 * CORPORATION RESERVES THE RIGHT TO INCORPORATE MODIFICATIONS TO THE
 * SOURCE CODE IN LATER REVISIONS OF IT, AND TO MAKE IMPROVEMENTS OR
 * CHANGES IN THE DOCUMENTATION OR THE PRODUCTS OR TECHNOLOGIES
 * DESCRIBED THEREIN AT ANY TIME.
 *
 * TOSHIBA CORPORATION SHALL NOT BE LIABLE FOR ANY DIRECT, INDIRECT OR
 * CONSEQUENTIAL DAMAGE OR LIABILITY ARISING FROM YOUR USE OF THE
 * SOURCE CODE OR ANY DOCUMENTATION, INCLUDING BUT NOT LIMITED TO,
 * LOST REVENUES, DATA OR PROFITS, DAMAGES OF ANY SPECIAL, INCIDENTAL
 * OR CONSEQUENTIAL NATURE, PUNITIVE DAMAGES, LOSS OF PROPERTY OR LOSS
 * OF PROFITS ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT, OR
 * BEING UNUSABLE, EVEN IF ADVISED OF THE POSSIBILITY OR PROBABILITY
 * OF SUCH DAMAGES AND WHETHER A CLAIM FOR SUCH DAMAGE IS BASED UPON
 * WARRANTY, CONTRACT, TORT, NEGLIGENCE OR OTHERWISE.
 *
 */

#ifndef _TWIC_UTIL_MACRO_H_
#define _TWIC_UTIL_MACRO_H_

#define TWIC_UTIL_UUID16(a,b) 0x ## b, a
#define TWIC_UTIL_UUID16_U64SET(a,b) a ## b, 0

#define TWIC_UTIL_UUID128(a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p) 0x ## p, 0x ## o, 0x ## n, 0x ## m, 0x ## l, 0x ## k, 0x ## j, 0x ## i, 0x ## h, 0x ## g, 0x ## f, 0x ## e, 0x ## d, 0x ## c, 0x ## b
#define TWIC_UTIL_UUID128_U64SET(a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p) a ## b ## c ## d ## e ## f ## g ## h, 0x ## i ## j ## k ## l ## m ## n ## o ## p

#endif /* _TWIC_UTIL_MACRO_H_ */

redpajama_set_name: RedPajamaGithub


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text:
Tygers of Pan Tang – Ritual Review
By Huck N Roll on November 20, 2019 in 2019, British Metal, Heavy Metal, Mighty Music, NWOBHM, Reviews, Heavy Metal, NWOBHM, 12 comments
Three years ago, Tygers of Pan Tang's self-titled twelfth album made me feel good about old NWoBHM bands, and their ability to craft enjoyable-enough songs. I hadn't revisited it until it was time to review their new album, Ritual. In fact, I even went and revisited the referred-to review above. I mean, there's always a chance that, because I was still in my rookie year as a member of the AMG Conglomerate, I was taking it easy on some bands. But I've been around for a long time now, and having a warm place in my atrophying heart for a band is not only unacceptable, it is now unheard of. Was their last album really "good," or was I being generous? Will the new one also be good, or can it follow the lead of fellow NWoBHM vets Diamond Head, and take things up a notch?1
Ritual opens with a rager of a song, "Worlds Apart," featuring a lightning-fast riff and a brilliant intro made for opening concerts. Sole founding member Robb Weir (if in fact it is him, and not co-guitarist Micky Crystal) writes and plays some killer riffs, and while it may be unintentional, he pays homage to guitar hero John Sykes with his style. Jacobo Meille, who has been with the band for fifteen years now, still sounds as charismatic as ever. In his upper register he reminds me of Geoff Tate, which isn't a bad thing at all, and he brings excitement and commitment to every lyric. Production is appropriately slick as well, processed to a degree typical of 80s metal without being overdone, with big guitar solos and even bigger (and at times repeated ad nauseum) choruses.
"Worlds Apart" isn't the only gloriously 80s metal anthem to be found on Ritual. Much like three years ago, Tygers of Pan Tang show themselves to be skilled songwriters. For the most part they stick to a standard time-tested-and-true formula, often executed to perfection. "Raise Some Hell" and "Damn You!" are catchy and memorable fast-paced rockers that don't hold back at all, and when the band gets a bit experimental on "The Art of Noise" it pays off with the heaviest song on the album, complete with an excellent bass riff during the song's midpoint. And for you hair metal fans out there, "Words Cut Like Knives" is the token power ballad, sappy to the extreme but well-executed.
Your better half might tell you that length doesn't matter, but trust me: it does. And on Ritual, Tygers of Pan Tang overstay their welcome by exactly three songs. 80s bands were never made to put out 53 minutes of music on a single album, and that is still the case here in 2019. "Destiny," "Rescue Me," and "Love Will Find a Way" could all have been left off this album, making it stronger and more vital for the culling. Cut this down to a svelte eight-song, forty-minute jaunt and we would have had a super record, but as it stands the average material drags down some truly strong songs. That's the key to longevity; for the ultimate example, look no further than Pretty Maids, who continually put out above-average records with no filler.
Even with the weaker tracks taken into consideration, Tygers of Pan Tang have released another strong album, showing that 2016's self-titled was no fluke – and that I wasn't an overrating fool back then2. When on their game, the band continues to write some of the best 80s-styled metal out there (click play on the video below for more proof), and that makes Ritual a worthwhile purchase for anyone who's a fan of the olde days, or of bands that play like they wish it still was.
DR: 6 | Format Reviewed: 320 kbps mp3
Label: Mighty Music
Websites: tygersofpantang.com/official | facebook.com/tygersofpantangofficial
Releases Worldwide: November 22nd, 2019
Show 2 footnotes
We didn't review their May album, The Coffin Train, but if I had, it would have been a solid 3.5. ↩
Let's not jump to any rash conclusions here. – Steel ↩
Tags: 2019, 3.0, British Metal, Diamond Head, Geoff Tate, Heavy Metal, John Sykes, Mighty Music, Nov19, NWOBHM, Pretty Maids, Review, Reviews, Ritual, Tygers of Pan Tang
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text:
Courage: Resurgence & Ecologist out now
Marianne Brown
| 4th January 2019
James Anderson, World Resources Institute
Introducing the latest issue of Resurgence & Ecologist magazine.
When I talk to other people about climate anxiety our experiences are often the same. First, there's a heavy feeling of powerlessness, which can be overwhelming, but often this is followed by a sense of grim determination. Perhaps this is where courage comes from.
In the words of Harper Lee's Atticus Finch, "real courage" is when "you know you're licked before you begin, but you begin anyway and you see it through no matter what". Now, more than ever, we need to muster our courage to make a change.
The latest edition of Resurgence & Ecologist magazine is out now!
From Heathrow airport in the UK to Germany's Hambach Forest and the Zone to Defend in France – as well as the growing non-violent movement Extinction Rebellion – the actions of peaceful activists across the world featured in the following pages show that feelings of dread can be transformed into optimism and hope.
Non-violent protest isn't the only way to do this, of course. Natalie Bennett writes in the Ecologist section: "Everyone has a role, from promoting actions on social media and answering questions from family and colleagues… to baking quiches and cakes for the protesters…"
In our Arts section, Alice Kettle writes about a project bringing together refugees, asylum seekers and concerned people across the world to create incredible textile landscapes and stitched 'forests' to form a "unique kind of activism". "I'm just an artist. I can't resolve these issues," she writes, "but I can show that I care."
The future doesn't have to be worst-case scenario, and if we work together it can be something to celebrate.
In our Keynotes feature, Kate Pickett and Richard Wilkinson lay out ways we can do this by addressing the inequality that is currently crippling society. "Change on the scale needed can only be achieved if large numbers of people commit themselves to achieving it," they write.
"We are the first generation to know we are destroying our planet and the last one that can do anything about it," WWF UK chief executive Tanya Steele said on the launch of their Living Planet report in October. The end of 2018 may be remembered as the moment the realities of climate breakdown hit the mainstream. There's still a chance 2019 will be known as the year we began to change things for the better.
Marianne Brown is editor of Resurgence & Ecologist. The latest edition of Resurgence & Ecologist magazine is out now.
Time to rebuild
Satish Kumar
| 28th October 2021
Satish Kumar received the P.E.A. environment award for most ecological family this week. Here he argues that cities should not be an impediment to sustainable living.
Tree equity
Julia Travers
| 3rd September 2021
The American Forests campaign is calling for more trees in Houston, Detroit, Seattle and other urban areas in the US.
Marianne Brooker
Change cannot come from the top down.
Rewilding Britain's waterways
| 25th February 2021
Beavers, Europe's largest rodent, are a keystone species who transform the landscape around them, creating new habitats.
New year cheer
People across the world are building resilience amid uncertainty.
| 4th November 2020
The current issue of Resurgence & Ecologist magazine offers a celebration of the night sky.


Sanctuary Offering a longed-for sense of calm and seclusion, Eton Estate's sublime native bushland setting inspires the character and ambience of this unique development, creating a haven which sits harmoniously within its surroundings. Immense consideration has been paid to the design of the enchanting gardens and communal areas which are responsive to the natural environment and enhance the feeling of sanctuary.
The brochure reflects the design of the gardens and communal areas which are responsive to the natural bushland environment. The brochure cover uses a Spot UV finish to resemble the shine of a glossy gum leaf, the sandstone layer is printed on curious Goya white to mimic the rough grainy texture of this finish used the gardens. The tipped in pages are carried throughout the brochure internals.
was preserved and integrated into a residential context.
all available lots at Lindfield's Eton Estate sold at auction.
in a top sale of $2.2m for an 880sqm lot.


Today I hand over the blog to my 14 year old daughter Daisy. It would appear I have two budding bloggers on my hands. So here it is #WhatDaisySays!
Although she has no talent of her own and has been forbidden by her father to pursue it, Sophie Callender longs for a magickal education. But she started a bookish rebellion in her father's library long ago, and her sheltered upbringing conceals a mysterious past and what may prove a catastrophic future. Her meeting with Gray sets off a series of events that will lead them to uncover a conspiracy at the heart of the kingdom and into the legend of the Midnight Queen, who vanished without a trace years before.
The Midnight Queen by Sylvia Hunter is an intriguingly written fantasy book based around a world of magick. This is due to be a trilogy and I am honestly excited to see where the writer takes the plot. Our two main characters are introduced within the first chapter. Gray (Graham Marshall), has been forced to stay at his professor's house for the summer for reasons unbeknown to the reader for a while into the book. Gray's character is a very intelligent, caring, young man. The visible hatred between Gray and the professor is brought to the reader's attention by our other main character, Sophie. Sophie was by far my favourite character. I think the themes in this book were really relatable and current. For instance, in the setting of the book Sophie is discouraged by her father from reading and learning about magick like the men in story do. I feel this was an exceptionally relevant theme, considering the modern feminist movements. Sophie's character was also very bubbly and talkative which combats Grays initial moodiness.
Within the first chapter I noticed that the writing style was very unusual. Whilst reading, the informal, friendly tone made it feel as if it was written in first person by Sophie, when in fact it's written in the third person. Sylvia Hunter has a very unique writing style that makes the book very easy to read. However, the book was very slow to get to the plot. This was the only downfall I found the book had. On one hand, I can see that because it took a while to get to the plot we got to get to know Gray and Sophie really well but on the other hand it does make the first 100 pages or so hard to power through.
Throughout the book the plot takes lots of unexpected twists and turns that I personally thought were quite clever. I enjoyed learning all about magick which was obviously one of the main themes in the book. Despite knowing magick obviously isn't real I still find it incredibly interesting to read different authors inventions of magickal worlds. I think Sylvia Hunter's magickal world went in depth enough to catch your interest but at the same time it doesn't feel like your reading one of Gray's study books from Oxford's Merlin College.
Three other characters that I thought were written very interestingly were: Amelia, Joanna and the professor. Firstly, Amelia was the character I loved to hate. You could tell that she was designed to be written in a very mean girl fashion. She's one of those girls whose pretty and she knows she can get anything with her looks- very manipulative. Joanna, who is one of the three sisters (Joanna, Amelia and Sophie) born to the professor is very outspoken and sassy. I enjoyed reading her character's dialogue and I thought it bought a funny, light hearted tone to the book. Joanna was very passionately against her father's views. Her father, the professor is written in a very old fashioned manner with very controversial and prejudice views against women. You find out early on that the girl's mother (whom died when they were fairly young) was very upset to find that Joanna (the youngest) was a girl because the professor had wanted at least one boy. You also find out that Amelia believes it's her father's job to 'pick' her a 'suitable' man. This dynamic makes very thought provoking, interesting reading.
What would a book be without romance? Sophie and Gray's romance develops very slowly from a place of trust, care and friendship. This like the plot develops very slowly but makes for very chilled out reading. There personalities are written to be very compatible and you see throughout the book how much they help each other.
Overall, I really enjoyed this book once the plot got going. The plot is full of very exciting twists and turns that I think almost any reader would enjoy and I personally thoroughly enjoyed the way the characters are written. I did also really enjoy the theme of female empowerment.
Aw bless! She should totally go for it!


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If you like stories about exotic locations, real men and emotions that will make you sigh and smile with the characters, you will like this story. I think it is a lovely ode to the celebration of life and love and can only recommend you read it, especially if you need cheering up.
I'm very pleased to say that I have. I've gotten the other kind too, so I guess it balances. The positive ones tell me I've done something right, and the negative ones tell me I still have a lot to learn, and that, no matter how I try, I'll never please everyone.