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Explanation: Quasars
(QUASi-stellAR objects) lie near the edge of the observable
Universe.
Discovered in 1963,
astronomers
were astounded that such objects could be
visible across billions of light-years, as this implies
they must emit prodigious
amounts of energy.
Where does
the
energy come from?
Many believe the quasar's central engine is a giant black hole
fueled by tremendous amounts of infalling gas, dust, and stars.
This
gallery of quasar portraits from the Hubble Space
Telescope offers a look at their local neighborhoods: the quasars themselves
appear as the bright star-like objects with
diffraction spikes.
The
images in the center and right hand columns reveal quasars
associated with disrupted colliding and merging galaxies
which should provide
plenty
of debris to feed a hungry
black
hole.
|
{
"pile_set_name": "Pile-CC"
}
|
Working for Médecins sans Frontières.
Médecins sans Frontières (MSF), the world's largest independent organization for emergency medical relief, needs nurses willing to volunteer their skills and their time to work in the field. Trevor Lines, RGN, a veteran of five MSF missions, explains what the work involves, why he does it and what you need to do if you want to apply.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Coenobita brevimanus
Coenobita brevimanus is a species of terrestrial hermit crab belonging to the family Coenobitidae, which is composed of coastal living terrestrial hermit crabs. From there it belongs to the genus coenobita, one of two genera split from the family, which contains sixteen species. The Latin origins of the species name, brevimanus, come from the adjective brevis ("small") and the noun manus ("hands"). It is known as the Indos crab or Indonesian crab because it is primarily distributed throughout the Indo-Pacific.
Description
C. brevimanus is one of the larger species in the genus Coenobita. The adults can grow up to .5 pounds (230 g). They can live 12–70 years and are known to grow to the size of a coconut. During the beginning of the crab's juvenile stage the middle of its carapace possesses a long reddish pigment area as does each side wall of the carapace. As the crab reaches one month old these areas develop into a brown stripe down the middle of the carapace and two brown bands on either side wall of the carapace. The rest of the carapace as well as the pereiopods slowly transition from a white color to a grayish color. Eventually, when they reach full adulthood, they are brownish red with violet shading on their limbs. The brown stripe and bands are still present in the adult crabs. They are darker than most other species of its genus. They have an abdominal lung and extremely reduced gills due to their terrestrial lifestyle. They also have a disproportionately large dark purple pincher and long black eye stalks which they can easily be identified by. There is also a pink variation of C. brevimanus in which their dominant pincher is pink instead of a dark purple. Compared to other species in their genus, they do not prefer large gastropod shells, and the armored variation of this crab, in which a tougher exoskeleton is present, specifically likes small shells that only cover their body past their third pair of walking legs. Although their availability and demand has risen in recent years, they are not commonly kept as pets due to their size, but they are the largest land hermit crab known to be in captivity.
Distribution and habitat
C. brevimanus is native to the east coast of Africa and south-west Pacific Ocean. It has also been reported in East Africa, the Philippines, Japan, China, and Taiwan. They usually reside inland and away from the coastline in moist environments such as rainforests because they do not like to get wet, but still require a high amount of humidity. Generally, they require at least eighty percent humidity and enjoy temperatures between eighty and eighty-five degrees, which influences their distribution greatly towards tropical zones. The present record of this species suggests a continuous distribution from the east coast of Africa to the south-west Pacific Ocean.
Behavior and ecology
C. brevimanus larvae is brooded inside the female's shell, then laid in seawater. This is the only time the adult C. brevimanus returns to the water after they reach adulthood. They grow from the larval planktonic stage to the magalopal stage before migrating from the sea to the land. They also develop a habit of acquiring discarded gastropod shells for inhabitation before migration. If gastropod shells are not present, often due to the collection for the souvenir market, they can be seen using soup cans and other litter as shells. After they acquire their shell, they migrate onto land. After this migration they are fully terrestrial, being the most terrestrial species in the genus Coenobita, often found over one hundred meters from the coast. As they grow on land, they tend to molt around every eighteen months, in which they burrow underground, molt, and then come up when their exoskeleton is no longer soft. This process can take upwards to a month. They are highly active during the month of July, with an increase in activity in the months leading up to July, and a decrease in activity after the month of July. Although they are terrestrial, they can only tolerate a 28% loss of body water. Beyond this point a severe disruption in oxygen transport occurs. They also have difficulty recovering from periods of dehydration. In order to prevent dehydration they fill their shells with brackish or fresh water. They have the ability to detect volatile chemicals in the air in relation to food and water sources and orient themselves accordingly, which is useful in finding food and unevenly distributed inland water supplies. They are omnivores and scavenger feeders who operate primarily at night. They tend to prefer fish over fruits when given the option between the two. They have also been known to prey on smaller species of hermit crabs, such as C. rugosus, making them not only scavengers, but also predators.
Taxonomy
Coenobita brevimanus was first taxonomically classified in 1852 by Dana.
References
Category:Hermit crabs
Category:Terrestrial crustaceans
Category:Crustaceans described in 1852
|
{
"pile_set_name": "Wikipedia (en)"
}
|
import * as R from 'ramda'
/**
* Accepts an object and returns a list of its leaves.
*/
// const getLeaves = when(
// is(Object),
// compose(
// (vals) => chain(getLeaves, vals),
// values,
// ),
// )
const createLeavesGetter = (predicate) => {
return R.ifElse(
R.allPass([R.complement(R.is(Function)), R.is(Object)]),
R.compose(
R.reject(R.isNil),
R.chain(R.when(R.complement(predicate), getLeavesWhich(predicate))),
R.values,
),
() => null,
)
}
/**
* Returns the list of the object's leaves that satisfy the given predicate.
* @param {Function<boolean>} predicate
* @param {Object} obj
* @returns {any[]}
*/
const getLeavesWhich = R.curry((predicate, obj) => {
return createLeavesGetter(predicate)(obj)
})
export default getLeavesWhich
|
{
"pile_set_name": "Github"
}
|
Q:
Does one congruence imply the other?
If $a \equiv b \pmod n \: \:$ and $\: \: a \equiv 0 \pmod n \: \:, \: b \equiv 0 \pmod n$
Is it implied that $a \equiv 0 \pmod b$ ? i.e if $b \leq a$
The specific context of this question is that of the multiples of 9. That is we know that for any multiple of 9, not only is the number divisible by 9, but also the sum of its digits. So is it true that the number is divisible by the sum of the digits?
Update Ok so I found a counterexample for the generalization of my question, but is the part about multiples of 9 true?
A:
No, it is not true that
$$a\equiv b\equiv 0\bmod n\implies a\equiv 0\bmod b$$
For example, we can look at $n=2$, $a=6$, and $b=4$.
For your other question: no, just because
$$n\equiv 0\bmod 9\implies \operatorname{digit\_sum}(n)\equiv 0\bmod 9$$
does not mean that
$$n\equiv 0\bmod 9\implies n\equiv 0\bmod \operatorname{digit\_sum}(n)$$
For example, consider $n=99$. Then $\operatorname{digit\_sum}(99)=18$ but
$99\not\equiv 0\bmod 18$.
|
{
"pile_set_name": "StackExchange"
}
|
Revised solar thermal calculations are good news for the RHI
The revised solar thermal calculation, the basis for payment under the domestic Renewable Heat Incentive (RHI), provides an uplift to renewable heat by as much as 85%. Great news for end users and solar thermal installers alike.
The Microgeneration Certification Scheme (MCS) published the new calculation as part of a far-reaching review of the standards under which solar heating systems are installed in the UK.
“We welcome the improvements to the energy calculation,” said Paul Barwell of the Solar Trade Association (STA). “Since the announcement of the domestic RHI tariffs in June, the industry has been waiting for clarity on this point. At last, solar installers can put the benefits of solar heating under the domestic RHI in front of potential customers.”
The STA has worked out that the changes to the energy calculation have increased the deemed renewable heat by between 14% for a two person household and 85% for a six person household, providing a significant boost to the value of the payments under the domestic RHI. In addition, the effect of the efficiency of the back-up heater (usually a boiler) is recognised, increasing the annual energy saving presented to the customer by at least 30%.
Stuart Elmes, Chair of the Solar Thermal Working Group at the STA and a contributor to the development of the new standards said, “Solar installers who took a look at the tariff of 19.2 p per kWh and decided that the domestic RHI wasn’t all that good, should look again at the numbers. The new calculation makes a big difference. We are also doing some work around the financial benefits of the hot water cylinder upgrade which we intend to reveal shortly.”
The STA is hosting a free Solar Thermal Seminar at the Solar Energy UK Event, NEC, next Tuesday (8th October), between 10.45 and 13.00. Delegates will hear about the new energy calculation, the domestic RHI and the impact on solar thermal return on investment.
|
{
"pile_set_name": "Pile-CC"
}
|
"use strict";
// Use the fastest means possible to execute a task in its own turn, with
// priority over other events including IO, animation, reflow, and redraw
// events in browsers.
//
// An exception thrown by a task will permanently interrupt the processing of
// subsequent tasks. The higher level `asap` function ensures that if an
// exception is thrown by a task, that the task queue will continue flushing as
// soon as possible, but if you use `rawAsap` directly, you are responsible to
// either ensure that no exceptions are thrown from your task, or to manually
// call `rawAsap.requestFlush` if an exception is thrown.
module.exports = rawAsap;
function rawAsap(task) {
if (!queue.length) {
requestFlush();
flushing = true;
}
// Equivalent to push, but avoids a function call.
queue[queue.length] = task;
}
var queue = [];
// Once a flush has been requested, no further calls to `requestFlush` are
// necessary until the next `flush` completes.
var flushing = false;
// `requestFlush` is an implementation-specific method that attempts to kick
// off a `flush` event as quickly as possible. `flush` will attempt to exhaust
// the event queue before yielding to the browser's own event loop.
var requestFlush;
// The position of the next task to execute in the task queue. This is
// preserved between calls to `flush` so that it can be resumed if
// a task throws an exception.
var index = 0;
// If a task schedules additional tasks recursively, the task queue can grow
// unbounded. To prevent memory exhaustion, the task queue will periodically
// truncate already-completed tasks.
var capacity = 1024;
// The flush function processes all tasks that have been scheduled with
// `rawAsap` unless and until one of those tasks throws an exception.
// If a task throws an exception, `flush` ensures that its state will remain
// consistent and will resume where it left off when called again.
// However, `flush` does not make any arrangements to be called again if an
// exception is thrown.
function flush() {
while (index < queue.length) {
var currentIndex = index;
// Advance the index before calling the task. This ensures that we will
// begin flushing on the next task the task throws an error.
index = index + 1;
queue[currentIndex].call();
// Prevent leaking memory for long chains of recursive calls to `asap`.
// If we call `asap` within tasks scheduled by `asap`, the queue will
// grow, but to avoid an O(n) walk for every task we execute, we don't
// shift tasks off the queue after they have been executed.
// Instead, we periodically shift 1024 tasks off the queue.
if (index > capacity) {
// Manually shift all values starting at the index back to the
// beginning of the queue.
for (var scan = 0, newLength = queue.length - index; scan < newLength; scan++) {
queue[scan] = queue[scan + index];
}
queue.length -= index;
index = 0;
}
}
queue.length = 0;
index = 0;
flushing = false;
}
// `requestFlush` is implemented using a strategy based on data collected from
// every available SauceLabs Selenium web driver worker at time of writing.
// https://docs.google.com/spreadsheets/d/1mG-5UYGup5qxGdEMWkhP6BWCz053NUb2E1QoUTU16uA/edit#gid=783724593
// Safari 6 and 6.1 for desktop, iPad, and iPhone are the only browsers that
// have WebKitMutationObserver but not un-prefixed MutationObserver.
// Must use `global` instead of `window` to work in both frames and web
// workers. `global` is a provision of Browserify, Mr, Mrs, or Mop.
var BrowserMutationObserver = global.MutationObserver || global.WebKitMutationObserver;
// MutationObservers are desirable because they have high priority and work
// reliably everywhere they are implemented.
// They are implemented in all modern browsers.
//
// - Android 4-4.3
// - Chrome 26-34
// - Firefox 14-29
// - Internet Explorer 11
// - iPad Safari 6-7.1
// - iPhone Safari 7-7.1
// - Safari 6-7
if (typeof BrowserMutationObserver === "function") {
requestFlush = makeRequestCallFromMutationObserver(flush);
// MessageChannels are desirable because they give direct access to the HTML
// task queue, are implemented in Internet Explorer 10, Safari 5.0-1, and Opera
// 11-12, and in web workers in many engines.
// Although message channels yield to any queued rendering and IO tasks, they
// would be better than imposing the 4ms delay of timers.
// However, they do not work reliably in Internet Explorer or Safari.
// Internet Explorer 10 is the only browser that has setImmediate but does
// not have MutationObservers.
// Although setImmediate yields to the browser's renderer, it would be
// preferrable to falling back to setTimeout since it does not have
// the minimum 4ms penalty.
// Unfortunately there appears to be a bug in Internet Explorer 10 Mobile (and
// Desktop to a lesser extent) that renders both setImmediate and
// MessageChannel useless for the purposes of ASAP.
// https://github.com/kriskowal/q/issues/396
// Timers are implemented universally.
// We fall back to timers in workers in most engines, and in foreground
// contexts in the following browsers.
// However, note that even this simple case requires nuances to operate in a
// broad spectrum of browsers.
//
// - Firefox 3-13
// - Internet Explorer 6-9
// - iPad Safari 4.3
// - Lynx 2.8.7
} else {
requestFlush = makeRequestCallFromTimer(flush);
}
// `requestFlush` requests that the high priority event queue be flushed as
// soon as possible.
// This is useful to prevent an error thrown in a task from stalling the event
// queue if the exception handled by Node.js’s
// `process.on("uncaughtException")` or by a domain.
rawAsap.requestFlush = requestFlush;
// To request a high priority event, we induce a mutation observer by toggling
// the text of a text node between "1" and "-1".
function makeRequestCallFromMutationObserver(callback) {
var toggle = 1;
var observer = new BrowserMutationObserver(callback);
var node = document.createTextNode("");
observer.observe(node, {characterData: true});
return function requestCall() {
toggle = -toggle;
node.data = toggle;
};
}
// The message channel technique was discovered by Malte Ubl and was the
// original foundation for this library.
// http://www.nonblocking.io/2011/06/windownexttick.html
// Safari 6.0.5 (at least) intermittently fails to create message ports on a
// page's first load. Thankfully, this version of Safari supports
// MutationObservers, so we don't need to fall back in that case.
// function makeRequestCallFromMessageChannel(callback) {
// var channel = new MessageChannel();
// channel.port1.onmessage = callback;
// return function requestCall() {
// channel.port2.postMessage(0);
// };
// }
// For reasons explained above, we are also unable to use `setImmediate`
// under any circumstances.
// Even if we were, there is another bug in Internet Explorer 10.
// It is not sufficient to assign `setImmediate` to `requestFlush` because
// `setImmediate` must be called *by name* and therefore must be wrapped in a
// closure.
// Never forget.
// function makeRequestCallFromSetImmediate(callback) {
// return function requestCall() {
// setImmediate(callback);
// };
// }
// Safari 6.0 has a problem where timers will get lost while the user is
// scrolling. This problem does not impact ASAP because Safari 6.0 supports
// mutation observers, so that implementation is used instead.
// However, if we ever elect to use timers in Safari, the prevalent work-around
// is to add a scroll event listener that calls for a flush.
// `setTimeout` does not call the passed callback if the delay is less than
// approximately 7 in web workers in Firefox 8 through 18, and sometimes not
// even then.
function makeRequestCallFromTimer(callback) {
return function requestCall() {
// We dispatch a timeout with a specified delay of 0 for engines that
// can reliably accommodate that request. This will usually be snapped
// to a 4 milisecond delay, but once we're flushing, there's no delay
// between events.
var timeoutHandle = setTimeout(handleTimer, 0);
// However, since this timer gets frequently dropped in Firefox
// workers, we enlist an interval handle that will try to fire
// an event 20 times per second until it succeeds.
var intervalHandle = setInterval(handleTimer, 50);
function handleTimer() {
// Whichever timer succeeds will cancel both timers and
// execute the callback.
clearTimeout(timeoutHandle);
clearInterval(intervalHandle);
callback();
}
};
}
// This is for `asap.js` only.
// Its name will be periodically randomized to break any code that depends on
// its existence.
rawAsap.makeRequestCallFromTimer = makeRequestCallFromTimer;
// ASAP was originally a nextTick shim included in Q. This was factored out
// into this ASAP package. It was later adapted to RSVP which made further
// amendments. These decisions, particularly to marginalize MessageChannel and
// to capture the MutationObserver implementation in a closure, were integrated
// back into ASAP proper.
// https://github.com/tildeio/rsvp.js/blob/cddf7232546a9cf858524b75cde6f9edf72620a7/lib/rsvp/asap.js
|
{
"pile_set_name": "Github"
}
|
Continuously coupled transcription-translation system for the production of rice cytoplasmic aldolase.
A continuously coupled cell-free transcription-translation system was developed for the production of rice cytoplasmic aldolase, an enzyme involved in both glycolytic and gluconeogenic pathways in eukaryotic cells. The system works with a continuous flow of feeding solution containing nucleoside triphosphates and amino acids into a 1-mL reactor containing wheat-germ extract, plasmid DNA, and transcription enzyme, and continuous removal of translation product through an ultrafiltration membrane fitted in the reactor. Addition of free nucleotide primer, m(7)G(5')ppp(5')G, to this reactor was necessary for efficient transcription, thus producing biologically active mRNA for translation. The rate of aldolase synthesis was constant during the continuous translation reaction. It was observed that from 3 h onward only aldolase was synthesized by the system. After 30 h, the total amount of protein synthesized reached 205.6 microg, which is comparable with the amount synthesized (255.6 microg) in the translation system only where separately prepared capped mRNAs were added to the reactor for translation. Autoradiogram and Western blot analyses of the translated product showed a distinct band corresponding to the calculated molecular weight of the protein. These results have shown the establishment of a continuously coupled eukaryotic transcription-translation system for the expression of genes from eukaryotic cells.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Challenge into Change is The Women’s Initiative’s annual writing contest honoring women’s stories of overcoming life challenges to find hope and healing.
In the lead-up to this year’s December 15 deadline for submissions, we’re revisiting the stories of resilience, hope and growth writers shared with us in 2016-17, starting with this powerful, lyrical poem about overcoming domestic violence by Donna Lloyd.
You Are
By Donna Lloyd
Domestic violence rocks a person's world.It turns everything upside down.It is a hurricane,that blows the fiercest of winds.It is a tsunami, that slams you like a freight train.It's an atomic bomb,destroying everything you hold dear.
You wake up one day –Your friends are gone.Your family is gone.But worst of all,You are gone.
You were born with a lightburning bright - deep inside you.It has always been there.When the dark days come,go and find this light.Take hold of its hand. You will do things you havelong since forgotten you could do.You have the power.You are worthy. You are strong.
How our judges and readers responded…
“What a moving, empowering poem.”
“I really like how your use of repetition evolves from images of destruction and pessimism to images of hope and optimism.”
About the author...
Donna is a survivor of childhood trauma and domestic abuse. Continuing on her healing path, she seeks to become a voice for the silent by raising awareness of these issues through her writing and art.
|
{
"pile_set_name": "Pile-CC"
}
|
Replication-competent adenovirus expressing TRAIL synergistically potentiates the antitumor effect of gemcitabine in bladder cancer cells.
Replication-competent adenovirus armed with therapeutic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been shown to sensitize cancer cells to chemotherapy and radiotherapy. However, the synergistic antitumor effect of replication-competent adenovirus expressing TRAIL and the cytotoxic chemotherapy in bladder cancer remains to be determined. Bladder cancer T24 cells or mouse tumor xenografts were infected with replication-competent adenovirus armed with human TRAIL (ZD55-TRAIL) alone or in combination with gemcitabine. The mRNA and protein levels of TRAIL were determined by "Reverse transcription polymerase chain reaction" and Western blotting, respectively. Cell viability was tested by CCK8 assay. Tumor growth in the mice was monitored every week by measuring tumor size. Cell apoptosis was detected by Annexin V-FITC staining and TUNEL assay. We found that adenovirus ZD55-TRAIL efficiently replicated both in cultured bladder cancer T24 cells and T24 mouse tumor xenograft as demonstrated by the overexpression of TRAIL and E1A. Gemcitabine did not affect the expression of TRAIL. In cultured T24 cells, ZD55-TRAIL enhanced the growth inhibitory effects of gemcitabine, accompanied by increased apoptosis. Similarly, ZD55-TRAIL synergistically enhanced the antitumor effect and induction of apoptosis following gemcitabine treatment in mouse T24 xenografts. In conclusion, replicative adenovirus armed with TRAIL synergistically potentiates the antitumor effect of gemcitabine in human bladder cancer. Our study provides the basis for the development of ZD55-TRAIL in combination with conventional chemotherapy for the treatment of bladder cancer.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
This invention relates to deceleration detecting valves adapted for use with vehicles such as automobiles or the like.
Deceleration detecting valves are widely used in hydraulic braking systems of vehicles such as automobiles, which systems usually comprise a master cylinder, a first circuit connecting the master cylinder with front wheel brakes, and a second circuit connecting the master cylinder with rear wheel brakes through a deceleration detecting valve. When the deceleration exceeding a predetermined amount occurs during application of the brakes, the deceleration detecting valve is actuated to cut off the supply of pressurized oil to the rear wheel brakes thereby preventing the so-called skidding phenomenon, increasing the braking efficiency and maintaining the directional control of the vehicle.
However, there is a shortcoming in such a hydraulic braking system is that when a failure occurs in the first circuit connecting the master cylinder with the front wheel brakes, and deceleration exceeding the predetermined amount occurs during braking of the vehicle by the rear wheel brakes, the deceleration detecting valve is actuated to cut off the supply of pressurized oil to the rear wheel brakes whereby the vehicle cannot sufficiently be braked. Accordingly, when a failure occurs in the circuit for the front wheel brakes, the rear wheel brakes cannot apply the desired braking force to the vehicle.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
If I’d never encountered the idea of a basic income before reading Laurie Penny’s recent article on it, I’d come away hating it. For Penny, it’s about replacing capitalism with something better. For me, it’s about improving the capitalism we already have.
Penny thinks that the idea is ‘blasphemy to conventional, liberal, “free-market” economists’. It’s not: we here at the Adam Smith Institute have proposed something along these lines for a couple of years, and Milton Friedman proposed a similar Negative Income Tax way back in 1962.
I suspect her utopianism will be off-putting to most people. She asks, “What would society look like if that sort of freedom were available to everyone: if advances in technology and productivity could benefit not only the very rich, but all of us?”, but most people actually benefit quite a lot from advances in technology and productivity already. 66% of British adults own a smartphone (also known as “the sum of all human knowledge, in your pocket”); wages are up by over 62% in real terms since 1986; and that doesn’t even mention the enormous global reduction in poverty in the age of neoliberalism.
Penny says that “unconditional basic income is a proposal that requires us to rethink the economic and ethical framework of neoliberal capitalism that has governed our lives for generations”, and for a basic income to work, “all that it requires is that we trust one another.” Er, thanks, but no thanks.
I’m a capitalist, neoliberal advocate of a basic income, or something like it. I don’t think it’s perfect, I don’t think it will solve every problem. I just think it would be an improvement, for three main reasons:
It addresses in-work poverty well. It reduces complexity in the welfare system. It facilitates other reforms that would raise overall living standards.
1. It addresses in-work poverty. Our existing welfare system is designed for a world where finding a job would be enough to give most people a tolerable standard of living. But in-work poverty is an increasing problem, particularly as good jobs for poorly educated workers become unviable, and the welfare system that we have at the moment isn’t well built for that.
This is where the robots come in. I’ve heard it said that automation of the economy is a lot like going to Australia – it’s great when you get there, but it can be a difficult journey. As robots replace them we probably will think of new things for people who used to work in law firms, factories, call centres and hospitals to do, but it might take some time.
Automation and globalization will both raise overall living standards, and in the case of globalization it will make very poor people in the developing world a lot better off, but we cannot guarantee that the jobs people get instead will be as good as their old ones. Working tax credits already begin to tackle this issue, but a basic income would reorient the whole system towards helping people who don’t have enough money, irrespective of why that is.
2. It reduces complexity in the welfare system. Our existing welfare system has built up a large amount of unnecessary complexity that could be streamlined. Like much public policy welfare is ‘path dependent’ – no two country’s welfare systems are the same, even if their welfare problems are. Much of the complexity in the welfare system has built up over time and exists only because of loss aversion: once we’ve started giving winter fuel payments to pensioners it’s quite difficult to stop.
Many but not all of these benefits are fundamentally about giving money to people who do not have enough of it. Housing benefit, the pension credit, jobseeker’s allowance, income support and tax credits all do this. But the case for a basic income does not need to stand or fall on whether we could replace all benefits with it. Some people inherently need more money to live decent lives, like the disabled, infirm and elderly. Reducing complexity is valuable but not the only, or indeed the main, appeal of the basic income.
3. It facilitates other reforms that would raise overall living standards. Many other policies that would increase total wealth are not very progressive, distributionally speaking. Tax systems are better when they do not tax things like investment and when they don’t exempt certain things from consumption taxes (like VAT), but doing these things ends up making lower earners pay more tax than we would like. One objection to immigration is that even though it makes natives richer overall, it has a small, temporary negative hit to the poorest natives. An easy way to correct that would be to redistribute the overall wealth gain to those poor natives so that they too are made better off in the short run as well as the long run.
Some pernicious government policies are ones that attempt ‘off balance-sheet’ redistribution. The minimum wage, for example, is hoped to be a redistribution from consumers and shareholders to low-paid workers – profits fall and prices rise to pay for their new, higher wages. The problems with it are that it has other unintended consequences, like causing unemployment for some workers, and that higher prices may hurt the poor as well. There’s no free lunch here – it would be more effective to tax people and then redistribute it directly to poorer workers. A basic income could replace policies like this.
|
{
"pile_set_name": "OpenWebText2"
}
|
Yes, Python is Slow, and I Don’t Care - mithunmanohar1
https://hackernoon.com/yes-python-is-slow-and-i-dont-care-13763980b5a1
======
scarface74
I was all ready to savage his opinion after reading the headline but I agree
looking at my architecture that I designed for the company I work for, CPU
isn't the bottleneck. Every time I try to increase performance by multi
threading as much as possible, the databases start screaming.
On the other hand, the idea that dynamic languages are more productive than
static languages are laughable. Statically type languages prevent a lot of
bugs and allow for a lot of automated provably correct refactorings that
simple cannot be done with a statically typed languages. You can't even
reliably do a "find usages" of classes using a dynamically typed language.
~~~
carlmr
>On the other hand, the idea that dynamic languages are more productive than
static languages are laughable. Statically type languages prevent a lot of
bugs and allow for a lot of automated provably correct refactorings that
simple cannot be done with a statically typed languages. You can't even
reliably do a "find usages" of classes using a dynamically typed languag
Exactly, I get quick and precise code completion, I catch plenty of errors
beforehand etc. I'd say I'm about 10x as productive in C# as in Python, with
similar amount of experience. Python only shines when there is a library that
does something really well that you need. For me any productivity advantage in
Python is from lots and lots of libraries.
Also in terms of maintainability, I find my C# code easy to read and modify a
year later when I've forgotten completely about it. In Python I need to rescan
all of the types into my head until I can understand what the program does.
I mean with var and dynamic, C# offers everything you need for duck typing
efficiency, while preserving the very important statically typed interfaces.
~~~
bluntfang
>In Python I need to rescan all of the types into my head until I can
understand what the program does.
Couldn't that be solved with sane variable naming conventions and
docstrings/documentation?
~~~
scarface74
Maybe. But it can be more easily solved on a strongly typed language where you
can right click on a method and do "find usages" and it can. E done
algorithmically.
------
freetime2
I pretty much agree with everything in the article - except for the bit where
he tries to quantify why python is better from a developer efficiency
perspective than other languages.
The main example he cites is a study that compares the amount of time writing
string processing routines in different languages - which is quite a bit
different from the work I do every day. I develop web apps which means I
generally work in very large code bases, and spend most of my time modifying
existing code rather than writing fresh code from scratch. I have found that
statically typed languages (java + typescript) and the fantastic IDE support
that comes along with them make it really easy to navigate around the code and
refactor things. Also - the compiler tends to catch and prevent a whole class
of bugs that you might otherwise only catch at runtime in a dynamically typed
language.
Of course there are other situations where I prefer to use Ruby as my
scripting language of choice - it all comes down to using the right tool for
the job at hand. Unfortunately I don't think the author gives enough
consideration to the trade-offs between static vs. dynamically typed
languages, and I think he would have been better just leaving that section out
as it isn't really necessary to prove his point that CPU efficiency isn't
important in a lot of applications.
Ultimately though I completely agree with his main point: "Optimize for your
most expensive resource. That’s YOU, not the computer."
------
mangecoeur
Python is also heavily used in science, where performance really does matter.
It's successful because of how highly ergonomic python apis can be built on
top of optimised C/C++/Fortran libraries.
That said, there is clearly a desire to write 'fast' code in python itself
without swapping to C. Cython helps, but to get really fast Cython code you
actually have to write with C-semantics (so you are basically writing C with
Python syntax).
Projects like numba JIT are interesting in that they can optimise domain-
specific code (i.e. numerical/array code) that's written in normal python
style. It also means jumping through a few hoops (although with the latest
version in many cases all you need is a single decorator on your hot
function). You can even do GIL-less multithreading in some cases.
Overall things are looking promising, with the addition of the frame
evaluation API and possible improvements to the python C-api that could make
JIT and similar extentions easier.
------
boomlinde
The author argues from his professional experience as a Python developer that
it's fast enough, that you'll spend most time waiting for I/O anyway, that you
can just throw more servers at the problem etc.
The problem is that his experience as a Python developer doesn't accurately
reflect the prevalence of problems where runtime CPU performance actually is
an issue. Of course not, because who in their right mind would make an
informed decision to solve such a problem in Python? Python has worked for him
because it is only useless for a category of problems that he hasn't had the
opportunity to solve because he's a Python developer. Outside this
professional experience, not everything is a trivially parallel web service
that you can just throw more servers at if CPU time exceeds I/O waiting.
It all really boils down to what your requirements are, whether you have all
the time and memory of a whole server park at your hands, or a fraction of the
time available in a smaller embedded system, how timely the delivery of the
software has to be and how timely it needs to deliver runtime results once
it's up and running. There are times where Python just isn't fast enough, or
where getting it fast enough is possible, but more convoluted and tricky than
implementing the solution in a more performant language. Developer time may be
more expensive than the platform that my solution is for, but that doesn't get
around the fact that it eventually will need to run with the available
resources.
------
agentgt
Unless we are talking like circa 1999 I don't think I have heard a complaint
yet that Python is slow. I'm curious who or where the author heard that from
(not specifically the people themselves but the domain they are in).
What I have heard complaints about Python are (and I don't agree with all
these points):
* Its not statically typed
* The python 2/3 compatibility
* It has some design flaws: GIL, variable assigning, mutable variables, lambdas, indentation (I don't agree with all these but this is complaints I have heard).
* The plethora of packaging (ie its not unified)
I guess one could argue its slow because it can't do concurrency well but that
really isn't raw speed.
Then the author started comparing string processing of programmer time from a
study which... doesn't help the authors point at all.
* Python has and will always be fast at string processing and most people know this
* The people that complain about python speed are almost certainly not doing string processing
* I have serious questions about the study in general (many languages have changed quite a bit since then)
~~~
pg314
> I'm curious who or where the author heard that from (not specifically the
> people themselves but the domain they are in).
In the telecom domain, I've dealt with data big enough that Python wasn't
really feasible. Think 100 of millions of records in CSV format that need to
be parsed and processed. Doing that in Python is going to be painful.
~~~
classybull
Python is insanely fast at data processing and analysis because it has very
fast libraries.
As a matter of fact, don't know if you've heard, but data processing it kind
of like.. Python's thing...
~~~
mattkrause
You're violently agreeing with each other.
Python _itself_ can be pretty slow. Doing image processing on data stored as
list-of-lists-of-integers would be brutally slow.
On the other hand, numpy is an import away, and it can be quite fast,
especially if it's been built with an optimized BLAS/ATLAS, etc.
~~~
AstralStorm
By blazingly fast you mean 100x slower than C++ equivalent and only 20x slower
is you're very careful to avoid accidental copies.
For reference, MATLAB is about 30x slower with no special care. Pure Java on
Hotspot was 5x slower except it dies on big data input due to very slow GC and
goes to 50x slow.
Source: handled big audio data from hdf5 database, gigabytes sized. C++
equivalent had no vectorization or magic BLAS or anything.
~~~
joshuamorton
As I'll often say to these comments, then you're doing things wrong. Numpy
code can be written to never leave the numpy sandbox, and at that point it
should be as fast or faster than naive c++ (because you'll be getting SSE and
stuff for free).
There's a reason almost all deep learning is done in python.
~~~
pg314
Not all data is a good fit for Numpy: some data is non-numeric or not a
homogenous array.
> There's a reason almost all deep learning is done in python.
The heavy-lifting in e.g. TensorFlow is done in C++. Bindings to Python make
sense because it is one of the few sanctioned languages inside Google, and it
is widely used outside of Google and easy to pick up.
~~~
joshuamorton
>The heavy-lifting in e.g. TensorFlow is done in C++. Bindings to Python make
sense because it is one of the few sanctioned languages inside Google, and it
is widely used outside of Google and easy to pick up.
That's exactly the same as with numpy. I'm not sure what your point is. C++ is
also one of the few sanctioned languages inside google, as is Java.
>Not all data is a good fit for Numpy: some data is non-numeric or not a
homogenous array.
I'm curious what kind of data you're working with that can't be represented
and effectively transformed in a tensor (numpy array).
~~~
pg314
> That's exactly the same as with numpy. I'm not sure what your point is.
I was replying to "there's a reason why...". You didn't specify that reason,
so from the rest of your comment I took it to mean that Python (with numpy)
was fast and good enough to write deep learning stuff. That doesn't seem to be
the case for TensorFlow.
> I'm curious what kind of data you're working with that can't be represented
> and effectively transformed in a tensor (numpy array).
I'm not intimately familiar with the internals of numpy, but my understanding
is that the basic data structure is a (multi-dimensional) array of values (not
pointers). That leads to a number of questions.
If you have an array of records (dtype objects), and one of the fields is a
string, am I correct that each element needs to allocate memory to hold the
longest possible value that can occur for that field? What if that is not
known beforehand?
How do you deal with optional fields (e.g. int or null)? Do you need to add a
separate boolean to indicate null?
How do you deal with union types, e.g. each record can be one of x types, do
you make a record that has a field for each of the fields of those x types? Do
those fields take up space?
~~~
joshuamorton
>You didn't specify that reason, so from the rest of your comment I took it to
mean that Python (with numpy) was fast and good enough to write deep learning
stuff. That doesn't seem to be the case for TensorFlow.
Tensorflow tensors are numpy arrays, or are transparently viewable as such.
>If you have an array of records (dtype objects), and one of the fields is a
string, am I correct that each element needs to allocate memory to hold the
longest possible value that can occur for that field? What if that is not
known beforehand?
Yes, although you can also store numpy arrays of pyobjects, which are arrays
of pointers. You'll be able to vectorize the code, but you won't get the same
performance improvements as with a normal numpy array, because that same level
of performance isn't possible with an array of pointers.
Note that for most machine learning applications, you'd preprocess your string
into a vector of some kind.
>How do you deal with optional fields (e.g. int or null)? Do you need to add a
separate boolean to indicate null?
Yes, but I'm not sure when you'd do that. That is, again in most machine
learning applications you'd be representing things as one-hot arrays or as
some kind of compressed high dimensional position vector, where 0 would
represent a lack of presence of some thing.
>How do you deal with union types
dt = np.dtype((np.int32,{'real':(np.int16, 0),'imag':(np.int16, 2)})
is a 32 bit int that can also be accessed as a 16 bit complex number via .real
and .imag.
------
icebraining
"It doesn't matter than Python is slow, besides we can use compiled libraries
to speed it up"
"People saying it doesn't matter that Python is slow are deluding themselves
and preventing Python from getting faster like JS did"
"Python is inherently harder to optimize than JS since it has <very dynamic
features>"
"Smalltalk/Lisp/etc are also very dynamic yet are much faster"
"The slowness of Python is harming the planet by being inefficient and
therefore wasting more energy/producing more pollution"
Did I miss any arguments? I know certain topics are bound to attract some
repetitive discussion, but "Python is slow" has been one of the worst.
~~~
dom0
> "Python is inherently harder to optimize than JS since it has <very dynamic
> features>"
Python is not a very dynamic language in the sense that you actually _can 't_
change a lot of stuff (and a number of the things you _can_ change just
segfault CPython). I think JS is more dynamic, for example. Or Ruby.
~~~
icebraining
These are not my arguments, mind you; I don't know enough to make them.
You've piqued my interest, though: can you give me an example of those things
that you can't change or that break CPython?
~~~
dom0
Things like the Carlo Verre hack (also a thing you can't change —any more— in
Python: builtins), editing objects during their construction (via e.g. gc)...
generally, the gc module allows other ways as well to crash your interpreter.
>>> import gc
>>> 'foo'.lower()
>>> gc.get_referents(str.__dict__)[0]['lower'] = str.upper
>>> 'foo'.lower()
segmentation fault (core dumped) python
(That's the method lookup cache)
A talk in this direction is
[https://www.youtube.com/watch?v=qCGofLIzX6g](https://www.youtube.com/watch?v=qCGofLIzX6g)
------
Waterluvian
Python is my Swiss army knife. I love it because it is a single tool that can
aid in almost every project I do. But if I'm doing one specific thing a lot, I
want that thing to be done well and done efficiently, so I'll reach for the
specific screwdriver I need.
Also most of my problems are IO bound so single threaded concurrency is fine.
But I represent a very small portion of the global problem space.
------
dom96
The fact that Python is slow isn't its only problem. What I care more about
nowadays is wasting my time hunting bugs that could have been avoided by a
static type system.
~~~
blumomo
Please tell me, do you write tests? I've learned that it's necessary. I do
100% code coverage and I'm enjoying TDD a lot.
~~~
virmundi
The whole point of static type systems is that they give you the "type tests".
100% code coverage just to get what the compiler would give you is a waste of
time. If python is supposed make developers more productive, this is just
dragging them down.
------
dahart
Python's value to me has always been that it's easier to get things done, not
it's speed. One time when I was interviewing a candidate for a coding job, the
candidate said she loved Python the most "because you can just yell at it and
it'll work."
It's both the breadth of the standard library and ecosystem, and the simple
language design, that make developing things in Python faster for me.
Doing problems on Project Euler has been an education for me in how algorithm
matters more than speed. Lots and lots of people spend hours writing long C++
codes that are easily beaten by a few lines of Python. It certainly goes the
other way too, and the wrong algorithm in Python is even that much slower and
more painful than the right algorithm in C++. But when the right algorithm is
used and the problem is solved in a few milliseconds, it really doesn't matter
which language uses more CPU cycles, all that matters is whether you saw the
insight that let you skip 99% of the search space, and how much time you spend
writing code.
------
_pmf_
Somewhat ironically, Python is used a lot for things that would benefit from
raw speed (data processing pipelines) and do not benefit at all from dynamic
typing (since the kind of property bags / data frame views over data are
easily replicated in statically typed languages). But Python's C extension API
is quite a bit easier than p.e. Matlab's MEX API (to me at least); can typical
Python IDEs compile and relink extension modules without an external build
step?
> Your bottleneck is most likely not CPU or Python itself.
With applications that are dominated by raw data processing, it's very, very
easy to be CPU dominated. Hell, I had one quite trivial data converter for
logfiles where the "parsing the printf string" part of Java's printf dominated
processing and writing a custom formatter halved processing time (while
regexes can be compiled, the format string cannot be precompiled and will be
interpreted each time); it's one of those things where I would intuitively say
"why did this moron write his custom formatter" if I stumbled upon it in a
code review. Intuitively, you'd expect this to be a simple case of an IO
dominated task (which it is now once the bottleneck has been removed).
If it's fire-and-forget batch jobs, you can get away with it, but if the
converter is part of a user facing fat client application that runs on a old
office laptop, you don't have that luxury.
------
kodablah
The article could be titled: "Yes, Python is Slow To Refactor and Maintain,
and I Still Don't Care".
I never understand why dynamic language enthusiasts primarily focus on new
code only. You have to discuss all sides of increased or decreased
productivity to make a rational argument.
~~~
hasenj
Python is optimized for getting interesting things done in a few lines of
code. Small scripts you write once and then forget.
For serious projects? IMO python is a disaster.
------
wyldfire
> Your bottleneck is most likely not CPU or Python itself.
I've found that this is often the case. Nearly always disk or network. But
it's sometimes surprising how little work you need to do to become CPU-bound.
This is the price we pay for such a tremendously dynamic language.
Indeed, the article's suggestions of C/Cython/PyPy are good ones to remedy the
problem when it occurs.
------
jayflux
I get the point this guy is making, but if you need something parallel for a
cpu bound task, throwing more hardware at the problem isn't the most efficient
solution if you can just use more cores. For example adding another quad core
when the first cpu is only using one core anyway is inefficient and expensive.
Right tool for the right job I suppose.
~~~
nhumrich
Python does multiprocess very well. You can easily use all cores on your
machine. Pythons main "disadvantage" is threading because of the GIL. But each
process gets its own GIL. So when you multi process, your not limited to one
core.
~~~
classybull
This. I had a problem where I needed to scrape roughly 20,000 html documents
daily, which is normally a pretty slow task. You have to open the file, load
it into memory, parse the DOM, and then run all of your selection methods.
Sequentially, it took about 60 minutes daily. Multithreading slowed it down
because it was CPU bound. Multiprocessing allowed me to run 12 processes
across 8 cores. That took the total processing time down to about 4 minutes or
so. And I was able to write the code in a day. Writing something similar in
Java or C++ would have taken me a week.
------
nadam
"It used to be the case that programs took a really long time to run. CPU’s
were expensive, memory was expensive. Running time of a program used to be an
important metric."
As hardware gets faster we give it new tasks that could not be achieved
before. Like rendering high resolution stereoscopic images using physically
based shading at 90 FPS on relatively cheap consumer hadware (VR). There are
still quite a lot of code that we call 'performance critical'. Most of that
code is written in C/C++ (and CUDA and glsl, and hlsl, etc...) today.
~~~
ivm
It's still expensive on client machines because most of the persons in the
world are NOT software engineers with 6-digit salaries.
They run cheap computers with HDDs and Windows polluted by a ton of 3rd party
crap. They don't know how to fix it and silently suffer.
I was cleaning a local vet clinic's devices recently – they were literally
switching between two computers to not wait 5 minutes of non-responsiveness
because some bloated software was occasionally consuming 100% of CPU.
~~~
mark-r
A lot of businesses these days prefer web apps. It's not hard to understand
why - all the hassle of system maintenance falls to the people who host the
app and can afford to know their stuff. If your Windows PC is suffering from
rot just replace it with a Chromebook.
~~~
ivm
"Just get money for a new device out of thin air and just replace all your
paid or even cracked Windows software with subscription-based alternatives
that will not work without Internet. Ah, also just relearn all your
workflows."
Sorry, but that's how being in a bubble looks like.
~~~
mark-r
I wasn't suggesting that businesses were anxious to replace things that
already work, I'm suggesting that as they acquire new software it's more
likely to be web-based.
Devices are often replaced on a schedule anyway, especially if they're leased.
~~~
ivm
I wasn't talking only about businesses in my previous reply. But most
businesses on the planet aren't bathing in money either.
You are speaking as a citizen of a rich country where devices are relatively
cheap and stable Internet is available everywhere.
------
VHRanger
The problem is not so much that python is slow. It's that in some scenarios
python can't be made fast.
Fast prototyping is great but being stuck with a prototype for deployment
isn't.
~~~
traverseda
>It's that in some scenarios python can't be made fast.
Can you give some examples of this? I mean, obviously with enough effort you
can "make python fast" since it has good C bindings, and can just be a thin
wrapper around fast stuff. Similar to how command line tools can be
ridiculously fast[^1] despite, ostensibly, running in bash.
So I'm a bit confused about what you're claiming. Organizational issues, it's
difficult to get management on board with an optimization pass?
[^1]: [https://aadrake.com/command-line-tools-can-be-235x-faster-
th...](https://aadrake.com/command-line-tools-can-be-235x-faster-than-your-
hadoop-cluster.html)
~~~
VHRanger
My point is do you have competent C programmers on your team?
That said, there is a point in some python prototypes where you "hit the
performance wall". For whatever reason, you'll need to look at one of the
options to make python faster and none of them are painless unless you're
already a serious C programmer.
------
traverseda
There's are still some big gains python could make, if python implementations
were better.
Micropython is equivalent to a real-time cooperative-multitasking OS. If it
had ~~better~~ support for things like cffi, you could implement posix on top
of it. I can imagine a laptop that runs gnu+python in the next few years.
That's a whole new usecase, simply because that implementation uses a lot less
ram. What usecases would we discover for a faster python?
Shared objects and proper sandboxing would also be huge.
~~~
jerf
"There's are still some big gains python could make, if python implementations
were better."
At this point, I would find it far easier to believe that you are
underestimating the difficulty involved in what it takes to speed up Python
than that there are enormous gains yet to be had in speeding up Python. I
suspect JS has had more optimization effort expended overall, but Python has
still had a ton of work by lots of smart people, and generally got an earlier
head start on optimization. (They didn't start trying to make JS "fast" right
away; they spent rather a lot of time getting JS's hookup to the DOM in the
face of things like .innerHTML working first, before anyone even cared to do
what we today do routinely without thought in plain ol' Javascript, let alone
with our glorious frameworks.)
There are enormous gains to be had in speeding up "a language that is like
Python except certain things are banned", but people have already done _that_
analysis too and discovered that broadly speaking, if you do that, too much
existing Python breaks. If you want to see something like that, check out the
RPython aspect of the PyPy project, which successfully implements a fast
subset of Python. But it is a noticeably restricted subset of Python; AIUI
it's not even close to something you can just drop in to your code and get
faster speeds.
One of the things that I've learned from Python and the other attempts to
speed up the scripting languages is that despite the mantra, yes, there _is_
in practice such a thing as an intrinsically slow language. (The theoretical
existence of a Python interpreter that can run all existing Python code at C
speeds doesn't do us much good if we have no idea after decades of very smart
people banging on the problem how to manifest it. Personally I'd suspect that
while such a beast theoretically exists it has an exponential complexity
startup cost or, if you prefer, exponential compilation costs. And probably a
pretty decent code and/or RAM bloat cost, too.) And Python is one of them.
Some of the reasons why it is so much fun to use are part of that intrinsic
slowness. Some of them really aren't.
I personally think there's a lot of up-and-coming languages that are exploring
the space of how to get those nicer programming abstractions and programmer-
convenient code without paying anywhere near the runtime cost that the dynamic
scripting languages of today do; it's one of the more exciting developments I
see coming up. People complain a lot about code bloat and poor performance of
our code since right now we have to choose between "fairly inconvenient but
fast" and "convenient but slow and bloated". Patience! Better choices are
developing, but they're still young.
~~~
monkmartinez
Will you please share the languages you thunk are up and coming?
~~~
jerf
Go is an early entrant into this space, but I think part of the reason it is
early is also that it is less ambitious. But to answer the ever-present
question on HN about "why would anyone ever use this language?", something
modern, almost as easy to use as a scripting language [1], and almost as fast
as a compiled language, doesn't actually have a lot of contenders. (Old
fogeys... like me!... like to observe that if you drop modern you have some
things like Delphi that fit that slot, but they're all pretty much dead now,
and Go has good support for concurrency in the modern processor environment.)
In the "you probably can't convince your boss yet" category I'd recommend
Crystal ([https://crystal-lang.org/](https://crystal-lang.org/)) and Nim
([https://nim-lang.org/](https://nim-lang.org/)).
Given the programming landscape and the general direction of things lately, I
also bet there's a couple of serious contenders developing out there that
haven't even hit HN yet.
[1]: For at least a broad class of problems. Put Go head-to-head with a
problem someone would use NumPy for and Go will go down in flames in the ease-
of-use and line count department. However I use Go for a lot of networks
servers (not even necessarily Web servers, but network servers) and the line
count for these comes out maybe 20% larger than Python, and it doesn't take
much developer cognitive energy for those extra lines. I've also used Go for
some command-line type apps where the line count is probably 50% over Python,
but I also got some significant wins from the type system and concurrency, so,
all in all there's a lot of things I can prototype with about the same mental
effort in Go as I could in Python. Being able to declare interfaces that
existing types conform to turns out to cover a surprising amount of those
"duck-type" scripting-type cases.
------
booshi
This keeps getting posted, and while it makes some valid points, it's a lot of
handwaving.
Arguably, other languages can get code out faster depending on the dev,
language, etc.
~~~
0xcde4c3db
Agreed. Things that are handwaved include:
1) Performance can be a genuine requirement of the product, i.e. if it's not
fast enough, it doesn't ship. You can't ship faster and cheaper by sacrificing
the thing you need to ship (well, you _can_ , but then you're shipping a
different product, not meeting the same requirements sooner; it's no different
than cutting a feature).
2) Many processes can't be horizontally scaled in an efficient way, period.
Not because the programmer is ignorant of some cool algorithm, but because the
problem is fundamentally expensive to parallelize. Maybe you end up getting
something like a 20% boost by having twice as many nodes, even after applying
all the cool algorithms. And you don't necessarily get that scalability in
your code base for free, either.
3) "Speed" in the mobile and embedded spaces is often as much about energy
efficiency and thermal management as getting done sooner.
4) The metrics for deciding that Python is faster to develop in only measure
small problems. People tend to shy away from Python for bigger projects, and
the reasons for this are pretty hotly debated.
------
bluedino
Many times when Python is blamed for being slow, it's the programmers fault.
Python is great that you can 'regular' people writing code in it quickly. The
problem is, these regular people don't always understand algorithms or things
like caches, threads, databases...
A lot of these users can just say "My department needs a $40,000 24 CPU server
with maximum RAM from MicroWay/SuperMicro, we need to run our codes faster",
when they are just trying to brute force things.
They understand the problem domain but don't have the programming skills to
use a computer to efficiently solve it.
But, these guys are all a step ahead of the ones who are stuck in the mindset
of "C is the only language fast enough for my work", while not even
understanding pointers and basic syntax and getting stuck on silly things like
text processing, which could be done in minutes in Python.
------
nhumrich
Author here. Surprised to see this toping HN. Appreciate all the feedback. Let
me know if you have any questions.
------
progman
Yes, time to market is important. However, you don't need to compromise
convenience of development for the sake of performance. If you twist your
Python code to get performance it takes time. If you need performance, and
like the syntax of Python then you should take a look at Nim [1]. With Nim I
develop as quickly as in Python while I get the performance of C.
[1] [https://nim-lang.org](https://nim-lang.org)
I believe application performance _is_ important on servers. It makes a
difference if your Shop software written in Python is able to handle 50
requests per second, or if the same software written in Nim can handle 500
rps. And by the way, Nim provides static typing which helps a lot to catch
errors at compile time.
~~~
cup-of-tea
Nim seems really good, but does it have a decent REPL these days? I'm not sure
if it would be as convenient with a statically typed language, but I like the
incremental development approach so much that I only use C if I absolutely
have to.
~~~
dom96
It doesn't. But you can grab Aporia (or some other tool) to quickly compile
and run some code, it replaces a REPL very well in my experience.
------
deadsy
Premise: It's more important to be productive than to have fast code.
Conclusion: Use Python. Is the premise true? For many cases- yes, but it
depends. If you are running an application on the cloud and your metric is
$/user/year and you have many users then saving some compute resources for
each user gets attractive and you don't want to just throw another VM at it.
Is the conclusion true? Garbage collection gives big productivity gains. Other
languages have GC. It's not nice to see your Python code die after a few days
because you messed up the type passed to a function. Other languages fix that
at compile time. Multicore is now. Other languages are built with better
multicore awareness.
------
__s
> without getting stuck in the weeds of the small things such as whether you
> should use a vector or an array
Yes, instead get into the weeds of tuple vs list
Not included in the graph of time-to-solve-problem static languages:
statically typed languages with type inference
~~~
scbrg
Given that they have exactly the same interface, that choice is really easy.
You go with one until it turns out to be insufficient, and then you switch to
the other and _not a single line of code_ has to change, except at the point
where you create the thing.
Incidentally, the same is true in many situations in Python, and that is (IMO)
one of its strengths.
------
agnivade
> However, this is no longer true, as silicon is now cheap. Like really cheap.
> Run time is no longer your most expensive resource.
Our client won't spend more money than a t2.medium instance on aws. Nothing we
can do about it. In that case, run time does become an expensive resource.
But I get the point that OP is trying to make. Just wanted to mention that not
all of us have the comfort of having enough resources on which our app runs.
------
fiatjaf
> It’s more important to get stuff done than to make it go fast.
This is not a real absolute. It is only valid when what you have to run will
not benefit a lot from performance or suffer a lot from lack of it.
The real guidance you can have in these matters is: how many times is my code
going to run per second?
Some programs are written to be run once a day, others 10000000 times in a
second. The first ones should be written in the language you're most
productive in, the second ones in the fastest possible language.
------
karmakaze
Putting aside the discussion regarding productivity, there is a case where I
have found execution time to matter. Scaling an application which uses an
unsharded database. The long transaction durations and number of connctions
were bottlenecking db throughput. The particular app was a Ruby/Rails
monolith.
------
nervous123
This sentiment is the reason for almost all software (especially on the web)
beeing a load of crap. It's slow, it's buggy and developers always give the
same excuse: CPUs and memory are cheap, therefore we can waste our customers
time.
Imagine what we could do with the amazing hardware we have, if people started
to do the sane thing and actually use the hardware to do things efficiently.
------
Thaxll
Giving EvE Online as an example is bad because that game artificially slow the
game loop to keep up with the number of players, would this happen with C++ on
a recent architecture? Probably not.
------
sedlich
In "What if CPU time is an issue?" we could also mention the nim language (and
not only cython) because it compiles (not only) to C and feels like python.
------
donatj
I know it's not trendy, but I would argue PHP is as productive for developers
as Python and has a MUCH faster runtime, particularly after 7.
------
snarfy
Slow doesn't matter when you scale horizontally.
------
hellofunk
Yeah? Well, Jimmy Crack Corn and _I_ don't care.
|
{
"pile_set_name": "HackerNews"
}
|
Q:
Correct "empty" return value for List[List[X]]
If I have a function List[A] => List[List[A]] and need to return an "empty" value, is there a theoretical preference between the following
a) Nil
b) List(Nil)
... or does it depend on the function?
For a concrete example, I could implement a function to split a list into sublists of length n or less as follows:
def sublists[A](xs: List[A], n: Int): List[List[A]] = {
val (ys, zs) = xs.splitAt(n)
if (zs.isEmpty) ys :: Nil
else ys :: sublists(zs, n)
}
If xs is empty this returns List(Nil). Do I need to include a check on whether xs is empty, returning Nil, for this function to be correct?
A:
Without doubt, the correct empty value for a List is the empty List, no matter what the type of the List elements is.
The same is true for more elaborated types. A set containing the empty set is very different from an empty set, and so forth.
Think of it like this: A list result allows you to ask: how many results do we have? If you use a list with an empty List as empty value, then the answer would be incorrectly 1.
|
{
"pile_set_name": "StackExchange"
}
|
One of the most stressful moments of any holiday occurs at check-in when you often wonder if your bag will be there to meet you the other end. Some 3,000 pieces of luggage go astray around the world every hour, the equivalent to 26 million lost or misplaced bags per year. But lost luggage nightmares could very soon be a thing of the past thanks to a joint initiative between Airbus, the telecommunication company T-Systems, and luggage manufacturer Rimowa.
They’ve come up with a special piece of luggage equipped with the ‘Bag2go’ system. It links up to your smartphone or tablet so you can track your bag in real time.
Airbus’ Innovation Manager Jan Reh described the design brief: “It was very important for us to come up with a solution that was very easy to use for the passengers. When you see this, this is a conventional bag tag and this will be something of the past. What we are looking for is to get this on an electronic display so that this information can be displayed on the case and you can control this with your smartphone, so you can look to see where your bag is.”
The idea is radical, the technology standard. A sim card is installed inside the bag. Two sensors weigh the bag and display an electronic tag. The bag then communicates directly with your smartphone as you punch in the flight details. A smartphone app uses GPS to track the bag and even lets you know if the bag is opened or manipulated.
Jan Reh says, “We hope that we can improve the overall baggage handling processes today with bag2go and this is also the aim. We are working together with the industry to see how we can solve and help the baggage handling and bag2go is one puzzle piece in this overall game to make baggage more controllable for airlines and to give passengers a better travel experience.”
It means that in the hotel lobby for example, that at the same time that you check out, you can check your bags in rather than wait to reach the airport to do it. From that moment on you know exactly where your bag is.
Torsten Chudobba, from T-Systems, says it’s less about groundbreaking systems and more about using what’s available efficiently: “We have not developed something new. We just brought existing technologies together and optimised this for tracking and tracing. It’s a combination of the new technology and ease of use and there is no further investment from the airport or wherever.”
The system is being tested throughout 2014 and airlines are very keen to participate because each lost item of luggage costs them around 73 euros to retrieve and return to its owner. IATA, which represents the airline industry, says this is close to 1.8 billion euros in lost revenue.
IATA representative Andrew Price is confident that the system will gain traction: “This new technology is a fantastic enabler that will help the business transform itself so that not only will fewer bags be mishandled but newer and more innovative ways of delivering those bags will be found. These technologies may seem like they are new today but within five years they will be absolutely commonplace.”
Bags often go through 14 different touch points between drop off and pick up on arrival. Bag2go can’t always prevent luggage heading to the wrong destination – but the system will be able to alert airlines when your bag has taken a mis-turn before it’s taken onto the wrong aircraft. And of course if it does end up at a different city from you, there is at least the peace of mind of knowing exactly where it is, which will greatly speed up its return to you.
Bag2Go is still in the prototype phase and Airbus expects it to cost around 20 per cent more than a conventional suitcase.
|
{
"pile_set_name": "OpenWebText2"
}
|
The planning of my gay wedding has sparked very interesting discussions among the people in my social and professional circles. After my beloved first proposed, we were met with happy greetings and best wishes from the members of our community. But when I started asking big questions about weddings, marriage, and social injustices I was often met with incredulous stares and upset feelings. Why talk about these "negative" topics during my supposedly blissful engagement period? Because I am a lesbian and my partner is genderqueer and we cannot enter into an institution that has traditionally been upheld as a union between a man and a woman without some amount of fear and skepticism.
I love straight people. Many of my closest friends are straight. They do the same things that we gays do, like Facebook and laundry, but they do them with a level of privilege that we gays do not have. When straight people of the same race get engaged they can mostly expect their communities to react with love, support, and validation of their union. When gay people get engaged, they might expect the same love and support from their communities, but they can also expect misunderstanding, hate, and ignorance. Straight people do not have to worry that a vendor will not work with them because of their sexual orientation. Straight people do not have to answer questions like "which one of you is the bride and which one is the groom?" Straight people may worry about their wedding outfits, but not because they are concerned that their gender identity will be misread or invisible if they get the outfit wrong. Straight people's families do not use the wrong pronouns.
Privilege is not a bad word. It is a reminder. I feel strongly that everyone should examine the ways in which they are privileged.
I am a Caucasian, cisgender, homosexual woman. I have racial privilege and I often ask myself, "what does it mean to be White?" It means I have been awarded unearned opportunities solely because of the color of my skin. It means people do not assume I am shoplifting when I enter an upscale store (even though I have messy hair and wear mud-caked hiking boots). It means I am not profiled by the police but I do move through airport security with relative ease. Privilege is multi-faceted and complex. I have gender privilege because I am cisgender (my gender identity matches the one I was assigned at birth), but I also do not have gender privilege because I am a woman (cisgender men are the winners of gender privilege in case you haven't noticed). This means that while people correctly identify my gender as woman and correctly use feminine pronouns, I also have to deal with strange men making objectifying and unwanted remarks about my breasts. See? More complex than trigonometry, right?
My fiancé is transgender. Xe was assigned-female-at-birth but identifies as genderqueer and uses the gender neutral pronouns xe/xyr/xem. No one ever uses xyr correct pronouns unless they are explicitly told to use them and even then some people flat-out refuse. I always wonder how a cis man would feel if everyone he encountered incorrectly called him "lady," or "ma'am," or "girl." And when he protested he was met with "well, I just see you as a woman so I'm going to call you 'her.'" How could that happen? How could someone look at a person's gender expression and misinterpret their gender identity? It happens every day. It happens to my fiancé every day. Xe is wounded moment by moment, day after day by micro-aggressions from people who do not have to think about gender.
So what do we do about it? I am done sitting in my bubble of wedding planning privilege. I am popping my bubble, donning the outfit of a warrior bride (think chainmail veil), and taking my vocal sword into the crowd and to my wedding!
Weddings are fun and love-filled, but they are also exclusive and riddled with heteronormativity. The Offbeat Bride world is acting as a support for those of us who do not want to adhere to the norm, but I challenge all of us to take it a step further. I am using my wedding as a political platform to speak out against issues of social injustice. I seek to open a discussion about power, privilege, and oppression and how all of us who are planning weddings in the 21st century can be agents of change.
No longer will we sit behind sweetheart tables, toasting to our love-filled privilege bubbles. No! We will engage in conversation every day, asking ourselves and each other tough questions like "how does privilege impact our lives?" We will alter our language to be more inclusive. We won't assume someone's gender but will instead ask, "what is your preferred pronoun?" We will no longer be afraid of offending people. We will offend! And then we will listen. We will listen with open minds and acceptance. We will understand that examination of wedding planning privilege is initially uncomfortable, but necessary for growth and change. We will hang out in the discomfort. And at our weddings, all people will dance because they feel safe and loved and seen.
Warrior Brides of the 21st century, unite!
|
{
"pile_set_name": "OpenWebText2"
}
|
using cloudscribe.Multitenancy;
namespace Microsoft.AspNetCore.Http
{
/// <summary>
/// Multitenant extensions for <see cref="HttpContext"/>.
/// </summary>
public static class MultitenancyHttpContextExtensions
{
private const string TenantContextKey = "cloudscribe.TenantContext";
public static void SetTenantContext<TTenant>(this HttpContext context, TenantContext<TTenant> tenantContext)
{
Ensure.Argument.NotNull(context, nameof(context));
Ensure.Argument.NotNull(tenantContext, nameof(tenantContext));
context.Items[TenantContextKey] = tenantContext;
}
public static TenantContext<TTenant> GetTenantContext<TTenant>(this HttpContext context)
{
Ensure.Argument.NotNull(context, nameof(context));
object tenantContext;
if (context.Items.TryGetValue(TenantContextKey, out tenantContext))
{
return tenantContext as TenantContext<TTenant>;
}
return null;
}
public static TTenant GetTenant<TTenant>(this HttpContext context)
{
Ensure.Argument.NotNull(context, nameof(context));
var tenantContext = GetTenantContext<TTenant>(context);
if (tenantContext != null)
{
return tenantContext.Tenant;
}
return default(TTenant);
}
}
}
|
{
"pile_set_name": "Github"
}
|
Influence of brown coal on limit of phytotoxicity of soils contaminated with heavy metals.
The paper gives knowledge and application values in efficiency of applying brown coal to limit uptake of heavy metals from contaminated soils by different plant species. The paper determines possibility and principles of using brown coal in reclamation of soils contaminated with heavy metals and rebuilding soils on devastated terrains like terrain in the influence zone of Copper-Smelter "Legnica". On the basis of pot experiment it was stated that increasing doses of brown coal limited phytotoxicity of soils. Results of the paper show that tested fertilizer could be applied on soils strongly contaminated with heavy metals giving long-lasting improvement of reclaimed soils.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Mándok became town in 2007. It is situated in northern part
of county, between upper curve banks of Tisza river.
Regulations on the Coat of Arms and flag of town (in Hungarian)
at <www.mandok.hu>.
Photos of the flag here
and here.
Description of Coat of Arms (in English) at <www.nemzetijelkepek.hu>.Zoltan Horvath, 21 February 2010
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
Open MPI in Xcode 3.2.6
I want to run Open MPI program in Xcode. I follow http://www.macresearch.org/compiling-running-and-debugging-mpi-programs-xcode tutorial. I am getting output for MPI_test executable. but when i am running mpiexec, i got the following error:
Failed to find or execute the following executable:
Cannot continue
A:
If you are running mpiexec from the command line, you are probably not starting in the correct directory. Your executable's directory is in either the Debug or Release directory in your project directory depending on which configuration you select when you build. If you named your project MPI_test, go into the appropriate directory and type ./MPI_test and make sure the program runs. If it doesn't, you're not in the correct directory. Once you've found the correct directory, you can type mpiexec -np 4 MPI_test and that should run as well.
If you are following the instructions to run mpiexec within Xcode, it wlll only work if you name your project MPI_test. Instead of setting the second argument in the custom executable to $(PROJECT_DIR)/$(CONFIGURATION_BUILD_DIR)/MPI_test, set it to $(PROJECT_DIR)/$(CONFIGURATION_BUILD_DIR)/$(PROJECT_NAME) and it will work no matter what you name your project as long as it's a valid command line program name (e.g. it can't have spaces).
|
{
"pile_set_name": "StackExchange"
}
|
Q:
switch/case for determining variable to assign to in Python
I'd like to use a "switch/case" structure to decide which variable to assign a value to based on some parameter:
a, b = [init_val] * 2
# This doesn't exist in Python.
switch param
case 'a':
a = final_val
case 'b':
b = final_val
The dictionary method described in the question Replacements for switch statement in Python? doesn't work here, since you can neither assign to a function call
a, b = [init_val] * 2
switcher = {
'a': a,
'b': b
}
switcher.get(param) = final_val
nor change the value of a variable by storing it in a dictionary:
switcher[param] = final_val # switcher['a'] is only a copy of variable a
I could just stick to "if/elif", but since I have often seen that nice dictionary solution (as in the aforementioned question) for determining an output based on some parameter, I'm curious to see if there's a similar solution for determining which variable, out of a set of variables, to assign a value to.
A:
Python, in general, does not have a built-in switch/case functionality. Instead, common practice is to use the elif keyword as such:
a, b = [init_val] * 2
if param == 'a':
a = final_val
elif param == 'b':
b = final_val
else:
pass # or do something else
|
{
"pile_set_name": "StackExchange"
}
|
[The analysis of detection rate of ambiguity of loci under HLA-typing by SSO technology].
The article deals with the results of HLA-typing of 1829 patients on loci HLA-A, HLA-B, HLA-DRB1 using kits of LABType SSO reagents (One Lambada, USA). The indicators of each locus ambiguity are determined: locus HLA-A - 4.43%, locus HLA-B--4.43%, locus HLA-DRB1--0.16%. The list of "rare" alleles was applied to analyze 13 types of determined ambiguities on locus HLA-A, 27 types on locus HLA-B, 3 types on locus HLA-DRB1.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
We use the stinkiest dryer sheets we can get our hands on. Brand isn't too important. If we can smell the unopened box from the end of the aisle that's the one we buy. Put at least one sheet in every cabinet, drawer, storage area, shelf - everywhere. Wearing gloves will keep your hands from smelling to high heaven for a couple of days.
No mice and no spiders in 20+ years. (We also remove all paper products when we put 'er into hibernation.)
IMHO brass wool is better than steel wool for plugging holes. Both work - but steel is more likely to rust.
I used dryer sheets and they seemed to work then I was told about Irish Spring soap, cut it in quarts and place it around, it worked the first winter then when the smell diminished the mice ate the soap! lol stick with the dryer sheets and check often for any signs
|
{
"pile_set_name": "Pile-CC"
}
|
Influence of blood volume on cerebrospinal fluid levels of arachidonic acid metabolites after subarachnoid hemorrhage: experimental study on the pathogenesis of cerebral vasospasm.
Based on accumulating data indicating the important role of arachidonic acid metabolites in the pathogenesis of cerebral vasospasm, we examined the influence of alterations in blood volume on the cerebrospinal fluid (CSF) level of the subarachnoid hemorrhage (SAH). Three separate injections of autologous blood into the cisterna magna of dogs within subarachnoid hemorrhage (SAH). Three separate injections of autologous blood into the cisterna magna of dogs within 72 hours were performed. Three experimental groups were formed, with an overall injected blood volume of 6, 9, and 12 ml. Arterial spasm was verified by comparison of the angiographic diameter of the basilar artery on Day 8 vs. Day 1. Additionally, light microscopic, scanning and transmission electron microscopic, and freeze cracking technique examinations of the basilar artery demonstrated the typical morphological features of proliferative vasculopathy. Increasing the volume of experimental SAH led to a linear decrease of the mean vessel diameter from 45% to 53% and finally to 75% of normal. Parallel to the reduction of angiographic vessel lumen, a volume-dependent significant increase of all three eicosanoids was demonstrated. A deficiency of prostacyclin concentration during the course of the experiment was not observed. Despite highly elevated CSF levels of vasodilating prostacyclin, however, severe angiographic constriction of the basilar artery occurred in the presence of high concentrations of TXA2 and PGE2. It is concluded that increasing volumes of SAH led to a concomitant release of arachidonic acid metabolites during posthemorrhagic clot lysis. From our data, it seems questionable whether a prostacyclin deficiency is an important underlying factor for the development of cerebral spasm.(ABSTRACT TRUNCATED AT 250 WORDS)
|
{
"pile_set_name": "PubMed Abstracts"
}
|
# {{classname}}
## Enum
{{#allowableValues}}{{#enumVars}}
* `{{name}}` (value: `{{{value}}}`)
{{/enumVars}}{{/allowableValues}}
|
{
"pile_set_name": "Github"
}
|
This invention is concerned primarily with crop roll forming machines. Specifically it is concerned with such apparatus which improve the core formation of crop material rolls and collect crop material particles lost from the crop package or loose crop material during the roll formation process and recycle those particles back into the roll forming region for inclusion within the completed roll package.
Historically it has been the custom to harvest forage crops by moving the crops, letting them dry in the field, forming the dried crop material into windows and passing a hay-baling machine over and along those windrows to form the crop material into rectangular bales. Recent practice has shown that the formation of crop materials into large compact rolls, rather than rectangular bales as formerly done, permitted the crop material to be deposited in roll form and left in fields for extended periods of time since the rolled material tends to provide a self-shedding protective covering from inclement weather. The ability to leave these rolled bales in fields thus obviated the additional steps of gathering the rectangular bales and transporting them to a storage area protected from the elements.
Several methods for forming compact rolls of crop material have evolved through the years. In one of these methods, a machine rolls a swath or windrow of crop material along the ground until a roll of desired size is obtained. Examples of machines utilizing this principle are shown in prior U.S. Pat. No. 3,110,145, dated Nov. 12, 1963. Another similar machine comprises the subject matter of prior U.S. Pat. No. 3,650,100, dated Mar. 21, 1972. One of the principal difficulties in using this method of forming rolls of crop material is that a certain amount of the material remains upon the ground without being included in the roll. Furthermore, dirt, clods of earth, stones and the like can also be picked up by the roll and included therein. This is undesirable under certain circumstances.
A later, and more successful, method of forming crop rolls comprises a machine in which a swath or windrow of material is picked up from the field and directed onto a lower conveyor. This conveyor transports the material to a roll forming region where an upper apron or flight of belts, usually positioned above and adjacent the conveyor, moves in a suitable direction to rotate the crop material with which it contacts. It has been a continuing problem for this type of roll forming machine to obtain an easily started compact roll core. Similarly, the loss of crop particles from this type of machine has been a lingering concern. Variations of this type of crop roll forming machine are illustrated in U.S. Pat. No. 3,859,909 to Mast, dated Jan. 14, 1975 and U.S. Pat. No. 3,722,197 dated Mar. 27, 1973. An improvement of the former type of machine as shown in prior U.S. Pat. No. 3,866,531 to Todd, dated Feb. 18, 1975, attempted to solve these problems through the use of leaf springs.
The increasing popularity of crop roll forming machines has seen their use broaden from rolling wintering forage for livestock to rolling high protein crops, such as alfalfa, for dairy livestock where the amount of crop material loss is critical. In this latter area especially, interest in the amount of high nutrient crop material lost during roll formation has intensified.
Additionally, crop roll forming machines have been used in a wider range of crop materials, thus presenting varying core formation problems peculiar to each type of crop. Roll forming machines of the type taught in Todd with leaf springs have proven extremely effective in virtually all types of crops. However, minor difficulties have been experienced with some crops that are short and extremely dry and brittle. Since the leaf springs are motionless they occasionally form a dead area where these extremely short, dry, and brittle crops accumulate since the crops are too brittle to withstand being raised through the vertical distance required for them to come to contact with the live, motion-imparting bale forming means. Such brittle crops occasionally will continue to build up until the roll forming machine becomes less efficient. A similar core forming problem can occur in this type of machine when used in loosely packed, low windrows. Such conditions will delay the formation of a core for the rolled crop material since there will be insufficient crop material being fed by the pickup means onto the floor and transported back to the leaf springs to be forced up and over the leaf springs into contact with the live bale forming means. Crop material, in this instance, will remain on the leaf springs until sufficient quantities of material are fed back to force the material up and over the leaf springs into contact with the bale forming means.
The foregoing problems are solved in the design of the machine comprising the present invention by substantially decreasing the amount of crop material lost during the roll formation process and by allowing the usage of the roll forming machine in a wider range of crops, such as corn, maize stubs and hay, with improved core formation.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
Q:
Generate a self working EXP system for levels
I am making a small game in C# and I can't figure out how to make a self working EXP system that gets the EXP you need to level up by the players current level.
This is how I want it to work.
1 = 75
2 = 75 + 75 = 150
3 = 75 + 75 + 75 + 75 = 300
4 = 75 + 75 + 75 + 75 + 75 + 75 + 75 = 525
How would I go about doing this?
A:
It appears that your pattern is "add one 75, add two 75s, add three 75s"... This could be written mathematically as:
s_1 = 75
s_{n+1} = s_n + 75 * n
This means that you can use use
(1 + level * (level - 1) / 2) * 75
|
{
"pile_set_name": "StackExchange"
}
|
Background {#Sec1}
==========
Earlier diagnosis and longer treatment durations contribute to rising expenditure on medicine for cancer care. Access to cancer treatment can be a challenge, since it is significantly affected by cost, particularly in low and middle-income countries. According to the Global Oncology Trend Report \[[@CR1]\], global spending on cancer medications rose from \$75 billion in 2010 to \$100 billion in 2014, 10.3% rise in spending. Medication cost is a strong predictor of adherence \[[@CR2], [@CR3]\] with the risk of cost-related non-adherence being higher for those with lower income and higher out-of-pocket (OOP) drug spending \[[@CR3]\].These growing costs inevitably provoke concern regarding the financial burden experienced by cancer patients \[[@CR1]\]. This concern is even more prominent in Asia because it is home to half of the world's extremely poor population \[[@CR4]\].
Asia accounts for 60% of the world population and 50% of the global burden of cancer \[[@CR4]\]. The projected increase in cancer incidence is predicted to be most significant in low and medium---income countries in Asia \[[@CR4], [@CR5]\].
Asia is very heterogeneous in terms of healthcare systems. With the exception of a few high-income countries such as Israel, Kuwait, Qatar, the Republic of Korea, Singapore, and the United Arab Emirates who enjoy well-developed health services, the vast majority of the Asian people face a substantial cancer burden because cancer care remains a low priority in healthcare planning and expenditure \[[@CR4]\]. In these countries, over 60% of the total healthcare expenditure comes from private resources, of which more than 80% is direct out of pocket payments, with catastrophic results for most families in these countries \[[@CR4]\]. Similarly, in the Middle East, spending per capita on cancer drugs is considerably less than in Europe or the US \[[@CR6]\]. The cancer drug expenditure as a percentage of total drug expenditure is very low in Middle Eastern countries \[[@CR6]\].
In this study, we aim to build on the existing body of work by providing comparable cancer drug retail prices across countries in the South-East Asian \[SEA\], Western Pacific (WP) and Eastern Mediterranean (EM) regions. A review based approach utilising selective content analysis has been adopted to achieve the objective of this paper. A previous study on comparing cancer drug prices focused on 18 high-income countries, member of economic co-operation and development (OECD) countries, in Europe and Oceania \[[@CR7]\]. To our knowledge, this is one of the very first initiatives taken to compare the retail price of cancer drugs across countries in the South-East Asia, Western Pacific and Eastern Mediterranean regions. By analysing and comparing the unit prices across Asian countries with differing gross national income (GNI) per capita, we are hoping to assist in improving procurements, price negotiations, and location of new supply sources, and ultimately to create an opportunity for patients in Asia to gain access to more affordable cancer treatments.
Methods {#Sec2}
=======
Country selection {#Sec3}
-----------------
The following criteria were adopted for the inclusion of countries:Geographically located in the South-East Asian, Western Pacific or Eastern Mediterranean regionsAvailability of drug pricing data published by respective pricing/health authorities.
Based on the inclusion criteria, Thailand was the only eligible country from South-East Asia, Malaysia and Taiwan were included from the Western Pacific, and Oman, Pakistan, the United Arab Emirates, Lebanon, Egypt, Saudi Arabia and Bahrain from the Eastern Mediterranean region. Countries in the Asia Pacific \[Australia and New Zealand\] were excluded from this study, despite being part of the Western Pacific region, as they had already been covered in previous studies \[[@CR7]\]. The included countries were classified into Low income \[LIC\], low middle income \[LMIC\], high middle income \[HMIC\] and high income \[HIC\] countries based on their GNI per capita, using the cut off points provided by the world bank website \[[@CR8]\]. The United Nation's 3-letter standard abbreviations \[ISO ALPHA-3 code\] were used to represent country names in Tables [1](#Tab1){ref-type="table"}, [2](#Tab2){ref-type="table"} and [3](#Tab3){ref-type="table"}. \[[@CR9]\]Table 1Data sources used in this studyCountriesData sourcesSpecificationUAEUnited Arab Emirates Ministry of Health Drug Department\
URL:<http://www.cpd-pharma.ae/downloads/Price-List-February/MoH-Price-List-as-on-07-Feb-2015.pdf>The data was retrieved from MOH, drug department. The Document includes both imported and generic drugs and it was last updated on Feb 2015.BahrainNational Health Regulatory Authority\
URL: <http://www.nhra.bh/SitePages/View.aspx?PageId=42>The Drug Price List includes both innovator and generic medicines prices. Last updated on 14 March 2016TaiwanNational Health Insurance Administration, Ministry of Health and Welfare URL: <http://www.nhi.gov.tw/query/Query1.aspx>The data was retrieved from Ministry of Health and Welfare of Taiwan. The Document includes both imported and generic drugs and it was last updated on June 2016.ThailandDrug And Medical Supply Information Center, Ministry of Public Health\
URL: <http://dmsic.moph.go.th/dmsic/index.php?p=1&type=3&s=3&id=p_drug_normal_en&lang=en>The Drug Reference Price list provides the medical supplies prices for commercial sector. Last updated on March 2015.MalaysiaPharmaceutical Services Division, Ministry of Health\
URL: <http://www.pharmacy.gov.my/v2/en/apps/drug-price>The Consumer Price Guide provides retail price list to serve as guidance to patients when purchasing medicines.LebanonMinistry of Public Health\
URL: <http://www.moph.gov.lb/Drugs/Pages/Drugs.aspx>The data was retrieved from the MoPH Drugs Public Price List. Last updated on 16 February 2016OmanMinistry of Health <https://www.moh.gov.om/en/web/dgpadc/resources>The data was retrieved from the Ministry of Health, Sultanate of Oman website from the list of registered drugs. Last updated on 17--05-2016.PakistanPharmaGuide book, Pakistan edition, 24th edition.The pricing data was retrieved PharmaGuide Book. This handbook is published annually providing essential prescribing and trade information. The pricing data was retrieved from the latest edition (24th) published on March 2016. Table 2Background information about drugs included in the analysis^a^Generic drug nameProduct nameFDA approved indicationsSelected presentationCountry coverageUnit price is price of:\#Missing dataAbiraterone acetateZytigaMetastatic castration-resistant prostate cancer120 tablets 250 mg7PAK, MYS, LBN1 TabBevacizumabAvastinNSCLC\
Metastatic Colorectal cancer, Glioblastoma\
Metastatic Renal cell carcinoma Metastatic Her2 negative breast cancer\
Metastatic cervical cancer.One 4 ml vial containing 25 mg/mL concentrate for solution for infusion.6MYS, SAU, OMN, LBN4 ml vialBortemozibVelcadeOne vial containing 3·5 mg powder for solution for injection.7EGY, PAK, SAU1 vialCabazitaxelJEVTANA®[Metastatic](http://www.cancer.gov/dictionary?CdrID=44058) hormone [refractory](http://www.cancer.gov/dictionary?CdrID=350245) [prostate cancer](http://www.cancer.gov/dictionary?CdrID=445079)One vial containing 60 mg concentrate and solvent for solution for infusion.4EGY, PAK,THA, SAU, BHR,TWN,1 vialCetuximabErbitux*K-ras* wild-type, *EGFR*-expressing metastatic colorectal cancer.\
Recurrent/metastatic head and neck cancerOne vial containing 5 mg/mL solution for infusion.4ARE, EGY, PAK, SAU,OMN, BHR1 vialDenosumabProlia[Unresectable giant cell tumor of bone in adults and skeletally mature adolescents](http://www.cancer.gov/about-cancer/treatment/drugs/Anchor-GCT)One pre-filled syringe containing 60 mg solution for injection6PAK, MYS, SAU, BHROne pre-filled syringeErlotinib HClTarcevaNon-small cell lung cancer.\
Pancreatic cancer.30 film-coated tablets 150 mg7MYS, SAU, LBN1 film-coated TabEverolimusAfinitorSubependymal giant cell astrocytoma.\
HER2-negative breast cancer.\
Progressive neuroendocrine Tumors of Pancreatic origin.\
Advanced renal cell carcinoma.30 tablets 10 mg8PAK, MYS,1 TabGefitinibIressaNon-small cell lung cancer30 film-coated tablets 250 mg7EGY, SAU,PAK1 film coated TabGemcitabineGemita (Atco)Ovarian cancer\
Breast cancer.\
NSLCLC\
Pancreatic cancer1 vial containing 1 g powder for solution for infusion.9SAU1 vialImatinib MesylateGlivec (Novertis)[Dermatofibrosarcoma protuberans](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44276&version=Patient&language=English).\
[Gastrointestinal stromal tumor](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44998&version=Patient&language=English).\
[Myelodysplastic](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45266&version=Patient&language=English)/[myeloproliferative neoplasms](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45210&version=Patient&language=English).\
[Systemic mastocytosis](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=455141&version=Patient&language=English).\
[Chronic Eosinophilic leukemia](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=426408&version=Patient&language=English).\
[Chronic Myelogenous Leukemia](http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44901&version=Patient&language=English)60 film-coated tablets 100 mg9BHR1 film coated TabInterferon Alpha - 2BInteron A (Schering PloughAIDS related Kaposi Sarcoma.\
Hairy cell leukemia.\
Melanoma.\
NHLOne multi-dose pen containing 3 million IU/0·5 mL solution for injection.6THA, EGY, MYS,OMNOne multi-dose penLapatinib ditosylateTykerb FCHER2 positive breast cancer,70 film-coated tablets 250 mg7MYS, BHR, TWN1 film coated TabNilotinibTasignaCML112 capsules 150 mg8PAK, MYS1 Cap112 capsules 200 mg6THA,LBN, OMN, BHR1 CapPaclitaxel AlbuminIntaxel 30 mg/5 ml injNSCLC\
Breast cancer pancreatic cancerOne vial containing 5 mg/ml powder for suspension for infusion.6ARE, EGY, SAU, BHR1 VialPanitumumabVectibix 400 mg/20 ml IVColorectal CancerOne vial containing 20 mg/ml concentrate for solution for infusion6THA, PAK, MYS, TWN1 VialPazopanibvotrient30 film-coated tablets 200 mg8PAK, MYS1 film coated TabPemetrexed Disodium HeptahydrateAlimta (Eli Lilly)non-squamous NSCLC\
Malignant pleural mesotheliomaOne vial containing 20 mg/ml solution for injection.9OMN1 VialSorafenibNexavar (Bayer Schering)Liver cancer\
Kidney cancer\
Thyroid cancer60 film-coated tablets 200 mg.5THA, MYS, OMN, BHR,LBN1 film coated TabSunitinib malateSUTENT (Pfizer)Kidney cancer\
Gastointestinal stromal tumour\
Pancreatic Neuroendocrine tumours28 capsules 12.5 mg7OMN, LBN, BHR1 Cap28 capsules 25 mg4THA, LBN, MYS, OMN, BHR, TWN,1 Cap28 capsules 50 mg6THA, LBN, MYS, OMN,1 CapTrastuzumabHerceptin (Roche)Her2 over expressing breast cancer\
Her2 over expressive Gastric or Gastroesophageal junction AdenocarcinomaOne vial containing 440 mg powder for concentrate for solution for infusion4THA, LBN, MYS, SAU,OMN, BHR1 VialOne vial containing 150 mg powder for concentrate for solution for infusion4ARE, EGYP, PAK, LBN, MYS, TWN,1 VialZolendronic acidZOLDICMultiple MyelomaOne vial containing 4 mg/5 ml concentrate for solution for infusion4ARE, LBN, MYS, OMN, BHR, TWN1 Vial^a^The National Cancer Institute. A to Z List of Cancer Drugs. USA: The National Institutes of Health U.S. Department of Health and Human Services, 2015 Table 3PPP-adjusted prices of the selected cancer originator drugs in the 10 surveyed countries converted to USDLow middle incomeHigh middle incomeHigh incomeGeneric namePresentationPAK(\$)EGY(\$)MYS(\$)LBN(\$)THA(\$)TWN (\$)OMN (\$)BHR (\$)ARE(\$)SAU(\$)Mean unit price for drugsHigh/Low ratioAbiraterone acetate 250 mg120 tabNA9724·22NANANANANANA8470·088867·6170·171·731 tabNA81·04NANA52·0259·1090·2164·3370·5873·90Bevacizumab 25 mg/mlInj. 100 mg (4 ml)NA1233·18NANA1473·00602·104122·80767·001157·95NA1559·506·85Bortemozib3.5 mg1 vialNANA3622·222243·964630·122443·023878·902771·382560·04NA3164·222·06Cabazitaxel 60 mg1 vialNANA11,492·57112·50NANA17,304·95NA11,421·76NA11,832·932·43Cetuximab 5 mg/ml1 vialNANA1100·491850·55997·12456·25NANANANA1101·104·06Denosumab 60 mg/ml1 ml prefilled syringeNA798·21NA607·36934·69417·41757·00NA665·27NA696·662·24ErlotinibHCl 150 mg30 film coated tab7315.3411,659·19NANANANANANA6837·45NA194·844·931 film coated tab243.84388·64NANA160.5478.76152.5789111.62227.915NAEverolimus 10 mg30 tabNA8565·02NANANANANANA8514·648697·73300·531·831 tabNA285·50NA274·21404·60220·25338·68307·24283·82289·92Gefitinib 250 mg30 film-coated tabletsNANANANANANANANA3938.70NA144·332·401 film-coated tabNANA173·85123·84157·5282·79198·89142·14131·29NAGemcitabine 1 gVial295·81210·77496·53227·33179·04271·28359·10256·57281·60NA286·452·77ImatinibMesylate 100 mg60 film-coated tab2485·805156·95NANANANANANA2920·713571·0256·923·411 film-coated tab41·4385·9563.4925·2374·1441·4372·47NA48·6859·50Interferon Alpha - 2B 1 m IU/injection1 multidose pen208·81NANA21·02NA26·80NA72·7165·69287·50113·7613·68Lapatinibditosylate 250 mg70 film-coated tablets3341.731926·91NANANANANANA2526·364190·3440·082·681 film coated tab47.7427·53NA32·3922·30NA54·68NA36·0959·86Nilotinib 150 mg112 capsNA2152·47NANANANANANA7906·289474·4366·075·561 capNA19·22NA59·1670·7643·68106·9573·6270·5984·59Nilotinib 200 mg112 caps15,113·642982·06NANANANANANA11,069·2512,631·8292·785·071 cap134·9426·62116·07NANA67·44NANA98·83112·78Paclitaxel Albumin 5 mg/ml1 vial213·07NA125624·90242·7091·86348·21NANANA274·296·80Panitumumab 20 mg/ml1 vialNA4932·74NANANANA7223·841291·005804·391482·964147·005·60Pazopanib 200 mg30 tabNA762·33NANANANANANA1604.181994·8952·203·191 tabNA25·411NA36.9251·5944·808157·9053·4766·496Pemetrexed Disodium Heptahydrate 500 mg1 vial2485·803295·96694·44624·77795·70502·78NA2879·243200·213307·961976·326·58Sorafenib 200 mg6 × 10's tablets8267·055025·56NANANaNANANA4920·296620·4697·231·911 tab137·7883·76NANANA72·27NANA82·00110·34Sunitinib malate 12.5 mg30 caps3597·662578·48NANANANANANA3323·223425·57108·221·751 cap119·9285·95150·47NA89·287·03NANA110·77114·19Sunitinib malate 25 mg30 caps7121·807134·08NANANANANANA6646·446851·71231·281·071 cap237·39237·80NANANANANANA221·55228·39Sunitinib malate 50 mg30 caps13,943·1810,762·33NANANANANANA13,292·8913,703·98405·561·491 cap464·77358·74NANANA312·31NA397·62443·096456·80Trastuzumab 440 mg1 vial4616·484686·10NANANA3930·91NANANANA4779·351·50Transtuzumab 1501 vialNANANANA1240·85NA2599·531857·335883·892133·521957·812·09Zolendronic acid 4 mg/5 ml1 vial674·72605·38NANA268·79NANANANA845·45598·593·15Mean unit price for every country708·75919·391803·51990·30658·09492·612355·60789·261496·34607·13Average unit price by world bank categories814.071150.631148.19
Data sources {#Sec4}
------------
The price of the cancer drugs in the ten included countries was retrieved from official pricing authorities or the respective Ministry of Health or equivalent websites \[Table [1](#Tab1){ref-type="table"}\]. The authors ensured that the prices were retrieved from the most recent price lists published by the respective countries. The prices retrieved for Bahrain, Lebanon, Oman and Taiwan were published in 2016 and the prices for the remaining countries were published in 2015. However, the exact publication date of the pricing data was unclear.
The GNI per capita \[USD\] of nine of the ten included countries was retrieved from the World Bank website. For Taiwan, however, the data had to be retrieved from Taiwan's national statistics bureau \[[@CR10]\] since the country is not a member of United Nations and was not listed on the World Bank website. The respective GNI per capita and country classifications are shown in Additional file [1](#MOESM1){ref-type="media"}: Table S2.
Medicine selection {#Sec5}
------------------
A cross--country comparison of 31 selected samples of cancer drugs was made by Vogler et al. \[[@CR7]\] whereby the selection of drugs was also dependent on the data availability and availability of comparable products in the market in at least ten countries. In this study, the same 31 drug presentations were chosen initially as a guide. The inclusion criterion for selecting a drug presentation was the availability its pricing data in at least four out of the ten countries.
Data analysis {#Sec6}
-------------
The price data were reviewed by the six co-authors. As the unit of measurement, we selected retail price per unit \[i.e. per tablet/capsule or per vial\]. Retail prices were chosen in this study because they represent the patients' actual out of pocket expenditure. Another advantage of using retail prices is that they include all the add-ons such as taxes, distribution and pharmacist fees; these add-ons sometimes lead to the final price costing more than double the actual cost of the drug \[[@CR11], [@CR12]\]. The other reason for the use of retail prices was that ex-factory prices are hard to measure accurately, especially in countries that have no publicly funded drug coverage. \[[@CR12]\]
Prices were only included if they referred to the same presentation in terms of pack size, strength and pharmaceutical form. Pricing data were originally extracted and presented in national currencies but later converted to USD using purchasing power parity (PPP) to allow fair comparison between different countries. Microsoft Excel was used for PPP-related calculations. Purchasing power parity rates were retrieved from the World Bank website \[[@CR8]\]. The purchasing power parity conversion rates used are presented in Additional file [1](#MOESM1){ref-type="media"}: Table S1. The mean unit prices were calculated for each drug presentation as well as for each country. The high/low ratio for each presentation was calculated by dividing the highest unit price of the presentation by the lowest unit price of the same presentation to analyze the inter-country variability of the price for every presentation. A high/low ratio of 10 implies that the highest unit price is ten times more expensive than the lowest unit price. All calculations were performed in Microsoft Excel. All statistical analyses were descriptive.
In order to present the price comparison more effectively, the results have been arranged into the World Bank categories and comparisons are made accordingly. Of the ten included countries, one country \[Pakistan\] is classified as a low-income country, one \[Egypt\] as middle-income, three \[Thailand, Malaysia and Lebanon\] as higher-middle income, and five \[the United Arab Emirates, Bahrain, Saudi Arabia, Oman and Taiwan\] as high-income countries.
Results {#Sec7}
=======
Upon applying the selection criteria for presentations, the following presentations that were originally in Vogler et al.'s study \[[@CR7]\] were excluded from this study due to a lack of pricing information for at least four countries: bendamustine \[HCl\], bevacizumab \[16 ml vial\], clofarabine, eribulin mesylate, lenalinomide, nelarabine, ofatumumab, plerixafor, sorafenib \[112-tablet pack\], temsirolimus and vemurafenib. On the other hand, five additional presentations for which price data was available in the included regions were added to the list: nilotinib 200 mg, sunitinib 12·5 and 25 mg, trastuzumab 440 mg, and sorafenib \[60-tablet pack\].
We were unable to find pricing data on sorafenib \[the 112-tablet box\] so we replaced it with the 60-tablet box for which pricing data was available. Moreover, we found adequate data for trastuzumab 440 mg in the regions of interest, therefore we added it to the list despite already having a presentation for this drug \[trastuzumab 150 mg\]. Although it was expected that the two would follow the same pattern, the pricing data was included to provide more information for the readers. The same was true for sunitinib \[12·5 mg, 25 mg and 50 mg\] and nilotinib \[150 mg and 200 mg\].
The final number of included presentations was 26. Table [2](#Tab2){ref-type="table"} provides an overview of the selected drugs with regards to their FDA-approved indications, selected presentation and country coverage. We only compared prices for the originator drugs because pricing policies for originator drugs differ substantially from generic vials.
Unit price {#Sec8}
----------
Table [3](#Tab3){ref-type="table"} represents prices per package as well as the calculated unit prices in USD using PPP. Upon estimating the PPP, cabazitaxel was the most expensive drug with a unit price of \$17,304·9/vial \[in Oman\]. Nilotinib 150 mg had the lowest unit price in USD \[\$19·22/tab in Egypt\].
The PPP adjusted USD unit prices for each medication are represented in Fig. [1](#Fig1){ref-type="fig"}. The different unit prices are connected to illustrate variations between countries. To ensure that the variations among prices is easy to discern for both low price and high price medications, the two have been presented in two different figures. Figure [1a](#Fig1){ref-type="fig"} represents cancer drugs with unit price between \$0--1000, while Fig. [1b](#Fig1){ref-type="fig"} represents cancer drugs with unit prices between \$1000--20,000.Fig. 1**a** Included cancer drugs with unit prices between 1-1000 USD stratified by country. **b** Included cancer drugs with unit prices between 1000-20,000 USD stratified by country
Mean unit price {#Sec9}
---------------
Six presentations \[23·1%\] had a mean unit price below \$100.00 and nine drugs \[34·6%\] had a mean unit price between \$100·00 and \$500·00. Eight drugs \[30·7%\] had a mean unit price of over \$1000.00, of which, one \[cabazitaxel\] had a mean unit price of over \$5000·00 \[\$11,832·9/vial\]. Overall, Taiwan had the lowest mean unit prices\[\$492·61\] and Oman the highest \[\$2355·6\]. So Overall, Taiwan had the lowest mean unit prices for all presentations.
The average unit prices by country income category were as follows: LMICs \$814.07, HMICs \$1150·63, HICs: \$1148·19. Using PPP-adjusted mean unit prices, the three most expensive presentations were found to be cabazitaxel \[\$11,832·93\], trastuzumab 440 mg \[\$4779·35\], and panitumumab \[\$4146·99\]. The three cheapest oncology drugs were lapatinib ditosylate \[\$40·08\], pazopanib disodium heptahydrate \[\$52·20\], and imatinib \[\$56·92\].
The high/low ratio {#Sec10}
------------------
The high/ low ratio data included in Table [3](#Tab3){ref-type="table"} allowed us to look at the price deviation between countries. The high/low unit price ratio was less than 3 for fourteen drugs \[53·80% of the 26 total included products\], between 3 and 6 for eight drugs \[30·77%\] and more than 6 for four drugs \[15·38%\]. The smallest high/low ratio was 1·07, which belonged to sunitinib malate 25 mg, and the largest high/low ratio belonged to Interferon alpha-2B \[13·68\] \[Table [3](#Tab3){ref-type="table"}\].
The frequency of unit prices ranked in quartiles {#Sec11}
------------------------------------------------
Box plots have been constructed based on the unit \$ price of the included drugs. The boxplot for low and high price cancer medicines have been presented separately in Fig. [2a and b](#Fig2){ref-type="fig"} to ensure that the differences are easy to discern. The box plot displays the inter-quartile range \[IQR\] as calculated by Microsoft Excel; the bottom and top of the box are the 25th and 75th percentiles \[the 1st and the 3rd quartiles, respectively\], and the band in the middle of the box is the median. The extended lines describe the bottom and top whiskers.Fig. 2**a** Boxplots of incuded cancer drugs with mean USD unit price between 1 and 1000. **b** Boxplots of included cancer drugs with mean USD unit price between 1,000 and 20,0000
Drug prices varied significantly across the included countries. Figure [3](#Fig3){ref-type="fig"} represents the frequency of unit prices, as of February 2016, ranked in quartiles \[Note: quartile 1 and 4 are not inclusive of the minimum and maximum values; these values have been categorized and represented separately using unique colours of their own\]. Thailand and Taiwan had prices at the lower end, prices in Lebanon mainly fell in the first quartile, while prices in the United Arab Emirates and Bahrain fell in the second and third quartiles. Prices in Oman and Saudi Arabia were at the upper end \[Fig. [3](#Fig3){ref-type="fig"}\]. Prices in Oman were ranked the most expensive for eight presentations (Additional file [1](#MOESM1){ref-type="media"}: Table S3).Fig. 3Frequency of PPP-adusted unit prices ranked in quartiles for each country
Prices in high income countries are at the upper end, and are ranked as the maximum for 13 of the included presentations, while prices in low middle income countries were ranked the most expensive for six presentations only \[Fig. [4](#Fig4){ref-type="fig"}\].Fig. 4Frequency of PPP-adjusted unit prices ranked in quartiles for each income group
Discussion {#Sec12}
==========
The aim of the present study was to survey and compare retail prices of anti-cancer drugs between high, middle and low-income countries in the South-East Asia, Western Pacific and Eastern Mediterranean regions. In the absence of a systematic pricing system, pharmaceutical companies determine the drug price according to what the society can afford, as people are ready to face a heavy financial burden when it comes to treating fatal diseases \[[@CR13]\]. In some developed countries, price regulation measures such as external reference pricing or international reference pricing have been widely used by policymakers to restrain drug costs. External reference pricing is defined by the WHO as: "*The practice of using the price\[s\] of a medicine in one or several countries in order to derive a benchmark or reference price for the purposes of setting or negotiating the price of the product in a given country"* \[[@CR14]\].
A list of 2010 cancer drug prices, has been published by the Management Sciences for Health based on the WHO's 17th edition of the Essential Medicines List \[[@CR15]\]. This is the only procurement tool available to the pricing authorities in LMICs, however, more support is needed such as an updated WHO essential medicine list section on oncology drugs along with cross-country pricing information and procurement guidance. Although the Western Pacific Region office of the WHO has developed a Price Information Exchange that provides comparative information on procurement prices for selected medicines across the Western Pacific region \[[@CR15]\], it has faced many challenges such as lack of cooperation from member countries. This is why we have attempted to undertake our own cross-country price comparison \[[@CR13]\].
Purchasing power parity conversion rates were used instead of exchanges rate in this review. Exchange rates determine the producers' actual profit from foreign sales in terms of domestic currencies \[[@CR16]\], and can be used when performing pharmaco-economic studies within a country since the expected exchange rate fluctuations would affect all drugs sourced from the same country, uniformly. In cross-country comparisons, however, to overcome the effect of large fluctuations in exchange rates, the PPP is used as an alternative sensitivity analysis \[[@CR17]\]. Purchasing power parity conversions are also argued to be more apt for comparisons at final consumer level \[[@CR16]\].
Our review showed extreme variation between drug prices across countries; the high/low ratios were as high as 13·68 \[PPP-adjusted\]. While patents can explain the price differences between drugs, they are not responsible for the price differences observed for the same medicine.
Greater transparency of price information among countries may assist with in-country negotiations between purchasers and suppliers. Information on the availability of cheaper medicines in neighbouring countries has the potential to encourage policy and managerial decisions at national levels in an effort to reduce prices \[[@CR15]\]. Economic evidence on the impact of external reference pricing is scarce. Only a few studies have explicitly analysed the impact of external price referencing on medicine prices. Stargardt et al., \[[@CR18]\] using an analytic model to simulate the effect of a price reduction in Germany demonstrated that every 1 EURO reduction in price in Germany would lead to a reduction of EURO 0.15 to EURO 0.36 in 15 European countries that use external reference pricing. Similar results were reported by Windmeijer et al. \[[@CR19]\] who investigated the result of external reference pricing implementation on prices in Netherlands. Our study can hence be used by officials to improve access to cancer treatment \[[@CR13]\].
Limitations {#Sec13}
-----------
Cross-country comparison of pharmaceutical prices is challenging because of the differing level of sales, frequent changes in exchange rates and the differences in the pharmaceutical presentations such as strength, pack size, dose and dosage form. Of the 57 countries in the South-East Asia, Eastern Mediterranean and Western Pacific regions (excluding Australia and New Zealand), we only managed to find reliable pricing information for ten countries only due to: \[i\] under-developed/incomplete/not-user-friendly websites of official pricing/heath authorities; \[ii\] use of languages other than English in official websites; \[iii\] lack of public access to official drug prices; and \[iv\] absence of an official institution to summarize/compare prices across Asia. However, we managed to include representative countries from different ranges of GNI per capita. The other key limitations of this study are as follows: Firstly, the prices may not reflect the true cost of medications because the retrieved data are the official prices as published by the pricing authorities without consideration of \[usually confidential\] discounts and rebates. Secondly, this study used retail prices, which include add-ons such as taxes and distribution fees. Understanding of the amount and sources of add-ons would identify potential targets for price reduction. Unfortunately, data on add-ons was limited and hence we were unable to estimate them. Thirdly, the use of PPP calculations for price comparison required the assumptions that the value of goods and services are homogeneous across countries and that international shipment of goods takes place instantaneously, and with no cost. Unit prices were used to compare results in this study, when interpreting the results of this study, it should be kept in mind that one unit may refer to the daily dose of a tablet, or monthly vial for injection or a weight based two weekly injections. Future studies should use the data provided in this study and perform a price comparison using monthly dose or total treatment cost, as a unit for measurement and comparison. Finally, pricing revisions are done at irregular intervals and the price lists may not be updated immediately. However, most recently available prices were used for calculations.
Conclusion {#Sec14}
==========
The significant price differences among Asian countries is very evident. Taiwan had the lowest mean unit price \[\$492·61\] and Oman the highest \[\$2355·60\]. Significant variation between drug prices across countries with the highest high/low ratio was seen for Interferon alpha-2B: 13.68. Cabazitaxel was ranked the most expensive drug in our sample with a mean unit price of \$17,304·95. These discrepancies indicate that greater price transparency is required. Our goal was to compare cancer drug prices and investigate whether the prices are significantly different among countries. Significant differences were found and reported accordingly, however, what this price differences mean in terms of access to cancer medications, government spending, and patient adherence, requires a much more in-depth analysis of each country's respective health care system, which was beyond the scope of this paper.
Our results can be used to help policy makers to compare the price of anti-cancer agents in their country with that in neighbouring countries to decide if further policy measures related to drug prices are required.
Key issues {#Sec15}
==========
Anti-cancer drug prices are highly variable in the South-East Asian, Western Pacific and Eastern Mediterranean regions.There is an association between price of anticancer drugs and income category of the country.Almost one in three drugs assessed in this study had a mean unit price of more than US\$ 1000.There is a need to review pricing policy in order to improve accessibility and affordability of cancer drugs in the selected countries.
Additional file {#Sec16}
===============
Additional file 1: Table S1.The purchasing power parity conversion rates used. **Table S2.** The respective GNI per capita and country classifications. **Table S3.** (XLSX 72 kb)
**Electronic supplementary material**
The online version of this article (10.1186/s12885-017-3888-y) contains supplementary material, which is available to authorized users.
The authors are thankful to Mr. Allah Buksh, PhD Scholar at school of Pharmacy, Monash University Malaysia for his assistance in retrieving the prices of anticancer drugs from Pakistan.
Funding {#FPar1}
=======
No funding from any public or private funding agency was obtained for this study.
Availability of data and materials {#FPar2}
==================================
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
TMK, LCM and MAH conceived the idea. TMK, LCM, MAH, KSL, CFN and MEE extracted data. SS, KSL and TMK analysed data. SS, TMK, LCM drafted the initial version of the manuscript. MAH, MEE, ZUD, CFN revised the manuscript with intellectual input. All authors have read and approved the final version of the paper for publication.
Ethics approval and consent to participate {#FPar3}
==========================================
Since it was a pricing review, ethics approval was deemed not necessary therefore not obtained.
Consent for publication {#FPar4}
=======================
Not Applicable.
Competing interests {#FPar5}
===================
The authors declare that they have no competing interests.
Publisher's Note {#FPar6}
================
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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{
"pile_set_name": "PubMed Central"
}
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News and updates for the BABS Genome education and outreach initiative of the School of Biotechnology and Biomolecular Sciences at UNSW Sydney, Australia. Join us as we sequence, assemble and analyse the genomes of some iconic Australian species.
Sunday, 5 November 2017
UNSW Genome Annotation workshop, Tuesday 21st November 2017
I am pleased to announce that we will be running a replacement for July’s cancelled Genome Annotation workshop at UNSW on Tuesday 21st November 2017, 1100-1400. This will use WebApollo, which is the genome annotation browser we will be using for community annotation of our snake genomes.
DESCRIPTION
This workshop will include a short background lecture on the fundamentals of gene prediction and genome annotation followed by a hands-on component where we will conduct manual curation exercises using Apollo.
|
{
"pile_set_name": "Pile-CC"
}
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Background {#Sec1}
==========
Although health literacy is an important predictor of health status \[[@CR1]\], it seems that a small percentage of people are adequately health-literate \[[@CR2]\]. Taking into account that it is difficult for the general population to follow the development of treatments in medicine, the very idea of health literacy is very broad and includes different concepts \[[@CR3]\]. These concepts range from understanding health information and clear comprehension of health risks to performance of basic mathematical operations in the health context, making the entire process of information uptake and translation into behavior very complexed and hard to follow. Recently, health numeracy has received attention as an application of numerical information in the health context. Two reviews of literature demonstrated that the field of health numeracy was not well explored with only few interventions for improving health numeracy levels were developed, usually without validated measures and rarely targeting health professionals \[[@CR4], [@CR5]\].
Repeated testing has recently been demonstrated as an effective method to increase the understanding of risk among students \[[@CR6]\], while numeracy levels tend to increase after courses using blended learning approach \[[@CR7]--[@CR9]\]. However, to the best of our knowledge, the effects of the numeracy intervention were not explored after longer periods of time using a standardized numeracy test.
The aim of our study was to compare objective and subjective numeracy levels between non-medical population and medical students in different levels of medical education using a cross sectional approach and to explore whether a blended course on research methodology could improve subjective and objective numeracy among undergraduate medical students after 3 months' period using a controlled before-and-after approach.
Methods {#Sec2}
=======
Study design {#Sec3}
------------
We used a cross sectional approach to study numeracy skills in non-medical student population (sociology students) and in medical students enrolled in the 1st, 3rd^,^ 4th, 5th and 6th year of a graduate medical curriculum. We also used a controlled before-and-after design to examine the effectiveness of a research methodology course in increasing numeracy skills among first-year medical students. The participation in the study was voluntary and participants were not rewarded for the participation. Each participant had to be enrolled in the current academic year for the first time, because including students who repeated a part or the whole study year could affect the validity of the results because they had probably been exposed to more numeracy-related content compared to those who were enrolled for the first time. Each participant used a personalized code for pseudo anonymization of the responses. The code consisted of the elements that could be easily remembered for the next measurement: the first letter of their mother's name, the first letter of their father's name, the first letter of the participants' name, the last two digits of their year of birth and the first letter of their place of birth. In this way, it was possible to pair the participants' scores in repeated measurements.
Setting {#Sec4}
-------
### Cross sectional study {#Sec5}
Medical students of the 1st, 3rd, 4th, 5th and 6th study year were tested in October 2017 at the time of enrollment in the 2017/2018 academic year. Second-year medical students were not included in the cross sectional study because they were tested twice with the same instruments in the controlled before-and-after study, and therefore their results could not be comparable to other years, who were tested only once. We also tested a group of sociology students from the University of Split Faculty of Humanities and Social Sciences before their first lecture in statistics, at the beginning of their first year. This group served as a non-medical control in order to compare the baseline results of medical students with a population of students who were not enrolled in a medical program but had similar high school education and national high school qualification exams \[[@CR10]\]. This baseline control group served to establish whether medical students already come to medical school with higher numeracy level compared to a student group with different education profile.
First-year students had finished high school 3 months before the beginning of the medical school. In order to enroll to the medical school or the faculty of social sciences, they had to complete high school and the pass a national standardized test in order to qualify for university enrolment. High school education does not have formalized education in statistics and probability; these themes are covered by general mathematics education.
### Controlled before-and-after study {#Sec6}
In June 2017, the first-year medical students (2016/2017 enrolment generation) at the University of Split School of Medicine (USSM) were tested at the first day of their research methodology course, at the end of the 2016/2017 academic year. The participants were tested again 2 weeks later, on the last day of the course, and 3 months after, after the summer break -- at the beginning of the 2017/2018 academic year. Similarly, the first-year students of the 2017/2018 academic year (non-intervention group) were tested after the introductory lecture on the first day of their first year, then 2 weeks later during the Biochemistry course, and again after 3 months at the beginning of their Anatomy course. The results from the first testing of first-year medical students were also used in the cross-sectional study, as they were tested in the same conditions as the third- to sixth-year students.
Description of the intervention {#Sec7}
-------------------------------
At the USSM, research methodology is a part of a vertically integrated evidence-based medicine (EBM) course, consisting of three separate courses held during the first 3 years of a six-year medical graduate program \[[@CR11]\]. Graduate medical curriculum lasts for 6 years and enrolls students after high-school education.
The intervention in the controlled before-and-after study was the first-year course (2 weeks' duration) comprised of 50 class hours of blended learning approach with combination of lectures, seminars and practical exercises in biostatistics and research methodology using face-to-face approach and online Modular Object Oriented Dynamic Learning Environment (Moodle) \[[@CR9], [@CR11]\]. The expected competencies gained after this first-year course are basic understanding of research methodology in medicine, critical evaluation of scientific reports, and understanding and application of basic biostatistics \[[@CR11]\].
Variables {#Sec8}
---------
We collected the data about the participants' sex, age and high-school grade point average (GPA). Previous research indicated that numeracy levels can be measured as subjective and objective construct, and that there is no evidence for optimality of one approach over another \[[@CR12]\]. In order to grasp a wide range of numeracy skills and perceptions, we used two numeracy assessment tools: 1) subjective -- where numeracy is self-assessment of numeracy based on the perception of one's abilities and/or preferences of numerical information, and 2) objective -- assessing the ability to perform numerical tasks and interpret numerical information. The set time to complete both measures was 25 min at all measurement times and for all groups. *Subjective Numeracy Scale* \[[@CR13]\] is a self-report measure where one of the subscales measures perceived ability to perform various mathematical tasks and the second one measures the preference for the use of numerical information over prose information. It consists of 8 questions, and the task of the participant is to assess his or her ability/preference considering numerical information on a scale from 1 to 6, where the higher result indicates higher subjective numeracy levels. The final score is the average of the answers (theoretical range 1--8) \[[@CR14]\]. The reliability of the scale in our study was α = 0.70 (95% confidence interval (CI) = 0.65 to 0.75).*The Numeracy Understanding in Medicine instrument* -- NUMi \[[@CR15]\] is a measure of objective numeracy, which consists of 20 numerical tasks placed in health context, with multiple choice answers. The task for the participant is to choose the correct result out of four possibilities offered. The instrument measures health numeracy in four different domains: *Number sense*, *Probability*, *Statistics* and *Tables and Graphs.* The final score is the sum of correct answers (theoretical range 0--20). The reliability of the scale in our study was α = 0.75 (95% CI = 0.70 to 0.79).
Both tests were translated by one of the authors (IB) from English to Croatian and back-translated by a professional translator. No inconsistencies between the translations were found. Names of the characters in the scenarios described in numeracy tests were replaced with Croatian names, in order to improve content validity.
Study size {#Sec9}
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We calculated the study sample size based on the data from previous research \[[@CR16]\] which compared participants' numeracy levels using the 6 item General Health Numeracy Test (GHNT) \[[@CR17]\], where participants from Faculty of social sciences had Mean (M) of 1.8 and Standard deviation (SD) was 1.20, and medical students had M = 3.4 (SD = 1.43). Using the online sample size calculator (<https://www.stat.ubc.ca/~rollin/stats/ssize/n2.html>) with α level set at 0.05 and power at 0.80, we estimated at least 13 participants per group.
Statistical analysis {#Sec10}
--------------------
We used Kolmogorov-Smirnov test to test the numerical variables for the normality of distribution. Due to the non-normality of the distributions, the data were presented as medians with 95% confidence intervals. Sex differences between the groups were tested using chi-squared test. The differences between groups on age, grade point average (GPA), and the results of subjective and objective numeracy measures were tested with Kruskal-Wallis test and Conover post hoc test if there were more than two independent groups. Mann-Whitney test was used to compare the differences between intervention and non-intervention groups. Friedman test was used for repeated measurements, with Conover post hoc comparison. In a complementary analysis, we used Bayesian ANOVA if there were more than two independent groups and Bayesian Repeated Measures ANOVA for repeated measurements. All statistical procedures were calculated using JASP 0.8.3.1 (JASP Team, 2017) and Bayes Factors were calculated assuming a default prior distribution \[[@CR18]\]. Bayes Factors (BF~10~) with values above three even after sequential analysis and robustness check indicated substantial evidence for the alternative hypothesis \[[@CR19]\]. In cases of discrepancies between frequentist and Bayesian statistics, we used the Bayesian approach to interpret the significance of the results.
Results {#Sec11}
=======
Cross-sectional study {#Sec12}
---------------------
In total, 272 students participated in cross sectional study, out of 388 eligible students (response rate = 70.1%). There was no difference between study years in the response rate (Table [1](#Tab1){ref-type="table"}). The only difference in baseline characteristics was an expected older age for higher study year students (Table [1](#Tab1){ref-type="table"}). Table 1Demographic characteristics of Sociology students from the Faculty of Social Sciences and students of the first, third, fourth, fifth and sixth year of medical studies (*N* = 272)Sociology (*n* = 27)Medicine 1st year (*n* = 54)Medicine 3rd year (*n* = 54)Medicine 4th year (*n* = 52)Medicine 5th year (*n* = 39)Medicine 6th year (*n* = 46)P\*Percentage of participants from eligible populations100%60%75.0%72.2%64.0%68.7%0.541Female sex (%)24 (88.9%)40 (67.7%)40 (74.1%)38 (73.1%)27 (71.1%)30 (65.2%)0.306Age in years (median, 95% confidence interval)19.0 (18.0 to 19.5)19.0 (18.0 to 19.0)21.0 (20.0 to 21.0)†22.0 (21.0 to 22.0)†23.0 (23.0 to 23.0)†23.0 (23.0 to 24.0)†\< 0.001Grade point average at the end of high school (median, 95% confidence interval)4.1 (4.0 to 4.3)‡4.8 (4.7 to 4.8)4.8 (4.7 to 4.9)4.7 (4.6 to 4.8)4.8 (4.7 to 4.9)4.8 (4.5 to 4.9)0.109\*Chi-square test for categorical variables and Kruskal Wallis test for continuous variables†Significantly different from 3rd, 4th, 5th and 6th year groups, Conover post-hoc test‡Significantly different from other groups, Conover post-hoc testIn Croatian higher education system, grade point average ranges from 2.0 (sufficient) to 5.0 (outstanding)
Sociology students had significantly lower subjective numeracy scores compared to other five groups, and first-year medical students had the lowest subjective numeracy score of all medical school groups (Table [2](#Tab2){ref-type="table"}). On the other hand, there was no difference between the first-year medical students and sociology students on objective numeracy results (Table [2](#Tab2){ref-type="table"}). Finally, fourth, fifth- and sixth-year medical students were always superior to first- and third-year students (Table [2](#Tab2){ref-type="table"}). Table 2Subjective and objective numeracy scores (median, 95% confidence interval) among students from the Faculty of Social Sciences and students of the first, third, fourth, fifth and sixth year of medical studies (*N* = 272)Numeracy testSociology (*n* = 27)Medicine 1st year (*n* = 59)Medicine 3rd year (*n* = 54)Medicine 4th year (*n* = 52)Medicine 5th year (*n* = 39)Medicine 6th year (*n* = 46)P†BF~10~‡Subjective^a^3.5 (3.1 to 3.6) §4.8 (4.6 to 5.0)4.6 (4.4 to 4.9) ‖4.9 (4.7 to 5.2)5.0 (4.9 to 5.1)5.0 (4.9 to 5.1)\< 0.0012.758 × 10^15^Objective^a^15.0 (15.0 to 16.0) \#17.0 (15.0 to 17.0)\*\*17.0 (16.0 to 17.0) ‖18.5 (17.0 to 19.0)19.0 (18.0 to 20.0)19.0 (18.0 to 19.0)\< 0.0012.359 × 10^10a^Subjective numeracy score is expressed as mean of answers to eight Likert type questions ranging 1--6; Objective numeracy is expressed as sum of correct answers on a scale from 0 to 20†Kruskal Wallis test‡Bayesian one-way ANOVA; BF -- Bayes Factor§Statistically significant from others, post-hoc Conover Iman test¶Statistically different from Sociology students only‖Statistically different from Sociology and Medicine 4th, 5th and 6th year groups\#Statistically different from Medicine 3rd, 4th, 5th, 6th year groups\*\*Statistically different from Medicine 4th, 5th, 6th year groups
Controlled before-and-after study {#Sec13}
---------------------------------
In total, 113 participants completed all three measurements (54 in the intervention and 59 in the non-intervention group) (Fig. [1](#Fig1){ref-type="fig"}). There were no differences between the intervention and non-intervention in sex distribution and grade point average (Table [1](#Tab1){ref-type="table"}). The non-intervention group was significantly younger than the intervention group at the time of measurement, because they were tested at the beginning of the academic year (October), whereas the intervention group was tested at the end of their first academic year (June) (Table [3](#Tab3){ref-type="table"}). Fig. 1Flowchart of participants who were part of controlled before-and-after study Table 3Demographic characteristics non-intervention (*n* = 59) and intervention group (*n* = 54) of medical students participating in the studyNon-intervention group (*n* = 59)Intervention group (*n* = 54)P\*Females (%)40 (67.7%)36 (66.7%)0.949Age in years (median, 95% confidence interval)19.0 (18.0 to 19.0)‡19 (19.0 to 19.0)\< 0.001Grade point average at the end of high school (median, 95% confidence interval)^b^4.8 (4.7 to 4.8)4.9 (4.8 to 4.9)0.377\*Chi square for categorical variables and Mann Whitney test for continuous variables‡In Croatian higher education system, grade point average ranges from 2.0 (sufficient) to 5.0 (outstanding)
Subjective numeracy was higher in the non-intervention group compared to intervention group at the first measurement, but it significantly decreased over time, resulting in intervention group scoring higher on the third measurement (Table [4](#Tab4){ref-type="table"}). Moreover, non-intervention group reached the same level of numeracy scores on their third measurement as the baseline results of the intervention group both on subjective (*P* = 0.301) and objective numeracy (*P* = 0.191). However, comparison of the differences between the third and the first measurement revealed that subjective numeracy decreased in the non-intervention group (mean difference (Md~diff~) = − 0.4, 95% CI = -0.4 to − 0.1), and significantly increased in the intervention group (Md~diff~ = 0.5, 95% CI = 0.3 to 0.7). On the other hand, the non-intervention group showed greater increase in objective numeracy results (Md~diff~ = 2.0, 95% CI = 1.0 to 3.0) compared to the intervention group (Md~diff~ = 1.0, 95% CI = 0.0 to 1.0**)**. Table 4Objective and subjective numeracy scores (median, 95% confidence interval) in non-intervention medical (*n* = 59) and intervention medical (*n* = 54) student groupsNumeracy testGroupFirst measurementSecond measurementThird measurementP†BF~10~‡Subjective numeracy^a^Non-intervention group4.8 (4.6 to 5.0) §4.5 (4.3 to 4.8)4.4 (4.3 to 4.8)\< 0.001990.99P¶\< 0.0010.1420.029Intervention group4.5 (3.8 to 4.8)4.3 (4.0 to 4.5)4.9 (4.5 to 5.1)0.1680.87Objective numeracy^a^Non-intervention group17.0 (15.0 to 17.1) ‖18.5 (18.0 to 19.0)19.0 (18.0 to 19.0)\< 0.0011.49 × 10^10^P¶\< 0.0010.0020.117Intervention group18.0 (18.0 to 20.0) \#19.0 (19.0 to 20.0)19.0 (19.0 to 20.0)\< 0.0011212.78^a^Subjective numeracy score is expressed as mean of answers to eight Likert type questions ranging 1--6; Objective numeracy is expressed as sum of correct answers on a scale from 0 to 20†Friedman non-parametric test for repeated samples‡Bayesian repeated measures ANOVA; BF -- Bayes Factor§Significantly different from the third measurement, Conover post-hoc test¶Mann Whitney test for independent samples‖Significantly different from other two time point measurements, Conover post-hoc test\#No differences were found between different time point measurements on post-hoc testing
Discussion {#Sec14}
==========
The cross sectional analysis in our study demonstrated that there are differences in numeracy levels between different years of medical curriculum. Higher years generally had higher both subjective and objective numeracy then lower years. Also, medical students do not seem to come to the medical school with already high numeracy skills, as they did not differ from first-year sociology students in objective numeracy. However, they have more confidence in their numerical skills, and their subjective numeracy scores were significantly higher than their first-year counterpart at the Faculty of Humanities and Social Sciences. A course in research methodology and statistics further increases their confidence in their numeracy skills, as in the controlled before-and-after study the intervention group of first-year students did not differ in objective numeracy scores compared to the non-intervention group which did not attend the course, but their subjective numeracy scores were significantly higher even 3 months after the course.
The results of our study have to be interpreted in view of several limitations. Due to the fact that the test used in this study measures basic health numeracy, the distribution of the results was skewed, which resulted in a ceiling effect for the participants with higher numeracy levels. We addressed this possible bias by determining changes in numeracy scores for each individual participant and comparing these differences between the groups. Moreover, the differences between the groups were small, often with only few points of difference between the groups, posing a question of their practical relevance. Finally, there could be differences between the groups in terms of motivation and/or readiness to learn numeracy skills at the beginning of the study because students were not aware of their deficit in objective numeracy levels, which could affect later results. Future research should consider assessing this construct at the pre-test stage, using focus groups, interviews or testing, to make the participants aware of their numeracy skills before the intervention, which could make them more motivated for learning.
To the best of our knowledge, this is the first study that assessed the development of health numeracy during medical education using both subjective and objective numeracy assessment and by testing for both short- and long-term retention of numeracy skills. Also, this is the first study that compared numeracy levels of future physicians with a population that had a different educational profile (in this case, sociology students). We tested sociology students only at the baseline because further testing of numeracy levels among sociology students would add complexity to the experimental model because sociology students have different course schedule and attend statistics course throughout the semester (sociology students have 90 h of statistics throughout the year, compared to a 50-h, two-week modular course in biostatistics and research methodology for first-year medical students), and different baseline attitudes towards numerical concepts. Thus, comparison of medical and sociology students would not be possible after 3 months because different factor could determine their numeracy competencies.
First-year medical students had similar results on objective numeracy compared to sociology students, indicating that students of different disciplines at the beginning of their studies have the same levels of objective health numeracy. This is probably the result of the similarity of their high-school education, as most university students come from grammar schools and have to pass the same national examination as a qualifying exam for university entrance \[[@CR10]\]. On the other hand, sociology students had lower levels of subjective numeracy compared to medical students' groups, which may be expected from students who are more oriented towards humanities and social sciences than from medical students who are oriented towards natural sciences. We could not identify studies comparing subjective and objective numeracy levels between different academic disciplines, so future research should explore this knowledge gap.
Our study extends previous research that assessed objective and subjective numeracy in a cross-sectional study design and showed that there were no differences in numeracy skills assessed using either objective or subjective approach \[[@CR12], [@CR20], [@CR21]\]. Our study tested an intervention to improve subjective numeracy using a controlled before and after study design and tested both a short-term effect (immediately after the intervention) and a long-term effect (3 months after the intervention).
Furthermore, our study is, to the best of our knowledge, the first use of NUMi for the population of medical students. NUMi is a very broad and sensitive measure of health numeracy (15), which could be the reason why we captured small but significant differences between the study groups. Considering that NUMi has been developed for the general population, the scores in our study were high in comparison to the lay population \[[@CR15]\]. We are not aware of a validated and standardized test that would capture higher-level objective numeracy such as may be expected from health professionals in evidence-based practice.
In the controlled before-and-after study, the non-intervention group had significantly improved scores on objective numeracy test compared to its basic scores 3 months before the intervention. It could be argued that this difference was a consequence of frequent exposure to numeracy testing because the scores improved in both non-intervention and intervention group after the initial measurement. Although the non-intervention group had lower results compared to the intervention group at initial measurement, the scores of non-intervention group at the third measurement were not different from the baseline result of the intervention group. Taking into account that the non-intervention group at their third measurement was at the same curricular stage as the intervention group at the baseline, it is possible that the absence of difference indicates that the improvement of health numeracy was due to the first-year curriculum. First-year medical students at the Medical School in Split attend courses in biophysics and biochemistry in their first months of training, where they have to perform numerical calculations embedded in an abstract rather than concrete medical content. It is possible that their basic objective numeracy is improved because of numerical exercises they performed for these courses \[[@CR6]\]. However, considering the fact that numbers they worked with were embedded in a non-medical context and represented abstract definitions, subjective numeracy decreased and remained low during the Anatomy and Histology and Embryology courses, which do not contain numerical applications. Further improvement in objective numeracy was observed in the intervention group after a mandatory research methodology and statistics course. It is possible that embedding numerical expressions in medical context resulted in the finding that subjective numeracy levels remained unchanged after 3 months post-course period, while at the same time subjective numeracy decreased in the non-intervention group, which did not have a course where numerical expressions were embedded in a medical context. However, research methodology and statistics course made very little practical difference in students' objective numeracy levels; which is often the case with individuals who have already high numeracy levels at the baseline \[[@CR6]\]. However, it is possible that more frequent courses in biostatistics and research methodology with numerical concepts in a medical context throughout the entire medical curricula could improve students' attitudes towards use and understanding of numerical concepts in everyday medical work.
The differences between the third and higher years of medical school in the cross sectional study should be interpreted in view of medical curriculum at the Medical School in Split. During the third year of the medical curriculum, students are exposed to numerical expressions embedded in a medical content (e.g. pathophysiology and pharmacology courses) and also attend a mandatory course in evidence-based medicine (addressing concepts such as number needed to treat, risk reduction, odds ratio, meta-analysis), which may have contributed to the high numeracy levels observed at their entrance to the fourth study year. Previous research also indicated that clinical maturity is an important factor which may contribute to the improvement of critical reflection and numerical understanding in health context, which may also be a reason why students at clinical years had higher scores \[[@CR22]\]. Moreover, at the clinical part of the medical curriculum, it is to be expected that students perform calculations in a clinical context daily, and thus keep their high numeracy levels. It has been shown that participants who learn numeracy in a relevant context have greater chance of improvement of both objective and subjective numeracy \[[@CR23]\]. This is supported by the evidence that professionals who perform everyday calculations in a clinical context have higher numeracy levels compared to medical students \[[@CR24]\]. These findings emphasize the importance of implementation of clinical context in all numeracy- and statistics-related courses and programs in medical education.
Conclusions {#Sec15}
===========
In conclusion, our study showed that both subjective and objective numeracy levels were higher among students at higher years of medical school. Research methodology and statistics course intervention did not make a difference between intervention and non-intervention group in objective numeracy scores, but the intervention group had higher subjective numeracy levels after 3 months. Although objective numeracy levels in medical student population are relatively high, courses in research methodology and biostatistics may possibly help to increase preferences towards numerical compared to verbal type of information and increase confidence in the use of numerical information in a medical context.
NUMi
: Numeracy Understanding in Medicine Instrument
SNS
: Subjective Numeracy Scale
**Publisher's Note**
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
AM and IB created the idea for the study. IB, RT and MM collected the data. IB and RT performed the statistical analysis and wrote the first draft. All authors participated in manuscript revisions and approved the final version of the manuscript, and all take the responsibility for the content of the manuscript.
This research was funded by the Croatian Science Foundation, grant No. IP-2014-09-7672 "Professionalism in Health Care"). The funder had no role in the design of this study, its execution and data interpretation.
The datasets used and analysed during the current study are available from the corresponding author on request.
Both studies were approved by the Ethical Committee of University of Split School of Medicine as a part of the research grant "Professionalism in Health Care" funded by the Croatian Science Foundation (Grant No. IP-2014-09-7672).
Not applicable.
The authors declare that they have no competing interests.
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Devices for sensing a fluid, for instance in a ventilation duct, do often have to be mounted in places where the available space is limited. Thus, lack of space is a great problem for mounting such devices.
In WO2006/078204 a device for sensing a fluid, such as in a ventilation duct, is disclosed. Even though the device in WO2006/078204 is relatively compact, there is still a need for improved sensing devices that may be mounted in limited spaces.
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Moapa River Indian Reservation
Moapa River Indian Reservation is an Indian reservation located northeast of Las Vegas, near Moapa. It is the land-base for the Moapa Band of Paiute Indians, a local band of Southern Paiute Indians. Moapa River Indian Reservation consists of 71,954 acres (29,119 hectares). As of the census of 2010, the population was 238, up from 206 in 2000.
Location and geography
The reservation is crossed from northeast to southwest by the I-15 highway. In the southeast, it is adjacent to Valley of Fire State Park. In particular, Exit 75 of the highway and the local road leading to the west park entrance (formerly Nevada 169, decommissioned in 2001), down to the entrance, belong to the reservation.
Energy
The reservation includes a 250 MW solar power generation facility known as Moapa Southern Paiute Solar Project which generates enough energy to power 111,000 homes, displacing around 341,000 metric tons of carbon dioxide annually. Another solar farm Eagle Shadow Mountain Solar Farm is being constructed in the reservation is a planned 300 MW solar project.
In 2019, Paiutes agreed with Berkshire Hathaway's NV Energy about two solar and battery projects:
8minutenergy Renewables develops the 300 MW(ac) Southern Bighorn Solar & Storage Center with 540 MWh (4 hours of 135 MW) storage.
EDF Renouvelables constructs the 200 MW(ac) Arrow Canyon Solar Project with 375 MWh (5 hours of 75 MW) storage, operational by 2023.
References
External links
US Census Bureau Tract Map for T2315 - Moapa River Indian Reservation
Category:Paiute
Category:Federally recognized tribes in the United States
Category:American Indian reservations in Nevada
Category:Populated places in Clark County, Nevada
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Thursday, August 13, 2009
WMR has learned from UN sources that the campaign by the Israel Lobby in the United States to discredit former Irish President and UN Human Rights Commissioner Mary Robinson was aided and abetted by a long-time UN liaison "consultant" who has worked for both Secretary Generals Kofi Annan and Ban Ki-moon.
The consultant attempted to put the imprimatur of the UN on a number of news stories that were placed in the major media. On May 10, former U.S. ambassador to the UN John Bolton, who is now a senior fellow with the neocon citadel, the American Enterprise Institute, penned a screed against Robinson in the Wall Street Journal that accused Robinson of tolerating an anti-Semitic, anti-Israel, and anti-American platform at the World Conference Against Racism in Durban, South Africa in 2001.
Major Jewish organizations in the United States criticized President Obama for awarding Robinson the Presidential Medal of Freedom at a White House ceremony yesterday. Obama was also criticized by the minions of the Israel Lobby for awarding the same medal to retired South African Anglican Archbishop Desmond Tutu. The same Israeli Lobby interests were also at the forefront of criticism of former President Jimmy Carter for his defense of the Palestinians and his likening their situation to blacks in apartheid South Africa. Carter was likewise accused of "anti-Semitism," a rather familiar refrain from apologists for Israel's brand of apartheid practiced against Palestinians and Israeli Arabs alike.
The program to discredit Robinson and Tutu may have had the opposite effect of what Jewish organizations and the Israel Lobby intended. The venal barrage against Robinson and Tutu, both of whom are highly thought of among UN diplomats, has created a backlash against both the Israel Lobby in the United States and Israel, according to our UN sources.
The actions against Robinson and Tutu are not helped by the fact that the Israeli government is refusing to cooperate with a UN probe into Israeli war crimes in Gaza.
Critics of the Durban conference cite the discussions held there about the nature of Zionism as a racist philosophy. If the case of former U.S. Representative and 2008 Green Party presidential candidate Cynthia McKinney is any indication, Israel has institutionalized racism. After McKinney and her party of human rights campaigners were arrested in international waters in June for trying to deliver critical humanitarian supplies to the beleaguered people of Gaza, McKinney was put into a prison in Ashdod, assigned prisoner number 88794, and segregated into a cell with female Ethiopian economic refugees. And if that bit of Jim Crow tactics with a Kosher flair was not enough, McKinney told WMR that she was subjected by her Israeli jailers to everything "but a full body search."
WMR has also learned that Israel's El Al Airlines is doing a booming business in transporting expelled critics of Israel back to their home countries. Last year, American Professor Norman Finkelstein, a critic of Israeli policies, was expelled from Israel after being detained for 24 hours. Last year, Israel also expelled American Professor Richard Falk, the UN's special rapporteur on the Palestinian territories, after being detained in a shabby Israeli prison cell. Finkelstein and Falk are both Jewish.
Other travelers to Israel, including Americans of Arab descent and those supporting the Palestinian cause, are routinely taken into custody by Israeli security forces, imprisoned, and expelled on the first available El Al flight.
WMR has learned from a source who was a close friend of the late John F. Kennedy, Jr. that the FBI originally treated the July 16, 1999, crash of his Piper Saratoga in the waters off Martha' Vineyard as a murder investigation. Kennedy, his wife Carolyn Bessette Kennedy, and his sister-in-law Lauren Bessette were killed when their plane plummeted into the Atlantic en route from Caldwell Airport in Essex County, New Jersey to Martha's Vineyard. Kennedy's wife was also three month's pregnant with a boy.
Kennedy was to drop off Lauren Bessette at Martha's Vineyard before flying to Hyannisport to attend his cousin Rory's wedding.
According to the Kennedy friend, the son of the late president and publisher of "George" magazine, was about ready to announce his run for the U.S. Senate from New York. Kennedy was acutely aware of his vulnerability and hired on a personal security team just prior to his announcing for the Senate. Kennedy also decided, unlike all previous flights, not to file a flight plan at Caldwell. Instead, Kennedy, instead of filing an FAA flight plan, provided his own "flight following" by having a Kennedy friend waiting at the Martha's Vineyard airport. When the plane was overdue the friend notified Woods Hole Coast Guard Station which, in turn, notified the FAA and other agencies.
According to the source, Kennedy, contrary to press reports, decided not to fly over open ocean from Montauk at the eastern tip of Long Island to the Vineyard but instead hugged the Connecticut and Rhode Island coast lines until flying direct to the island. Kennedy did not identify his ultimate destination on the radio - he said that6 he was flying "east of Teterboro."
Fearing for his safety, Kennedy thought it best to be within sight of the coastline. According to the Kennedy friend, Kennedy told him his plans prior to his departure. Kennedy had also arranged for all the onboard bags, including his own and that of his family, to be hand searched by security personnel at Caldwell prior to departure. Kennedy decided not to take along a co-pilot because he felt his flight was somewhat of a risk. Kennedy's friend said Kennedy was always concerned about the "underdog" and did not want to put a co-pilot in any potential danger. In any event, Kennedy felt confident of his and his family's security since he had retained a security firm to provide for his protection prior to his Senate run announcement.
Media reports at the time of the disappearance suggested that the weather near Martha's Vineyard was "hazy" and Kennedy may have become disoriented, causing the crash. However, the Kennedy friend states that this was not the case and cites the fact that visibility around the Vineyard was clear at 9:41 pm when the plane disappeared from the sky. The following is from the National Transportation Safety Board (NTSB) report on the crash and quotes the Martha's Vineyard tower manager:
"During an interview, the tower manager stated that no actions were taken to augment or edit the ASOS during his shift. He also stated the following:
'The visibility, present weather, and sky condition at the approximate time of the accident was probably a little better than what was being reported. I say this because I remember aircraft on visual approaches saying they had the airport in sight between 10 and 12 miles out. I do recall being able to see those aircraft and I do remember seeing the stars out that night...To the best of my knowledge, the ASOS was working as advertised that day with no reported problems or systems log errors.'"
ASOS is the Automated Surface Observation System. Media reports claimed that visibility was around 2 miles with haze, a far cry from what the tower manager at Martha's Vineyard stated to the NTSB.
The weather report around the time of the crash also indicated clear weather in the area:
Some twelve minutes after Kennedy's plane crashing, visibility around Martha's Vineyard was reported at 10 miles, described as near perfect conditions by professional pilots.
There were also questions raised about Kennedy's piloting skills. However, he had logged in 310 hours. The NTSB report also reported Kennedy's most recent flight record:
"In the 15 months before the accident, the pilot had flown about 35 flight legs either to or from the Essex County/Teterboro, New Jersey, area and the Martha's Vineyard/Hyannis, Massachusetts, area. The pilot flew over 17 of these legs without a CFI [Certified Flight Instructor] on board, including at least 5 at night. The pilot's last known flight in the accident airplane without a CFI on board was on May 28, 1999."
Kennedy's most recent three legs were with a CFI on board and along the same route taken on July 16 but significant rain and a 800 foot ceiling. Kennedy had, according to his friend, been flying for 17 years. Before Kennedy flew the Piper Saratoga he flew a Cessna 182.
There were also media reports that Kennedy was impeded by a foot cast from an accident he suffered while parasailing. However, according to Kennedy's friend, the cast had aready been removed when Kennedy took to the skies on July 16.
The Kennedy friend also stated that he learned from an FBI agent, as well as a Secret Service agent, who were friends of the Kennedy family that the FBI originally treated their investigation of the plane crash as a possible murder. Kennedy no longer enjoyed Secret Service protection as a protected person, according to the friend.
FBI agents, after the crash, fanned out across convenience and other stores in the Caldwell, New Jersey area and asked if anyone had recently purchased epoxy. According to the French magazine, France Dimanche, a pilot at the Caldwell airport had reported he heard a "weird noise" coming from Kennedy's plane on takeoff. The FBI theorized that a whistle had been glued on the aft section of the plane in order to emit a distinct, unique, and high-pitched noise for the benefit of someone on the ground who wanted to correctly identify the plane when it descended for landing at Martha's Vineyard.
The FBI asked pilots if a whistle attached to the rear of a plane such as Kennedy's could be heard from the cockpit. The answer from all the pilots was no because the sound would only be heard by those on the ground as the plane passed overhead while descending to an audible range. There was also a belief that if the whistle had been fashioned from a water-soluble material, such as plaster-of-paris, it would have dissolved in the seawater.
The FBI discovered that there was "suspicious boating activity" in an area of Martha's Vineyard where Kennedy's plane was descending to 2000 feet for its final approach to the airport. The "suspicious" boaters claimed to be fishing for striped bass. However, when the FBI asked local fishermen to corroborate the suspicious boaters' story, they stated that the particular area where they were discovered was not an area where Atlantic striped bass would be found. In fact, salt water striped bass do not start to run in Massachusetts coastal waters in great numbers until the autumn.
The FBI also found an unusual number of extra batteries in the fishermens' boat. The FBI was suspicious of the boat's contents because after the plane's wreckage was discovered, investigators found, according to Kennedy's friend, that every light bulb, including that in the emergency flashlight, had been blown out on the plane and every circuit board, including those in the engine sensors and other electronic equipment, had been literally "melted." FBI agents on the scene preliminarily concluded that a "massive electromagnetic event" caused Kennedy's plane to crash. FBI agents also found that the cockpit voice recorder (CVR) had its battery removed, possibly before the flight. Every simulation the FBI conducted of a plane in Kennedy's situation, with all lights off at night and with only the engine and the vacuum pump-operated attitude indicator functioning, resulted in the same result: the plane crashing into the water.
Before the FBI could begin examining the ocean floor for any "special equipment" that may have been thrown overboard from the fishing boat, their "murder" investigation was abruptly called off by FBI headquarters in Washington.
Kennedy was preparing to re-tool "George" magazine to take on investigations of a number of major stories, not least of which was the actual story behind the assassination of his father in Dallas on November 22, 1963. According to an article in Germany's Bild am Sonntag on August 1, 1999, Kennedy was also preparing to meet with the deputy chief of Mossad, Amiran Levine, at the Oak Room in Manhattan's Plaza Hotel the Wednesday after Kennedy was killed. The subject was the assassination of Israel's Prime Minister Yitzhak Rabin in 1995 and that Rabin was assassinated by one of his body guards and not the convicted murderer Yigal Amir.
Kennedy's friend said the real priority of the "George" publisher was to re-open the case of the assassination of President John F. Kennedy and the role that the father of the all-but-announced Republican presidential candidate for the upcoming 2000 election -- George W. Bush -- played in the assassination. Apparently, some documents had come into Kennedy's possession that pointed to George H. W. Bush as a prime participant, on behalf of the CIA, in President Kennedy's murder.
On a 1997 visit to see Cuban President Fidel Castro in Havana for an interview for "George," the Cuban President reportedly told Kennedy a number of details about those behind his father's assassination. The occasion of Kennedy Jr.'s visit was the 35th anniversary of the Cuban missile crisis between his father and Soviet Premier Nikita Khrushchev. According to Kennedy's friend, Castro confided to Kennedy that a mafia ring headed up by Meyer Lansky, who lost his Cuban gambling holdings to Castro's revolution, and a Canadian Zionist veteran of Israel's Haganah army, Louis Bloomfield, were the primary planners of the Dallas "hit" on his father. Jack Ruby, who killed the alleged assassin Lee Harvey Oswald, worked directly for Lansky's organization, Kennedy was told.
Although the information on J.F.K. Jr.'s plans to more thoroughly examine the facts of his father's assassination came from a single source -- a friend of the late Kennedy Jr. -- this editor is in a unique position to corroborate part of the story.
On Saturday, July 17, 1999, I was driving to a hotel in Crystal City, Virginia to proctor a certification examination for a group of computer security professionals. Listening to the radio, the bulletin came across that John F. Kennedy Jr.'s plane was missing. The news came as a body blow. In a few weeks, I was scheduled to meet with Kennedy at his magazine's offices in Washington, DC to discuss hiring on as one of a few investigative journalists Kennedy wanted to dig deep into a number of cases, but most importantly that of his father's assassination. Kennedy had made initial contact with me via a colleague with The Village Voice. I signaled my readiness to do whatever Kennedy wanted because, first of all, I have always been an admirer of the Kennedy family, and after twelve years under Bush presidencies, that admiration has developed into a loyalty for which I make no apologies.
My past discussions with President Kennedy's press secretary Pierre Salinger and Texas Governor John Connally led me to believe that the young Kennedy was on to the story of a lifetime -- a lifetime that for Kennedy Jr. would be tragically snuffed out early.
After I heard the news report about Kennedy's plane and knowing of his plans, I knew deep down that he was gone and that the renewed investigation of America's worst crime of the 20th century was dead along with him. Little did I realize at the time, but I heard the news about Kennedy as I was driving along Route 110 past the side of the Pentagon where the worst crime of the 21st century would take place under the administration of George W. Bush.
In the end, Hillary Clinton was elected to the U.S. Senate seat that Kennedy was to run for. Kennedy's sister, Caroline Kennedy Schlossberg, would see her own hopes to be appointed to the Senate seat dashed when, according to John H. Kennedy Jr.s' friend, Senator Charles Schumer and Barack Obama chief of staff Rahm Emanuel conspired to have New York Governor David Paterson appoint a virtual unknown, Kirsten Gillibrand, to the seat. Caroline Kennedy was instead offered a consolation prize of the post of U.S. ambassador to the Vatican, a position that Schumer and Emanuel knew in advance she would never accept.
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1. Introduction {#sec1}
===============
Drug-induced immune haemolytic anaemia (DIIHA) is rare and occurs in about one per million per year \[[@B1]\]. The severity of DIIHA varies from acute severe intravascular haemolysis to subacute milder forms of extravascular haemolysis \[[@B2]\]. There are numerous drugs that have been incriminated in DIIHA. Common drugs causing DIIHA include antimicrobials (42%), nonsteroidal anti-inflammatory drugs (15%), and antineoplastic drugs (11%) \[[@B3]\]. Some of the common antibiotics causing DIIHA are cephalosporins, levofloxacin, nitrofurantoin, and piperacillin/tazobactam \[[@B4]\]. DIIHA is not commonly seen with co-amoxiclav, and we report a case of a DIIHA occurring in a 53-year-old male patient, prescribed this drug. Since DIIHA is generally under-reported, clinicians need to be aware about this rare but life-threatening adverse reaction to commonly prescribed drugs and its diagnosis and management.
2. Case Report {#sec2}
==============
A 53-year-old male with a history of bronchial asthma (on inhaled salbutamol and corticosteroids) and diabetes mellitus (on gliclazide and metformin) presented to the National Hospital of Sri Lanka with fever, constitutional symptoms, dysuria, and left-sided loin pain for three days. Review of the other systems was normal. There were no known allergies to food or drugs. Patient informed about previous antibiotic usage as an outpatient; however, he was not sure which antibiotics were used and records were not traceable. However, he has not received intravenous antibiotics previously. On examination he was febrile, with significant left-sided renal angle tenderness, with normal vital signs, and no hepatosplenomegaly. The rest of the systemic examination was normal. He was empirically diagnosed with left-sided pyelonephritis and started on intravenous co-amoxiclav (1.2 g three times per day) on the day of presentation. Initial laboratory tests on admission showed a normal haemoglobin level of 13.7 g/dl (normal range 13--16.5 g/dL), a white blood cell count of 11,400/*μ*L (normal range 7,000--11,000/*μ*L), and a platelet count of 221,000/*μ*L (normal range 150,000--450,000/*μ*L). His urine microscopy showed a field full of pus cells, without any red cell or casts. Serum creatinine was normal (93 *μ*mol/l) and remained in the normal range throughout admission. Inflammatory markers were markedly elevated on admission (C-reactive protein 400 mg/dl). The initial clinical diagnosis was confirmed by ultrasound scan of the kidneys, which did not reveal any other abnormalities, including hepatosplenomegaly.
On day 3 of the admission, apart from mild fatigue, fever and other symptoms, including loin tenderness, have improved. However, physical examination revealed a pale conjunctivae and mucous membranes, along with mild icterus, but the rest of the systemic examination was normal. He did not complain of any bleeding manifestations, including melena, and digital rectal examination was normal. Repeat blood counts on day three revealed a reduction in the haemoglobin (9.5 g/dl) and C-reactive protein (190 mg/dl) levels. He had a reticulocyte production index of 4.6 (reticulocyte count 15%; haematocrit 30.0%), with indirect hyperbilirubinaemia (total bilirubin 17.6 *μ*mol/L; indirect bilirubin 11.4 *μ*mol/L), with normal hepatic transaminase levels. Changes in haemoglobin and red cell indices are summarized in [Table 1](#tab1){ref-type="table"}. A review of the peripheral blood smear revealed polychromasia, red cell agglutination, and numerous nucleated red blood cells (RBCs), without evidence of bite cells or blister cells to indicate G6PD deficiency. Direct Coombs test was positive with IgG and C3d. Antibody screening was negative. His haemoglobin dropped to 4 g/dl on post-admission day 7 (reticulocyte production index 4.4%, haematocrit 13.2%). The following investigations for other causes of acquired haemolytic anaemia were negative: hepatitis B and C serology, retroviral screening, mycoplasma antibody, Ham test, EBV/CMV IgM antibodies, and anti-nuclear antigen (ANA).
In view of a possible DIIHA co-amoxiclav was changed to intravenous ciprofloxacin (400 mg twice daily). Additionally, 2 units of cross matched blood were transfused (blood group A positive). He reported improvement after the blood transfusion and discontinuation of co-amoxiclav. His haemoglobin gradually increased, and at day 6 after discontinuation of co-amoxiclav, it was 9.5 g/dL. The drug review showed that the only new drug prescribed to him was co-amoxiclav for the empirical treatment of pyelonephritis. Other drugs were unchanged and could not have accounted for the onset and subsequent improvement after discontinuation of co-amoxiclav. The patient had no further haemolytic episodes. The patient was doing well at the follow-up one month later. Using the Naranjo adverse drug reaction probability scale (our patient scored 7, which makes the drug reaction "probable"), the patient\'s diagnosis was confirmed as haemolytic anaemia, possibly caused by co-amoxiclav \[[@B5]\].
3. Discussion {#sec3}
=============
Immune haemolytic anaemia occurs when IgG and/or IgM antibodies bind to the surface of the red cells, initiating cell destruction via the complement and reticuloendothelial systems. The condition is classified into either autoimmune, alloimmune, or drug-induced, depending on the antigenic stimulus responsible for the immune response \[[@B3]\]. The patient presented in this case report satisfies the diagnostic criteria for immune haemolytic anaemia, as he met the clinical and serological criteria of haemolysis (indirect hyperbilirubinaemia, decreasing haemoglobin level, and peripheral blood smear consistent with haemolysis), along with a positive Coombs test \[[@B6]\]. Co-amoxiclav is an antibiotic used to treat a number of bacterial infections, and it is a combination consisting of amoxicillin and beta-lactamase inhibitor, clavulanic acid. To our knowledge, DIIHA due to co-amoxiclav is only rarely described in the literature, although other beta-lactam antibiotics, including amoxicillin, are known to cause DIIHA \[[@B7], [@B8]\].
Several mechanisms causing DIIHA are described in the literature. In general, DIIHA can be mediated through drug-induced antibodies or through a mechanism called nonimmunologic protein adsorption \[[@B3]\]. Drug-induced antibodies can be either drug-dependent (DDA) or drug-independent antibodies (DIA) \[[@B3], [@B9]\]. DDAs need the presence of the drug to bind and lyse red cells, while DIAs can bind erythrocytes in absence of the causative drugs. However, DIIHA due to DIAs cannot be distinguished serologically from autoantibodies mediating warm autoimmune haemolytic anaemia, and hence, diagnosis depends upon clinical improvement on cessation of the causative drug \[[@B10]\]. The mechanism of co-amoxiclav-induced immune haemolysis resembles ceftriaxone induced haemolysis and is characterized by "immune complex-type" reactions \[[@B10]\]. Immune complex-type reactions occur with DDAs as a result of loose binding with red cells, while a covalent binding will result in a so-called "drug-adsorption mechanism" (penicillin-type) reaction \[[@B3], [@B9]\]. In cases of DDA-mediated DIIHA, the antibody screen is typically negative and only positive if tested in the presence of the drug or with RBC coated with the drug, respectively \[[@B10]\]. Although not performed in the current patient, this can be used as a test to confirm the diagnosis, where mixing washed group O RBCs, patient serum and the implicated drug will result in a strongly positive Coombs test. Subsequently, specificity can be demonstrated by showing that the Coombs test is negative when normal serum is used instead of patient serum and when drug is omitted from the reaction mixture.
Management of DIIHA includes the discontinuation of the suspected drug and red cell transfusion, resulting in a haemoglobin improvement over 7--10 days \[[@B3]\]. Our patient improved with these measures. There is no proven benefit and therefore no recommendation for steroid therapy in DIIHA, at least as far as drug-dependent antibodies are involved, and withdrawing the culprit drug is the most important step \[[@B10]\]. In cases of drug-independent antibodies, which are autoantibodies, steroid therapy can be tried, but also in these cases, the immediate withdrawal of the responsible drug is the most important therapeutic measure \[[@B10]\]. If glucocorticoids are required, they are recommended to be given for 1--3 weeks (1--2 mg/kg/day orally) \[[@B4], [@B5]\]. Intravenous steroids are reserved for those with severe haemolysis, requiring a rapid response, and other immunosuppressants such as cyclophosphamide and azathioprine can also be used in those who do not respond.
In conclusion, DIIHA is underestimated and under-reported, as many cases may not lead to dramatic haemolysis, requiring interventions. However, with increasing antibiotic use and increased reliance on newer generations of antibiotics, such rare but life-threatening adverse reactions may be more frequent. Therefore, it is essential for clinicians to recognize this rare complication caused by commonly prescribed drugs and be aware of its accurate diagnosis and management.
Conflicts of Interest
=====================
The authors declare that they have no conflicts of interest.
######
Changes in haemoglobin and red cell indices.
Days
---------------------------------------------------------- ------ ------ ------- ------- ------
Number of red cells (x10^9^/L) 4.61 3.43 1.24 1.98 3.20
Haemoglobin (g/dL) 13.7 9.5 4 6 9.6
Haematocrit (HCT) (%) 39.4 30.8 13.2 19.7 29.7
Mean corpuscular volume (MCV) (fL) 85.4 89.8 106.4 99.5 92.8
Mean corpuscular haemoglobin (MCH) (pg) 29.7 27.7 32.2 30.3 30
Mean corpuscular haemoglobin concentration (MCHC) (g/dL) 34.7 30.8 30.3 30.4 32.3
Red cell distribution width (RDW) (%) 12.7 14.7 17.7 24.2 17.8
Reticulocyte count 1.5% 5.9% 15% 11.6% 5.4%
Reticulocyte index 1.3% 3.9% 4.4% 5.1% 3.6%
[^1]: Academic Editor: Tatsuharu Ohno
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We've been saying it all along: Jobs jobs jobs. Without one, you simply can't pay your mortgage. And that's exactly what the Mortgage Bankers Association said in its Quarterly Delinquency Survey today: "Job losses continue to increase and drive up delinquencies and foreclosures because mortgages are paid with paychecks, not percentage point increases in GDP."
So while you may think the economy is improving a bit, that doesn't mean that the foreclosure crisis is improving.
But what about that government's Home Affordable Modification Program (HAMP) which is supposedly helping hundreds of thousands of borrowers to avoid foreclosure? Well it is, but it's not keeping pace with the problem.
The MBA reports that in Q3 the seasonally adjusted delinquency rate rose to 9.64 percent of all loans outstanding, up 40 basis points from Q2. Loans in the foreclosure process rose to 4.47 percent, up 17 basis points from Q2. Add it up and 14.41% of all loans in the U.S. are either delinquent or in foreclosures. Do I really need to tell you that that's a new record?
Now for a few caveats. Many the loans that are in the modification trial period under HAMP (which is supposed to be three months) are listed in the 90-day+ delinquency bucket, so it's quite possible that those loans will not go into foreclosure. However, the increase in the overall delinquency rate was driven by prime, fixed-rate loans, and those are loans that are far harder to modify. Why? Because they're not delinquent due to some reset or faulty loan product or bad underwriting, they're going bad because the borrower has lost his/her job and has no income. The bank can try to wait it out a few months to see if the job situation changes, but it's likely that loan is going to fail, period.
Should I get started on the FHA now? You know I have to. Here's the MBA's work:
The foreclosure rate on FHA loans also increased, despite having a large increase in the number of FHA-insured loans outstanding. The number of FHA loans outstanding has increased by about 1.1 million over the last year. This increase in the denominator depresses the delinquency and foreclosure percentages. If we assume these newly-originated loans are not the ones defaulting and remove the big denominator increase from the calculation results, the foreclosure rate would be 1.76 percent rather than 1.31 percent reported.
So just go back to 10th grade math. You would think that if there were so many more FHA loans in the total pool that even if the delinquencies bumped up a bit, the percentage share would decrease. Not so, because a whole lot of FHA loans are going bad.
"Yesterday’s subprime is today’s FHA,” said Toll Brothers CEO Bob Toll at a UBS home builder conference in New York. “It’s a definite train wreck and the flag will go up in the next couple of months: Bail us out. Give us more money.” And that from the luxury home builder.
One more thing from the MBA:
The number of loans 90 days or more past due or in foreclosure is now a little over 4 million as compared with 3.9 million new and previously occupied homes currently for sale, although there is likely some overlap between the two numbers. The ultimate resolution of these seriously delinquent loans will put added pressure on the hardest hit sections of the country.
Yes, four states (CA, NV, AZ, FL) continue to bear the brunt of the crisis, accounting for 43 percent of total U.S. foreclosures. 25 percent of all loans in Florida are in trouble. But the problem is spreading, especially in the Carolinas and Georgia and in states you might not expect like Utah.
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Q:
50 random unique elements from an array of 1000 elemens?
What is the simplest way to get 50 random unique elements from an array of 1000 elements ?
text = new Array();
for(i=0;i<1000;i++){ text[i]=i; } //array populated
// now I need to get 50 random unique elements from this array.
A:
The obvious (to me) way is to shuffle the array, then take the first fifty elements. This question has a good way to shuffle an array, and you can then slice the first fifty elements. This guarantees the elements will be unique.
So, using the function there:
fisherYates(text);
text = text.slice(0, 50);
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{
"pile_set_name": "StackExchange"
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Utah Utes women's soccer
Utah Utes women's soccer represents the University of Utah in the Pac-12 Conference of NCAA Division I soccer. The team is coached by Rich Manning. The team plays its home games at Ute Soccer Field.
History
Utah women's soccer began as an NCAA-affiliated program in the 1995–96 school year when the Western Athletic Conference began to sponsor women's soccer. The program earned its first NCAA tournament bid in 2002.
All-time record
References
Category:Utah Utes women's soccer
Category:1995 establishments in Utah
Category:NCAA Division I women's soccer teams
Category:Pac-12 Conference women's soccer
Category:Soccer clubs in Utah
Category:Association football clubs established in 1995
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{
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Karbalayi Safikhan Karabakhi
Karbalayi Safikhan Karabakhi (Azerbaijani language: Kərbəlayı Səfixan Sultanhüseyn oğlu Qarabaği) (c. 1817 - 1910) was an Azerbaijani architect and one of the representatives of Karabakh architecture schools. Buildings by Kerbalai Sefi Khan Karabagi included traditional and romantic elements. Designs of Karabagi, such as those for mosques in Aghdam and Barda, employ simple devices based on Azerbaijani architectural traditions.
Works
A characteristic feature of creativity of Karabakhi was rational and skillful use of traditional local architecture. The socket of Yukhari Govhar Agha Mosque built by him in 1883, states in Arabic: "Made by Karbalayi Safikhan Karabakhi. 1301."
Among the constructed projects by Karabakhi, includes a mosque in Barda (1868), the Agdam Mosque, the Tatar Mosque in Odessa, the Mosque Qarabaghlar in Ashgabat and other civic buildings in Nagorno-Karabakh region.
He is also responsible for creating a single type of mosques with their unique organization of internal space - the division of stone columns on the two-story gallery and the use of domed ceilings in Nagorno-Karabakh region.
References
Category:19th-century Azerbaijani architects
Category:20th-century Azerbaijani architects
Category:People from Shusha
Category:1817 births
Category:1910 deaths
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{
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Q:
what this integer value means?
I found this on one of the android tutorials site.
The whole program illustrates the bouncing ball with custom view.
I could not understand this line.
private int xVelocity = 30;
xVelocity = xVelocity*-1;
What this * means?
If i remove this * than the animation in drametically changed.
And another thing that invalidate() method of view class is same as repaint() of java???
Any help Would be appericiated.
A:
Multiplication.
xVelocity*-1
Multiply xVelocity by -1.
xVelocity-1
Subtract 1 from xVelocity.
And another thing that invalidate() method of view class is same as repaint() of java?
Yes, invalidate() marks the view as dirty and therefore schedules a redraw.
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{
"pile_set_name": "StackExchange"
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MyLoveReader
====
简介
----
Android平台上的多功能文档阅读器，支持PDF、TXT、WORD、EXCEL阅读。
功能界面借鉴了IReader的形式，“书架”形式展示颇具动态性。
演示图片
----
+
功能简介
----
*PDF文档阅读
*TXT文档阅读
*DOC文档阅读
*EXCEL文档阅读
收尾
----
By kiritor
个人博客:[CSDN:Kiritor](http://blog.csdn.net/kiritor "Title")
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{
"pile_set_name": "Github"
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Bill of Rights
A bill of rights, or the Bill of Rights, is a declaration of the rights that a citizenry have.
It may also refer to:
Declaration of Right, 1689, a document, given as a speech, that declared the rights all citizens of England should have
Bill of Rights 1689, the bill of rights passed by the Parliament of England, as amended several times
United States Bill of Rights, written 1789, ratified 1791
Declaration of the Rights of Man and of the Citizen, 1789 French document
Second Bill of Rights, proposals by United States President Franklin D. Roosevelt in 1944
Universal Declaration of Human Rights, 1948 United Nations document
Canadian Bill of Rights, an Act of the Canadian Parliament in 1960
International Bill of Human Rights, 1976 United Nations document
Canadian Charter of Rights and Freedoms, in the Canadian Constitution of 1982
New Zealand Bill of Rights Act 1990
See also
Consumer Bill of Rights
Homeless Bill of Rights
Taxpayer Bill of Rights
Academic Bill of Rights
Veterans' Bill of Rights
G.I. Bill of Rights, better known as the G.I. Bill
Homosexual Bill of Rights, drafted by North American Conference of Homophile Organizations
Library Bill of Rights, published by the American Library Association
Environmental Bill of Rights or Agenda 21
Creator's Bill of Rights, comic writers and artists
Donor's Bill of Rights, for philanthropic donors
Law Enforcement Officers' Bill of Rights
California Voter Bill of Rights, adaptation of the Voting Rights Act
Islamic Bill of Rights for Women in the Mosque
New Jersey Anti-Bullying Bill of Rights Act
Credit Cardholders' Bill of Rights, contained within the Credit CARD Act of 2009
Sexual Assault Survivors' Bill of Rights (Sexual Assault Survivors' Rights Act)
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{
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Q:
Que tecnología se usa para servir peticiones HTTP compatible con Python
Estoy montando una aplicación en AWS y bueno, este mundo es nuevo para mi.
Expongo el problema
Tengo experiencia con Apache/PHP, Apache es quien me ayuda a servir las peticiones HTTP y PHP es el lenguaje de Backend.
El lenguaje de backend que estoy utilizando en este nuevo proyecto es Python, pero mi pregunta es ¿Cuál es la tecnología que me ayuda a servir las peticiones?
¿Puedo instalar Apache/Python, o cuál sería el dúo perfecto?
Se que esto puede tener muchas variantes dependiendo de cada experiencia y necesidades del proyecto, pero sinceramente estoy perdido en que instalar y que no.
Gracias por su orientación
A:
Parte python
Para la parte python es típico usar "micro-frameworks" que se ocupen de enrutar las peticiones, según la URL, a las funciones apropiadas. Estas funciones reciben parámetros, ejecutan una funcionalidad (típicamente consultas a bases de datos y transformaciones de los resultados a la forma necesaria para el cliente).
Si quieres que el resultado sea una página HTML, suelen usarse mecanismos de "templates", que son algo parecido a lo que hace PHP, es decir, un fichero que parece HTML pero que en ciertas zonas tiene marcadores que señalan dónde deben volcarse los valores de ciertas variables. Python lee uno de esos templates, configura las variables, y llama a una función que retorna el HTML que se devuelve al cliente.
También es posible que el servicio no devuelva HTML para que sea visualizado en un navegador, sino sólo los datos para que el cliente los trate a su antojo. De este modo el cliente podría ser una aplicación móvil, por ejemplo. En este caso la tendencia es devolver los datos en JSON y diseñar la API siguiendo la filosofía REST.
Entre este tipo de microservicios, el más popular es Flask, combinado con jinja2 para los templates HTML. También se usa en ciertos entornos Bottle, que tiene la ventaja de que es un simple archivo python más fácil de instalar, pero mucho más limitado que Flask.
Últimamente están saliendo más frameworks similares, inspirados en Flask pero implementados usando el paradigma asíncrono (para Python 3.6+), como Vibora.
En principio estos frameworks son capaces de servir peticiones por sí solos, es decir, sin necesidad de poner "delante" un servidor como Apache. Simplemente se ejecutan con python y quedan escuchando en el puerto que les digas, al cual ya se podría conectar directamente el cliente, hacer sus peticiones HTTP y recibir la respuesta, ya sea en HTML o JSON. La respuesta podría ser simplemente un archivo HTML estático leído del disco, por lo que pueden reemplazar completamente a un servidor web estándar.
Servidor en producción
Si bien esto suele usarse durante el desarrollo, pues hace muy sencillo lanzar el servidor localmente para pruebas, una vez que quieras llevarlo a producción no se suele usar ya el mini-servidor incluído en el framework por cuestiones de rendimiento.
Por ejemplo, si usas Flask, éste está implementado en un único proceso y un único hilo. Esto implica que sólo puede atender a los clientes de uno en uno. Si un cliente hace una petición que tarda un poco en resolverse, los demás clientes que hayan llegado poco después tendrán que esperar su turno pues hasta que no se haya terminado de atender al primero no se pasará al siguiente. Esto es un problema especialmente si queremos usar algún mecanismo de "notificación push" hacia el cliente, como Long poll, Server Sent Events o WebSockets, ya que estas tecnologías requieren una conexión permanente con cada cliente, haciendo por tanto que sólo se pueda tener un cliente conectado. Los enfoques asíncronos pueden manejar varios clientes dentro de un solo hilo, pero son conceptualmente más complejos de programar y entender.
Por esto lo típico es que una aplicación de éstas sea ejecutada por otro entorno, que pueda lanzar varias en paralelo, en varios procesos y varios hilos dentro de cada proceso.
WSGI
Desde hace ya muchos años, python tiene un "estándar" llamado WSGI acerca de cómo debe comunicarse un servidor de estos con la aplicación python que haya por debajo. Los frameworks antes mencionados son todos ellos compatibles con este estándar, lo que permite usar cualquiera de ellos con el servidor que elijas (que soporte también WSGI).
Por ejemplo, gunicorn sería un posible servidor (en este caso está también escrito en python) que se ocupa de cargar tu aplicación (Flask por ejemplo), e instanciarla varias veces, en varios hilos (también admite "green threads", que son por así decir falsos hilos, más ligeros, gestionados por gunicorn en lugar de ser hilos del operativo). Todo esto es transparente a tu aplicación que se programaría igual que si fuera a ejecutarse sola, excepto por la forma en que se arranca.
Otro posible servidor es uwsgi, en este caso escrito en C y por tanto más rápido que gunicorn.
Proxy (nginx)
Tanto si usas gunicorn como uwsgi como cualquier otro servidor compatible con WSGI, ese servidor quedará escuchando peticiones en cierto puerto. Aunque podrías hacer que ese puerto fuese el 80 y por tanto ya pueda recibir tráfico HTTP de internet, lo habitual es no hacerlo así, sino añadir otra capa intermedia más. Por ejemplo, tu servidor WSGI escucharía en el puerto 5000 (o el que quieras), y sólo admitiría conexiones desde localhost, y no desde Internet.
En la misma máquina tendrías un servidor web estándar (Apache, o más frecuentemente nginx), que actuaría de proxy.
Sería este servidor quien recibiría el tráfico desde internet (y podría ocuparse por ejemplo de los certificados y el protocolo HTTPS), podría servir archivos estáticos en ciertas carpetas y estaría configurado para que, cuando lleguen peticiones a una cierta URL, éstas sean redireccionadas al localhost:5000, donde estaría escuchando tu servidor WSGI.
Todo junto
Una combinación bastante típica sería tener nginx como servidor "dando la cara" a internet, atendiendo peticiones HTTP en el puerto 80 y/o HTTPS en el 443. Detrás de él estaría por ejemplo uwsgi escuchando en el puerto 5000 y nginx estaría configurado para que todas las peticiones a la ruta /myapp sean redirigidas a localhost:5000. Allí las recibe uwsgi y se las pasa a uno de los hilos/procesos que él mismo lanzó durante el arranque donde está Flask esperando peticiones (por el protocolo WSGI). Flask analiza la ruta concreta (ej: /myapp/usuario/22?q=foobar) y le pasa la petición a la función apropiada dentro de tu código python, la cual ya recibe los parámetros como una función python normal. La función puede retornar HTML o JSON, según te interese, y flask recogerá esa respuesta, la convertirá a una respuesta HTTP válida añadiendo las cabeceras necesarias que indican su tipo y se la pasará a uwsgi, el cual a su vez decidirá el método de transporte HTTP apropiado y añadirá alguna cabecera extra que pudiera hacer falta, enviando todo ello a nginx, el cual simplemente se la envía al cliente (quizás cifrándola antes si estamos usando HTTPS).
El esquema sería por tanto:
PETICION:
Cliente -[HTTPS]-> nginx:443 -[socket]-> uwsgi:5000 -[WSGI]-> Flask -[call]-> función python
RESPUESTA:
funcion python -[return]-> Flask -[WSGI]-> uwsgi -[socket]-> nginx -[HTTPS]-> cliente
Espero haberte ayudado a formarte una idea del panorama, que como ves es bastante diferente al del mundo PHP en el que es más típico que el mismo servidor web (Apache) pueda ejecutar el código (PHP) mediante un plugin o mod.
En Full Stack Python tienes muchísima más información sobre frameworks, WSGI, despliegue, servidores, etc.
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Estamos aquí para motivarte y
desafiarte!
Co-founder / Managing Director Enlighten
Caitrin Lepeltier:
Growing up in a multicultural environment I understood from an early age the importance of acquiring strong communication skills to enjoy life fully and face the challenges of a diverse and ever-changing world around me.
Learning new languages can be exhilarating and allows us to connect with people on a deeper level and discover new cultures.... Read more
I started my career in Paris working in public relations where speaking foreign languages was a vital tool in reaching out to clients abroad and creating new markets.
In 2013 after a change in my career path and years of experience as an English teacher, I created Enlighten Languages. The aim is to provide students with a unique learning opportunity related to their personal needs or that of their company.
I am personally committed to making sure each and every course is effective and meaningful, enabling students to reach their fullpotential inside and outside the workplace. Today I am proud to work with an exceptional team of qualified, motivated, teachers in France and Spain from different countries and professional backgrounds. Each one brings to our Enlighten team a unique story, talent and personality.
We have a common goal: we want to equip our students for fluent and coherent communication across the globe. I hope you will be part of our exciting enterprise!
School Coordinator
Daniel:
Hi! I’m Daniel from eastern Pennsylvania. I have two roles at Enlighten: School Coordinator and teacher. My role as a School Coordinator is to organize our students’ classes to make sure ... Read morethey fit as perfectly as possible into their busy weekly schedules. I also facilitate the link between our clients and our team, assisting with the weekly reporting. I particularly enjoy working on our immersion programmes abroad and advising clients about courses, destinations and I stay in touch during their stay with our partner schools all over the world to ensure they are getting the very best experience. Having grown up with an American father and an Italian mother, I understand the importance of being able to communicate with people from different countries and I realize the difficulties linked to learning a new language. My main goals as a teacher are to make sure I always offer an interesting and fun experience to every one of my students to boost their confidence through tailor-made activities.
Pedagogical Manager
Richard:
Hello! I'm Ric from Exeter in the south-west of England. As pedagogical manager in France I am here to help the team with teaching materials which are specifically designed ... Read moreto the students needs. I believe that every person is unique and therefore requires a unique learning experience. Working in this role is also rewarding as I am in contact with students and teachers at all times so can keep track on the progress each individual makes throughout their lessons. My goal when teaching is to enable the student to speak confidently about all aspects of life, both general and specific to business. I believe in active and lively lessons, In which the student can learn whilst debating real life situations with passion. I enjoy being part of the Enlighten team in Lyon, as I am able to meet people from all walks of life who have different language orientated goals.
Office Manager
Alexia:
Hello, I’m Alexia, Madame Back-office! One could think that I am rather annoying, well yes, I am ?! I am the one who insists on the administrative tasks being done correctly at Enlighten ... Read morealongside our teacher's creativity. I work on a daily basis to assist clients in preparing the financing of courses for their employees, learners in the organization of their tests, trainers in doing their reporting. My HR career, in industrial and service companies, allows me to perfectly know and understand our customers requirements and especially to anticipate their needs.
Head of French as a Foreign Language
Stefan:
My name is Stefan. I am from Auxerre, the department of Yonne in France. I studied management, information systems and French as a Foreign Language in Lyon. ... Read moreOn a parallel to a few years of research in semantics, I started a career in teaching very early on at University Jean Moulin Lyon 3, in different schools, companies and also individuals. I taught FLE in France and abroad, especially in Denmark. I am passionate about Scandinavia. Enlighten entrusts me with the management and educational responsibility of courses in French as a Foreign Language. Enlighten works in total confidence with its team of teachers who, in order to respond to the requirements of their learners, implement their own tools and their methodology as well. The diversity and creativity of each teacher is an invaluable asset in achieving progress with our students.We also create and organize intensive courses, total immersion in the true spirit of discovery. Indeed, our pedagogical approach is based on active approach, ie to really live into the foreign language in order to use it effectively with real language skills. This approach involves creating diverse scenarios during the courses, and the practice of new skills in very real situations, in the context of immersion courses. The main purpose of our Enlighten school is to support our learners efficiently and with goodwill throughout their foreign language learning journey. We help them succeed in their project of becoming independent speakers and therefore opening up to the world.
English Teacher & Head of Translations
Anne-Marie:
Hi, my name is Anne-Marie and I come from Melbourne, Australia. I have been living in Lyon for 6 years and have been part of the Enlighten team for nearly two years. ... Read more I do telephone lessons, in-company teaching and translations for Enlighten, and feel that the team atmosphere is really what makes Enlighten different, as it creates a relaxed and friendly environment for the teachers and the students. I have a Masters degree in translation, which I enjoy because it allows me to think about and participate in the relationship between language and culture. My priority as a teacher is to help my students to feel comfortable and relaxed in English, and to encourage them to view language learning as an interesting experience rather than just a tool or an obligation. In the classroom I try to create a friendly and informal environment where students can express themselves without stress.
English Teacher & Business Developer Nice
Jay T.:
Hi, my name is Jay and I am the team leader in the south of France for Enlighten team Nice! I’m originally from Newport Beach, California and have an extensive background ... Read morein finance and accounting. I’m happy to say that I’ve lived on four different continents, travelled to over 60+ countries, lived in New York City and Philadelphia for four years apiece and speak 3 languages. Since arriving in France over 6 years ago, I have focused solely on teaching English (perhaps less money but way more satisfying!). Aside from teaching English, my students appreciate my laid-back Californian attitude, passion for improving their English and the fact that we can discuss at length anything and everything under the sun! That is all for now with my sincere thanks and appreciation!
English Teacher & Team Leader Toulouse
Marie:
Hello! I’m Marie, an English teacher from Philadelphia in the US. Growing up with an American father and a French mother, I became aware of the particular issues that ... Read morespeakers of multiple languages face. I’ve been living and teaching in Toulouse for six years and enjoy helping business professionals and independent learners alike progress towards their goals, gain confidence, and feel at ease as they discover the satisfaction of expressing themselves in English. I find purpose in giving my students the tools they need and in guiding them as they pursue their interests. I joined the Enlighten team in 2015.
English Teacher & Team Leader Paris
Antonio:
Hi! I'm Antonio from Oxford in the UK. I have been living in France and particularly in the Paris region since I left university (not Oxford university 🙂 ) back in the early 90s.... Read more
I have been an English language trainer for many years, but only recently joined the Enlighten training team.
Being bilingual in French and English enables me not only to better understand the mistakes French learners make, but also the difficulties and challenges they are confronted with when communicating in English.
Whenever possible I try to demonstrate the connections and patterns that exist between French and English and as a result this encourages risk taking and develops self-confidence, both of which are crucial in language learning.
English Teacher
Liam:
My name is Liam, and I’m originally from sunny Tampa, Florida. After working in the field of Human Resources for several years and helping other people find their perfect careers, ... Read moreI decided it was time to follow my own advice. I arrived in Lyon in 2015, and I’ve been teaching English ever since which I find very rewarding. I especially enjoy teaching Business English and preparing students for English proficiency examinations. Working with the Enlighten team is fun and varied and our courses are an excellent way to help students develop their confidence and proficiency in both learning and using the English language. I enjoy every minute with our students. Language is about communication, and my goal is to help you find your “voice” in English.
English teacher
Sophie:
Hello! I'm Sophie and I'm an English teacher from Leicestershire in England. I have been teaching English for 3 years. After completing my training in Argentina I went on ... Read moreto work for several language institutes and bilingual primary schools teaching students of all ages and abilities. I joined the Enlighten team in Toulouse this year. Thanks to my background in Drama and Modern Foreign Languages my teaching style is energetic and informal with lots of role plays, games and debates.
English Teacher
Esther:
Hi, I'm Esther! I'm from near Birmingham in England and studied French at the University of Leeds. I joined to the Enlighten team in October. ... Read moreEnlighten provides a fun, relaxed, and practical way to teach and learn languages. Enlighten allows flexibility to organise personalised lessons, so that they fit in with the student and the teacher - making it possible for you to learn languages amidst your busy, daily life. I believe that in learning a language, speaking early and often is key. Whatever your interests, I try to tailor lessons to things that students enjoy talking about. Personally, I love food so I enjoy exploring the similarities and differences between French and British cuisine. I often use videos and role plays to help students improve pronunciation, vocabulary, and most importantly, confidence!
English Teacher
Pamela:
I previously worked as a lawyer in the UK and my business background makes understanding the demands of students easier. By drawing upon my own professional ... Read moreskills I am able to enhance students learning experience by relating my classes to true life. I am delighted to be part of the Enlighten team. I have been teaching English in Lyon for about 3 years to a variety of students but particularly enjoy Enlighten as my students are very motivated and want to learn. I also appreciate the team spirit at Enlighten as there is a real willingness to work together.
English Teacher
Rosario:
Hello! My name is Rosario. I recently started to work with Enlighten in Toulouse, France. I come from a bilingual and bicultural family, English mother and Spanish father. ... Read moreTherefore, I started studying Translation and Interpretation to stimulate my curiosity for modern languages and cultures.
My experience in teaching started at my mother's English academy in Spain. Furthermore, I have worked as a Language Assistant in Toulouse where I also decided to do a Master’s in Teaching English as a Foreign Language. This experience confirmed my desire of becoming a teacher! I realised that I am dedicated teacher for whom teaching, and pleasure go hand in hand. I rely heavily on forming good relationships with my students. I also believe that innovation and creative ideas are active learning techniques that encourage and engage students in my classes.
English Teacher
Patrick:
Hello! I’m Patrick, and I’m originally from a town near Miami, Florida, in the United States. I moved to Bordeaux in 2017, after a few years of traveling throughout the ... Read moreworld. I have a Masters degree in a discipline related to history, and I teach lower level university courses to students in the US via the internet. I’ve been teaching English here in France for a bit longer than a year, while simultaneously learning the French language (so I’m a student, too!) I have extensive teaching experience in a traditional classroom/group setting, as well as experience teaching in companies and in a one-on-one setting with individual students. My teaching style is relaxed and fun while still focusing on the student’s goals – I find that when students are at ease, they express more confidence in their abilities and are better able to retain new information. I’m glad to be a part of the Enlighten team and am eager to meet and work with students in Bordeaux.
English Teacher
Alex:
Hey I’m Alex. I joined the Enlighten team recently and am an English trainer based in Bordeaux. I come from Kent in England and have been in France since 2015. What I ... Read moreenjoy most about teaching is enabling a person to grow, overcome fears and gain new abilities. Aiding development in others and watching their confidence expand is a real pleasure. Here in Bordeaux I am the Enlighten Team leader and enjoy coordinating our work and schedules as well as organizing events in your companies and afterworks. When I’m not at work you’ll probably find me in the kitchen experimenting with a new dish, at a café with my head down in a great book, tinkering with my bike or enjoying a lovely glass of Bordeaux red with my pals at a terrace.
English Teacher
Fiona:
Hi, I’m Fiona, and I’m originally from the UK. However, I moved to France in 2016 from South Africa, where I’d been living for five and a half years, working in an orphanage ... Read moreand a school for disadvantaged children. I originally trained as a Speech and Language Therapist and worked for the National Health Service for several years before giving it all up to move to South Africa. I love teaching English, because I’m passionate about helping people develop to their full potential and speak English well so that they can communicate more effectively in this globalised world. In the words of Nelson Mandela, “If you talk to a man in a language he understands, that goes to his head. If you talk to him in his language, that goes to his heart”. I try to make my lessons fun, engaging and relevant to the needs of individual students, using a wide range of resources and materials to help them develop their skills. I love seeing people develop and grow in confidence in their abilities, daring to speak English as and when required. I am delighted to be part of the Enlighten team based in Rennes.
English Teacher
Willow:
Hello, my name is Willow, I’m originally from Leeds in the North of England! I moved to France when I was just a child. My parents wanted me and my siblings to be bilingual, so I ... Read moretotally understand how intimidating learning a new language can be! I strive to make my lessons fun, dynamic and tailored to your needs. My objective is to give the skills needed to tackle real life and professional situations in English with confidence. Don’t be scared, challenging yourself is what learning is all about. I’m crazy about history, culture and literally anything to do with art. I love working on the Enlighten team in Bordeaux and living in my adoptive country France; nevertheless I am still a British girl at heart...
English Teacher
Elizabeth:
Hello! I'm Elisabeth, initially from Sheffield in England and now settled in Marseille. I did an MA in English Literature and after several years working as a teacher in the classroom ... Read morenow choose to give training in companies. I'm delighted to be able to work with enlighten who invest in each individual's needs… and know that to keep making progress, you have to keep having fun! I enjoy tailoring courses that will develop real skills as well as their curiosity for the English language.
English Teacher
Nicky:
Hi Guys, I’m Nicky. I’m 34 years old from Wales, UK and I’m still pretty fresh to the teaching game, but I’m definitely loving every minute of it. I moved to Lyon Nov 2017 from Australia, ... Read morewhere I lived for 4 years. With a strong passion for travel, culture, food (especially cheese) and adventure, France seemed like the perfect place to be. I love the language, the city and France itself, and I look forward to embarking on this new journey with all of you.
English Teacher
Nick:
Hi! I’m Nick from Miami, FL in the US. I joined the Enlighten team in 2018 in Paris. Though my background is in Engineering, I have been teaching English since 2010 ... Read morewhen I moved to Italy. This drastic career change was due to my love of languages. I've been living in France for about a year now, which is exciting for me as I've been studying French since I was a child.
English Teacher
English Teacher
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“They’re ready to do things, they want to do things,” Trump said. “You know, they’re good people. They’re patriots. They love this country.”
The president said lawmakers must tackle the issue of mental health, calling the suspected gunman in the massacre at Marjory Stoneman Douglas High School a “sicko.”
Trump said he is pledging to take action on guns, “unlike” his predecessor, President Obama.
“For many years … people sitting in my position did not take action,” Trump said. “We’re going to take action.”
But Obama did take action, or tried to. Following the 2012 massacre at Sandy Hook Elementary School in Newtown, Conn., he created a task force to study possible actions and backed a bipartisan bill to expand background checks. But the legislation failed to pass the Republican-controlled Senate. Obama called it a “pretty shameful day for Washington.” In 2016, Obama announced a series of executive actions to reduce gun violence.
President Trump speaks at a meeting on school safety with state and local officials. (Photo: Evan Vucci/AP)
At the White House Thursday, Trump said he “called many senators” the night before to gauge their support for expanded background checks.
“They’re into doing background checks that they wouldn’t be thinking about maybe two weeks ago,” the president said.
Earlier Thursday, Trump doubled down on the suggestion he made at a meeting Wednesday with school shooting survivors and family members that teachers and administrators ought to be armed.
“Highly trained teachers would also serve as a deterrent to the cowards that do this,” Trump added. “Far more assets at much less cost than guards. A ‘gun free’ school is a magnet for bad people. ATTACKS WOULD END!”
At the school safety meeting, Trump floated another idea: paying teachers “a little bit of a bonus” to carry guns.
“I want my schools protected just like I want my banks protected,” the president said. “We have to harden our sites.”
Trump said that for would-be killers, gun-free zones — such as those at U.S. schools — “is like going in for ice cream.”
“We need offensive as well as defensive,” he said. “If we don’t have offensive measures within these schools, you’re just kidding yourselves, folks. … Unless you’re going to have offensive capability, you’re wasting your time.”
The president suggested violent imagery on the Internet and in video games are also to blame for shaping the thoughts of troubled teenagers.
“We have to look at the Internet because a lot of bad things are happening to young kids and young minds and their minds are being formed, and we have to do something about maybe what they’re seeing and how they’re seeing it,” Trump said. “And also video games. I’m hearing more and more people say the level of violence on video games is really shaping young people’s thoughts. And you go one further step and that’s the movies.”
Trump also said he sees active shooter drills, which have been commonplace in schools since the 1999 massacre at Columbine High School in Colorado, as a “very negative thing.”
“I don’t like it. I’d much rather have a hardened school,” Trump said. “I think it’s crazy. I think it’s very hard on children.”
Trump also turned his attention to other issues beyond school safety, including the Justice Department’s prosecution of MS-13 gang members.
“They’re killing people — not necessarily with guns, ’cause that’s not painful enough,” Trump said. “This is what they think. They want to do it painfully and they want to do it slowly. So they cut them up with knives. They don’t use guns, they use knives, because they want it to be a long, painful death.”
Trump deplored inaction by so-called sanctuary cities in California on assisting U.S. Immigration and Customs Enforcement officers in deporting MS-13 members. The president threatened to pull ICE from the state altogether.
“We’re getting no help from the state of California,” Trump said. “Frankly, if I wanted to pull our people from California, you would have a crime nest like you would never see.”
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The present invention relates to semiconductor structures, and particularly, to antifuse structures having an integrated heating element and methods of programming thereof.
Electrically operable fuses are utilized within the field of integrated circuit devices and processes for a number of purposes, including programming alterable circuit connections, or replacing defective circuit elements with redundant circuit elements. One type of electrically operable fuse, a so-called “antifuse”, is a device having two conductors and an intervening dielectric layer, where the dielectric layer is subject to breakdown upon application of sufficient voltage and current to the conductors. The resistance across the dielectric layer of the antifuse encodes the “on” or “off” state of the antifuse.
A typical (pre-breakdown) “off” resistance for antifuses having a dielectric layer of silicon nitride (SiN), “gate oxide”, i.e. silicon dioxide (SiO2) formed by the gate oxide forming process, or silicon oxide-silicon oxynitride-silicon oxide (ONO) is more than 1 GΩ. After breakdown, resistance across the dielectric layer is measurably lower, indicating the “on” state. Thus, the on-off state of the antifuse is read using a resistance measuring circuit.
At present, a high voltage and a current of several milliamperes may be required to adequately break down the dielectric of antifuses on an integrated circuit. Such required high currents impose minimum size constraints on the antifuses and wiring thereto, thereby requiring significant integrated circuit area to implement, while also negatively affecting the flow of production testing and repair of new chips. Provisions must also be made to safeguard the integrated circuit from being negatively affected by the required high programming voltage. The high programming voltage may give rise to concerns for electrostatic discharge protection (ESD) and the reliability of the integrated circuit.
In order for the state of an antifuse to be reliably read, the post-breakdown resistance must be in the megaohm range or below and, for yield reasons, this must be achieved for virtually all of the antifuses on the integrated circuit. Gate oxide antifuses typically require currents in the several milliampere range to achieve such post-breakdown resistance. However, such currents and the required high voltage are close to integrated circuit design constraints based on ESD protection and reliability considerations.
Antifuse technology through the use of dielectric breakdown is well understood. For example, U.S. Pat. No. 5,250,459 (the '459 patent), issued to Lee and entitled “Electrically Programmable Low Resistive Antifuse Element” embodies this concept. FIG.1 of the '459 patent illustrates a conventional antifuse element 14 comprising a first electrode 11, a dielectric layer 12 and second electrode 13, all fabricated on substrate 10. To program antifuse element 14, that is to change the antifuse element from a high impedance state to a low impedance state, the conventional practice is to damage dielectric layer 12 by applying an electric field across dielectric layer 12 at first electrode 11 and second electrode 13. The electric field, if strong enough, will cause the dielectric layer 12 to breakdown, thus forming a conductive filament between first electrode 11 and second electrode 13. To reliably damage the dielectric layer 12, application of high programming voltages and currents are typically required. Gate oxide antifuses typically require several volts and currents in the several milliampere range to achieve such post-breakdown resistance.
This presents a problem in that the voltage/current required to program the antifuse must pass through standard CMOS logic without damaging it. One conventional solution, for example as described in U.S. Pat. No. 6,750,530 (“the '530 patent”), assigned to the assignee hereof and entitled “Semiconductor Antifuse With Heating Element,” is to form a heating element adjacent to, but not part of or in contact with, the antifuse element. Such a solution provides indirect heating, however, no component of the antifuse itself is involved in the generation of the heat. There are several drawbacks to such a solution utilizing indirect heating. First, additional processing steps are required to place a heat generation source in proximity to the antifuse. A resistive heating element (depicted as element 305 in FIG. 6B of the '530 patent) must be placed in the proximity of the antifuse (depicted as element 300 in FIG. 6B of the '530 patent). This requires additional process steps, thus increasing complexity and potential for yield loss. Second, although sufficient heat may be generated, transferring the heat to the antifuse is inefficient because of the indirect nature of the heating that occurs. For example, as illustrated in FIG. 6B of the '530 patent, to raise the temperature of antifuse dielectric layer 330, heat energy must radiate from heating element 305 through thick dielectric layer 340, which is about 0.5 microns thick. This heat transfer path is inefficient and requires a high programming current to travel through heating element 305 to produce sufficient indirect heating of dielectric layer 330. Additionally, the heat energy will disperse radially from heating element 305, thus further reducing the amount of heat energy that will reach the dielectric layer 330. Also, some amount of delay will occur from a point in time when the external heating element is activated to when the heat energy reaches the antifuse element. This delay is a function of both the distance between the external heating element and the antifuse element and the heat transfer characteristics (e.g. thermal conductivity) of the dielectric material that separates the external heating element and the antifuse element. The dielectric material that separates the external heating element and the antifuse element is typically a poor thermal conductor. Heat loss will occur as the heat energy passes through the insulator. Therefore, the size of the external heating element will have to be increased to account for such heat loss. Finally, the overall size of the programmable circuit is increased by adding a separate heating element, thus negatively impacting the size of the integrated circuit on which such antifuse structures reside.
Therefore, a need exists for an integrated, self-heating, less complex, reduced size, and more efficient antifuse structure where the antifuse dielectric layer is heated directly by the antifuse structure itself, not by an external heating element.
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Canadian chosen for competitive NYC-based fellowship
A Toronto student was one of 15 people recognized for their involvement in student life with a fellowship at Yeshiva University (YU) this year.
Michali Sturm, who studied marketing at the YU’s Sy Syms School of Business, graduated this past spring. Although she was planning to move back to Toronto after graduation, she decided to stay in New York City once she was offered the fellowship position.
She is one of two non-Americans chosen for the fellowship this year – the other, Marganit Rauch, is from London, England.
Now in its 10th year, the program gives graduates the opportunity to work for YU while developing leadership skills and connections through working on projects to improve campus life.
It was created in 2004 to keep some of the school’s best students involved in campus life, as well as giving them the opportunity to begin their careers with involvement in Jewish organizational work, said university president Richard Joel.
“It’s a group of passionate, very unique individuals who all have very different experiences at YU, but have a similar underlying goal to enhance and give back as much as they can to the institution,” Sturm said.
Some of the activities include skill-development workshops, leadership-training seminars, and meetings with various professors. The participants also get the opportunity to learn from people such as philanthropists Michael Steinhardt and Ronald Stanton, author A.J. Jacobs and human rights activist Brooke Goldstein.
Sturm said the fellowship is helping her move toward her goal of working in market research. She said the fact that the fellowship is so people-oriented – she’s working in YU’s Office of Student Life – makes it similar to working in marketing.
“In market research, you work with the consumer mind to come up with a better product,” she said, adding that she’s doing exactly that in her fellowship – working with the student body to find ways to improve the school.
She described her experience at the school as very positive. Not only was she able to learn in small classrooms, getting to know the professors, but she also became very involved in several campus groups, including the marketing club, fashion club and a number of business clubs.
“The more I became involved in the school throughout my time there, the more I benefited from it,” she said.
That’s why she decided to accept the fellowship. “I wanted to do it from a different perspective, and have the opportunity to give back.”
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|
{
"pile_set_name": "Pile-CC"
}
|
---
abstract: |
A system of three particles undergoing inelastic collisions in arbitrary spatial dimensions is studied with the aim of establishing the domain of “inelastic collapse”—an infinite number of collisions which take place in a finite time. Analytic and simulation results show that for a sufficiently small restitution coefficient, $0\leq r<7-4\sqrt{3}\approx 0.072$, collapse can occur. In one dimension, such a collapse is stable against small perturbations within this entire range. In higher dimensions, the collapse can be stable against small variations of initial conditions, within a smaller $r$ range, $0\leq r<9-4\sqrt{5}\approx 0.056$.
PACS: 47.50.+d, 05.20.Dd
author:
- |
Tong Zhou[^1] and Leo P. Kadanoff[^2]\
The James Franck Institute\
The University of Chicago\
Chicago, IL 60637
title: Inelastic Collapse of Three Particles
---
[2]{}
Introduction
============
A system of particles interacting only through inelastic collisions is a useful idealization of granular materials, and has been much investigated recently[@1; @2; @3; @4; @5; @6; @7; @8; @9; @10]. Inelasticity can make such a system evolve into a collapse state, in which several of the particles collide an infinite number of times in a finite time interval.
Inelastic collapse in one dimension is well understood[@1; @2; @3; @4]. In two dimensions, McNamara and Young carried out numerical investigations and found some evidence for inelastic collapses of three particles[@5]. To understand the collapse mechanism in higher dimensions, we study the behavior of three particles in a particular model. Our model involves collisions which preserve the total momentum and the components of the momentum perpendicular to the line of centers. The component of the relative velocity along the line of centers is reversed (as in an elastic collision) and reduced by the restitution coefficient, $0\le r \le 1$. We look at a situation in which one particle (labeled zero) takes part in all collisions. The other two particles (labeled one and two) are alternatively a collider and a spectator. We assume that all particles have the same mass, and that particles one and two have identical radii.
There are two possible reasons that previous numerical studies might have shown collapse. One scenario is that the collapsed state is represented by one or many attractive fixed points, so that the collapsing orbit can be stable against small variations in initial data. The other scenario is that each orbit is unstable but that the infinity of collapsing orbits produces an observable collapse probability. For the specific example of three particles, we find an attractive fixed point for all dimensions and sufficiently small coefficient of restitution, $r$. Thus, we establish the possibility of the first scenario. The second scenario is still possible, but we have seen no evidence for it. For a larger $r$, there is an interval in which the fixed point is unstable against changes in the initial conditions.
For dimensions greater than one, after the collapse has occurred, the particles can separate from one another. Thus beyond $d=1$, inelastic collapse is an event, not an end-point, in the “lives” of the particles.
To study the collapse, we use the methods of dynamical systems theory. Specifically, we examine the situation in which particles one and two are very close to particle zero and aimed so that the system is very close to the collapsing fixed point. Figure 1 shows a typical configuration. Particle $0$ keeps colliding with particle $1$ and particle $2$ repeatedly, and an inelastic collapse may occur. After many collisions, the distances between the particles become small, and the remaining collisions take place so rapidly that the relative motion of the particles is small. Therefore, in the inelastic collapse, the angle $\theta$ approaches a limiting value as the number of collision goes to infinity. We identify the constant-$\theta$ fixed point and then investigate its stability. We find that a fixed point of an inelastic collapse exists only when the final $\theta$ obeys: $$\cos\theta \geq \frac{4\sqrt{r}}{1+r}.
\label{eq:A}$$ A collapse state will occur whenever this criterion holds and also steric effect do not block off the required collisions. (For example such a blockage will always occur at $\theta = \pi$.) The stability analysis implies that for the collapse to be stable against small perturbations in the initial velocities, a stronger condition is required, namely $$\cos\theta >\frac{2\root 3 \of r (1+\root 3 \of r)}{1+r}.
\label{eq:B}$$
The collision model
===================
We use the standard model of inelastic collision: due to a collision the component of the relative velocity of the colliders along the line of centers, changes by a factor of $-r$. We denote by $\vec{u}_j$ and $\vec{x}_j$ the velocity and the position of the $j$th particle at the instant before a collision occurs. Let us consider a collision between particles $1$ and $0$. In the course of the collision, the velocities of the particles change to: $$\begin{aligned}
\vec{u}_1' & = & \vec{u}_1 - \vec{\Delta}, \nonumber \\
\vec{u}_0' & = & \vec{u}_0 + \vec{\Delta}, \nonumber \\
\vec{u}_2' & = & \vec{u}_2.
\label{eq:1}\end{aligned}$$ Here, the momentum transfer is $\vec{\Delta}$. It must point in the direction of the line of centers. In terms of the coefficient of restitution, $r$, this transfer is given by the expression $$\vec{\Delta} = \frac{1+r}{2} (\vec{x}_1-\vec{x}_0) [(\vec{x}_1-\vec{x}_0)
\cdot
(\vec{u}_1-\vec{u}_0)].$$ Here we have assumed that the radii of the colliding particles sum to unity so that, at the point of collision: $$(\vec{x}_1-\vec{x}_0)^2 = 1.
\label{eq:3}$$
To do dynamical systems theory, we wish to look at the very same process repeatedly. Therefore, we introduce the superscripts, $c$, denoting the collider and $s$ denoting the spectator particle, as well as a subscript, $n$, to denote the instant before the $n$th collision occurs (Figure 1). For simplicity, we take the velocity and the position of particle $0$ to be zero. In order to make sure that the velocity of particle $0$ continues to vanish after the collision, we view the post-collision system from a frame moving with velocity $\vec{u}_0'=
\vec{\Delta}$. Then equations (\[eq:1\]) - (\[eq:3\]) read $$\begin{aligned}
\vec{u}_{n+1}^s & = & \vec{u}_{n}^c - 2 \vec{\Delta}, \nonumber \\
\vec{u}_{n+1}^c & = & \vec{u}_{n}^s-\vec{\Delta}.
\label{eq:3a}\end{aligned}$$ These equations are supplemented by the conditions: $$\vec{\Delta} = \frac{1+r}{2} (\vec{x}_{n}^c) (\vec{x}_{n}^c \cdot
\vec{u}_{n}^c),$$ $$(\vec{x}_{n}^c)^2 = 1.$$ Additionally, both the velocity and the position of particle $0$ vanish. Notice that a collider becomes a spectator immediately following a collision. The above equations are complemented by the equations corresponding to the positions of the particles at the next collision, $$\begin{aligned}
\vec{x}_{n+1}^s & = & \vec{x}_{n}^c + t_n \vec{u}_{n+1}^s, \nonumber \\
\vec{x}_{n+1}^c & = & \vec{x}_{n}^s + t_n \vec{u}_{n+1}^c.
\label{eq:5}\end{aligned}$$ The time interval between the $n$th and the $(n+1)$th collisions, $t_n$, is such that the magnitude of $\vec{x}_{n+1}^c$ is unity.
Flat Surface Approximation
==========================
We now seek fixed points in these equations. We assume that the time between collisions is sufficiently small so that the $t_n$ terms in equations (\[eq:5\]) are negligible and consequently $$\begin{aligned}
\vec{x}_{n+1}^s & = & \vec{x}_{n}^c, \nonumber\\
\vec{x}_{n+1}^c & = & \vec{x}_{n}^s,
\label{eq:apr}\end{aligned}$$ during the approach to the fixed point.
We wish to find a fixed point in the components of the velocity in the direction of the lines of centers. Specifically, we would like to investigate how this component decreases in each iteration. We can define: $$\vec{x}_{n+1}^c \cdot \vec{u}_{n+1}^c \equiv k_n \vec{x}_{n}^c
\cdot \vec{u}_{n}^c.
\label{eq:8}$$
Taking the dot product of equations (\[eq:3a\]) respectively into $\vec{x}_{n}^s$ and $\vec{x}_{n}^c$, and using equations (\[eq:apr\]) gives $$\vec{x}_{n+1}^s \cdot \vec{u}_{n+1}^s = -r \vec{x}_{n}^c \cdot \vec{u}_{n}^c,
\label{eq:9a}$$ $$\vec{x}_{n+2}^c \cdot \vec{u}_{n+2}^c = \vec{x}_{n+1}^s \cdot \vec{u}_{n+1}^s+\frac{1+r}{2}
\vec{x}_{n+1}^c \cdot \vec{u}_{n+1}^c\cos\theta.
\label{eq:9}$$ Equations (\[eq:8\])-(\[eq:9\]) thus imply the recursion satisfied by the scaling factor $k_n$ $$k_{n+1}=-\frac{r}{k_n}+\frac{1+r}{2}\cos\theta.
\label{eq:rok}$$ Fixed points can be found by setting $k_{n+1}=k_n$ in (\[eq:rok\]), $$k^2 - k \frac{1+r}{2}\cos\theta +r=0.$$ As a result, the fixed point of the scaling factor has two possible values $$k_\pm =\frac{1+r}{4}\cos\theta \pm
\sqrt{\left(\frac{1+r}{4}\cos\theta\right)^2-r}.
\label{eq:11}$$ Equation (\[eq:11\]) is one of the major results of our study.
In every collision, the colliding particle must approach particle $0$. Hence, $\vec{x}_c \cdot \vec{u}_c$ must be negative in every iteration. This is possible only if $k$ is a positive real number. One kind of failure arises when $k$ is complex. Then the real part of the dot product will change sign infinitely often and no fixed point can be reached. Thus, for inelastic collapse to occur, the quantity under the square root in equation (\[eq:11\]) must be positive. This positivity still permits both signs of $\cos\theta$. However, if the roots are real and the cosine is negative, both roots will be negative. Hence neither is a possible solution for inelastic collapse. The only remaining possibility is that inelastic collapse may occur under the condition on the cosine given by equation (\[eq:A\]). According to that statement, when $r\rightarrow 0$, $\theta$ can have a value between $0$ and $\frac{\pi}{2}$. On the other hand, when $\theta =0$, the well-known one-dimensional result is recovered [@2], [*i.e.*]{}, inelastic collapse is possible for $0\le r< 7-4\sqrt{3}$. Regions (a) and (b) in figure 2 are the region of $r$ and $\theta$ for which we may have inelastic collapse.
We now consider the stability of the above fixed points. Stability will imply that a small change in the initial conditions will leave the system in a collapse state, or in other words, changes will still permit an infinite number of collisions. There are two collapse fixed points distinguished by the values of the two multipliers $k=k_+$ and $k=k_-$. Subtracting $k_\pm$ from both sides of (\[eq:rok\]) yields $$\frac{k_{n+1}-k_\pm }{k_n-k_\pm }=\frac{k_\mp}{k_n}.$$ It is seen that $k_-$ corresponds to an unstable fixed point, while $k_+$ corresponds to a stable one. Henceforth, we use $k$ to denote the stable fixed point $k\equiv k_+$.
Next, we investigate the time interval between successive collisions. Assume that relative motion of the two colliding particles between each pair of collisions covers a distance which is very small in comparison to their radii. Then, we can think of the surface of the particles as flat. After the $n$th collision, the colliding particle moves away from the surface and covers a distance $t_n \vec{x}_{n+1}^s
\cdot \vec{u}_{n+1}^s$. In the next step, this particle moves back over the same distance, which is given by -$t_{n+1} \vec{x}_{n+2}^c
\cdot \vec{u}_{n+2}^c $ and reaches the surface. Thus, the ratio of times is $$\frac{t_{n+1}}{t_n}= \frac{-\vec{x}_{n+1}^s \cdot \vec{u}_{n+1}^s}
{\vec{x}_{n+2}^c \cdot \vec{u}_{n+2}^c}.$$ This result may be simplified with the aid of equations (\[eq:8\])-(\[eq:9a\]) to give $$\frac{t_{n+1}}{t_n}=\frac{r}{k^2}.
\label{eq:14}$$ Let $d$ denote the shortest distance between two particles. The distance ratio equals the product of the time ratio and the velocity ratio, $k$, $$\frac{d_{n+1}}{d_n}=\frac{r}{k}.
\label{eq:15}$$
We performed numerical simulations of the collision process by considering three inelastic particles moving in two-dimension with random initial conditions. When collapse happens, we compared the ratios calculated from simulations with the predictions of equations (\[eq:8\]), (\[eq:14\]), (\[eq:15\]). We found excellent agreement (Figure 3), indicating that the fixed points are attractive and indeed correspond to collapse
Validation of the Flat Surface Approximation
============================================
As observed in the last section, making the approximation (\[eq:apr\]) simplifies dramatically the original system and it can be described by a single ratio $k_n$. It is as if the particles have flat surfaces, so that the effect of the tangential components of the velocities of particles $1$ and $2$ can be ignored. This is true only if the time intervals are negligible, so that (\[eq:apr\]) can be obtained from (\[eq:5\]). We will see when such a simplification is valid, and we will set a criterion for the range of validity of the approximation.
In our way to equations (\[eq:9a\])-(\[eq:9\]), we neglected the terms like $t_n (u_{n}^c)^2$ in comparison to $\vec{x}_{n}^c \cdot
\vec{u}_{n}^c$, by using the approximation (\[eq:apr\]). As noted above, the former terms decrease as $(\frac{r}{k^2})^n$, while the latter terms decrease as $k^n$. Thus, the flat surface approximation is reliable only when $r<k^3$ so that terms proportional to $t_n$ can be safely ignored. This condition can be explicitly written as, $$r<\left(\frac{1+r}{4}\cos\theta
+\sqrt{\left(\frac{1+r}{4}\cos\theta\right)^2-r}\right)^3,$$ which can then be simplified into the form of condition (\[eq:B\]). The region of stability determined by this condition is region (a) in Figure 2. The maximum possible value of $r$ for stable behavior is $r_c=9-4\sqrt{5}$.
To this point, our calculation did not rely on the circular geometry of the particles. The name “flat surface” suggests that when criterion (\[eq:B\]) is satisfied, particles do not experience the curvature of their surfaces, and collide as if they are flat. This calculation is valid for arbitrary particle shapes when (\[eq:B\]) is satisfied.
We also observe that when criterion (\[eq:B\]) is satisfied, the time interval $t_n$ decreases faster than the radial component of the velocities. In such a situation, collapse happens so quickly that all other effects, external or internal, have no essential influences to the process. One can further consider arbitrary interactions between the particles as well as arbitrary external fields, as long as all the interactions depends only on the relative positions. Since the particles’ relative positions only change very little during the process of collapse, all the effects of the interactions on, say, particle $1$ can be replaced by a constant total force acting on it which induces an constant acceleration. This acceleration has very little effect in the tangential direction since time interval is too small for it to change the tangential component of the velocity. When the flat surface approximation is valid, the time interval is even too small to change the radial velocity component. We conclude that the the previously obtained fixed points are unchanged.
Circular Geometry
=================
In the previous sections, the calculation were performed by neglecting the $t_n$ terms completely out of equations (\[eq:5\]) and the fixed points for inelastic collapse were found when the final state satisfied condition (\[eq:B\]). After understanding the characteristic behavior of the collapse, we can do a more rigorous calculation to investigate how the system behaves outside the region satisfying (\[eq:B\]).
We now see that during the collapse process, the radial velocity components of particles $1$ and $2$ monotonically decrease till they vanish at the moment of singularity, while their tangential components approach limiting values as the number of collision diverges. Hence, we take those tangential components as constants, and concentrate on the radial components in the calculation of fixed points.
For simplicity we study in detail one collision in the situation where particle $1$ has a zero radius while particle $0$ has a unit radius. Since the theory depends only upon the sum of the two radii, this case subsumes all others. Here we denote the initial instant with a subscript $i$, and the instant before the collision with $f$. We drop the superscripts since only particle $1$ is considered. We also assume the particles are very close, $d\ll 1$, and $-\vec{u}\cdot \vec{x}_i
\ll u_t$, where $u_t$ is the magnitude of the tangential velocity component of particle $1$. The collision time is $$t=\frac{1}{u_t}\left(\frac{-\vec{u}\cdot \vec{x}_i
}{u_t}-\sqrt{\left(\frac{\vec{u}\cdot
\vec{x}_i}{u_t}\right)^2-2d}\right).
\label{eq:19}$$ Immediately before the collision, the radial velocity component of particle $1$ equals $$-\vec{u}\cdot \vec{x}_f =\sqrt{(\vec{u}\cdot \vec{x}_i )^2-2du_t^2}.
\label{eq:20}$$
Equation (\[eq:19\]) gives the quantity needed to complete the equation set (\[eq:3a\])-(\[eq:5\]). In order to abbreviate this calculation, we introduce an effective centrifugal acceleration. In the above calculation, if we view the situation in a frame rotating with an angular velocity of $u_t$, around an axis perpendicular to both $\vec{u}$ and the line of centers, passing through the center of particle $0$, then particle $1$ has zero tangential velocity, and the effect of the tangential velocity can be represented by a centrifugal acceleration $a_1=u_t^2$. This substitution is justified by noticing that we can get exactly the same expressions as (\[eq:19\]) and (\[eq:20\]) by using this acceleration. We do not need really use such a rotating frame. We use $a_1$ as an effective centrifugal acceleration to replace the tangential component of the velocity with the same effects.
After these preparations, we are in a much clearer position. Particle $1$ and particle $2$ respectively have centrifugal accelerations $a_1$ and $a_2$, which are all in the radial directions. Equation (\[eq:apr\]) is again a good approximation. Particle $1$ is moving on a line, and so is particle $2$. We can further drop the vector notation. In the following, we use $u$ to denote the radial component of the velocity of particles $1$ and $2$ immediately before a collision, with its positive direction pointing towards the center of particle $0$. Consequently, $a_1=-u_{1t}^2$ and $a_2=-u_{2t}^2$.
The equation set (\[eq:3a\])-(\[eq:5\]) reduces to $$\begin{aligned}
u_{n+1}^s & = & -ru_n^c+a_{n+1}^st_n \nonumber \\
u_{n+1}^c & = & u_n^s+\frac{1+r}{2}\cos\theta\cdot u_n^c +a_{n+1}^ct_n \nonumber \\
d_n & = & u_{n+1}^c\cdot t_n-\frac{1}{2}a_{n+1}^ct_n^2 \nonumber \\
-d_{n+1} & = & -ru_n^c \cdot t_n+\frac{1}{2}a_{n+1}^st_n^2 \nonumber\\
a_{n+1}^c & = & a_n^s \nonumber \\
a_{n+1}^s & = & a_n^c
\label{eq:set}\end{aligned}$$ where $d_n$ is the distance between the spectator and particle $0$ at the instant of the $n$th collision. Recall that $t_n$ is the time interval between the $n$th and $(n+1)$th collisions.
One simple case can be fully carried through, the case $a_1=a_2\equiv
a$. In this case, particle $1$ and particle $2$ are in a symmetrical situation so that the recursion relation of the system can be obtained after a single collision.
As we did before, we use two nondimensional numbers $k_n$ and $\alpha_n$ to describe the evolution of the system: $$k_n\equiv\frac{u_{n+1}^c}{u_n^c}\quad\mbox{and}\quad\alpha_n\equiv\frac{-a\cdot t_n}{u_n^c}.$$
Starting from (\[eq:set\]), after some straightforward calculation, we get following recursion relation: $$k_{n+1}=\sqrt{\left(\frac{1+r}{2}\cos\theta
-\frac{r}{k_n}\right)^2-(1+r)\cos\theta \frac{\alpha_n}{k_n}},
\label{eq:27}$$ and $$\begin{aligned}
\alpha_{n+1} & = & \frac{1+r}{2}\cos\theta -\frac{r}{k_n}
-\frac{\alpha_n}{k_n}\nonumber\\ & - &
\sqrt{\left(\frac{1+r}{2}\cos\theta
-\frac{r}{k_n}\right)^2-(1+r)\cos\theta \frac{\alpha_n}{k_n}}.
\label{eq:28}\end{aligned}$$
Suppose the fixed point is $(\alpha,k)$, then from (\[eq:28\]), we have $$\alpha =\frac{-k^2+\frac{1+r}{2}\cos\theta\cdot k-r}{k+1}.
\label{eq:29}$$ Since $\alpha\ge 0$ from its definition, the right hand side of the above equality must be nonegative. Thus, there must exist two real solutions of $k$ satisfying r.h.s.$=0$. And we readily recover the condition (\[eq:A\]).
Substituting (\[eq:29\]) into (\[eq:27\]), we have $$\begin{aligned}
k^4 & = & \left(\frac{1+r}{2}\cos\theta\cdot k-r\right)^2\nonumber\\ &
& -(1+r)\cos\theta\cdot k\frac{-k^2+\frac{1+r}{2}\cos\theta\cdot
k-r}{k+1}.
\label{eq:31}\end{aligned}$$ Of course, $k_\pm$, which appeared before, are solutions of (\[eq:31\]). From (\[eq:29\]) we learn that $(0,k_\pm )$ are fixed points. Let us look at other solutions of equation (\[eq:31\]) which satisfy $$\begin{aligned}
k^3+\left(1+\frac{1+r}{2}\cos\theta\right)k^2-\left(r+\frac{1+r}{2}\cos\theta\right)k\nonumber \\
-r=0.\end{aligned}$$ This equation has one and only one solution of $k$ in the interval $[0:1]$. We denote the corresponding fixed point as $(\alpha_0,k_0)$. Of the three relevant fixed points, $(0,k_-)$ is unstable, and we concentrate on the stability condition for the other two fixed points.
Suppose that $(\alpha_n,k_n)$ has a small deviation from the fixed point $(\alpha, k)$. then $$\left( \begin{array}{c} \delta k_{n+1}\\ \delta\alpha_{n+1}\end{array} \right) =\left( \begin{array}{cc} A_{11} & A_{12}\\A_{21} & A_{22} \end{array} \right) \left( \begin{array}{c} \delta k_n\\ \delta\alpha_n\end{array} \right)$$ where $$\begin{aligned}
A_{11} & = & \frac{1}{2k^3}\left[ 2\left(\frac{1+r}{2}\cos\theta -\frac{r}{k}\right)r+(1+r)\cos\theta\cdot\alpha\right] \nonumber \\
A_{12} & = & -\frac{(1+r)\cos\theta}{2k^2} \nonumber \\
A_{21} & = & \frac{\alpha +r}{k^2}-A_{11} \nonumber \\
A_{22} & = & \frac{(1+r)\cos\theta-2k}{2k^2} \nonumber\end{aligned}$$ Let us denote by $\lambda$ the eigenvalue of matrix $A$, hence we have $$\lambda^2-b\lambda+c=0
\label{eq:39}$$ where $$\begin{aligned}
b & = & \frac{1}{2}-\frac{1}{k}+\left[(1+r)\cos\theta-\left(\frac{1+r}{2}\cos\theta\right)^2\right]\frac{1}{2k^2}\nonumber\\
& & +r(1+r)\cos\theta\cdot\frac{1}{k^3}-\frac{3r^2}{2k^4},\nonumber\\
c & = & \frac{r^2}{k^5}.\nonumber\end{aligned}$$ For the fixed point $(0,k_+)$, $$b=\frac{r}{k_+^3}(1+k_+)\quad\mbox{and}\quad c=\frac{r^2}{k_+^5}.$$ So $$\lambda_1=\frac{r}{k_+^2}\quad\mbox{and}\quad \lambda_2=\frac{r}{k_+^3}.
\label{eq:eig}$$ The point $(0,k_+)$ is an attractive fixed point if and only if $r<k_+^3$. Hence we recover the condition of (\[eq:B\]). If we only require $\lambda_1<1$, we can recover condition (\[eq:A\]).
For the fixed point $(\alpha_0,k_0)$, we find that $\alpha_0>0$ if and only if the condition of (\[eq:B\]) is satisfied, but that condition also decides the range of $(r,\theta)$ inside which we will have $$1-b+c<0$$ From equation (\[eq:39\]) we know that one eigenvalue of matrix $A$ is larger than $1$, implying that the corresponding fixed point is unstable. We conclude that there are no additional stable fixed points beyond those which satisfy condition (\[eq:B\]), and there are no stable collapses outside that range in the case $a_1=a_2$.
We believe this is true for the general situation of $a_1\ne a_2$. When condition (\[eq:B\]) is violated, our simulations show that even though the particles can be very close, they will get apart before having collided an infinite number of times.
From the above calculation, and specifically equation (\[eq:eig\]), we can see the parameter space $(r,\theta)$ can be divided into three regions (Figure 2):
a\) When condition (\[eq:B\]) is satisfied, both the eigenvalues of matrix $A$ are smaller than unity. The fixed point is stable in all directions in space $(\alpha, k)$. It is the collapse region.
b\) When condition (\[eq:B\]) is violated but the condition (\[eq:A\]) is satisfied, the eigenvalue $\lambda_2>1$, while $\lambda_1<1$. In this region, particles can have any number of collisions before they might eventually separate.
c\) When the condition (\[eq:A\]) is violated, both eigenvalues of matrix $A$ are larger than unity. Collapse does not occur.
The above calculation is independent of the sources of the accelerations, which could be the interactions between particles. The calculation confirms our previous argument that interactions are irrelevant in the process of collapse[^3].
We also observe that in the above calculation, the circular geometry of the particles is not essential. The calculation is also valid for arbitrary shape of the particles, with the corresponding radius of curvature replacing the radii used. Even though the radius of curvature is not relevant in deciding the behavior of collapse process—the radii do not show up in the expression of the stable fixed point or condition (\[eq:B\]), it does have some effects. The centrifugal acceleration, which obviously is important in deciding the probability of collapse, is inversely proportional to the radius. So chances are larger for collapse to happen when the colliding point is at a position on the surface with a larger radius of curvature.
Conclusion
==========
We demonstrated analytically the existence of inelastic collapse for three particles in all dimensions. At the last moment of collapse, the three particles have a cyclic behavior, which is characterized by a fixed point. We have established the range of the parameters for which the fixed point exists and the range for which it is stable.
Acknowledgments {#acknowledgments .unnumbered}
---------------
We would like to express our thanks to Y.Du, S.Esipov, H.M.Jaeger, M.Mungan, S.R.Nagel, N.Schörghofer and W.R.Young for very helpful discussions and especially to Eli Ben-Naim for continued advice and discussions. This work was supported in part by NSF-DMR and in part by DOE.
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[^1]: Email: tongzhou@control.uchicago.edu
[^2]: Email: LeoP@uchicago.edu
[^3]: But when there is a sufficiently strong attraction, e.g. gravity, between particles so that the directions of the accelerations are reversed, we want fixed points with $\alpha\le 0$. Then the fixed point $(\alpha_0,k_0)$ becomes stable when condition (\[eq:B\]) is violated. Inelastic collapse can happen in a much larger region of $(r,\theta)$.
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{
"pile_set_name": "ArXiv"
}
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The primacy of positivity: practical applications for speech-language pathologists.
Healthcare professionals, including speech-language pathologists, generally assume that their clients will be happy after they have "gotten better" or somehow achieved their goals; which is not an unreasonable assumption, and which is a belief shared by the majority of clients. It may not, however, be entirely helpful. Such an approach may well contribute to a range of problems including negative, self-defeating emotions such as frustration which could impede treatment progress. Rather than waiting until success is achieved, happiness and positivity should come first and foremost. By promoting the "primacy of positivity" speech-language pathologists can help their clients better achieve their goals, leveraging off the energy and motivation created.
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{
"pile_set_name": "PubMed Abstracts"
}
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It’s Wine o’Clock Somewhere!
#1 On Sundays, Chateaus are closed too
This one is obvious, but it was the mistake we made when we got to Chateau Margaux and the gates were locked and all we could do was stick our hands through the bars in order to take a picture of the beautiful Chateau that used to be an ancient Roman bath.
The entrance through the (closed) gates of Chateau Margaux
#2 Don’t drink too much at the first Chateau you visit
You’re at a blooming chateau in beautiful Bordeaux! Don’t guzzle these wines down like the ones sold in Tesco’s for £8.99. Instead enjoy it, savour it, and learn how to observe the wine’s rôbe (colour), its legs running down the side of the glass once you’ve swirled it round (the amount of oil), its smell, its taste, and lastly how to elegantly suck air into your mouth while the wine is still in it without choking (to further aerate it in order to bring out more of its taste while it’s touching your palate). Besides, there are plenty more chateaus to visit and you don’t want to get too drunk on the first one.
#3 It will take up the whole day
Chateau Lynch-Bages’s barrels kept in a controlled environment below ground
It takes about an hour just to walk through the fermentation vats and to see where and how the barrels of wine are kept. Plus, a good guide will probably be knowledgeable and would want to share every little detail, such as one guide who said how spiders can sometimes crawl into barrels so they have to decant the wine from an old barrel to a new one every few years. This does not include the time you will take to photograph every little corner of the place if you’re asian like me (and all the selfies), as well as shopping (I have seen people ship crates home). Even if you don’t take the tour in every chateau — you certainly can’t anyway — some of them have a restaurant you can stop for lunch as well as a souvenir shop and many other attractions, as is the case with Chateau Lynch-Bages. So don’t plan to do anything before dinner time.
#4 It’s always sunny in…no. No, it isn’t
When you visit a vineyard, obviously you would want to see bright green rows of grape vines reaching acres and acres into the hillside, not masked by sheets of rain. So plan your trip around June-August when it is nice and sunny.
#5 Don’t compare prices of bottles you find in Bordeaux with the same ones back home
The ones in Bordeaux will definitely be cheaper (sans tax), but it could be expensive by Bordeaux standards. Because there is such a wide array to choose from, don’t be afraid to ask your guide whether they think you’re paying for the label/brand or for the wine’s taste. And of course, always have an open mind and be willing to try lesser-known wines from smaller vineyards (boutique wines) because it is mostly likely that those grapes are grown in a strictly controlled terroir (appellation d’origine contrôlée).
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PACAP and VIP stimulate Ca2+ oscillations in rat gonadotrophs through the PACAP/VIP type 1 receptor (PVR1) linked to a pertussis toxin-insensitive G-protein and the activation of phospholipase C-beta.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are hypothalamic factors that play roles in the regulation of anterior pituitary cell activity. PACAP exists in 2 forms physiologically, a 38 amino acid form (PACAP38) and a form possessing the N-terminal 27 amino acids of PACAP38 (PACAP27). We have previously shown that PACAP38 stimulates an increase in [Ca2+]i in rat gonadotrophs. In an attempt to identify the PACAP receptor type underlying this effect, we compared the potency of PACAP38, PACAP27 and VIP to stimulate Ca2+ changes in identified single rat gonadotrophs. All 3 peptides at 100 nM were capable of stimulating high amplitude Ca2+ oscillations, which were also observed in the absence of extracellular Ca2+. The order of potency of these peptides was PACAP38 > PACAP27 > VIP, and a potent antagonist of the PACAP/VIP type II binding site ([4-CI-D-Phe6, Leu17]-VIP) failed to block these responses, suggesting that these effects are mediated through a PACAP/VIP type 1 receptor (PVR1). The Ca2+ responses to PACAP38 and VIP were unaffected by overnight treatment of the cells with pertussis toxin (PTX; 250 ng/ml) indicating that these responses are mediated by a PTX-insensitive G-protein. Finally, the Ca2+ responses stimulated by PACAP38 and VIP were blocked by the phospholipase C-beta blocker U73122 (5 microM). In summary, PACAP stimulates Ca2+ oscillations in rat gonadotrophs through the activation of the PVR1 linked to a PTX-insensitive G-protein and the activation of phospholipase C-beta. VIP can stimulate the same pathway in rat gonadotrophs, although it is at least 100 fold less potent than PACAP38.
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{
"pile_set_name": "PubMed Abstracts"
}
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Q:
Perl: Safe templating language
Here are already several questions in SO about the safe template languages, like:
Safe ERB Language?
templating system that is safe for end users to edit
Is there a “safe” subset of Python for use as an embedded scripting language?
Is Django's templating markup for views safe for end user editing like rails liquid templating
but the above questions are for asp, ruby, python.
My question is: What templating language can allow to be edited by users in perl based web-app?
I want allow for users edit pages, (like in an wiki) with some programming possibilities, so full featured mean with cycles, conditionals, variable substitutions, includes and so on.
Is TT "enough safe"? Is here another solution as TT?
A:
Template::Toolkit Should be fine, as long as you limit what parameters are passed to the template. If you pass classes, the templates will be able to call any method on those classes, and any method on the return values of those classes, etc. It's much better to only pass Hashes.
HTML::Template Is also a good option, and it only allows hashes by default, so you are much less likely to leave open a hole that lets the template authors execute arbitrary code.
In either case, make sure that you read the documentation for whatever you use, and clean the output in order to prevent cross-site scripting attacks. Do not rely on people customizing the templates to get the output encoding correct for you.
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{
"pile_set_name": "StackExchange"
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Introduction {#Sec1}
============
In contrast to mammals, lampreys show spontaneous and successful functional recovery after a complete spinal cord injury (SCI) and this is in part due to their impressive ability for axonal regeneration^[@CR1]--[@CR8]^. But, even in lampreys, not all descending neurons of the brain are able to regenerate their axons through the site of injury after a complete spinal cord transection^[@CR4],[@CR9]--[@CR12]^. The lamprey brainstem contains approximately 30 large individually identifiable descending reticulospinal neurons that vary greatly in their ability for axonal regeneration after SCI, even when their axons run in similar paths in a spinal cord that is permissive for axonal regrowth^[@CR4],[@CR12],[@CR13]^. Some identifiable descending neurons of lampreys are considered "good regenerators" (i.e. they regenerate their axon more than 55% of the times; the I3, I4, I5, B2, B5 and B6 neurons) and others are considered "bad regenerators" (i.e. they regenerate their axon less than 50% of the times; the M1, M2, M3, I1, I2, B1, B3, B4 and Mth neurons)^[@CR4],[@CR6],[@CR12]^. This indicates that interactions with the extrinsic spinal cord environment and intrinsic differences between descending neurons affect their regenerative abilities after SCI. Recent work has also shown that identifiable descending neurons of lampreys that are known to be "bad regenerators" slowly die after a complete SCI and are also "poor survivors"^[@CR12],[@CR14],[@CR15]^. The death of these neurons after SCI appears to be apoptotic as indicated by the appearance of TUNEL labelling and activated caspases in their soma^[@CR14]--[@CR18]^. This offers a convenient vertebrate model to study the inhibition or promotion of neuronal survival and axonal regeneration in the same in vivo preparation and at the level of single neurons.
In mammals, SCI leads to a massive release of aminoacidergic neurotransmitters (glycine and GABA:^[@CR19],[@CR20]^; glutamate:^[@CR21]--[@CR23]^). Excessive glutamate release after SCI is responsible for excitotoxicity and neuronal death^[@CR21],[@CR22]^. High extracellular glutamate levels result in excessive activation of glutamate receptors, triggering massive Ca^2+^ influx into cells, which leads to neuronal death^[@CR24]^. Extracellular glycine could also contribute to glutamate excitotoxicity^[@CR20]^, since it is a co-agonist of the *N*-methyl-D-aspartate glutamate receptor^[@CR25]^. The phenomenon of excitotoxicity has been mainly studied in intrinsic spinal cord cells; however, retrograde damage to neurons is also likely due to the fact that Ca^2+^ ions gain access to the axoplasm of damaged axons^[@CR26]^. In contrast to glutamate, it has been reported that GABA could have neuroprotective effects after different types of central nervous system (CNS) damage^[@CR27]--[@CR31]^. The activation of pre-synaptic GABAB receptors causes inactivation of voltage-dependent Ca^2+^ channels (see^[@CR32]^), which could prevent the influx of Ca^2+^ ions due to glutamate release. In addition, it has been shown that GABA can modulate and promote neurite outgrowth in vitro or during development (for reviews see^[@CR33],[@CR34]^). However, a role for GABA and GABAB receptors in neuroprotection and especially in axonal regeneration after SCI has not been reported yet.
In lampreys, glutamate induces an inhibition of neurite outgrowth in reticulospinal neurons in vitro due to Ca^2+^ influx^[@CR35]^. Electrophysiological studies have also suggested that low intracellular Ca^2+^ levels due to downregulation of Ca^2+^ channels could facilitate axonal regeneration in axotomized descending neurons of lampreys^[@CR36]^. More recently, we have reported that, as in mammals, there is a massive release of glutamate, GABA and glycine from most spinal cord neurons close to the lesion site following a complete SCI^[@CR37]--[@CR39]^. Between 1 and 3 days after the injury, we observed the extracellular accumulation of GABA in the form of "*halos*" around some axotomized axons of descending neurons close to the site of injury. Statistical analyses revealed a significant correlation between GABA accumulation and a higher survival ability of the corresponding identifiable descending neurons^[@CR37]^. An electrophysiological study in the spinal cord of lampreys has also found a correlation between higher GABAergic inhibition and a better recovery of function in spinal lesioned animals^[@CR40]^. These data prompted us to hypothesize that, in lampreys, increased GABA signalling after SCI could be favouring the recovery process by promoting survival and axonal regeneration of descending neurons. Here, we address this question for the first time in vivo in any vertebrate and provide gain and loss of function evidence showing that endogenous GABA, acting through GABAB receptors, promotes survival and axonal regeneration of identifiable descending neurons after SCI in lampreys.
Materials and methods {#Sec2}
=====================
Animals {#Sec3}
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All experiments involving animals were approved by the Bioethics Committee at the University of Santiago de Compostela and the *Consellería do Medio Rural e do Mar* of the *Xunta de Galicia* (License reference JLPV/IId; Galicia, Spain) or the Institutional Animal Care and Use Committee at the Marine Biological Laboratory (Woods Hole, MA) and were performed in accordance to European Union and Spanish guidelines on animal care and experimentation or the National Institutes of Health, respectively. During experimental procedures, special effort was taken to minimize animal suffering and to reduce the use of animals. Animals were deeply anaesthetized with 0.1% MS-222 (Sigma, St. Louis, MO) in lamprey Ringer solution before all experimental procedures and euthanized by decapitation at the end of the experiments.
Mature and developmentally stable larval sea lampreys, *Petromyzon marinus* L. (*n* = 115; between 95 and 120 mm in body length, 5 to 7 years of age), were used in the study. Larval lampreys were collected from the river Ulla (Galicia, Spain), with permission from the *Xunta de Galicia*, or provided by Lamprey Services, Inc. (Ludington, MI, USA) and maintained in aerated fresh water aquaria at 15--23 °C with a bed of river sediment until their use in experimental procedures. Lampreys were randomly distributed between the different experimental groups.
SCI surgical procedures {#Sec4}
-----------------------
Animals were assigned to the following experimental groups: control unlesioned animals or animals with a complete spinal cord transection that were analyzed 1 week post-lesion (wpl), 2 wpl, 4 wpl, 10 wpl or 12 wpl. Within the 2, 10 and 12 wpl groups, the injured animals were assigned to either control or treatment groups. Table [1](#Tab1){ref-type="table"} summarizes the number of animals assigned to each experimental group and condition. Each experiment was carried out in at least two different batches of animals. Complete spinal cord transections were performed as previously described^[@CR41]^. Briefly, the rostral spinal cord was exposed from the dorsal midline at the level of the 5th gill by making a longitudinal incision with a scalpel (\#11). A complete spinal cord transection was performed with Castroviejo scissors and the spinal cord cut ends were visualized under the stereomicroscope. After spinal transections, the animals were returned to fresh water tanks and each transected animal was examined 24 h after surgery to confirm that there was no movement caudal to the lesion site. Then, the animals were allowed to recover in individual fresh water tanks at 19.5 °C and in the dark.Table 1Table showing the number of animals included in each experimental group and also the total number of identifiable descending neurons that were included in the analysesAnimalsTotal number of neurons included in the analysesM1M2M3I1I2I3I4I5B1B2B3B4B5B6MthChanges in gabab1 expressionControl71111128--5859--109--791 wpl710101412--12969--139--11144 wpl61012129--6665--65--57GABA treatment (2 wpl)Control6\*1111101291112712111212111212Treated568896995101010107910Baclofen treatment (caspase activation, 2 wpl)Control7\*1312111491314814131414121414Treated71213131471413614131414131313GABOB treatment (12 wpl)Control15303029292430302930303030303030Treated14262524282428272825242628232824Baclofen treatment (axonal regeneration, 12 wpl)Control7121213141214141114121414141213Treated11212121221922222122222222222222Gabab1 morpholino (ISH, 2 wpl)Control36----6----------------------Treated47----8----------------------Gabab1 morpholino (axonal regeneration, 10 wpl)Control9181818181818181818181818181818Treated13262626252626262626262626262626Total115Please note that in the in situ hybridization experiments, only the neurons that were unequivocally identified in at least two brain sections were included in the quantifications. In the FLICA experiments, six animals were used as controls for both the GABA and baclofen treatments and an extra animal was used as a control only for the baclofen treatment (asterisks)
In situ hybridization {#Sec5}
---------------------
For gabab1 in situ hybridization, the head of the animals was fixed by immersion in 4% paraformaldehyde (PFA) in 0.05 M Tris-buffered saline (TBS; pH 7.4) for 12 h. Then, the brains were dissected out, washed and embedded in Neg 50^TM^ (Microm International GmbH, Walldorf, Germany), frozen in liquid nitrogen-cooled isopentane, sectioned on a cryostat in the transverse plane (14 μm thick) and mounted on Superfrost Plus glass slides (Menzel, Braunschweig, Germany). In situ hybridization with a specific riboprobe for the gabab1 subunit of the sea lamprey gabab receptor (GenBank accession number KX655780; see Suppl. Figure [1](#MOESM1){ref-type="media"}) was conducted as previously described^[@CR42]^. Briefly, brain sections were incubated with the sea lamprey gabab1 DIG-labelled probe at 70 °C and treated with RNAse A (Invitrogen, Massachusetts, USA) in the post-hybridization washes. Then, the sections were incubated with a sheep anti-DIG antibody conjugated to alkaline phosphatase (1:2000; Roche, Mannhein, Germany) overnight. Staining was conducted in BM Purple (Roche) at 37 °C. In situ hybridization experiments were performed in parallel with animals from the different experimental groups (control, 1 wpl, 2 wpl and 4 wpl) and the colorimetric reaction was stopped simultaneously for all sections from the different groups of animals.
Drug treatments {#Sec6}
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The following drugs were used to treat the animals following the complete spinal cord transection: GABA (Sigma; Cat\#: A2129; MW: 103.12 g/mol), GABOB (a GABA analogue; Sigma; Cat\#: A56655; MW: 119.12 g/mol) and baclofen (a GABAB receptor agonist). Baclofen was acquired from two different companies: for the experiments of caspase activation, we used baclofen from Molekula (Newcastle, UK; Cat\#: 31184509; MW: 213.66 g/mol), and for the experiments of axonal regeneration, we used baclofen from Carbosynth (Berkshire, UK; Cat\#: FB18127; MW: 213.66 g/mol). The drugs were applied in the water where the animals were left after the SCI surgical procedures (GABA at a concentration of 500 µM, GABOB at a concentration of 50 µM and baclofen at a concentration of 125 µM). The concentrations of baclofen and GABA were selected based on previous in vitro electrophysiological studies in lampreys^[@CR43]^. Since GABA does not easily cross the blood--brain barrier, it was applied at a high concentration and only in the first days after the injury when the spinal cord is still disrupted. We assumed that GABOB and baclofen also cross the blood--brain barrier as in mammals, since the blood--brain barrier of lampreys is similar to that of higher vertebrates^[@CR44],[@CR45]^. While we do not know the final concentration of the drugs in the CNS, we were confident that this application route allows access to the CNS as there were changes in the swimming behaviour of unlesioned animals in pilot experiments using baclofen and GABOB at these concentrations (not shown). Since these drugs are water soluble, control lesioned and non-treated animals were left in fresh water only. The animals that were analyzed for caspase activation 2 wpl were treated with GABA or baclofen during 4 days from the day of injury and replacing the drug and water every day during those 4 days. The animals that were analyzed for axonal regeneration 12 wpl were treated with GABOB or baclofen during the 12 weeks replacing the drug and the water four times each week. The animals were always kept in the dark during the drug treatments to prevent light degradation of these drugs.
Morpholino treatment {#Sec7}
--------------------
Application of morpholinos was performed as previously described in ref.^[@CR13]^. Briefly, the spinal cord was transected at the level of the 5th gill (see surgical procedures), and morpholinos (20 µg in lamprey internal solution: 180 mM KCl, 10 mM HEPES, pH 7.4; designed by GeneTools, LLC; Philomath, OR) were added at the time and site of SCI soaked in a small piece of Gelfoam (Pfizer; New York, NY). These included an active splicing-blocking gabab1 morpholino (5′-ACGTCTGCAACGGAGAGTCATGAGA-3′) generated against the boundary between the second intron and the second exon of the partial sea lamprey gabab1 sequence (Suppl. Figure [1](#MOESM1){ref-type="media"}), and a 5-base pair mismatch gabab1 negative control morpholino (5′-ACcTCTcCAACcGAGAcTCATcAGA-3′). During recovery, the morpholinos are retrogradely transported to the cell soma of descending neurons where they can knockdown the expression of the target mRNA^[@CR13],[@CR46]--[@CR48]^. Animals were allowed to recover for 10 wpl to analyze the effect of gabab1 knockdown (KD) in axonal regeneration of identifiable descending neurons. In situ hybridization was used to control the efficacy of the gabab1 morpholino KD in animals processed at 2 wpl.
Detection of activated caspases in whole-mounted brain preparations {#Sec8}
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The Image-iT LIVE Green Poly Caspases Detection Kit (Cat. No. I35104, Invitrogen, USA) was used to detect activated caspases in identifiable descending neurons (the M1, M2, M3, I1, I2, I3, I4, I5, B1, B2, B3, B4, B5, B6 and Mth neurons; see Suppl. Figure [2A](#MOESM2){ref-type="media"}) of larval sea lampreys 2 weeks after the complete spinal cord transection and the GABA or baclofen treatments. This kit contains 1 vial (component A of the kit) of the lyophilized FLICA reagent (FAM--VAD--FMK). The reagent associates a fluoromethyl ketone (FMK) moiety, which can react covalently with a cysteine, with a caspase-specific aminoacid sequence (valine--alanine--aspartic acid (VAD)). A carboxyfluorescein group (FAM) is attached as a fluorescent reporter. The FLICA reagent interacts with the enzyme active centre of an activated caspase via the recognition sequence, and then attaches covalently through the FMK moiety. Experiments for the detection of activated caspases in whole-mounted brain preparations were done as previously described^[@CR16]--[@CR18]^. Briefly, brains from control and treated 2 wpl animals were dissected out and immediately incubated in 150 µL of phosphate buffered saline (PBS) containing 1 μL of the 150× FLICA labelling solution at 37 °C for 1 h. Then, the brains were washed with PBS. Brains were fixed in 4% PFA in PBS for 2 h and 30 min at 4 °C. Next, the brains were washed with PBS, mounted on Superfrost Plus glass slides, and mounted with Mowiol.
Retrograde labelling of descending neurons with regenerated axons {#Sec9}
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At 10 (morpholino treatments) or 12 (GABOB and baclofen treatments) wpl, a second complete spinal cord transection was performed 5 mm below the site of the original transection and the retrograde tracer Neurobiotin (NB, 322.8 Da molecular weight; Vector; Burlingame, CA) was applied to the spinal cord lesion with the aid of a Minutien pin (\#000). The animals were allowed to recover at 19.5 °C with appropriate ventilation conditions for 7 days to allow the transport of the tracer from the application point to the neuronal soma of identifiable descending neurons (the M1, M2, M3, I1, I2, I3, I4, I5, B1, B2, B3, B4, B5, B6 and Mth were analyzed; see Suppl. Figure [2A](#MOESM2){ref-type="media"}). Since the original SCI also was a complete spinal cord transection, only neurons whose axons regenerated at least 5 mm below the site of injury were labelled by the tracer. Brains of these larvae were dissected out, and the posterior and cerebrotectal commissures of the brain were cut along the dorsal midline, and the alar plates were deflected laterally and pinned flat to a small strip of Sylgard (Dow Corning Co., USA) and fixed with 4% PFA in TBS for 4 h at room temperature. After washes in TBS, the brains were incubated at room temperature with Avidin D-FITC conjugated (Vector; Cat\#: A-2001; 1:500) diluted in TBS containing 0.3% Triton X-100 for 2 days to reveal the presence of Neurobiotin. Brains were rinsed in TBS and distilled water and mounted with Mowiol.
Imaging and quantifications {#Sec10}
---------------------------
An Olympus photomicroscope (AX-70; Provis) with a 20× Apochromatic 0.75 lens and equipped with a colour digital camera (Olympus DP70, Tokyo, Japan) was used to acquire images of brain sections from the in situ hybridization experiments. Images were always acquired with the same microscope and software settings. For the quantification of the level of gabab1 positive signal in identifiable descending neurons, first we established the intensity rank of positive colorimetric in situ signal. For this, we analyzed 10 random images from different descending neurons of control and lesioned animals. The "histogram" function in Image J shows the number of pixels in each image in a range of intensity from 0 to 255. With these images, we compared the intensity values in regions with clear in situ signal and the intensity values in regions without in situ signal. Based on this, we established a value of 179 as the lower limit to consider the colorimetric in situ signal as positive. Then the number of pixels of positive in situ signal was quantified for each section of each identified descending neuron. In brain sections, the identification of some of the specific descending cells becomes more difficult than in whole-mounts. Thus, only the cells that were unequivocally identified in at least two different sections were included in the quantifications (the M1, M2, M3, I1, I3, I4, I5, B1, B3, B4, B6 and Mth neurons; see Suppl. Figure [2A](#MOESM2){ref-type="media"}). Then, we calculated the average number of positive pixels per section for each individual neuron (see Table [1](#Tab1){ref-type="table"}) and these data were used for statistical analyses. The experimenter was blinded during quantifications.
The quantification of the intensity of FLICA labelling was done as previously described^[@CR18]^. Briefly, photomicrographs were acquired with a spectral confocal microscope (model TCS-SP2; Leica, Wetzlar, Germany). Images were always acquired under the same microscope conditions for control or treated animals. Quantification of mean fluorescent intensity (mean grey value) of each identifiable neuron was done using the Fiji software. In whole-mounted brain preparations, the specific descending neurons are easily identifiable based on their morphology and rostro-caudal and dorso-ventral anatomical location. The experimenter was blinded during quantifications. The data from each individual identifiable neuron (see Table [1](#Tab1){ref-type="table"}) were used for statistical analyses.
The percentage of neurons with regenerated axons (labelled by the Neurobiotin tracer) with respect to the total number of analyzed neurons (see Table [1](#Tab1){ref-type="table"}) was calculated for each type of identifiable descending neuron using an Olympus microscope or a Zeiss AxioImager Z2 microscope. The percentage of neurons with regenerated axons with respect to the total number of analyzed neurons in each animal was also calculated and these data were used for statistical analyses. The experimenter was blinded during quantifications. For the figures, images were taken with the Olympus microscope or the spectral confocal microscope (model TCS-SP2; Leica).
After quantifications, contrast and brightness were minimally adjusted with Adobe Photoshop CS4 or CS6 (Adobe Systems, San José, CA, USA). Figure plates and lettering were generated using Adobe Photoshop CS4 or CS6 (Adobe Systems).
Statistical analyses {#Sec11}
--------------------
Statistical analysis was carried out using Prism 6 (GraphPad software, La Jolla, CA). Data were presented as mean ± S.E.M. Normality of the data was determined only when *n* numbers were higher than 10 by using the D'Agostino-Pearson omnibus test, and the homoscedasticity was determined by the Brown-Forsythe test. The in situ hybridization data that were normally distributed and homoscedastic were analyzed by a one-way ANOVA. Post-hoc Dunnett's multiple comparison tests were used to compare pairs of data. In situ hybridization data that were not normally distributed (or when the *n* numbers were lower than 10) were analyzed by a Kruskal--Wallis test and post-hoc Dunn's multiple comparisons test. The results of control vs. treatment groups were analyzed by a Student's *t*-test (for normally distributed data) or a Mann--Whitney *U* test (for non-normally distributed data). The in situ hybridization data after morpholino application were analyzed by a Mann--Whitney *U* test. The significance level was set at 0.05. In the figures, significance values were represented by different number of asterisks: 1 asterisk (*p* value between 0.01 and 0.05), 2 asterisks (*p* value between 0.001 and 0.01), 3 asterisks (*p* value between 0.0001 and 0.001) and 4 asterisks (*p* value \<0.0001).
Results {#Sec12}
=======
Increased expression of the gabab1 subunit in identifiable descending neurons after SCI {#Sec13}
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GABAB receptors are obligate heterodimers formed by gabab1 and gabab2 subunits^[@CR49]^. In previous work, we reported the expression of the gabab1 and gabab2 receptor subunits in identifiable descending neurons of adult sea lampreys under normal conditions^[@CR42]^. Here, we used gabab1 in situ hybridization first to confirm that this receptor is also expressed in identifiable descending neurons of mature larval sea lampreys (Suppl. Figure [2B](#MOESM2){ref-type="media"}; Fig. [1a, c, e](#Fig1){ref-type="fig"}) and then to quantify changes in its expression after SCI (Fig. [1a--g](#Fig1){ref-type="fig"}; Suppl. Figure [3](#MOESM3){ref-type="media"}). The M1, M2, M3, I1, I3, I4, I5, B1, B3, B4, B6 and Mth neurons were included in the analyses (see Material and Methods). This revealed a significant increase in the expression of the gabab1 subunit in the M2 (ANOVA, *p* = 0.0049), M3 (ANOVA, *p* = 0.002), I1 (Kruskal--Wallis, *p* = 0.0009), I3 (Kruskal--Wallis, *p* = 0.0097), B1 (Kruskal--Wallis, *p* = 0.015) and B3 (Kruskal--Wallis, *p* = 0.0178) neurons (Fig. [1g](#Fig1){ref-type="fig"}; Table [2](#Tab2){ref-type="table"}) in 1 wpl animals as compared to control unlesioned animals. Subsequent power calculations (using 80% power) indicated that the sample sizes were appropriately powered. Although a similar trend was observed for the M1, I4, I5, B4, B6 and Mth neurons in 1 wpl animals as compared to control unlesioned animals, statistical analyses did not reveal significant changes in the expression of the gabab1 subunit in these neurons (Suppl. Figure [3](#MOESM3){ref-type="media"}; Table [2](#Tab2){ref-type="table"}). At 4 wpl, the expression of the gabab1 subunit was not significantly different to control unlesioned animals in all identifiable descending neurons and returned to control levels (Fig. [1g](#Fig1){ref-type="fig"}; Suppl. Figure [3](#MOESM3){ref-type="media"}; Table [2](#Tab2){ref-type="table"}). This shows that the complete SCI induced an acute increase in the expression of the gabab1 subunit in descending neurons, which, together with the accumulation of GABA around the axons of identifiable neurons^[@CR37]^, supports the possible role of endogenous GABA as a neuroprotective and pro-regenerative molecule after SCI in lampreys.Fig. 1Changes in the expression of the gabab1 subunit in identifiable descending neurons after a complete SCI.**a**, **c** and **e** Photomicrographs of transverse sections of the brain showing the expression of the gabab1 transcript in descending neurons of control animals. **b**, **d** and **f** Photomicrographs of transverse sections of the brain showing the expression of the gabab1 transcript in descending neurons of lesioned animals at 1 wpl. **g** Graphs showing significant changes (asterisks) in the number of gabab1 positive pixels per section of the soma of identifiable descending neurons. The mean ± S.E.M. values are provided in Table [2](#Tab2){ref-type="table"}. Scale bars: 20 µmTable 2Mean ± S.E.M. values of the number of gabab1 positive in situ pixels/section in identifiable descending neurons of control and injured animalsGabab1 positive pixels/sectionControl1 wpl4 wplM1258,170 ± 86,006320,350 ± 78,104148,657 ± 43,920M2237,552 ± 61,602618,158 ± 176,397131,367 ± 19,089M3144,448 ± 56,162423,439 ± 93,05985,245 ± 16,702I1140,858 ± 94,768627,179 ± 137,246176,392 ± 74,810I339,783 ± 17,599204,914 ± 49,09961,945 ± 34,492I468,678 ± 11,645147,613 ± 44,90345,723 ± 7,610I537,027 ± 21,46362,221 ± 13,38054,634 ± 23,587B1198,893 ± 57,286429,418 ± 43,503202,694 ± 75,156B3184,112 ± 51,392488,947 ± 86,189161,864 ± 70,596B4183,470 ± 49,454317,944 ± 79,980274,012 ± 88,414B6222,515 ± 105,034456,303 ± 87,734273,466 ± 101,442Mth201,230 ± 84,794395,530 ± 90,345139,834 ± 31,750Refers to Fig. [1](#Fig1){ref-type="fig"} and Suppl. Figure [2](#MOESM2){ref-type="media"}
GABA and baclofen treatments inhibit caspase activation in descending neurons after SCI {#Sec14}
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To test our hypothesis, we first analyzed the effect of GABA and baclofen (GABAB agonist) treatments in caspase activation in identifiable descending neurons after a complete SCI using FLICA labelling (Fig. [2a--i](#Fig2){ref-type="fig"}). As previously shown, in control lesioned animals, there is a statistically significant correlation between the intensity of FLICA labelling and the long-term survival and regenerative abilities of identifiable neurons (not shown;^[@CR18],[@CR50]^). At 2 wpl, animals treated with GABA or baclofen during 4 days showed a significant inhibition of caspase activation (fluorescence intensity of FLICA labelling) in identifiable descending neurons as compared to control animals (GABA: Student's *t*-test, *p* \< 0.0001; baclofen: Student's *t*-test, *p* \< 0.0001; Fig. [2j, k](#Fig2){ref-type="fig"}). This suggests that GABA can inhibit apoptosis in descending neurons after SCI by activating GABAB receptors.Fig. 2GABOB and baclofen treatments inhibit caspase activation in identifiable descending neurons.**a**, **d** and **g** Photomicrographs of whole-mounted brains showing identifiable descending neurons with intense FLICA labelling in control animals. **b**, **e** and **h** Photomicrographs of whole-mounted brains showing identifiable descending neurons with a reduction in FLICA labelling in GABA-treated animals. **c**, **f** and **i** Photomicrographs of whole-mounted brains showing identifiable descending neurons with a reduction in FLICA labelling in baclofen-treated animals. **j** Graph showing significant changes (asterisks) in the level of caspase activation (intensity of fluorescent FLICA labelling) after the GABA treatment. **k** Graph showing significant changes (asterisks) in the level of caspase activation (intensity of fluorescent FLICA labelling) after the baclofen treatment. Rostral is up in all photomicrographs. Scale bars: 100 µm
GABOB and baclofen long-term treatments promote axonal regeneration in descending neurons after SCI {#Sec15}
---------------------------------------------------------------------------------------------------
Then, we studied the long-term effect of increasing GABAergic signalling in axonal regeneration after a complete SCI. Retrograde neuronal tract-tracing with Neurobiotin showed that a treatment with either GABOB (Fig. [3](#Fig3){ref-type="fig"}) or baclofen (Fig. [4](#Fig4){ref-type="fig"}) during 12 weeks post-lesion significantly promoted axonal regeneration of identifiable descending neurons after a complete SCI as compared to control animals (GABOB: Student's *t*-test, *p* = 0.0129 (Fig. [3h](#Fig3){ref-type="fig"}); baclofen: Mann--Whitney *U* test, *p* = 0.0004 (Fig. [4h](#Fig4){ref-type="fig"})). The baclofen used in these experiments (from Carbosynth) was also tested to confirm that it had the same effect in the activation of caspases as the baclofen acquired from Molekula. This baclofen also inhibited caspase activation significantly in identifiable descending neurons as compared to control animals in a different set of experiments (Mann--Whitney *U* test, *p* \< 0.0001; not shown). This shows that an increase in GABAergic signalling through GABAB receptors promotes axonal regeneration after a complete SCI.Fig. 3A long-term GABOB treatment promotes axonal regeneration of identifiable descending neurons.**a**, **c** and **e** Photomicrographs of whole-mounted brains showing different reticulospinal populations with regenerated identifiable neurons in control animals, as identified by retrograde labelling. **b**, **d** and **f** Photomicrographs of whole-mounted brains showing different reticulospinal populations with an increased number of labelled (regenerated) identifiable neurons in treated animals. **g** Graph showing the percentage of regenerated neurons (with respect to the total number of analyzed neurons) for each identifiable cell in control and GABOB-treated animals. **h** Graph showing significant changes (asterisks) in the percentage of regenerated neurons per animal after the GABOB treatment (control: 37.27 ± 3.33%; GABOB: 49.79 ± 4.16%). Arrows indicate descending neurons that regenerated in GABOB-treated animals but not in controls animals. Rostral is up in all photomicrographs. Scale bars: 50 µmFig. 4A long-term baclofen treatment promotes axonal regeneration of identifiable descending neurons.**a**, **c** and **e** Photomicrographs of whole-mounted brains showing different reticulospinal populations with regenerated identifiable neurons in control animals. **b**, **d** and **f** Photomicrographs of whole-mounted brains showing different reticulospinal populations with an increased number of labelled (regenerated) identifiable neurons in treated animals. **g** Graph showing the percentage of regenerated neurons (with respect to the total number of analyzed neurons) for each identifiable cell in control and baclofen-treated animals. **h** Graph showing significant changes (asterisks) in the percentage of regenerated neurons per animal after the baclofen treatment (control: 46.17 ± 7.15%; baclofen: 77.91 ± 3.56%). Arrows indicate descending neurons that regenerated in baclofen-treated animals but not in controls animals. Rostral is up in all photomicrographs. Scale bars: 100 µm
Endogenous GABA signalling through GABAB receptors promotes axonal regeneration after SCI {#Sec16}
-----------------------------------------------------------------------------------------
To test whether endogenous GABA also promotes regeneration by activating GABAB receptors, we decided to use morpholinos to knockdown the expression of the gabab1 subunit in descending neurons after a complete SCI (Fig. [5](#Fig5){ref-type="fig"}). First, we used in situ hybridization to confirm that the active gabab1 morpholino is able to knockdown the expression of the gabab1 mRNA in identifiable neurons of 2 wpl animals (Fig. [5a--e](#Fig5){ref-type="fig"}). As an example, we analyzed the M1 (Fig. [5a, b](#Fig5){ref-type="fig"}) and the I1 neurons (Fig. [5c, d](#Fig5){ref-type="fig"}). The active gabab1 morpholino was able to significantly knockdown the expression of the gabab1 mRNA in identifiable descending neurons as compared to the gabab1 mismatch control morpholino (M1: Mann--Whitney *U* test, *p* = 0.0111; I1: Mann--Whitney *U* test, *p* = 0.0057; Fig. [5e](#Fig5){ref-type="fig"}). Then, neuronal tract-tracing showed that the treatment with the active gabab1 morpholino significantly inhibited axonal regeneration of identifiable descending neurons 10 weeks after a complete SCI as compared to the animals treated with the gabab1 mismatch control morpholino (Mann--Whitney *U* test, *p* = 0.0133; Fig. [5f--m](#Fig5){ref-type="fig"}). This confirms that, in lampreys, endogenous GABA promotes axonal regeneration of descending neurons after a complete SCI by activating GABAB receptors.Fig. 5Gabab1 morpholino treatments inhibit axonal regeneration of identifiable descending neurons.**a**, **c** Photomicrographs of transverse sections of M1 (**a**) and I1 (**c**) neurons showing the expression of the gabab1 transcript in control animals. **b**, **d** Photomicrographs of transverse sections of M1 (**b**) and I1 (**d**) neurons showing the decreased expression of gabab1 transcript in gabab1 morpholino-treated animals. **e** Graphs showing significant changes (asterisks) in the number of gabab1 positive pixels per section in the soma of M1 and I1 neurons after the gabab1 morpholino treatment. **f**, **h** and **j** Photomicrographs of whole-mounted brains showing different reticulospinal populations with regenerated identifiable neurons in animals treated with the control morpholino. **g**, **i**, **k**: Photomicrographs of whole-mounted brains showing different reticulospinal populations with fewer regenerated identifiable neurons in animals treated with the active gabab1 morpholino. **l** Graph showing the percentage of regenerated neurons (respect to the total number of analyzed neurons) for each identifiable cell in control and active gabab1 morpholino-treated animals. **m** Graph showing significant changes (asterisk) in the percentage of regenerated neurons per animal after the morpholino treatment (control mismatch morpholino: 43.89 ± 3.26%; gabab1 active morpholino: 33 ± 5%). Arrows indicate descending neurons that regenerated in gabab1 morpholino-treated animals but not in controls animals treated with the mismatch control morpholino. Rostral is up in photomicrographs (**f**) to (**k**). Scale bars: black, 20 µm; white, 50 µm
Discussion {#Sec17}
==========
Here, we have provided gain and loss of function data, using pharmacological and genetic treatments, showing that endogenous GABA signalling through GABAB receptors promotes neuronal survival and axonal regeneration of identifiable descending neurons of lampreys after a complete SCI.
The analysis of the changes of expression of the gabab1 subunit in response to a complete SCI revealed a significant increase in the expression of this subunit in some identifiable descending neurons (with other neurons showing a similar trend). As stated in the introduction, massive glutamate release and the subsequent activation of glutamate receptors lead to an increase in Ca^2+^ influx into cells, which causes excitotoxicity and neuronal death after SCI^[@CR21],[@CR22],[@CR24],[@CR51]^; see^[@CR52]^. GABAB receptors can cause the inactivation of voltage-dependent Ca^2+^ channels (see^[@CR32]^). Therefore, this increase in the expression of GABAB receptors could compensate for the influx of Ca^2+^ into axotomized descending neurons caused by massive glutamate release. The acute increase in the expression of the gabab1 subunit in descending neurons and the massive release of GABA after SCI^[@CR37]^ appears as one of the mechanisms favouring neuronal survival and axonal regeneration after SCI in lampreys. As far as we are aware, no study has analyzed the expression of gabab subunits after SCI in mammals. Only a few mammalian studies have looked at changes in the expression of this receptor following other types of nervous system injuries (sciatic nerve ligation:^[@CR53]^; traumatic brain injury:^[@CR54]^; ulnar nerve transection:^[@CR55]^; cerebral ischaemia:^[@CR56]^). In contrast to the present results in lampreys, these studies showed that the expression of GABAB receptors decreases after the injury in different regions of the brain^[@CR54]--[@CR56]^. This could be a key difference between regenerating and non-regenerating animals, since axons of the later do not show good regenerative abilities after CNS injuries. Interestingly, and in agreement with the results in lampreys, Huang and colleagues^[@CR56]^ reported that an elevation in the protein expression of GABAB receptors in the cerebral cortex promotes neuroprotection after ischaemic damage.
There is some controversy on the topic of whether descending neurons of the brain of mammals die after SCI. Some studies have shown the death of brain neurons after SCI^[@CR57]--[@CR63]^. On the other hand, two recent reports did not find evidence of the death of corticospinal neurons after SCI^[@CR64],[@CR65]^, and suggested that these neurons only suffer atrophy but do not die^[@CR65]^. In any case, the death or atrophy of descending neurons of mammals appears to involve apoptotic mechanisms as shown by the appearance of TUNEL labelling and activated caspase-3 immunoreactivity in these neurons after the injury at spinal levels^[@CR60]--[@CR62]^. Recent work in lampreys has also shown that identifiable descending neurons known to be "bad regenerators" are actually "poor survivors" after a complete SCI^[@CR8],[@CR12],[@CR14],[@CR50]^. These neurons enter in a process of slow and delayed death after SCI^[@CR8],[@CR12]--[@CR18]^ that is initiated by caspase activation in the injured axon at spinal levels^[@CR17],[@CR18]^. The death of these neurons also occurs through apoptotic mechanisms as shown by the appearance of activated caspases^[@CR15]--[@CR18]^, TUNEL labelling^[@CR14],[@CR15]^ and Fluoro-Jade® C labelling^[@CR12],[@CR18]^. Recent results have shown that there is a significant correlation between the intensity of caspase activation 2 wpl and the long-term regenerative^[@CR18]^ and survival^[@CR50]^ abilities of identifiable descending neurons of lampreys after SCI. Present results indicate that the activation of GABAB receptors by GABA/baclofen can inhibit caspase activation after SCI in identifiable descending neurons, which is a key step to preventing the development of apoptosis and promoting neuronal survival. Previous work in other models of CNS injury also showed that a baclofen treatment can inhibit caspase activation (model of kainic-acid-induced seizure in rats:^[@CR29]^; models of ischaemic brain injury in rats:^[@CR27],[@CR31]^; model of chemical hypoxia in retinal ganglion cells in rats:^[@CR66]^). Our study shows that the activation of GABAB receptors can also prevent apoptosis after a traumatic SCI.
Of major importance is the fact that our results also support the role of GABA as a molecule that promotes true axonal regeneration of descending neurons through the site of a complete SCI. Behavioural analyses were not performed to establish a relationship between increased regeneration and improved functional recovery after the treatments. First, because in our case, control animals usually reach the highest level of recovery when using the Ayers test (see ref.^[@CR39]^) and also because the treated animals were in the drugs until the day of analysis. Experiments using a gabab1 morpholino demonstrated that endogenous GABA acts as a pro-regenerative factor after SCI by activating GABAB receptors. The morpholino experiments suggest that GABA might promote regeneration by activating GABAB receptors expressed in the axotomized descending neurons. But, we cannot rule out the possibility that GABA could also promote the regeneration of descending neurons indirectly by inhibiting other cells expressing GABAB receptors, like intrinsic spinal cord neurons^[@CR39],[@CR42]^ that could have also taken the morpholino in our experiments. Our data agree with previous in vitro or developmental studies regarding the role of GABA and GABAB receptors in neurite outgrowth^[@CR67]^. López-Bendito and coworkers^[@CR67]^ showed that the GABAB antagonist CGP52432 decreases the length of the leading process in migrating inhibitory neurons in brain slice cultures of mice. Also, both GABA and baclofen stimulate retinal ganglion neurite outgrowth in *Xenopus* cultures, and the GABAB antagonist CGP54262 shortened the developing optic projection in vivo^[@CR68]^. But, as far as we are aware, our results are the first in vivo demonstration showing that GABA promotes axonal regrowth after a CNS injury by activating GABAB receptors. Present and previous^[@CR37]^ results indicate that the GABAergic system of lampreys responds successfully to a SCI to limit retrograde degeneration and promote the regeneration of descending pathways.
Conclusion {#Sec18}
==========
We have revealed a major role of GABA and GABAB receptors in promoting the survival and regeneration of individually identifiable descending neurons of lampreys following a complete SCI. Now, it would be of interest to decipher the underlying mechanisms behind the neuroprotective and pro-regenerative effect of GABA. Based on previous results in lampreys showing a negative effect of Ca^2+^ in neurite outgrowth^[@CR35],[@CR36]^, a decrease in Ca^2+^ levels due to the activation of GABAB receptors could be one of the key events in the inhibition of apoptosis and activation of axonal regeneration by GABA. In future studies, it might be also interesting to analyze changes in gene expression elicited by GABA signalling and the activation of GABAB receptors to reveal new pathways involved in axonal regeneration and neuronal survival in lampreys.
The present results provide further support for the idea suggesting that the lesioned spinal cord is a "new spinal cord"^[@CR69]^ and the importance of understanding the changes that occur after SCI in different neurotransmitter systems in the brain and in the spinal cord above and below the site of injury. This study adds to previous work revealing anatomical^[@CR37]--[@CR39],[@CR70],[@CR71]^ and physiological^[@CR40],[@CR72],[@CR73]^ changes in different neurotransmitter systems above and below the lesion in recovered lampreys and highlights the importance of understanding these changes before applying neuropharmacological interventions in SCI patients. Specially, when drugs affecting neurotransmission might not only modulate locomotor circuits, but also affect the process of neuronal regeneration and recovery (e.g. serotonin inhibitors/toxins: see refs.^[@CR72],[@CR74]^; GABOB/baclofen: present results).
Our results provide a strong basis to translate this knowledge to mammalian models of SCI for the development of new therapies for patients with SCI. A recent large observational cohort study has found that the early administration of gabapentinoids (which are administered as anticonvulsants for SCI patients) improves motor recovery following SCI^[@CR75]^. Interestingly, baclofen is also already in use in the clinic, even for the treatment of SCI patients with spasticity^[@CR76]^ or neuropathic pain^[@CR77]^, which could facilitate the clinical translation of similar results in pre-clinical models of SCI.
Electronic supplementary material
=================================
{#Sec20}
Supplementary Figure 1 Supplementary Figure 2 Supplementary Figure 3 Supplementary figure legends
These authors contributed equally: Antón Barreiro-Iglesias, María Celina Rodicio
Edited by: A. Verkhratsky
**Electronic supplementary material**
**Supplementary Information** accompanies this paper at (10.1038/s41419-018-0704-9).
**Publisher\'s note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Grant sponsors: Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund 2007--2013 (Grant number: BFU2014-56300-P) and Xunta de Galicia (Grant number: GPC2014/030). D.R.-S. was supported by a fellowship from EMBO (Ref.: 7010) to carry out a short-term stay at the laboratory of JRM. A.B.-I. was supported by a grant from the Xunta de Galicia (Grant number: 2016-PG008) and a grant from the crowdfunding platform *Precipita* (FECYT; Spanish Ministry of Economy and Competitiveness; grant number 2017-CP081). The authors would like to acknowledge the following individual donors of the crowdfunding campaign in *Precipita*: Blanca Fernández, Emilio Río, Guillermo Vivar, Pablo Pérez, Jorge Férnandez, Ignacio Valiño, Pago de los Centenarios, Eva Candal, María del Pilar Balsa, Jorge Faraldo, Isabel Rodríguez-Moldes, José Manuel López, Juan José Pita, María E. Cameán, Jesús Torres, José Pumares, Verónica Rodríguez, Sara López, Tania Villares Balsa, Rocío Lizcano, José García, Ana M. Cereijo, María Pardo, Nerea Santamaría, Carolina Hernández, Jesús López and María Maneiro. The authors thank the staff of *Ximonde* Biological Station for providing lampreys used in this study, and the Microscopy Service (University of Santiago de Compostela) and Dr. Mercedes Rivas Cascallar for confocal microscope facilities and help. We also thank the Director of the Central Microscopy Facility at the Marine Biological Laboratory, Louie Kerr, for technical assistance and the Marine Biological Laboratory in Woods Hole (MA) for providing support for these experiments. This article is dedicated to the memory of José Manuel Pérez Cancela (20/11/1975--05/03/2018) from the *Ximonde* Biological Station.
Conflict of interest {#FPar1}
====================
The authors declare that they have no conflict of interest.
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{
"pile_set_name": "PubMed Central"
}
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When Erik Finman received $1,000 from his grandmother in 2012, he invested it in bitcoin, the then-obscure form of online currency. A year and a half later, he sold his investment for $100,000 and used the earnings to launch Botangle.com, an online tutoring service that runs on video chat.
That's not bad for an entrepreneur who's only 15 years old.
The business now has more than 20 staffers (including programmers, designers and animators) and over a 100 active users. Although the user base is relatively small, the company attracted much buzz after Finman participated in a Reddit Q&A, offering tips for startups and answering questions about finding success with bitcoin.
"Some people can't comprehend how a 15-year-old could do something like this," Finman told Mashable. "What a lot of people don’t understand, young or old, is that you can create anything you want with no barrier to entry on the Internet."
Botangle, which launched in May, allows users to video chat and learn about any subject from computer programming and dance lessons to art and French classes instructed from, say, someone in Paris. Lessons are specialized and one-on-one, so users can set up a schedule that works best for them.
15-year-old Erik Finman is running his Botangle startup on money earned from selling Bitcoin.
Finman, who is from rural Idaho and calls the schools in his region "limited," came up with the concept after wanting access to more classes not offered nearby.
"I read 'Without Their Permission: How the 21st Century Will Be Made, Not Managed' by Alexis Ohanian and it taught me that I could do anything through the Internet," he said. "I wanted to use the beauty of the open and free web so people like myself can get access to a great learning experience; whether they're from rural Idaho, New York or even Africa."
But he said finding staffers who take both the business and himself seriously has presented a challenge.
"Whenever I interview a potential candidate for a job, I always ask if being part of a team with a 15-year-old bothers them," he said. "Sometimes that’s the end of the conversation right there, and other times people lie — and that shows later on. It’s pretty easy to tell when it happens, but the team I have now are super supportive, and they don’t treat me any differently than anyone else."
Finman says he typically pays his employees in bitcoin: "I'm sharing the wealth of bitcoin because I have no doubt it will be huger [sic] than anyone can imagine right now," he said. "Bitcoin is like the Internet in the '90s."
But employees can choose what they want to charge for their lessons by the hour or minute. Finman currently earns 30% of that but said he'll be dropping it to 15% royalty in the Botangle 2.0 update.
Finman may be young, but he's had teaching and technology on the brain for years; in fact, he started teaching older kids in his neighborhood about robotics when he was 9. He's been continuing his education through his own site too, specifically taking advantage of programming courses to compliment the classes he's enrolled in at his local community college, North Idaho College.
"I plan to talk to them about providing an online learning system for their college," he said
Although he's clearly passionate about bringing education to more people through the Internet, he doesn't have plans to get a college degree of his own. The higher schooler most recently switched to home schooling to focus on Botangle.
"I actually have a deal with my parents that if I make a million dollars before I turn 18, I don't have to go to college," he said. "I’m going to do it or die trying."
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{
"pile_set_name": "OpenWebText2"
}
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List of 1994 box office number-one films in the United Kingdom
This is a list of films which have placed number one at the weekend box office in the United Kingdom during 1994.
See also
List of British films — British films by year
1994
Category:Lists of 1994 box office number-one films
Box office number-one films
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{
"pile_set_name": "Wikipedia (en)"
}
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#pragma once
#include <Common/Base/hkBase.h>
#include "hkbModifier_0.h"
#include "hkbHandle_1.h"
#include "hkbSenseHandleModifierRange_0.h"
class hkbSenseHandleModifier : public hkbModifier
{
public:
HK_DECLARE_CLASS_ALLOCATOR( HK_MEMORY_CLASS_BEHAVIOR_RUNTIME );
HK_DECLARE_REFLECTION();
public:
HK_FORCE_INLINE hkbSenseHandleModifier(void) {}
HK_FORCE_INLINE hkbSenseHandleModifier( hkFinishLoadedObjectFlag flag ) : hkbModifier(flag)
, m_ranges(flag)
, m_handleOut(flag)
, m_handleIn(flag)
, m_localFrameName(flag)
, m_sensorLocalFrameName(flag)
{}
enum SensingMode
{
SENSE_IN_NEARBY_RIGID_BODIES = 0,
SENSE_IN_RIGID_BODIES_OUTSIDE_THIS_CHARACTER = 1,
SENSE_IN_OTHER_CHARACTER_RIGID_BODIES = 2,
SENSE_IN_THIS_CHARACTER_RIGID_BODIES = 3,
SENSE_IN_GIVEN_CHARACTER_RIGID_BODIES = 4,
SENSE_IN_GIVEN_RIGID_BODY = 5,
SENSE_IN_OTHER_CHARACTER_SKELETON = 6,
SENSE_IN_THIS_CHARACTER_SKELETON = 7,
SENSE_IN_GIVEN_CHARACTER_SKELETON = 8,
SENSE_IN_GIVEN_LOCAL_FRAME_GROUP = 9,
};
// Properties
hkbHandle m_handle;
hkVector4 m_sensorLocalOffset;
hkArray<hkbSenseHandleModifierRange> m_ranges;
hkRefPtr<hkbHandle> m_handleOut;
hkRefPtr<hkbHandle> m_handleIn;
hkStringPtr m_localFrameName;
hkStringPtr m_sensorLocalFrameName;
hkReal m_minDistance;
hkReal m_maxDistance;
hkReal m_distanceOut;
hkUint32 m_collisionFilterInfo;
hkInt16 m_sensorRagdollBoneIndex;
hkInt16 m_sensorAnimationBoneIndex;
hkEnum<SensingMode,hkInt8> m_sensingMode;
hkBool m_extrapolateSensorPosition;
hkBool m_keepFirstSensedHandle;
hkBool m_foundHandleOut;
hkReal m_timeSinceLastModify;
hkInt32 m_rangeIndexForEventToSendNextUpdate;
};
extern const hkClass hkbSenseHandleModifierClass;
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{
"pile_set_name": "Github"
}
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The present disclosure relates generally to dynamoelectric machines. More specifically, this disclosure relates to an apparatus for termination of conductors of a stator having six phases and concentrated leads in a vehicle alternator and method of manufacture of the apparatus.
Electric machines, such as alternating current electric generators, or alternators, are well known. Prior art alternators typically include a stator assembly and a rotor assembly disposed in an alternator housing. The stator assembly is mounted to the housing and includes a generally cylindrically shaped stator core having a plurality of slots formed therein. The rotor assembly includes a rotor attached to a generally cylindrical shaft that is rotatably mounted in the housing and is coaxial with the stator assembly. The stator assembly includes a plurality of wires wound thereon, forming six phases. The stator lead wires are typically concentrated in a small area, perhaps even in consecutive slots, and are routed to and connected to a stator terminal assembly.
Stators having six phases typically have stator terminal assemblies which include six electrically conductive tracks. One end of each conductive track is connected to the stator lead wires and another end is connected to a diode pair or similar switching elements of a rectifier bridge. To successfully dissipate diode heat, it is desirable to have the twelve (six pairs of) diodes physically spread out around the alternator circumference. The resultant conductive tracks, therefore, have one end in close proximity to each other (stator lead end) and another end spread out (diode pair end). At the stator lead end, the conductive tracks often interfere with each other and it is a common practice to partially dispose one track on top of another in the axial direction. This is vernacularly called a dual layer track stator terminal assembly. This results in a terminal assembly having a thickness that can in some instances block airflow within the alternator. Such conditions can present rectifier cooling issues. In addition, a dual layer track, if there were a way to reduce that thickness would be viewed as taking up valuable space that could be used, for example, for rectifier cooling fins. Furthermore, the dual layer track stator terminal assembly requires that each track be formed individually and is otherwise difficult and costly to manufacture because of the need to stack the individual tracks. Conversely, when a plurality of conductor tracks are arranged such that the tracks are not partially disposed on top of other tracks in the axial direction, these conductor tracks are considered as being disposed in a single layer.
It is desirable, therefore, to provide a stator terminal assembly of a six phase alternator, with reduced thickness to alleviate properties of the electric machine such as rectifier cooling issues, and also to provide a stator terminal assembly of simplified manufacturability.
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{
"pile_set_name": "USPTO Backgrounds"
}
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In the New York City underground scene, Joe Caro led an allstar band which included trumpeter Chris Botti, saxman Lenny Pickett, Late show drummer Anton Fig, bassist Will Lee, trumpeter Randy Brecker and saxman Andy Snitzer among several other notables performing every Tuesday night at the NYC club, The Metropolitan Café. What started out as a 2 week gig, continued for 8 years and became the home base for many New York City session musicians at a time when New York music clubs were far and few...
Majestic K Funk, at its core, comprises brothers Michael (vocals) and Jameel Young (vox and drums). They have been performing in NY since the 70s and have worked with such greats as Luther Vandross, Marcus Miller and Jaco Pastorius. In the 90s, they were joined by Miguel Mateus (bass) who has collaborated with musicians such as Greg Errico, Sim Cain, Dennis Davis and Bernie Worel. Majestic K Funk performs weekly and has shared the stage with Blue Magic, The Manhattans, Ohio Players and The Whispers.
Click on the ticket link above and select the General Admission ticket PLUS $20 Dinner special to save 30% on your dinner (does not include TIP). Select your dinner option on the page during checking-out when you review your online order and BEFORE finishing the check process.**
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A User's Guide to They Might Be Giants
A User's Guide to They Might Be Giants is a 2005 compilation album by the group They Might Be Giants.
In the April 29, 2005 "TMBG News" online newsletter, bandmember John Flansburgh describes the album as such:
"Rhino is releasing the single disc compilation A User's Guide To They Might Be Giants – kind of a simple reduction of Dial-A-Song – on May 3. It is a very interesting introduction to the band. If you were looking for a single disc to lay on the uninitiated, this might be the one. The liner notes, put together with our pal Barbara Glauber, are quite extensive. We've tried to compile all the songs and all the shows since the band's inception. Obviously this was a bit of a research nightmare (I'm not even sure if the show list includes in-stores!) but it is a very interesting object to look at, especially if you have good near-field vision."
Although it is referred to as a condensed version of Dial-A-Song: 20 Years Of They Might Be Giants, it includes two songs not on Dial-A-Song, "John Lee Supertaster" and "Clap Your Hands" and adds two different versions of songs, the original versions of "Why Does the Sun Shine?", and "Don't Let's Start" as opposed to the live and single versions respectively found on Dial-A-Song.
Song origins
Tracks 1, 3, 7, 10 and 18 originally from Flood (1990)
Track 2 originally from John Henry (1994)
Tracks 4, 5 and 22 originally from They Might Be Giants (1986)
Tracks 6 and 13 originally from Mink Car (2001)
Tracks 8, 11 and 20 originally from Lincoln (1988)
Tracks 9 and 15 originally from Factory Showroom (1996)
Tracks 12, 14, 21 and 29 originally from Apollo 18 (1992)
Track 16 originally from Severe Tire Damage (1998)
Track 17 originally from Boss of Me EP (2000) and is the theme song for Malcolm in the Middle, although a shorter version is usually used
Track 19 originally from Why Does The Sun Shine? (The Sun Is a Mass of Incandescent Gas) EP (1993)
Tracks 23, 27 and 28 originally from No! (2002)
Track 24 originally from Long Tall Weekend (1999)
Track 25 originally from Don't Let's Start EP (1987), and later Miscellaneous T (1991)
Track 26 originally from More Music from the Motion Picture Austin Powers: The Spy Who Shagged Me (1999)
Track listing
All songs by They Might Be Giants unless otherwise noted
"Minimum Wage" – 0:47
"Meet James Ensor" – 1:33
"Particle Man" – 1:59
"Don't Let's Start" – 2:34
"She's an Angel" – 2:37
"Cyclops Rock" – 2:38
"Istanbul (Not Constantinople)" (Jimmy Kennedy, Nat Simon) – 2:38
"Purple Toupee" – 2:40
"James K. Polk" (Matthew Hill, They Might Be Giants) – 3:04
"Birdhouse in Your Soul" – 3:20
"Ana Ng" – 3:23
"The Guitar (The Lion Sleeps Tonight)" (They Might Be Giants, Hugo Peretti, Luigi Creatore, George David Weiss) – 3:49
"Bangs" – 3:09
"The Statue Got Me High" – 3:06
"New York City" (Robynn Iwata, Lisa Marr, Lisa Nielsen) – 3:02
"Doctor Worm" – 3:01
"Boss of Me" – 2:58
"Your Racist Friend" – 2:54
"Why Does the Sun Shine? (The Sun Is a Mass of Incandescent Gas)" (Louis Singer, Hy Zaret) – 2:53
"They'll Need a Crane" – 2:33
"I Palindrome I" – 2:22
"Put Your Hand Inside the Puppet Head" – 2:12
"John Lee Supertaster" – 2:01
"Older" – 1:58
"We're the Replacements" – 1:50
"Dr. Evil" – 1:48
"No!" – 1:29
"Clap Your Hands" – 1:22
"Spider" – 0:51
References
External links
A User's Guide to They Might Be Giants on This Might Be a Wiki
Category:Rhino Records compilation albums
Category:They Might Be Giants compilation albums
Category:2005 compilation albums
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In the upcoming “Roseanne” reboot, Darlene’s son Mark, played by Ames McNamara, likes to wear dresses. But executive producer and star Sara Gilbert says the character is not a transgender character — he’s just a little boy.
“He’s not a transgender character. He’s a little boy,” Gilbert told Entertainment Weekly. “He’s based on a few kids in my life that are boys who dress in more traditionally feminine clothing. He’s too young to be gay and he doesn’t identify as transgender, but he just likes wearing that kind of clothing and that’s where he is at this point in his life.”
Gilbert said that his interest to dress in girl clothes is addressed in multiple episodes but one episode in particular focuses on it more “heavily.”
See Video:New 'Roseanne' Teaser Mocks Itself for Bringing Dan Back From the Dead
“We did a lot of research because we wanted to make sure and do it properly,” said Gilbert. “This character is not transgender.”
Gilbert wanted to create this character because she believes it “represents the world” as part of a show that’s always done exactly that.
Also Read:'Roseanne' Revival: Here's How Sarah Chalke Will Fit In
“We can do it through the dynamics of the family,” she added. “I know kids like that and it seemed like a great character. One kid in particular that I know is so sweet, funny, charming, and great. In a way the character– that’s one element of the character that he dresses that way, but he’s also based on this kid I know in a lot of other ways. I don’t want to pigeonhole him and say just because he dresses this way that’s the only thing about him. He happens to dress that way but he’s an amazing, creative, brilliant kid, which you will see, and so is the kid, Ames, who plays him.”
The nine-episode revival, starring Roseanne Barr, John Goodman, Laurie Metcalf and Michael Fishman premieres on March 27.
Related Video:
Watch Today Show on Yahoo View.
Related stories from TheWrap:
Roseanne Deletes Tweets Threatening to 'Retire Right Now' After Online Beef With Liberals
ABC's 'Roseanne' Reboot Sets Spring Premiere Date
'Roseanne' Revival Finally Confirms Johnny Galecki's Return
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Still common in some adverbial uses, but no longer used as an adjective.
Etymology Edit
(This etymology is missing or incomplete. Please add to it, or discuss it at the Etymology scriptorium.)
Noun Edit
hama
Inflection Edit
Inflection of hama nominative sing. hama genitive sing. haman partitive sing. hamad partitive plur. — singular plural nominative hama — accusative haman — genitive haman — partitive hamad — essive-instructive haman — translative hamaks — inessive hamas — elative hamaspäi — illative ? — adessive hamal — ablative hamalpäi — allative hamale — abessive hamata — comitative hamanke — prolative hamadme — approximative I hamanno — approximative II hamannoks — egressive hamannopäi — terminative I ? — terminative II hamalesai — terminative III hamassai — additive I ? — additive II hamalepäi —
Derived terms Edit
References Edit
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Dark Star Safari
Dark Star Safari (2002) is a written account of a trip taken by author Paul Theroux from Cairo to Cape Town via trains, buses, cars, and armed convoy. Theroux had lived in Africa as a young and idealistic early member of the Peace Corps and part of the reason for this trip was to assess the impact on Africa of the many years of aid from Western countries. His assessment is generally critical of the long-term impact of aid programs.
Throughout the duration of the trip Theroux describes the writing of an erotic novella. This novella was eventually published in 2003, amongst a collection of short stories, as "The Stranger at the Palazzo D'Oro".
References
External links
Booknotes interview with Theroux on Dark Star Safari, May 18, 2003.
Official site
Rossouw, Henk. "Classic review: Dark Star Safari", Christian Science Monitor, 27 September 2009.
Kirkus Reviews. "Dark Star Safari", [Kirkus Reviews], 15 December 2002.
Gerhart, Gail M. "Dark Star Safari: Overland From Cairo to Cape Town", Foreign Affairs, November/December 2003.
Category:2002 non-fiction books
Category:Books by Paul Theroux
Category:Books about Africa
Category:Houghton Mifflin books
Category:American travel books
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Product Description
Rambler Half Gallon Jug
The Rambler Half Gallon Jug is built to take on the wild, whether that's rough tumbles from the truck cab or fishing the Texas flats in August. Like the rest of the Rambler series, it's constructed from 18/8 Stainless Steel, has Double-wall Vacuum Insulation, and comes ready with our No Sweat Design. But this Rambler Jug is also outfitted with our MagCap and dock, so your cap is never out of reach while you grab a drink. The one-inch of lid insulation locks in your drink's temperature unlike any other water jug out there. If you want to take your cold (or hot drinks) further for longer, Rambler Half Gallon Jug has you covered.
The Half Gallon Jug is 10 in tall and 6 in wide.
Features & Highlights
Complete with all the features you expect from a Rambler: 18/8 stainless steel, double-wall vacuum insulation, and a No Sweat Design
The Half Gallon Jug also has a full inch of Lid Insulation which ensures your drinks stay frosty or piping hot longer
Outfitted with YETI's MagCap which locks into its dock so you can chug without worry
Give your Rambler Jug a home in the truck bed or ATV with the Rambler Jug Mount (sold separately)
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Q:
Term for insulting words which sound grand?
I don't mean euphemisms or backhanded compliments (or the reverse). It's the words which sound grand, but actually have a bad meaning (e.g., jumentous: smelling strongly like a beast of burden). Is there any word to define this conceptually?
A:
Some phrases to describe the process: damning with faint praise, a left-handed compliment, asteism.
Some examples:
Brave (often means stupid: "That's brave of you!")
Interesting (can mean boring: "How very interesting." or stupid: "An interesting idea. Why don't you present that at the next staff meeting?")
Special (its sense of developmentally disabled was originally meant as a polite euphemism, as in the Special Olympics or special needs... but because of that association, one can sneer at anything by calling it "special", while appearing to praise it. "Oh, did your kid make that mug for you? Well, isn't that special?")
Great personality (when you're being set up for a blind date, if your friend tells you that your date has "a great personality", it means s/he is ugly. Or at least that's the cliché.)
A:
Sesquipedalianism is the habit of using long (sesquipedalian, or "foot-and-a-half") words; it doesn't specifically mean "using long words in order to disguise insults", but a few people I know who are habitual sesquipedalianists1 do so for exactly that reason.
Obscurantism is "deliberate obscurity or evasion of clarity"; if you habitually use long words to hide your true meaning, you're an obscurantist.
I can't think of any word that combines those meanings with the specific intent to hide insults.
1 This word doesn't seem to actually exist yet, so I'm coining it. "Sesquipedalian" is the adjective form, but it refers to the words themselves, not the people who [mis]use them.
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Background {#Sec1}
==========
Regular physical activity (PA) is widely recommended throughout the human lifespan to maintain health and physical fitness \[[@CR1]--[@CR3]\]. Menopause is a critical state in the life of women generally accompanied by dysregulation in the cardio-metabolic profile resulted from critical changes in body composition such as excessive accumulation of fat at visceral level. Increase of physical activity level could modulate these negative changes both in body composition and cardio-metabolic profile. Elderly women who are physically active possess less risk of functional limitations and a higher health-related quality of life \[[@CR4], [@CR5]\]. Furthermore, osteoporosis, sarcopenia, risk of falls \[[@CR6], [@CR7]\], dementia, depression, loss in cognitive function \[[@CR6]\], and the risk of some type of cancers \[[@CR8]\] can be reduced by regular PA. Part of the cardio-metabolic health including physical performance, systolic/diastolic blood pressure, resting heart rate, fasting levels of plasma glucose and insulin level, abdominal visceral adipose tissue, weight, BMI, sedentary behavior are also positively influenced by PA in elderly women \[[@CR3], [@CR6], [@CR9]--[@CR12]\]. However its effect on certain metabolic parameters, such as lipid levels are not unequivocal. Some investigations have proved that PA favorably modifies lipid parameters among elderly women \[[@CR9], [@CR13]\], while others failed to demonstrate significant effect \[[@CR10], [@CR14]--[@CR17]\].
Insulin-like growth factor 1 (IGF-1) is a basic peptide composed of 70 amino acids, which is thought to play a central role in metabolism \[[@CR18]\], cancer development \[[@CR19]\], CV diseases \[[@CR20]\] and aging \[[@CR21]\]. In adults high levels of IGF-1 are associated with increased cancer risk \[[@CR22]\] and CV diseases. A population-based study examining the association of different IGF-1 levels with mortality, cardiovascular disease, and cancer in the elderly has found a U-shaped relationship between IGF-1 level and fatal CV diseases, which means that both high and low levels of IGF-1 were associated with increased risk of CV mortality. Significant associations of serum IGF-1 with fatal or non-fatal cancer were not observed in this elderly population \[[@CR23]\]. Serum IGF-1 level is declining with age \[[@CR24]\] and postmenopausal women generally display even lower levels of IGF-1 compared to elderly men \[[@CR21]\] which may in part explains increased CV mortality in postmenopausal women. Low levels of IGF-1 are associated with osteoporosis \[[@CR25]\], disability \[[@CR26]\], neurodegenerative illnesses such as Alzheimer dementia and brain atrophy \[[@CR27]\] and increased risk of CVD \[[@CR28]\]. The anti-inflammatory and anti-oxidant effects of higher IGF-1 level on blood vessels have also been investigated \[[@CR29]\]. The development of impaired glucose tolerance and type 2 diabetes is also more expected in patients with low IGF-1 levels \[[@CR24], [@CR30]\]. Regular PA has several health preserving effects and it has been examined previously how it may modulate IGF-1 level. Some investigations have demonstrated positive effect of especially resistance training on IGF-1 levels \[[@CR31]--[@CR34]\], while aerobic exercise training had no considerable effect on IGF-1 concentrations \[[@CR33], [@CR35], [@CR36]\].
Elderly women usually do not report only physical but also psychological and social changes during menopause that affect their global and CV health \[[@CR37]\]. General psychological-, and emotional well-being, and optimism are related to health promoting behaviors including healthy eating and lifestyle habits and self-care, supporting CV and overall health of elderly patients \[[@CR38]--[@CR40]\].
The aim of our study was to investigate whether 12 weeks of an applied home- and center- based physical training program is sufficient to change functional capacity, some important cardio-metabolic parameters, IGF-1 level and psychological items of elderly female patients with moderate to high CV risk.
Methods {#Sec2}
=======
Ethics approval and consent to participate {#Sec3}
------------------------------------------
The investigation was approved by the Regional Ethics Committee of the University of Pécs (No. 5829) and was conducted in accordance with the ethical principles stated in the Declaration of Helsinki. A written informed consent was obtained from all subjects.
Patients {#Sec4}
--------
Sixty female non-smoker patients with moderate to high CV risk (mean age: 67.4 ± 5 years) were enrolled into our study (Table [1](#Tab1){ref-type="table"}). Patients were recruited either from primary care or from internal medicine and cardiology outpatient care by different physicians. They voluntarily agreed to participate in the study and then were randomly assigned either to the CV preventive training program or to the control group. Participants in both groups met the following inclusion criteria: ejection fraction (EF) ≥55% and metabolic equivalent (MET) ≥5. Exclusion criteria were the following: previous CV events, heart failure, inducible myocardial ischemia and arrhythmias on an exercise stress test. Medication and drug therapy were not modified during the study in either groups (Table [2](#Tab2){ref-type="table"}). It was also suggested to the control group not to change their usual physical activity level in the next 12 weeks.Table 1Characteristics of the study population, *n* = 60population characteristictraining group (*n* = 30)control group (*n* = 30)*p* valuehypertension29 (96%)27 (90%)0.30diabetes mellitus10 (33%)9 (30%)0.78dyslipidemia19 (63%)15 (50%)0.29chronic kidney disease2 (3.3%)0 (0%)0.15Table 2Medication therapy during the 12 week training program, *n* = 60medicationtraining group (*n* = 30)control group (*n* = 30)*p* valuestatins19 (63%)15 (50%)0.29antiplatelet drugs9 (30%)7 (23%)0.56β-blocker15 (50%)14 (46%)0.79RAAS inhibitor20 (66%)14 (46%)0.12calcium channel blocker8 (26%)9 (30%)0.77antidiabetic drugs10 (33%)9 (30%)0.78diuretics12 (40%)8 (26%)0.27RAAS renin--angiotensin--aldosterone system
Study design {#Sec5}
------------
At baseline patients were examined using electrocardiography (ECG) and echocardiography to exclude unknown cardiac problems that could limit their ability to exercise. Then they were tested on treadmill according to the Bruce protocol to assess functional capacity. The intensity of the training was defined as 50--70% of the peak maximal oxygen consumption (VO2max), starting at 50% and gradually increased to 70%. Metabolic laboratory such as fasting glucose, hemoglobin A1c (HgbA1c), total cholesterol (TC), low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride (TG), IGF-1 measurements and SF-36 (36-Item Short Form Survey) Questionnaire were performed. Upon reaching week 12, all tests were repeated, with the exception of echocardiography.
Home-based walking program {#Sec6}
--------------------------
A daily walking program was implemented, which could be performed in a 10--15 min workout and could be completed by the patients solely on their own. For appropriate estimation of the daily walking program our patients were asked to wear a personalized activity tracker on their wrist \[[@CR41]\]. These trackers did not only registered the daily footsteps but also motivated our elderly women to achieve the daily activity goal of 10,000 footsteps based on health expert's recommendation \[[@CR42], [@CR43]\].
Aerobic exercise training program {#Sec7}
---------------------------------
The aerobic exercise training program began with warm-up exercises (breathing exercises and stretching of the large joints) for 5--10 min three times weekly. In the second phase, patients participated in a moderate-intensity training. The training involved static (exercises with a medicine ball, half-squats, toe raises and body flexions) and dynamic (walking, jogging, ball games e.g., basketball, football) exercise elements. The intensity of the training was defined as 50--70% of the peak maximal oxygen consumption (VO~2~max), starting at 50% and gradually increased to 70%. The aerobic phase lasted 35--40 min. Finally, relaxation exercises were performed (stretching and breathing exercises) for 10 min. The exercise training was supervised by a cardiologist and conducted by a physiotherapist. Pulse and blood pressure were taken prior to, during (20 min after starting the training) and at the end of the training period.
Blood collecting {#Sec8}
----------------
At baseline and after 12 weeks, blood samples were obtained from the antecubital vein in both groups. The blood was collected into one clot activator-coated and gel-containing (5 ml), one potassium EDTA-coated (3 ml) and one sodium fluoride and potassium oxalate-coated (2 ml) Vacutainer tubes were sent for laboratory measurements and one potassium EDTA-coated (3 ml) Vacutainer tube was sent for IGF-1 measurements.
IGF-1measurements {#Sec9}
-----------------
IGF-1 levels were measured using Human IGF-1 Quantikine ELISA Kit (R&D Systems; Cat. No.: RD-DG100). EDTA-plasma samples were collected from patients at the beginning and after the 12th week, the samples were stored at − 74 °C until performing the assay. The assay employs a quantitative sandwich immunoassay technique. The IGF-1 assay protocol was carried out according to the manufacturer's instructions.
Psychological surveys {#Sec10}
---------------------
SF-36 Questionnaire was applied to examine the psychological effects of the 12 week home - and center based training program on the perception of health. It is a self-administered questionnaire measuring health over 8 dimensions (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health). Both the training- and the control group rate their health status on a scale from 0 (worst health) to 100 (best health).
Statistical analysis {#Sec11}
--------------------
A sample size and power analysis was performed for the overall population using PASS software. For the sample size of *n* = 28 patients (1:1 enrollment ratio of interventional and control group) needed to detect a true difference of d = 2 in MET levels with 95% power, where type I error probability is α = 0.05.
Statistical analysis was performed using the IBM SPSS statistical software version 23. Data were shown as mean ± standard deviation (SD). Significance level was defined as *p* \< 0.05. To check differences in the interventional and in the control group we performed dependent-t test. For testing how the two groups varied in time the interaction of time x group effect was applied. The normality was analyzed by Kolmogorov-Smirnov test. All the studied parameters in both groups showed no significant deviation from a normal distribution (*p* \> 0,05; df:56). The nonparametric Wilcoxon Rank test was applied to analyze potential changes in psychological functioning and in the number of foot-steps, since these were ordinal variables. Data were shown as median and IQR.
Results - within groups {#Sec12}
=======================
Home-based walking and center based physical training program increased patients' exercise capacity and improved metabolic parameters {#Sec13}
-------------------------------------------------------------------------------------------------------------------------------------
Home-based walking program resulted in a significant improvement in daily physical activity (4232 \[IQR: 3162--7219\] vs 8455 \[IQR: 6757--11,488\] foot-steps) among our female patients (*p* \< 0.001). We did not register any adverse events during the trial. The combined home-based and center based physical training program improved exercise capacity, described by the significantly increased metabolic equivalent (MET) in the training group (*p* = 0.002) (Fig. [1](#Fig1){ref-type="fig"}). Exercise capacity did not change in the control group.Fig. 1Significant changes in metabolic equivalent (MET) within and between the groups. Values are shown baseline and 12 weeks (mean ± SD). Levels of significance *p* \< 0.005. \*: *p* = 0.002 regarding baseline to 12 weeks in the training group; \#: *p* \< 0.01 regarding the training group compare to the control group after 12 weeks
Total cholesterol, LDL cholesterol, TG, and HgbA1c level indicated a significant decrease during the investigated period (*p* \< 0.05), the other measured laboratory parameters did not show significant changes in the training group (Table [3](#Tab3){ref-type="table"}). None of the laboratory parameters changed in the control group.Table 3Changes in metabolic laboratory parameters and IGF-1 level after 12 weeks physical activity in the training group. *N* = 30; values are baseline and 12 weeks means±SD. Levels of significance: *p* \< 0.05measured parametersbaseline12 week*p* valueHgbA~1C~ (mmol/l)6.24 ± 0.676.06 ± 0.580.007total cholesterol (mmol/l)5.17 ± 1.134.77 ± 1.120.042LDL-cholesterol (mmol/l)3.37 ± 1.052.81 ± 0.980.003HDL-cholesterol (mmol/l)1.46 ± 0.391.51 ± 0.46nstriglycerides (mmol/l)1.68 ± 0.711.28 ± 0.710.002IGF-1 (ng/ml)59.68 ± 27.3766.79 ± 22.740.006
Body weight (BW) and body mass index (BMI) differed neither in the training group, nor in the control group after 12 weeks (data are not shown).
Home-based walking and center-based physical training program increased IGF-1 level {#Sec14}
-----------------------------------------------------------------------------------
Serum IGF-1 significantly increased after 12 weeks in the training group (Table [3](#Tab3){ref-type="table"}), while it decreased in the control group (*p* \< 0.05).
Home-based walking and center-based physical training program increased patients' physical functioning {#Sec15}
------------------------------------------------------------------------------------------------------
Participants of the training group reported significantly fewer limitations in their everyday physical functioning (p \< 0.05), however in the other examined psychological items no significant change could be observed following the training program (data are not shown). Participants in the control group did not report any changes in their psychological conditions (data are not shown).
Results -- between groups {#Sec16}
=========================
Home-based walking and center-based physical training program increased patients' exercise capacity and IGF-1 level, and improved lipid parameters {#Sec17}
--------------------------------------------------------------------------------------------------------------------------------------------------
The interaction of time x group effect revealed, that the training group significantly differed from the control group in four parameters including MET (*p* = 0.003) (Fig. [2](#Fig2){ref-type="fig"}a), LDL-cholesterol (*p* = 0.046) (Fig. [2](#Fig2){ref-type="fig"}b), triglyceride (*p* = 0.001) (Fig. [2](#Fig2){ref-type="fig"}c) and IGF-1 levels (*p* \< 0.001) (Fig. [2](#Fig2){ref-type="fig"}d) after the intervention.Fig. 2Box plots of cardio-metabolic parameters and IGF-1 level at baseline and after 12 weeks between the training-, and the control group. n = 60. Levels of significance: p \< 0.05. **a** Significant difference in MET between the groups. *p* = 0.003. **b** Significant difference in LDL-cholesterol level between the groups. *p* = 0.046. **c** Significant difference in triglyceride level between the groups. *p* = 0.001. **d** Significant difference in IGF-1 level between the groups. *p* \< 0.001
The training group did not differ from the control group in the other investigated cardio-metabolic parameters (total-cholesterol-, HDL-cholesterol-, and HgbA1c level) after the training program (data are not shown).
Home-based walking and center-based physical training program and psychological status {#Sec18}
--------------------------------------------------------------------------------------
Psychological testing did not show significant differences between the training group and the control group (data are not shown).
Discussion {#Sec19}
==========
In our present study we investigated the effects of a home-, and center based physical training program on functional capacity, metabolic laboratory, IGF-1 levels and psychological parameters in elderly female patients with moderate to high CV risk. The organized training program resulted in a significantly improved functional capacity, metabolic status including LDL cholesterol, triglyceride, HgbA1c and IGF-1 level, and physical functionality.
Maintenance of a physically active lifestyle is a great challenge especially for the elderly population \[[@CR4]\] and women are less likely to adhere physical training programs compared to men \[[@CR44]\]. We assumed that a combined, home-based walking and a center based training program fits well to the everyday life of the elderly ladies, and a center-based exercise program led by a physiotherapist might be effective and enjoyable for this special patient population. Walking is a low cost and easy way of PA for the elderly \[[@CR45]\]. Most of the studies reported that the normal daily activity of healthy adults is only 4000 to 6000 steps \[[@CR46], [@CR47]\] and in older women it is even lower \[[@CR48], [@CR49]\]. Although in our study the elderly female patients could not completely fulfill the daily target of 10,000 steps, still the achieved significant improvement in daily PA (4232 \[IQR: 3162--7219\] to 8455 \[IQR: 6757--11,488\] footsteps) is a great performance taking into accounts their age and co-morbidities.
After 12 weeks of the home- and center- based physical training program, we could demonstrate an average of 0.7 MET improvement in functional capacity (8.17 ± 1.57 to 8.87 ± 1.76). According to data in the literature an increase by 1 MET in cardiorespiratory fitness could reduce the risk of all causes and CV mortality by 13 and 15%, respectively \[[@CR50]\]. Furthermore, the training group significantly differed from the control group in MET level after the intervention, suggesting that the training program significantly improved the functional capacity of our elderly female patients.
In our study we observed a significant decrease in the total cholesterol as well as in LDL cholesterol and TG levels in the training group, while in the control group no change could be observed in the metabolic parameters. In addition, the training group significantly differed from the control group in LDL cholesterol and triglyceride levels after the training program, referring that the observed favorable changes are due to the home- and center-based training program. Data in the literature regarding the effects of PA on lipid levels in general populations and also in elderly females is controversial. Examining the reasons behind this phenomenon we found some interesting observations. Fonong et al. reported that 2 months regular leisure time activity in elderly woman and men is too short to induce changes in body composition and plasma lipid levels \[[@CR16]\]. Nieman et al. could not demonstrate changes in HDL-cholesterol after 12 weeks cardiorespiratory exercise in previously sedentary elderly women. They indicated that women tend to have higher HDL-cholesterol level than men, furthermore it is harder to increase the already higher HDL-cholesterol level, and PA mostly has more favorable effects on young or middle aged than elderly women \[[@CR17]\]. Di Blasio et al. failed to report improvement in lipid levels after 13 week moderate intensity exercise program among postmenopausal women. They observed a decrease in spontaneous daily PA during the training program which may negatively affected the efficiency of the program \[[@CR10]\]. On the other hand, Fahlman et al. demonstrated favorable changes in plasma lipoprotein profile after 10 weeks endurance or resistance training among elderly women, although LDL-cholesterol level decreased significantly only in the resistance training group \[[@CR13]\]. Kemmler et al. reported decreased plasma lipid levels after 26 months intense exercise program among postmenopausal women \[[@CR9]\]. Examining our and the above described different training programs we may realize that those physical training programs were able to induce significant changes in lipid levels in elderly females which either contained resistance training \[[@CR13]\] or was intense and long enough \[[@CR9]\] or could effectively increase the daily physical activity level, like the present home- and center- based exercise program.
It was previously demonstrated that regular PA improves plasma glucose level as well as plasma insulin concentration \[[@CR10], [@CR11], [@CR51]\]. In accordance with previous studies following the home- and center- based training program HgbA1c significantly decreased among our elderly female patients, contributing significantly to the positive metabolic effects of PA. In the control group no change could be observed in the HgbA1C level.
At baseline low levels of IGF-1 were measured in our study (Table [3](#Tab3){ref-type="table"}). In the training group significant increase in IGF-1 levels could be observed but still remained below the average level of healthy middle-aged female adults \[[@CR52]\]. Moreover, the training group differed significantly from the control group in IGF-1 levels after the intervention, suggesting that the home- and center-based training program caused the beneficial changes in the IGF-1 levels. It is known that IGF-1 level markedly declines with aging which is also referred to as somatopause and this could be more robust around the time of menopause \[[@CR53], [@CR54]\]. It has been previously proved that resistance training improved IGF-1 levels in healthy adults \[[@CR31]\], elderly males \[[@CR32]\], patients with sarcopenic obesity \[[@CR33]\], and also in postmenopausal women \[[@CR34]\]. No association has been previously reported between aerobic PA levels and IGF-1 concentrations in postmenopausal women \[[@CR33], [@CR35], [@CR36]\]. However, in a large cross-sectional study the effect of physical activity on hormone levels were examined among the postmenopausal women, a more intense PA estimated by the Cambridge Index was associated with higher IGF-1 concentrations \[[@CR55]\]. Based on previous results and our findings it seems that in the case of aerobic exercise training a more intensive PA level is needed to change IGF-1 level. The decrease in IGF-1 levels in the control group may be due to the lack of regular PA.
Besides objective measurements SF36 questionnaire was applied in our study to measure the psychological well-being of our elderly female patients. The physical functionality, which is the patients' subjective judgement of their physical state has been improved after our home-, and center- based training program, meaning they have experienced fewer limitations during their everyday physical tasks, like shopping, walking or bathing. This better physical functionality was in accordance with the improved functional capacity measured by treadmill. However, no significant improvement could be measured in other examined psychological parameters. A longer follow up period may be necessary for achieving significant changes in other psychological parameters. A previous study examining 6 month exercise training in postmenopausal women attenuated the unfavorable psychological changes associated with menopause \[[@CR56]\].
Our study indicated, that elderly women with moderate to high CV risk were able to achieve the level of physical activity necessary to result in favorable changes in cardio-metabolic profile and IGF-1 level. The subjective perception of their physical performance has also changed positively.
Study limitation {#Sec20}
----------------
Participating in an exercise intervention cannot be blinded which means a general limitation in these types of investigations. Moreover our study group was relatively small, so further measurements with a larger population are needed to substantiate our findings.
Conclusion {#Sec21}
==========
The present study demonstrated a significant improvement in several cardio-metabolic parameters such as functional capacity, physical functioning, total as well as LDL cholesterol, TG, HgbA1c and IGF-1 levels of elderly female patients with moderate to high CV risk after 12 weeks of home- and center-based training program.
Achieving significant changes in IGF-1 and lipid levels by a physical training program seems to be more difficult than in the case of other cardio-metabolic parameters. According to our findings and data in the literature in order to improve IGF-1 level and lipid parameters in elderly women physical training programs should either contain resistance training elements or be intensive enough or effectively increase the daily physical activity level.
CV
: Cardiovascular
CVD
: Cardiovascular disease
ECG
: Electrocardiography
EF
: Ejection fraction
HDL
: High density lipoprotein
IGF-1
: Insulin-like growth factor 1
LDL
: Low density lipoprotein
MET
: Metabolic equivalent
PA
: Physical activity
SD
: standard deviation
SF-36
: 36-Item Short Form Survey
TC
: Total cholesterol
Vo~2~max
: Peak maximal oxygen consumption
**Publisher's Note**
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank all participants for their contribution to this study. The authors wish to thank Marta Wilhelm and Alexandra Nagy for their kind help in psychological analysis.
DP: patients' examination, supervising the exercise stress tests, literature research, study design, data curation, and a major contributor in writing the manuscript. BS: statistical analysis regarding laboratory, biochemical (IGF-1) and exercise training data. DK: patients' examination, help in statistical analysis. PP: data analysis regarding treadmill test and home-based walking program. KK: literature research, data analysis regarding IGF-1 measurements. KT: supervision and conceptualization of the manuscript. ESZ: patients recruiting, echocardiographic examinations, evaluating the exercise stress tests, literature research, study design, methodology, manuscript writing, supervision of the manuscript. All authors read and approved the final manuscript.
Author's information {#FPar1}
====================
Not applicable.
The work was supported by TÁMOP-4.2.2 D-15/1/KONV-2015-0009 project of the Széchenyi 2020 program.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
The investigation was approved by the Regional Ethics Committee of the University of Pécs (No. 5829) and was conducted in accordance with the ethical principles stated in the Declaration of Helsinki. A written informed consent was obtained from all subjects.
All participants approved to publish their data anonymously.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
|
{
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[Ultrasonographic guidance of percutaneous biopsies and punctures].
Real time ultrasonography is routinely used for guidance of percutaneous punctures towards small targets, with three goals: 1. Aspiration biopsies for analysis of an abnormality detected with ultrasonography. 2. Injection of contrast media inside normal structures (urinary, biliary or pancreatic tract) or abnormal collection (cysts, pseudocysts). 3. Treatment by percutaneous sclerosis, aspiration, decompression, drainage.
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{
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.bd-testimonials
background-color: $background
.bd-testimonial
align-items: flex-start
display: flex
justify-content: center
.bd-testimonial-tweet
background-color: $scheme-main
.bd-more-loves
align-items: center
display: flex
justify-content: center
margin-top: 1.5rem
text-align: center
.button
height: auto
padding: 0.75em 1.5em
span
transform-origin: center center
transition: transform $speed $easing
&:hover
span
transform: scale(1.04)
+mobile
.bd-testimonials
padding: 1.5rem
.bd-testimonial
margin-bottom: 1.5rem
+tablet
.bd-testimonials
padding: 3rem
.bd-testimonial + .bd-testimonial
margin-top: 1.5rem
+desktop
.bd-testimonials
min-height: 595px
+widescreen
.bd-testimonials
min-height: 653px
+fullhd
.bd-testimonials
min-height: 632px
.bd-rainbow
animation: rainbow 8s ease infinite
background-image: linear-gradient(124deg, $orange, $red, $purple, $blue)
background-size: 800% 800%
.hero.bd-is-love
.title,
.subtitle
color: $scheme-main
@keyframes rainbow
0%
background-position: 1% 80%
50%
background-position: 99% 20%
100%
background-position: 1% 80%
.bd-hug
align-items: flex-start
display: flex
justify-content: center
+mobile
.bd-hug
margin: 1.5rem
.bd-embrace
text-align: center
&:not(:first-child)
margin-top: 1.5rem
&:not(:last-child)
margin-bottom: 1.5rem
.bd-embrace-button
margin-top: 0.75rem
+tablet
.bd-embrace
align-items: center
display: flex
justify-content: center
&:not(:first-child)
margin-top: 3rem
&:not(:last-child)
margin-bottom: 3rem
.bd-embrace-button
margin-left: 1.5rem
.bd-hugs
display: flex
flex-wrap: wrap
padding-bottom: 3rem
.bd-hug
margin-top: 1.5rem
width: calc(33.3333% - 1rem)
&:nth-child(1),
&:nth-child(2),
&:nth-child(3)
margin-top: 0
&:nth-child(3n-1),
&:nth-child(3n)
margin-left: 1.5rem
.bd-shoutout
background-color: $background
padding: 2rem
text-align: center
&:not(:last-child)
margin-bottom: 3rem
.bd-shoutout-text
&.title
opacity: 0.8
&.subtitle
opacity: 0.5
.bd-shoutout-button
margin-top: -0.75rem
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"pile_set_name": "Github"
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Mandirow, Qasr-e Qand
Mandirow (, also Romanized as Mandīrow; also known as Mānderīyū and Mānderow) is a village in Talang Rural District, Talang District, Qasr-e Qand County, Sistan and Baluchestan Province, Iran. At the 2006 census, its population was 490, in 92 families.
References
Category:Populated places in Qasr-e Qand County
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{
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新型コロナウイルスの感染が拡大する中、厚生労働省が、軽症や症状がみられない人に宿泊施設などで療養してもらうためのガイドラインを示したことに対し、埼玉県内のホテルなどでつくる組合は「到底受け入れがたい」としたうえで、やむをえず宿泊施設に協力を求める場合は、感染防止対策や補償などの条件を話し合って決めることなどを求める要望書を埼玉県に提出しました。
新型コロナウイルスの感染拡大に伴い厚生労働省は、軽症や症状がみられない人については、自宅や宿泊施設で療養してもらうためのガイドラインを示し、自治体に対し準備を進めるよう求めています。
これに対し、埼玉県内のおよそ300のホテルや旅館が加盟する「埼玉県ホテル旅館生活衛生同業組合」は６日、要望書を埼玉県に提出しました。
要望書では「安易なホテル旅館の利用は、感染のおそれがあり到底受け入れがたい」としたうえで、やむをえず宿泊施設に協力を求める場合は、従業員の感染防止対策や経済的な補償などについて、具体的な条件を話し合って決めることや、協力する施設に医療従事者を駐在させることなどを求めています。
組合は「受け入れたあとに、風評被害で廃業する可能性もある。これ以上の損失は避けたいので、双方が納得したうえで進めてほしい」と話しています。
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Story highlights Larry Nassar was team doctor for the Michigan State University gymnastics and women's crew teams
Nassar served as the USA Gymnastics physician through four Olympics
(CNN) The Michigan attorney general has received more than 50 additional complaints since a former USA Gymnastics and Michigan State University doctor was arrested Monday and accused of sexually assaulting female minors throughout his career.
Former USA Gymnastics physician Dr. Larry Nassar was arrested and charged with three counts of criminal sexual assault of a person under 13 years old, according to court documents. A conviction could result in a life sentence.
Officials did not detail the nature of the new complaints, including the number of victims, in a joint news conference held by Michigan State Police Chief Jim Dunlap and the Attorney General's Office on Tuesday. An investigative team will be dedicated to vetting the new complaints against Nassar, Dunlap said.
Nassar, 53, was the team physician for the Michigan State University gymnastics and women's crew teams as well as an associate professor in the College of Osteopathic Medicine. Nassar, who is married with three school-aged children, served as the USA Gymnastics physician through four Olympics.
Court documents say the sexual assault Nassar is charged with occurred between 1998 and 2005, with the first incident on July 1, 1998. The victim in that case was not a patient nor a gymnast who worked with Nassar, according to Attorney General Bill Schuette.
Read More
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Wenceslao Fernández Flórez
Wenceslao Fernández Flórez (1885 in A Coruña, Galicia – 1964 in Madrid) was a popular Spanish journalist and novelist of the early 20th century. Throughout his career, he retained an intense fondness for the land of his birth.
Early life and career
His father died when he was fifteen years old, forcing Wenceslao to abandon his education and dedicate himself to journalism. His first job was with A Coruña's La Mañana, and he went on to write for El Heraldo de Galicia, Diario de A Coruña and Tierra Gallega. At the age of eighteen he was given a senior position at Diario Ferrolano. He later returned to A Coruña to work at El Noroeste.
He kept close friendship with Galician nationalism leaders and other intellectuals . Among his friends we find: Manuel Maria Puga and Parga -Picadillo-, Carré brothers, Tettamanci, Manuel Casas, Angel Castillo and others. All of them were older than him, but who really makes a huge impression in his way of thinking was Castelao, which was one of the most frequently illustrators for his works.
Work in Madrid and novels
In 1914 Flórez moved to Madrid, where he worked at El Imparcial and Diario ABC, where he started the parliamentary column Acotaciones de un oyente. He had begun writing novels - La tristeza de la paz (1910), La procesión de los días (1915) and Luz de luna (1915), and Volvoreta (1917).
In translation
The Seven Pillars; translated by Sir Peter Chalmers Mitchell, London, Macmillan and co.,ltd., (1934), 288 p.
Seduced. In:
Works
The sadness of Peace (1910)
The procession of Days (1914)
Moonlighting (1915)
Dimensioning of a listener (Parliamentary Chronicles, 1916)
Volvoreta (1917), adapted into a film by José Antonio Nieves Conde in 1976
The Devil's Eye (1918)
Entered a Thief (1922)
Vulgar tragedies of life (1922), an anthology of short stories
Bluebeard's Secret (1923)
Visions of neurasthenia (1924)
Women's Footsteps (1924)
The seven columns (1926)
Immoral Story (1927)
The man who wanted to kill (1929), adapted for the screen by Rafael Gil in 1942 with Antonio Casal ( The man who wanted to kill and again by Rafael Gil in 1970 with Tony Leblanc ( The* man who wanted to kill )
Artificial Ghosts (1930), an anthology of short stories
Those who did not go to war (1930)
The evil Carabel (1931), adapted into a film by Edgar Neville in 1935, by Fernando Fernan Gomez in 1956 and Rafael Baledón in 1962
The man who bought a car (1932)
Knight Adventures Rogelio Amaral (1933)
An island in the Red Sea (1938)
The novel number 13 (1941)
The Living Forest (1943), adapted into a film by Joseph Neches in 1945, by José Luis Cuerda in 1987 written by Rafael Azcona and Angel de la Cruz and Manolo Gomez in 2001
The bull, the bullfighter and the Cat (1946)
Pelegrin system (1949)
Fireworks (1954)
Goalkeeper in goal (1957)
Category:1885 births
Category:1964 deaths
Category:People from A Coruña
Category:Spanish journalists
Category:Spanish male novelists
Category:Members of the Royal Spanish Academy
Category:Galician writers
Category:20th-century Spanish male writers
Category:20th-century Spanish novelists
Category:20th-century journalists
Category:Male journalists
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What you have to know to become a top affiliate and earn money online. Get Paid For E-Mails, Surveys, Games, and More. Join Inboxdollars. EARN 10% RESIDUAL INCOME For Life By Referring New Members If you want to be a top affiliate there are important things that you should know before begin promoting an affiliate program. If you follow these recommendations you will save time and money on the steps to enrichment. 1 The first and very important thing that you have to do is to cre...
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The University of Hawaii football team’s training camp rolled on Tuesday morning at Joseph Platt Cooke Field in Manoa where the ‘Bows are just 17 days away from their season opener against California in Australia.
Among the things that head coach Nick Rolovich is working on with the team outside of schematics and technique is experiencing game-style stress situations.
It’s very difficult to recreate the kind of anxiety that comes with playing under the lights in a college football game, but among the drills that are being used to test the team’s nerves was a punt return challenge this past weekend.
Three players were selected to field punts on Clarence T.C. Ching Field Saturday with a quite simple scenario presented. Catch two of the three punts and the team would be relieved of extra conditioning.
The first player was freshman defensive lineman Alesana Sunia, who failed to catch the punt. With the pressure on, sophomore linebacker Malachi Mageo kept the team alive with a clean catch. Which then left it all in the hands of junior offensive lineman Dejon Allen, who did not disappoint.
Number-50 took a booming punt from Rigoberto Sanchez and not only cleanly caught it against his chest, but returned it to the end zone with his entire team along side him.
“It’s pretty stressful, because everyone is hoping I catch it and I’m thinking about the ball, and it’s in the air and I’m thinking about if I’m going to catch it or not,” said Allen. “It’s pretty stressful, but I got the job done. Yeah, I’m definitely going to do that if he wants me too.”
Rolovich posted video of the celebration on Instagram, and many noticed one player’s reaction in particular. Senior defensive back Dejaun Butler did a handspring back flip as the rest of the team danced in the end zone, leading KHON2 sports director Rob DeMello to ask Butler where he learned how to do that.
“Honestly, I really learned from some guys at my junior college. We used to go out there and guys would be doing some crazy flips and I would be like, I could do that. I know I got the athletic ability to do some flips,” said Butler.
When asked if UH fans could see that celebration in a game, the defensive back responded, “I mean you might see that. You might have to see that.”
Week 1 was a win. Let’s see if they continue to grind. A video posted by Nick Rolovich (@rolovich) on Aug 7, 2016 at 10:44pm PDT
However, not everyone was impressed with Butler.
“Yeah, not impressed at all,” joked sophomore slot back Dylan Collie. “I think his landing was a little off. It was a little out of control. That initial spring off the top could use some serious work. I don’t think he spent enough time watching Rio. I spent the weekend watching Rio so just stay tuned for the next little moment, and I think you’ll see a much better roundoff back tuck.”
Wow, judges are brutal.
Rainbow Warriors continue training camp Wednesday with the last practice open to the public set for Friday morning.
The ‘Bows will hold a controlled scrimmage on Saturday at Aloha Stadium. Kickoff against California in Australia is set for Aug. 26.
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~ Keith & I were in constant contact - he was helpful in attempting to transfer tickets to me via TM. Unable to do so with Phish tix so he had them printed and shipped right away. Thanks Keith!12/10/13
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{
"pile_set_name": "Pile-CC"
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100 4 16
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{
"pile_set_name": "Github"
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Utah State (2-4) vs. Fresno State (1-6) Game Preview
Broadcast
It’s the battle of embattled head coaches, with Tim DeRuyter’s era on life support at Fresno State after a miserable start, and Matt Wells struggling at Utah State after losing three straight and four of the last five.
The Aggies just can’t get their offense going, even with a terrific quarterback in Kent Myers and a good enough running game to keep things moving. It’s a problem that top back Devante Mays is struggling with a knee injury – the offense can’t afford to lose weapons – but for the season to turn around, the passing game has to start making something happen down the field.
Fresno State can’t get anything working at all.
The offensive line isn’t generating any sort of a push for a ground game that hasn’t shown up, and while Chason Virgil is doing what he can, he’s not enough.
The Bulldogs aren’t creating their own breaks, turning it over 12 times on the year and with just one takeaway in the last three games.
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Producers of the Chicago engagement of Spamilton have announced that the parody, originally scheduled to play through May 28, will now have an open-ended run. The production kicked off a 10-week run at Royal George Theatre’s Cabaret/Studio Theatre March 3 and officially opened March 12.
“We feel very fortunate to have found such success here in Chicago with the talented local company we’ve brought together at the Royal George. This Chicago cast is unbelievably great!” commented Spamilton creator Gerard Alessandrini in a statement. “What a way to be welcomed to the Windy City! We can’t wait to see what the summer holds for the success of Spamilton here in Chicago.”
The Chicago cast is made up of Donterrio Johnson, Adam LaSalle, Michelle Lauto, Eric Andrew Lewis, Yando Lopez, and David Robbins. Chuckie Benson and Ariel Richardson are the understudies for the production.
Scroll through photos from opening night, with special guests Wayne Brady and the cast of Hamilton in Chicago, below:
Penned by Forbidden Broadway creator Alessandrini, Spamilton is a musical parody of the smash hit Hamilton. The Chicago staging is produced by John Freedson, David Zippel, Alessandrini, Margaret Cotter and Liberty Theatricals, in association with JAM Theatricals.
The show was originally scheduled to run for only 18 performances in New York, but has been extended numerous times at the Triad nightclub in Manhattan where it continues to play.
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Q:
Switch primary key constraint to a new column
I want to switch the primary key away from my existing identity column
to a different column.
This is my table:
CREATE TABLE dbo.ParkingLot
(
ID int IDENTITY(1,1) PRIMARY KEY,
Address ???,
Status ???,
newID ???
);
I want to remove the primary key on the ID column and instead have newID be the primary key (this is a new column but it is already populated with values).
A:
Drop primary Key constraint and Re-Add a new one
You have to drop the primary key constraint and add a new one
Drop primary key Constraint
-- Return the name of primary key.
SELECT name
FROM sys.key_constraints
WHERE type = 'PK' AND OBJECT_NAME(parent_object_id) =
N'Tablename';
GO
-- Delete the primary key constraint.
ALTER TABLE Production.Tablename
DROP CONSTRAINT PK_Tablename;
GO
Add new primary key Constraint
ALTER TABLE Tablename ADD CONSTRAINT pk_NewPrimary PRIMARY KEY (Newid)
References
Delete Primary Keys
Change primary key column in SQL Server
|
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Serie A Preview: Main Rivals Continue To Play Catch Up To Juventus
Elvis Iwuamadi
4 months ago
Turin club remain favourites for domestic crown, but title contenders are closing the gap
Italy’s Serie A campaign gets underway on 18 August with the same cat and mouse tale continuing to dominate the competitive theme at the top end of the table. Defending champions Juventus have had it all their own way for over half a decade now, but the previous campaign gave indications that the tide may well be about to turn.
Last season was not the procession to the title that many envisaged, and with other clubs being bold in the transfer market over the summer window, we may well see some stuff competition over the coming months. The Juventus party could be over, however briefly that may turn out to be.
Before you go any further, head on over to the Oddsshark website, find your favourite betting agency and get your own account up and running using your credit card. As a brand new customer and with the Serie A season preparing for the big kick off, there should be several promotions and offers for you to take advantage of ahead of the action starting.
Where should I be investing my money?
Despite that caveat, it is still Juventus who come into the new season as the overwhelming favourites to retain their crown. You can back the Old Lady at a price of just 1.40 to retain their domestic dominance, for another season at least.
Boss Massimilliano Allegri has developed a fine side, capable of going far in the UEFA champions League as well as performing strongly on the domestic front. The team remain undefeated in pre-season, and comfortably beat German giants Bayern Munich 2-0 last week before playing out a 1-1 draw with Benfica.
In addition, Allegri is looking to add top quality players to an already star studded squad. The club are being linked with a move for former midfielder Paul Pogba, but even more excitingly, they have already announced the arrival of World Player of the Year Cristiano Ronaldo, from Real Madrid.
And the 33 year old goes right to the top of the favourites list to finish this Serie A campaign as leading goal scorer. You can back the Portuguese ace to do so at just 1.61, and given his record over the last decade or so it would be a brave soul who would bet against him.
Indeed, with their new arrival, such is the expected dominance of Juventus in this upcoming season, you can bet on a league table that does not include them. A trio of clubs – Napoli, Roma and Inter Milan – are all priced identically at 3.50 to finish up as “best of the rest”, with AC Milan at 6.50 to achieve that feat, according to Oddsshark.
And Napoli might feel more than most that they have a chance of toppling the champions. It was the Neapolitan outfit that finished as runners up last season, just four points behind Juventus after pushing them for nine tough months.
Veteran boss Carlo Ancelotti has replaced the departed Maurizio Sarri, who left for Chelsea, and the former Real Madrid and Bayern Munich coach certainly has the wherewithal to make Napoli title contenders once again. Ancelotti starts his reign at his new club away to Lazio, and the visitors are the favourites, at 2.37, to take all three points.
Another club with title aspirations will be AS Roma, who finished a distant third last season but have one major weapon in their armoury: the firepower of Edin Dzeko. The Bosnian forward has been one of the most consistent goal scorers in Italy over the past two season and is renowned for hitting the ground running – he needs little time to find his feet at the start of a season.
Dzeko is at 17.00 to finish the season as top scorer, odds that seem exceptionally high given his record of 45 goals in his last 73 league games. Roma have lost Brazilian goalkeeper Alisson, but they have a forward capable of firing them to the title.
Inter Milan find themselves in a similar situation to Roma. Argentine striker Mauro Icardi is the Nerazzurri’s big hope for this season, and he is at just 7.00 to finish the season as the league’s top scorer – only Cristiano Ronaldo is at a shorter price than Icardi.
Like Napoli and Roma, Inter are at 8.00 to win their first league crown of the decade, and with esteemed coach Luciano Spalletti in the dugout, not to mention the exciting arrival of Lautaro Martinez from Argentine club Racing, they may well pull a few surprises this season. Inter start the campaign away to Sassuolo and are at just 1.72 to pick up all three points.
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SDB - “Petpets -- oh I collect them,” one scornful person (who wishes not to be
named) sneered. “They’re a bit silly. I keep them in my Safety Deposit Box, and
play with them from time to time.”
Agree? If you do, I had better change your mind. I am Livvy, a Whoot from
Mystery Island, and I have written this article to campaign for Petpet Rights.
No article has ever been written by a Petpet before, thought lots have
been written about them. No, I think it’s about time our voices were
heard.
For a long time I have been working for correct treatment of our kind. I am
a Petpets Spokesperson, and have been worried about the way we are thought of
for a long time. Some people think of us as objects, some think of us as shrunken
pets with pea-sized brains. This is wrong. Not only are our brains plum sized,
we are also intelligent and can think for ourselves. Not convinced? Read on.
First of all, I had better explain what a Petpet is, and its current role
in society. There are many different species, just like Pets -- there are all
sorts, from flying to burrowing, water based to fiery types, shy, quiet ones
to outgoing, loud ones. Each species has a stereotype- for instance, a Hornsby:
“They are sad and prefer to be alone.” Some are like this, but I know
a fair few who have permanent grins attached to their faces, and are forever
holding parties. Every Petpet is different.
Currently, they can be bought in a shop and sold to people for a certain amount
of Neopoints. Alternatively, the free ones that live in Neopia can be discovered
by owners, and held captive to play nanny to their spoilt pets. I am lucky enough
to live with an open-minded family that accept I will not be treated like this.
Dayon, the silver Zafara I live with, has always encouraged me with my work
for stopping cruelty, and the majority of pets treat their small friends with
respect and thoughtfulness.
There are a few pets that don’t, however. I have heard of Petpets being left
alone in a Safety Deposit Box for months on end, because the pet is “bored”
and moves onto the next one. It’s not on people! Whenever I encounter cruelty,
I have an argument with the owner. They are always petrified of me of course
(I’m six inches tall, and have talons I’m not afraid to use!) but somehow they
just don’t want to listen.
One reason for the barrier is that a lot of species cannot speak English.
Some can only speak Petpetish, the unique language that nobody understands except
the species themselves. This shouldn’t stop communication though -- they can
be taught English, though it might take some time. It has even been known that
pets can learn Petpetish! This is very rare though, and consists of lots of
different squeaks and burps that are hard for pets to distinguish from one another.
I have set up a council of Petpets fighting for our rights. F.E.P.E (Fighting
for the Equality of Petpets Everywhere) members feel very strongly about our
cause. Here they explain their feelings and experiences, all Petpetish having
been translated for easier reading.
“I hate it when pets treat us badly,” complains Snowales, a young Catamara.
“I cannot speak English, I can only speak Petpetish. But just because I don’t
speak to them, doesn’t mean I don’t have feelings! My pet understands this,
but a Petpet I know was treated intolerably.”
“Petpet cruelty is not a punishable offence,” Zero the Anubis growls. “I used
to live with a horrible pet that dressed me up like a doll, and discarded me
for a newer model when she tired of me. I was lucky enough to escape that, but
for many others the hell still lives on.”
“I-am-very-unhappy, very unhappppy,” sings Stinky the Spardel, a talented
entertainer. “I-am-marvellous, and I-neeevver get work because of my breeeeeed.
People assume I’m stuuuuuuupid-but-I’m not. I can do scales and eeeeeeverything….”
He adds a trill for effect.
“For years I lived in pain,” Buterbur, a remarkably pretty young Angelpuss
whispers. Tears from in her yellow eyes, as she relates her tale. “I had to
live in dust bins. People used to kick me and bear bruises. Thanks to F.E.P.E,
I have been relocated and live with a lovely family now. I just hope no other
Petpet has to go through what I did, because it’s agonising.”
So you have heard their stories- first a Catamara that is frustrated because
of her lack of English, an Anubis that was dressed up like a doll, a talented
but jobless singer Spardel that is the subject of prejudice and a pretty Angelpuss
that for a long time had no hope of a good life. F.E.P.E (that’s Fighting for
the Equality of Petpets Everywhere, in case you had forgotten) has been tirelessly
working for a while now. Everyone mentioned above is part of the council. If
you are a Petpet reading this, and want to take part in our campaign, get your
pet’s owner to drop Arden a Neomail- she’s Dayon’s owner and she helped me with
this article.
So what can I do? That’s what you’re thinking. Well, basically, the purpose
of this article is to stop cruelty, so hopefully after this you will think twice
before selling on your Petpet, or trading it in before getting a new model.
F.E.P.E (That’s the Fighting for the… oh forget it!) wants to hear of any harm
doing to them. Keep Petpets happy, look after them, and talk to them if you
can, respect them and keep them company.
We want to hear your Petpet stories. Have you been treated like dirt
because you refused to wear a pink tutu? Did your owner abandon you? Are you
a victim of Petpet crime? Neomail all to arden_starr, and she’ll pass on the
messages. Adieu, owners, pets and Petpets alike. We shall meet again. If you
don’t mind, I’m going to put my pen down, my talons are killing me. Phew --
that’s the last time I write an article for The Neopian Times.
Owners Note: A big thank you to all the Petpets involved, their pets and
their owners. Mrmirine, istillcantthinkanyth and squinkygyrl -- thank you very
much! PLEASE NOTE: F.E.P.E is a figment of Livvy’s imagination. Please ignore
her.
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
OpenCV for Android: Error Program "sh" not found in PATH
I tried to build OpenCV4Android SDK in Eclipse, using the official tutorial here. I followed all those instructions, and while trying to build those OpenCV library projects from OpenCV4Android SDK, I got this error:
Invoking autoreconf in build directory: C:/Android-64/Opencv4Android/sdk/java/
Configuration failed with error
(sh -c "autoreconf -i"
Cannot run program "sh": Launching failed
Error: Program "sh" not found in PATH
PATH=[C:\Windows\system32;C:\Windows;C:\Windows\System32\Wbem;C:\Windows\System32\WindowsPowerShell\v1.0\;c:\Program Files (x86)\Microsoft SQL Server\100\Tools\Binn\;c:\Program Files\Microsoft SQL Server\100\Tools\Binn\;c:\Program Files\Microsoft SQL Server\100\DTS\Binn\;C:\Program Files\TortoiseSVN\bin;C:\Program Files\Microsoft\Web Platform Installer\;C:\Program Files (x86)\Microsoft ASP.NET\ASP.NET Web Pages\v1.0\;C:\Program Files (x86)\Windows Kits\8.0\Windows Performance Toolkit\;C:\Program Files\Microsoft SQL Server\110\Tools\Binn\;C:\Program Files (x86)\MATLAB\R2013a\bin;C:\Program Files (x86)\IDM Computer Solutions\UltraEdit\]
)
This is the first time I am trying to build a C++ code in Eclipse (previously I used VS), so I doubt this might be a problem of compiling C++ code in Eclipse. After some internet search, I've turned on the PE Windows Parser in Properties->C/C++Build->Settings->Binary Parsers in Eclipse, but the error still remains. How can I solve this? Thanks in advance.
A:
Try installing CYGWIN, and provide the path to the bin directory of cygwin in PATH inside Environment Variable of Windows (before the declaration of Windows Toolkit). Maybe the Windows Toolkit is not working for you.
|
{
"pile_set_name": "StackExchange"
}
|
Q:
Is there a symbol for "taking a derivative of something"?
When presented with an equation, say, $y=5x^3+7x^2+4x+9$, you can write on the second line, $\frac{dy}{dx}=15x^2+14x+4$. Similarly, $f(x)=5x^3+7x^2+4x+9$ and $f'(x)=15x^2+14x+4$. But is there a way to write "the derivative of $5x^3+7x^2+4x+9$ is $15x^2+14x+4$" in just one line?
What should l write, $\frac{dy}{d5x^3+7x^2+4x+9}=\cdots$? That fraction just gives me a headache trying to understand it.
What about $f'(5x^3+7x^2+4x+9)=\cdots$? For all the reader knows, $f(x)$ could be anything, and the writer wanted them to plug in $5x^3+7x^2+4x+9$ into the original $f(x)$ and then take the derivative.
So has anyone come up with a better way to write this that does not involve defining anything and then using the newly defined function/operator?
A:
You would denote the derivative of $5x^3+7x^2+4x+9$ as
$$\frac{d}{dx}(5x^3+7x^2+4x+9)$$
That is the only notation I've ever seen unless the expression is expressed as a function.
A:
A common choice of notation is $D_{x}(5x^3 + 7x^2 + 4x + 9)$. The subscript indicates the variable with respect to which one is differentiating.
A:
The most common choice is $\frac{d}{dx}$.
If the variable is clear from context, you can use a plain $D$.
If you have several variables and you only want to differentiate with respect to one, it's best to write it as a partial derivative with $\frac{\partial}{\partial x}$ or $\partial_x$.
I have also seen notations like $(5x^3+7x^2+4x+9)'$ or $(5x^3+7x^2+4x+9)_x$, but I would strongly recommend using $\frac{d}{dx}$ instead.
There are several kinds of derivatives, and it's good to use notation that is compatible with them (uses similar syntax).
It is easy to replace $\frac{d}{dx}$ with a $\frac{\partial}{\partial x}$, a $\nabla$, a $\Delta$ or a $d$.
|
{
"pile_set_name": "StackExchange"
}
|
###### Significance Statement
Efficient goal-directed behavior requires dynamical control allocation and an estimation of how much control is invested in a particular situation. The neurobiological mechanisms that are associated with this dynamical adjustment are widely elusive. To the best of our knowledge, this study is the first to investigate the relevance of the dopaminergic system with a focus on dopamine D1 and D2 receptors. Our findings suggest that only the DRD1 receptor system seems important for dynamical adjustments of how much cognitive control is invested in a particular situation. Theoretical implications of this finding are discussed.
Introduction {#s1}
============
The ability to flexibly exert cognitive control in order to adapt to dynamic environments is key to successful goal-directed behavior ([@CIT0006]; [@CIT0019]; [@CIT0003]; [@CIT0026]). It is not, however, the best strategy to always invest the maximal possible amount of cognitive control irrespective of the situation at hand ([@CIT0041]; [@CIT0022]; [@CIT0038]). Complex tasks require cognitive control, with increases in complexity usually translating to increases in control requirements ([@CIT0033]; [@CIT0034]; [@CIT0006]; [@CIT0036]; [@CIT0004]). Simple tasks with low complexity, however, often seem to benefit from decreases in cognitive control. In such tasks, automatization is more expedient than cognitive control in that it makes information processing as well as response generation faster and less error-prone ([@CIT0003]). Upregulating cognitive control can hence have adverse effects on performance in situations with low task complexity or where automatized processes would be optimal ([@CIT0037]; [@CIT0048]; [@CIT0003]; [@CIT0046]; [@CIT0056]). Therefore, goal-directed behavior is best driven by a dynamical allocation of control ([@CIT0003]; [@CIT0022]), which matches the complexity or demands of a given situation, rather than always exerting high levels of control ([@CIT0022]). Another factor that further adds to this need for "metacontrol" ([@CIT0018]; [@CIT0022]; [@CIT0001]) is that cognitive control processes require effort and are capacity-limited ([@CIT0032]; [@CIT0015]; [@CIT0023]; [@CIT0049]; [@CIT0028]; [@CIT0030]; [@CIT0044]; [@CIT0014]; [@CIT0027]; [@CIT0055]; [@CIT0054]). The central question here is how metacontrol is achieved, that is, how cognitive control is adapted or regulated in situations with different control requirements ([@CIT0010]; [@CIT0018]).
The neurobiological mechanisms that drive and modulate metacontrol, especially the adaptation of response selection to varying cognitive control demands, have, however, remained largely elusive. Yet, it is already known that the dopaminergic system may play a key role in this process ([@CIT0018]). In this context, the dual-state theory ([@CIT0042]; [@CIT0012]; [@CIT0013]) describes the interplay of 2 relevant, functionally opposing "states" that are brought about by antagonistic effects of dopamine D1 and D2 receptors: Dopamine D1 receptor activation fosters a so-called "D1 state" that is characterized by stable mental representations. This rigidity makes it hard to switch between different (neuronal) activations, but at the same time allows to shield task-related activation against distractions and competing input ([@CIT0042]; [@CIT0012]). The D1 state should therefore be optimal in situations with high demands on cognitive control that require stable processing. In contrast to this, dopamine D2 receptor activation fosters a so-called "D2 state" that allows for easy and flexible shifting between different neuronal representations. However, it comes at the cost of lower representation stability, which impairs the ability to effectively shield task-related activation against distractions and competing input, thus making it prone to interference. When interpreting this state as a reduction in cognitive control ([@CIT0025]; [@CIT0021]; [@CIT0005]; [@CIT0040]; [@CIT0051]), it should make the D2 state optimal in situations that do not impose high demands on cognitive control so that information processing can be fairly automatic. To examine how D1 and D2 receptor processes modulate metacontrol, we genotyped 2 single-nucleotide polymorphisms (SNPs) in the *DRD1* (rs4532) and *DRD2* (rs6277) receptor genes.
Rs4532 is located in the 5′ untranslated region of *DRD1*, and the minor G allele has been associated with higher D1 receptor efficiency ([@CIT0009]; [@CIT0035]), which has previously been linked to increased cognitive control ([@CIT0024]; [@CIT0045]; [@CIT0002]). Therefore, *DRD1* G allele carriers should be more inclined to the dopamine D1 state than A allele carriers ([@CIT0045]).
Rs6277 is a synonymous SNP (Pro319Pro) where homozygous T allele carriers have been shown to display greater striatal dopamine D2 receptor density ([@CIT0020]; [@CIT0016]), which has previously been associated with decreased cognitive control ([@CIT0024]; [@CIT0045]; [@CIT0002]). It can be assumed that homozygous T allele carriers are more inclined towards a dopamine D2 state ([@CIT0011], [@CIT0012]) than CT and CC carriers ([@CIT0045]).
In summary, our study investigated the effects of *DRD1* and *DRD2* receptor genotypes in 195 healthy individuals, who were assessed with an experiment consisting of 2 complementary tasks ([@CIT0003]; [@CIT0056], [@CIT0057]). Subjects responded to the same set of stimuli in both tasks, but the demand for cognitive control was manipulated by asking them to either follow a less complex rule (easy task/low cognitive control requirement) or a more complex rule (hard task/high cognitive control requirement). We hypothesized that DRD1 (rs4532) G allele carriers should be better able than noncarriers to exert cognitive control in situations with high cognitive control demand (i.e., when task rules are complex). This should be reflected by better behavioral performance (i.e., higher accuracy/faster response times \[RTs\]) in the task version with a complex rule but not necessarily in case of low control requirements (i.e., the easy task). We further hypothesized that DRD2 (rs6277) T allele carriers should have lower control than noncarriers. This might impair performance in high control situations (i.e., in the high demand task) but could also yield a benefit in the low demand task. However, we were less certain about our hypotheses on DRD2 effects, as we previously observed DRD2 effects on task set switching under high cognitive control demands ([@CIT0045]). Against this background, it could also be possible that there are no effects of DRD2 receptor genotypes in the easy task, since the task used for this study requires neither to flexibly switch between several task goal representations, nor high levels of cognitive control.
Materials and Methods {#s2}
=====================
Sample {#s3}
------
A total of 195 healthy young participants (137 females, 57 males) between 18 and 32 years of age (mean 23.9, SD 3.2) were included in this study. All participants were of Caucasian descent, reported no psychiatric or neurologic diseases, and stated to have normal or corrected-to-normal vision. Depression was ruled out using the Beck Depression Inventory scores (mean = 4.4, SD = 4.2). Each participant received a financial reimbursement of 25 €. All participants gave written informed consent and were treated in accordance with the Declaration of Helsinki. The study was approved by the local ethics committee of the TU Dresden, Germany.
Please note that while our work group has used the same SNPs to investigate other functionally unrelated questions in previous studies ([@CIT0045]; [@CIT0002]), none of the individuals included in the current sample took part in these previous studies.
Genotyping {#s4}
----------
Genomic DNA was extracted from whole blood samples. The *DRD1* rs4532 SNP and *DRD2* rs6277 SNP were genotyped using polymerase chain reaction-restriction fragment-length polymorphism. SNP rs4532 is located in the 5′ untranslated region of *DRD1* and rs6277 is a synonymous SNP (Pro319Pro) within the coding sequence of *DRD2*. Primers were designed with Primer Express 2.0 software (Applied Biosystems). Details of the methodology and primer sequences are available on request.
Task and Experimental Setup {#s5}
---------------------------
During the experiment, the participants sat in front of a 17-inch CRT computer monitor at a viewing distance of 57 cm. Participants were asked to respond with 2 keys (left and right Ctrl key) on a regular QWERTZ keyboard with their left and right index fingers, respectively. The software Presentation (version 14.9. of Neurobehavioral Systems, Inc.) was used for stimulus presentation and response recording.
A modified version of an experimental paradigm developed by [@CIT0003] was used in this study. The paradigm consists of 2 separate tasks, called "automatic" and "control" task. However, since they differ in the complexity of the task rules and thus in the level of cognitive control required, we decided to refer to them as "easy" and "hard" task, respectively.
Following the protocol by [@CIT0003] and to keep possible order effects constant across genotype groups, all participants first performed the hard and then the easy task version. As mentioned above, we defined metacontrol as the adaptive and demand-specific allocation of cognitive control as a function of task complexity ([@CIT0018]; [@CIT0022]; [@CIT0001]). This implies that metacontrol is an adaptive (i.e., flexible) process but also responsive to the demand on cognitive control. Using a fixed consecutive order design, we decided to focus on the demand on cognitive control rather than the adaptability processes to (1) replicate the findings by [@CIT0003] and (2) avoid confounding metacontrol with task switching processes. Thus, the fixed consecutive task order in our block-wise design measures the ability to up- and downregulate cognitive control depending on the demand on cognitive control capacities rather than the ability to flexibly switch between varying cognitive control demands.
Each trial began with the presentation of a single visual stimulus in the middle of a black screen for 2000 ms or until a response was given (see [Figure 1A](#F1){ref-type="fig"}). The stimuli varied in shape (square or diamond), color (green or red), and size (small: about 2.5 cm in diameter or large: about 5 cm in diameter). In both tasks, all 8 possible combinations of stimulus characteristics were presented equally often (see [Figure 1B](#F1){ref-type="fig"}). In the easy task, participants were instructed to react only to the shape of the stimuli. Whenever the target stimulus was a diamond, the left Ctrl key had to be pressed with the left index finger. Whenever the target stimulus was a square, the right Ctrl key had to be pressed with the right index finger. In the hard task, participants were asked to respond to a combination of target size and color (see [Figure 1B](#F1){ref-type="fig"}). The left Ctrl key had to be pressed when the target stimulus was large and red or when it was small and green. The right Ctrl key had to be pressed when the target stimulus was large and green or when it was small and red. If no response was given within 2000 ms, stimulus presentation was stopped and the trial was coded as "miss." A 500-millisecond feedback was given 700 milliseconds after the target stimulus offset to tell participants whether their response was correct ("+") or incorrect ("−"). After the feedback, there was another fixation cross for 500 milliseconds before the next trial was presented. Each task was divided into 5 equal blocks 96 trials each. Hence, each task (easy and hard) comprised a total of 480 trials. Behavioral measures (accuracy and mean response times of correct answers) were collected separately for the easy and hard task version.
{#F1}
Statistical Analyses {#s6}
--------------------
The behavioral data (RTs and accuracy) were analyzed using SPSS Statistics 24. We ran separate mixed-effects ANOVAs with the between-subject factor "genotype" (AA vs AG vs GG for DRD1 rs4532; CC vs CT vs TT for DRD2 rs6277) and the within-subject factor "task" (easy task vs hard task). Greenhouse-Geisser corrections were applied whenever necessary. In the results section, the reported mean values are followed by the SEM as a measure of variance.
Results {#s7}
=======
Genotype Groups {#s8}
---------------
Of the n = 195 participants, 86 were homozygous for the *DRD1* rs4532 A allele, 86 were A/G carriers, and 23 were homozygous for the G allele. Due to the rather low frequency of GG genotype carriers, the AG and GG genotypes were combined into 1 group for further analyses. The observed frequencies for A and G allele were 66.2%. and 33.8%, respectively. Six subjects could not be genotyped with respect to the *DRD2* rs6277 SNP. Of the remaining 189 participants, 49 were homozygous for the C allele, 98 were C/T carriers, and 42 were homozygous for the T allele. The observed frequencies for C and T allele were 51.9% and 48.1%, respectively. The distribution of genotypes did not significantly differ from the Hardy--Weinberg equilibrium (*P* = .596).
Task Performance Data {#s9}
---------------------
Behavioral performance is illustrated in [Figure 2](#F2){ref-type="fig"}.
{#F2}
DRD1 {#s10}
----
The analysis of the hit RTs showed a main effect of task (*F*(1,193) = 1647.96; *P* \< .001; ηp2 = 0.895), with longer RTs in the hard task (678 ms ± 8) compared with the easy task (463 ms ± 5). No other main or interaction effects were significant for hit RTs (all *F* \< 0.498, *P* \> .481).
The accuracy analysis revealed a main effect of task (*F*(1,193) = 295.49; *P* \< .001; ηp2 = 0.605), with higher accuracy in the easy task (97.0% ± 0.2) compared with the hard task (92.9% ± 0.3). There was also a main effect of genotype (*F*(1,193) = 8.54; *P* = .004; ηp2 = 0.042), with higher accuracy in the AG&GG group (95.6% ± 0.3) compared with the AA group (94.3% ± 0.4). Importantly, there was an interaction of task × genotype (*F*(1,193) = 14.05; *P* \< .001; ηp2 = 0.068). Post-hoc *t* tests showed that both genotype groups had a significant task effect (i.e., significantly higher accuracy in the easy task than in the hard task; all *t* \< 11.83, *P* \< .001). However, the task difference (easy minus hard) was significantly larger for the AA group (5.0% ± 0.4), than for the AG&GG group (3.2% ± 0.3) (*t*(145.96) = 3.60, *P* \< .001). Importantly, this effect was driven by a significant genotype difference that could be found in the hard task (*t*(193) = −3.54, *P* = .001; AA group: 91.7% ± 0.6 vs AG&GG group: 94.0% ± 0.4) but not in the easy task (*t*(193) = −1.23, *P* = .219; AA group: 96.8% ± 0.3 vs AG&GG group: 97.3% ± 0.3). To confirm that there was indeed no main effect of genotype group in the easy task, we conducted additional Bayesian analyses as suggested by [@CIT0052] using the template by [@CIT0031]. With this analysis, the probability of the null hypothesis being true, given the observed data, p(H~0~\|D), can be determined. Values \<0.5 indicate that the alternative hypothesis is more likely to be true than the null hypothesis. Values between 0.5 and 0.75 provide weak evidence, values between 0.75 and 0.95 give positive evidence, and values between 0.95 and 0.99 give strong evidence for the null hypothesis being true ([@CIT0039]). Regarding the main effect of genotype group in the easy task, a value of p(H~0~\|D) = 0.951 was obtained for the accuracy data. This provides strong evidence that the DRD1 genotype did not modulate performance in the easy task.
DRD2 {#s11}
----
The analysis of the hit RTs showed a main effect of task (*F*(1,190) = 1442.91; *P* \< .001; ηp2 = 0.884), with longer RTs in the hard task (676 ms ± 8) compared with the easy task (462 ms ± 5). No other main or interaction effects were significant for hit RTs (all *F* \< 0.960, *P* \> .385). The accuracy analysis revealed a main effect of task (*F*(1,190) = 247.14; *P* \< .001; ηp2 = 0.565), with higher accuracy in the easy task (97.2% ± 0.2) compared with the hard task (93.1% ± 0.4). No other main or interaction effects were significant for accuracy (all *F* \< 2.25, *P* \> .108). To confirm that there was indeed no main or interaction effect of genotype, we conducted additional Bayesian analysis. For the main effect of genotype, we obtained a value of p(H~0~\|D) = 0.987 for hit RTs and p(H~0~\|D) = 0.954 for accuracy. For the interaction of task × genotype, we obtained a value of p(H~0~\|D) = 0.993 for hit RTs and p(H~0~\|D) = 0.983 for accuracy. This constitutes strong evidence for the null hypothesis.
Discussion {#s12}
==========
In the current study, we examined the relevance of the dopamine D1 and D2 receptor system for cognitive control processes using a molecular genetic approach. More specifically, we examined whether D1 and D2 receptor-related processes play different or opposing roles for metacontrol, which is defined as the adaptive and demand-specific allocation of cognitive control as a function of task complexity ([@CIT0018]; [@CIT0022]; [@CIT0001]). This kind of metacontrol is an important competence, as a cognitive control system that always exerts the same level of cognitive control (i.e., irrespective of how much control is optimal or needed) is highly dysfunctional and has been proven detrimental to performance in situations with low control requirements ([@CIT0022]; [@CIT0047]). In short, the obtained results show that *DRD1* genotypes modulated performance in the harder version of the applied task, which requires a higher level of cognitive control. *DRD1* genotypes did not, however, modulate performance in the easier version of the applied task, which requires a lower level of cognitive control. In contrast to this, *DRD2* genotypes modulated performance in neither the easy task nor the harder task. This lack of effects was supported by Bayesian analyses. This pattern of results has important implications for our understanding of the effect of dopamine receptor functions on cognitive control.
The *DRD1* rs4532 G allele has been associated with higher D1 receptor efficiency ([@CIT0009]; [@CIT0035]), which has previously been linked to improved cognitive control ([@CIT0024]; [@CIT0045]; [@CIT0050]; [@CIT0002]). Based on this, we had hypothesized that *DRD1* G allele carriers should be more inclined to the dopamine D1 state than A allele carriers and, as a consequence, perform better in the high demand task (but not necessarily in the low demand task). Our results of improved performance in the high demand task only are hence well in line with previous reports on the control-promoting effects of the G allele as well as our hypotheses. In the hard task version, participants were asked to respond to a combination of 2 independent stimulus features. This imposes rather high demands on working memory processes, as several aspects need to be considered for successful response selection. Matching this, the maintenance of stable representations in neural networks has been attributed to be a major aspect of the D1 state ([@CIT0012]). The results on the *DRD1* genotype effects are thus well in line with the predictions of the dual state theory. This finding allows to draw the conclusion that improved DRD1 signaling is associated with improved cognitive control in cases of high control demands. Inferences about meta-control should not, however, be based on this finding alone, as the lack of DRD1 effects in the low demand task means that we did not demonstrate any (detrimental) effects of DRD1 on the disengagement of control, which has previously been argued to be beneficial in tasks with low control demands ([@CIT0003]; [@CIT0046]).
The *DRD2* rs6277 T allele has been associated with greater striatal dopamine D2 receptor density ([@CIT0020]; [@CIT0016]), which has previously been linked to decreased cognitive control ([@CIT0024]; [@CIT0045]; [@CIT0002]). We therefore hypothesized that T allele carriers should be more inclined towards a dopamine D2 state ([@CIT0011], [@CIT0012]; [@CIT0045]). We further reasoned that they should have lower levels of control and therefore show worse performance in the high demand task, but potentially beneficial effects in the low demand task. However, we did not observe either of these 2 effects, and Bayes statistics provided strong evidence for the null hypothesis in both cases.
When trying to understand the lack of DRD effects on the hard task, it could be helpful to look at how dopamine is thought to promote cognitive control. Evidence suggests that D1 receptor-mediated effects in the prefrontal cortex and the striatum are promoted by medium DA concentrations ([@CIT0053]; [@CIT0029]; [@CIT0012]), while very low (and also very high) DA concentrations foster a D2 state ([@CIT0012]). According to the inverted U-shape function between dopamine concentrations and working memory performance ([@CIT0017]; [@CIT0008]), increases in working memory or cognitive control demands necessitate higher DA levels for optimal performance. It is thus likely that optimal performance in the hard task requires higher DA concentrations than optimal performance in the easier task, because the latter has comparatively lower control or working memory demands. Within a medium range, higher DA concentrations likely lead to a stronger modulation of D1 compared with D2 receptors. This suggests that genetic variations in *DRD1*, rather than *DRD2*, seem to modulate performance in the hard task with high control requirements.
With respect to the lack of DRD2 effects on the easy task, it could be helpful to look at the dual-state state theory. The D2 state confers the advantage of easier access of information to neural networks, which should improve flexibility in terms of switching between different task set representations ([@CIT0012]), but is also a relevant prerequisite to become processed quite automatically or with low cognitive control ([@CIT0025]; [@CIT0021]; [@CIT0005]; [@CIT0040]; [@CIT0051]). Against this background, we had expected DRD2 T allele carriers to thrive in the easy task due to having higher striatal dopamine D2 receptor density ([@CIT0020]; [@CIT0016]), which has previously been suggested to decrease cognitive control ([@CIT0024]; [@CIT0045]; [@CIT0002]). Yet, enhanced access to task rule representations in the D2 state might be especially advantageous in situations that require to flexibly switch between several (task rule) representations ([@CIT0012]). While the stimuli used in this study did have task-irrelevant features, the task itself did not require the participants to actively switch back and forth between different task set representations. Instead, the task adapted from [@CIT0003] focused more on the general difference between high and low control requirements in a block-wise design. Thus, the paradigm only assesses the general ability to up- or downregulate cognitive control capacities depending on the demand on cognitive control load. It is hence possible that the factor that determines the functional relevance of DRD2 signaling is the question of whether flexibility is necessary, rather than whether the updating threshold is lowered. This is also supported by findings showing that *DRD2* genotype effects are evident in situations with high control demands that also require cognitive flexibility ([@CIT0045]). It could therefore be possible that DRD2 effects would only emerge if a "mixed" block was introduced to the paradigm, which cues the participants to flexibly switch between the low and high demand task. As we did not anticipate this and therefore included no such experimental block, this will however remain speculative until tested in future studies.
Nevertheless, the current findings have important implications for the ongoing debate on how dynamical adjustments of cognitive control emerge in the process of metacontrol ([@CIT0003]; [@CIT0018]; [@CIT0022]). It has been suggested that the updating threshold represents a metacontrol parameter, that is, a factor that facilitates dynamical adjustments of cognitive control ([@CIT0018]). Modulations of the updating threshold, which determine how easily information gets access to response selection processes, have been suggested to play a central role ([@CIT0018]). While the updating threshold clearly differs between dopamine D1 and D2 states ([@CIT0012]), the current data show that this factor does not seem to modulate performance in situations with low control demands, which should benefit from a low updating threshold. It therefore seems that a simple updating threshold does not provide a comprehensive explanation of how dynamical adjustments in cognitive control emerge in situations with little demand for switching between multiple representations. In other words, modulations of the updating threshold alone seem insufficient to enable dynamics akin to metacontrol. It has however been suggested that the dopamine-dependent calculation of costs and benefits plays an important role in deciding how to select a response and how much control needs to be invested ([@CIT0007]; [@CIT0043]; [@CIT0022]).
It should furthermore be noted that even though we found solid evidence for both the presence of DRD1 effects and the absence of DRD2 effects on the assessed behavior, the assessed data do not allow to draw any conclusion about the interaction of these 2 dopaminergic transmitter systems. The main reason for this limitation is that our sample lacks the power (i.e., is not sufficiently large) to properly investigate potential epistasis effects of the interaction of the 2 SNPs. Therefore, we cannot provide information on how the alleles of the DRD1 rs4532 and DRD2 rs6277 SNPs interact in the assessed meta-control measures.
In summary, we investigated the relevance of dopamine D1 and D2 receptor signaling for cognitive control allocation or metacontrol by assessing performance in 2 experimental blocks, which differed in the degree of required cognitive control. Given that dopamine D1 and D2 receptors have been suggested to exert opposing effects on cognitive control, we investigated the impact of 2 SNPs in the *DRD1* (rs4532) and *DRD2* (rs6277) genes on metacontrol in 195 healthy young adults. Matching previous reports of higher receptor efficiency, we found carriers of the *DRD1* G allele to outperform noncarriers in cases of high control requirements. Yet, we found no effects of *DRD2* genotypes on high control requirements and no effects of either SNP on low control requirements (as confirmed by add-on Bayesian analyses). Our findings suggest that higher *DRD1* receptor efficiency may improve performance when a high degree of cognitive control is required, probably by promoting a "D1 state," which is characterized by highly stable task set representations. The lack of effects for DRD2 signaling might be explained by the fact that the "D2 state" is thought to enhance flexible switching between task set representations, when our task only featured 1 task set at any given time. Given the overall lack of effects on the easy task, the obtained data do not, however, allow for strong conclusions on complementary DRD1 and DRD2 effects on metacontrol, that is, control allocation in situations with different control requirements. Hence, future studies should explore more elaborate or alternative explanations by putting them to the test.
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) SFB 940 project B8.
Statement of Interest {#s0104}
=====================
None.
[^1]: N.Z. and W. B. contributed equally.
[^2]: A.-K.S. and C.S. shared senior authorship.
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CHICO — On Friday night, following one of the most disheartening losses in recent memory for the Chico State men, point guard Jay Flores texted coach Greg Clink with some reassurance.
“Get some sleep,” Flores said. “We’ll be better tomorrow.”
Flores and the Wildcat men made good on that promise.
Flores scored 18 points, including four critical free throws in the final seconds, and Chico State came back from 12 down in the second half to knock off Cal State L.A. 69-66 on Saturday night at Acker Gym.
“I feel like these guys have the kind of character that if they’re pushed in the right direction, they’ll follow,” Flores said. “We never felt out of it. We felt a few stops away. I’m not saying it was a special win or anything like that, but it speaks volumes about our team.”
Chico State (12-4, 6-4 California Collegiate Athletic Association) found itself down 10 with 6:30 left in regulation, but the Wildcats chipped away. A three-point play from Jason Conrad, followed by a layup from Amir Carraway, drew the score to 57-53, and Chico State made it a one-possession game when Conrad knocked down a couple free throws at the 4-minute mark.
Then Damario Sims — perhaps the Wildcat most desperately seeking vindication after one of the worst shooting nights of his career — connected on two straight 3s to keep his team in the mix, before Jordan Semple banked in a jumper with 41 seconds left that gave Chico State the 65-64 lead.
“Damario’s my roommate, he’s one of my best friends in the world, and he was so upset last night because he knows he can make those shots,” Flores said. “There’s not a guy I’d rather have shooting there. I was almost expecting them to go in, honestly.”
Leland Jones had a chance to give the Golden Eagles the lead from the free throw line, but missed both attempts with 21 seconds to go. Flores hit two free throws afterward, and Cal State L.A. responded with a quick layup to reinstate its deficit of a solo point with 11 seconds left, but Flores got two more free throws before the Wildcats got their biggest stop of the game, with Quinton Watkins and Jones missing on 3s to end it.
“I thought the response we had, whether we won or lost, was phenomenal,” Clink said. “To go through what we went through and play as hard as we did, I’m extremely proud. This is a win that I’m as proud of as any.”
Cal State L.A. (10-4, 6-4), true to its dominant defensive form, held the Wildcats to 10 points midway through the opening period, but Chico State held its own and trailed just 16-10 as it tried to find a way through the Golden Eagles’ athletic half-court defense. But the Wildcats’ sudden shooting woes resurfaced against Cal State L.A. — perhaps more expectedly, considering the visitors’ defensive pedigree — and the Golden Eagles began to extend the lead by converting more than half their shots to that point and cleaning up the glass as well. But instead of folding up camp, the Wildcats buckled down in the second half, converting 65 percent of their field-goal attempts and getting the stops they needed at the most crucial times.
Conrad finished with 12 points, and Chris Robinson had a game-high 25 for Cal State L.A. With the win, Chico State moved into a four-way tie for third place.
WOMEN
Cal State L.A. 57, Chico State 56
Lacy Ramon hit two go-ahead free throws with 3.5 seconds left to give the Golden Eagles (9-5, 7-3) the win over the Wildcats (8-6, 5-5), who could not capitalize despite forcing 25 turnovers.
Synchro Bull led all scorers with 17 points and nine rebounds, and Natasha Smith had 10 points.
Chico State struggled to find a rhythm against Cal State L.A.’s zone defense, but the Wildcats finally got the surge they were looking for with 6 minutes to go, putting together an 8-0 run sparked by two Synchro Bull buckets and three Golden Eagle turnovers to create a 48-47 advantage, Chico State’s first lead of the game.
Cal State L.A. reclaimed it from the free-throw line with 1:28 to go, before the Wildcats responded in the same fashion to take a 56-55 lead with 40 seconds to build on it or hold it. They failed at the first with a turnover, leaving 16 seconds for the Golden Eagles to respond, and Cal State L.A. caught a major break with 3.5 seconds left when Sam Messersmith was whistled for a foul on seemingly innocuous contact as Ramon drove toward the basket and lost the ball. Ramon hit both free throws for the 57-56 lead, and the Wildcats threw the ball away on their last possession to end it.
Cal State L.A. opened up with some gritty play to earn an 18-11 lead midway through the first half, displaying a zone look the Wildcats struggled to crack as their shots weren’t falling. The Golden Eagles compounded Chico State’s frustration by dominating the boards, using their superior size to punish the hosts on the blocks. Cal State L.A. carried its seven-point lead to the 4-minute mark of the first half before a Jazmine Miller 3 cut the lead to 26-22.
Half of Chico State’s shot selection in the first half was from that range, and the Wildcats simply were cold, shooting 2 of 18 on 3s as part of a 25-percent mark from the field.
Chico State started its trek back with 5 minutes gone in the second half when Bull rolled in a left-handed layup to cut the lead to 37-35. But the Wildcats got sloppy after that, relegated to the Golden Eagles’ trudging pace, and the visitors constructed a 47-39 lead midway through the half.
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Ben Roethilsberger threw for 462 yards against the Broncos but managed a lone touchdown in the 24-17 loss. And it's the passes he didn't complete that leave a bad taste in his mouth after Denver snapped Pittsburgh's six-game winning streak.
On Monday, the veteran quarterback called out rookie wide receiver James Washington for botching what should've been a much easier catch -- and possibly a touchdown. Late in the third quarter and with the score tied, 17-17, Washington was wide open down the sideline. Roethlisberger let it go and instead of staying on his feet, this happened:
It looks nice, sure, but when you lay out for a ball and don't need to extend your arms to make the catch you probably should've stayed on your feet. Which brings us back to Roethlisberger.
"He has to make it," Big Ben said Monday during his weekly appearance on 93.7 The Fan, via the Pittsburgh Tribune-Review. "I just think he didn't trust his hands. For some reason, he jump/dove. I'm not really sure what he was doing. We look at it (on film), and coach got on him pretty good yesterday. We took a long, hard look at it. James needs to run through that, and it's a touchdown."
Washington was targeted three times in Denver and didn't register a catch. For the season, the 2018 second-round pick has eight receptions for 77 yards and a touchdown. That's a bad day for JuJu Smith-Schuster, the second-year wide receiver (also a former second-rounder) who also was inconsistent during the first half of his rookie season. Things didn't start to come together until Week 8, when Smith-Schuster had 193 receiving yards against the Lions. He then had four more games of at least 75 receiving yards and through 11 games this season Smith-Schuster already has 77 catches for 1,055 yards.
Washington, who was drafted to replace Martavis Bryant, hasn't come close to Smith-Schuster's rookie production at any point this season.
"Yes, he's a rookie, but you're not going to be out there if you're not going to make those plays for us," Roethlisberger said, adding "He needs to have confidence in himself,. When you have trust and confidence in yourself, you use your hands and you catch the ball. I felt like when he jumped and dove, whatever you want to call it, it showed a lack of confidence in himself and his hands."
As it stands, Washington is seventh on the team in receptions, behind Smith-Schuster, Antonio Brown, James Conner, Vance McDonald, Ryan Switzer and Jesse James.
The Steelers will host the Chargers on Sunday, 8:20 p.m. ET, NBC, stream on fuboTV (try for free).
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Peyronie's disease is characterized by the presence of dense fibrous tissue within the tunica albuginea about the corpus cavernosum of the penis, and is often associated with penile pain, curvature, or a palpable plaque. Infectious, traumatic, autoimmune and genetic causes have been proposed to be causative for Peyronie's. These characteristics are often associated with erectile dysfunction and may cause pain to the partner as well. Treating this disease has been done using injections of various kinds as well as surgical intervention to straighten the penis. More recent therapies include injecting collagenase to reduce the fibrotic tissue. The plaques have been theorized to be caused by an injury creating a break within the tunica; others have postulated that they are caused by a fibrotic disorder or unknown causes not related to injury. It is desired to provide a treatment that addresses the affected penile tissue and to address the potential for future reoccurrence of the condition.
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Conte, Anderson, lab Vice President James Valente and veteran track coach Remi Korchemny are charged with conspiring to distribute human growth hormone, testosterone cream and a designer steroid called THG to star athletes through the Bay Area Laboratory Co-operative in Burlingame. All four men have pleaded not guilty and are free on bail.
...In the two days after the hearing, The Chronicle published articles based on transcripts of grand jury testimony by Bonds, of the San Francisco Giants, and the New York Yankees' Jason Giambi. Giambi said he took steroids supplied by Anderson; Bonds described using similar-looking substances obtained from his trainer but said he thought they were flaxseed oil and arthritis cream.
That's not the only leak that the defense believes the Government has made to the media:
Among the most damaging leaks was a secret recording the Chronicle described in an October published report. A voice the Chronicle claimed to be Anderson's was heard saying he provided steroids to Bonds.
The U.S. Attorney on the case has asked the Department of Justice to investigate the leak. Once again, the Government investigates itself.
CrimProf Blog thinks either the defense or a government employee leaked the transcript. I rule out the defense. The Chronicle in discussing its decision to release the information, gives away a big clue:
Under federal law, only prosecutors, case agents, government and court employees and others on that side of the fence are prohibited from disclosing matters that occur before the grand jury. The defense is under no such prohibition. If a person associated with the defense had been the source, there would be no federal secrecy provision for the Chronicle to consider enforcing.
That leaves the Government, case agents and persons working for them. Why doesn't the Judge just call all of them into chambers, put them under oath, and ask if they were the source of the leak or if they know who was? They will know that if the leaker ever surfaces elsewhere, and they lied to the judge, they will face perjury charges as well as obstruction charges and lose their jobs. One of them might just cave under such pressure. Who should the Judge call? I'd start with these people, all listed in the Department of Justice press release on the Indictment:
The prosecution is the result of an 18-month investigation overseen by the U.S. Attorney's Office as well as special agents of the Internal Revenue Service Criminal Investigation Division, the Food and Drug Administration Office of Criminal Investigations and the San Mateo County Narcotics Task Force. In addition, the Bureau of Immigration and Customs Enforcement provided assistance in connection with the investigation. Jeff Nedrow is the Assistant U.S. Attorney who is prosecuting the case with the assistance of Susan Kreider.
Update: I would just like to point out that if a defendant had received grand jury transcripts from the Government as part of discovery in his criminal case, which would only happen after indictment, and the Court issued an order preventing the defense from sharing them with anyone outside the defense team, it would be a violation for the defense to have provided them to the Chronicle.
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Alkuun julkinen anteeksipyyntö. Vuonna 1997-98 vedin Nelosella poliittista keskusteluohjelmaa nimeltä Ylähuone. Kerran arvovaltaisen raadin vieraana oli kiistelty hahmo, lääkäri Mikko Paunio. Hän oli jo vuonna 1991 kirjoittanut kirjan Vihreä valhe, jossa hän oli analysoinut vihreän liikkeen ideologisia lähtökohtia erittäin kriittisesti. Vihreän Langan silloisena kolumnistina – poliittisesti sitoutumattomana mutta tiedostamattani umpivihreänä – en niistä mielipiteistä oikein piitannut. Ja koska hain ohjelmaan usein pientä diskreettiä draamaa ja latentteja vitsejä, lankesin huonoon käytökseen. Tein sen Paunion kustannuksella. Pyysin ohjaajaa kuvaamaan minua kun nojaan käsi poskella pöytään, kolme sormea pystyssä. Paunion puhuessa sormet vähenivät molemmilta puolin yhteen.
Olen hävennyt elettäni. Olin ikävä ja arrogantti.
Nykyisin Paunio on lääkintöneuvos ja maailmanpankissa kansainvälisen uran tehnyt tutkija. Tänään hän on julkaissut uuden kirjan Vihreä valhe – valheen sysimustat juuret, sen salakavalat lonkerot ja murheelliset seuraukset. Kyseessä on jatko-osa neljännesvuosisata sitten kirjoitettuun teokseen. Paunion mukaan vihreällä aatteella on suora yhteys viime vuosisadan antihumanistisiin ja totalitäärisiin ideologioihin.
Nyt meillä on jo perspektiiviä arvioida, oliko ensimmäinen raflaava pamfletti oikeilla jäljillä. Uudessa kirjassaan Paunio käy läpi ideologisen katsauksen jälkeen, millaista jälkeä vihreä ympäristöpolitiikka on saanut aikaan mm. jätehuollossa. Miljardien panostuksella on hukattu energiaa ja tehty suurta ympäristövahinkoa. Tunnustan, että omatkin silmäni avautuivat muutama vuosi Ylähuoneen jälkeen, lainsäädäntötyössä. Nimenomaan jätepolitiikka oli seikka, joka ensimmäisenä muutti täysin käsitykseni ideologian uskottavuudesta (ks. linkki 10 vuoden takaa: Saako luvan olla järkevä).
Suosittelen tutustumaan kirjaan, enkä paljasta siitä liikoja, mutta yhden ajankohtaisen ja hyvin läpimenneen valheen haluaisin nostaa esiin. Viimeksi törmäsin siihen viikonloppuna kun paneelikeskustelussa mainitsin uusiutuvan energian markkinoita vääristävät ylisuuret tuet. Joku yleisöstä huusi: entäs fossiilisen energian tuet. Olisin halunnut vastata mutta aika loppui.
Vihreiden painavin argumentti uusiutuvien tuen puolesta on väite, että fossiilisia tuetaan kymmenkertaisesti. En ole koskaan kuullut kenenkään perustelevan kunnolla tätä väitettä: mitä se tuki oikein on.
Paunion kirja antaa siihen mielenkiintoisen vastauksen.
Väitteen takana on harhaanjohtava rinnastus. Sen mukaan uusiutuvia tuetaan vain noin sadalla miljardilla dollarilla vuodessa (tämä luku on muuten alakanttiin) kun taas fossiilisten energioiden tuki olisi noin tuhat miljardia dollaria. Aika moni menee hiljaiseksi kun kuulee tämän. Paitsi, ettei se ole ihan totta. Tästä väitetystä fossiilisen tuesta yli puolet nimittäin tarkoittaa sitä mitä tapahtuu kehitysmaissa, kuten Saudi-Arabiassa, Nigeriassa, Iranissa tai Venezuelassa, kun öljymaat myyvät kansalaisilleen öljyä alle maailmanmarkkinahinnan. Jos tynnyri öljyä maksaa maailmanmarkkinoilla 100 dollaria, ja Saudi-Arabiassa kansalaisille 2 dollaria, tämä erotus on sitä vihreiden laskemaa fossiilisten tukea.
No mutta eihän se oikeasti ole – se on silmänkääntötemppu, sillä ei kai kukaan vihreäkään vakavissaan voi väittää, ettei kehitysmaiden köyhillä olisi oikeutta maansa öljyvaroihin eli oikeutta liikkua autolla. Myös Saudi-Arabian Egyptille lahjoittama öljy katsotaan sellaiseksi fossiilisen energian tueksi. Ilman tätä lahjoitusta eivät autot Egyptissä liikkuisi. Kehittyneissä maissakaan ei ole mitään suoraa fossiilisen energian tukea vaan kyse on verohelpotuksista, kuten esimerkiksi silloin kun fossiiliseksi luokiteltu turve saa kilpailuetua kivihiileen verrattuna – minkä tämä hitaasti uusiutuva biomassa todella ansaitseekin.
Kun seuraavan kerran törmäätte väitteisiin, että fossiilisia tuetaan uusiutuviakin enemmän, kysykääpä siis tarkat perustelut. Törmäätte vaivautuneeseen hiljaisuuteen, sillä se ei ollut oikea argumentti. Se oli vihreästä työkalupakista vetäisty argumentti, väistöliike, jonka ei ollut tarkoituskaan olla totta.
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Production Rails Tuning with Passenger: PassengerMaxProcesses - itsderek23
http://blog.scoutapp.com/articles/2009/12/08/production-rails-tuning-with-passenger-passengermaxprocesses
======
jeremyw
_Generally speaking, you want to fill up as much RAM as possible with
passenger processes without utilizing swap in order to maximize you
performance and throughput._
Uh, what?
On a single-app box with real traffic (as the article implies), look first to
CPU. If your average request spends 50% time in db/services and 50% time in
processing/render, using more than 2-3 passenger procs per core (i.e. 100%
core utilization) is less efficient and a waste of memory. Multiply by cores.
(Back off a bit for db on the same machine.)
You want plenty of spare memory for OS cache, to keep your code and static
files in memory -- that is, your disk reads should be zero.
And don't do swap, kids.
~~~
jnewland
Excellent point, Jeremy. This article didn't talk at all about the CPU/RAM
balance, which is a important to consider when scaling any application. In my
experience, a large number of Rails apps are more RAM bound than CPU bound due
to large gems/libraries/codebases.
Having additional Passenger processes available even when CPU bound will allow
for greater throughput (if at a less-than-ideal speed) than having requests
back up on the queue, however - especially if those requests spend a good
amount of time waiting on DB, memcached, or other external API calls.
~~~
jeremyw
If you're CPU-bound, you can't have greater throughput, by definition. Once
you calculate your non-cpu latency (50% in my example) ceil(1/latency%) is
your limit per core, before you start wasting resources.
~~~
jnewland
You can't gain any more cycles, of course, but you _can_ gain throughput by
adding processes to an already cpu-bound app by giving faster incoming
requests a place to go instead of sitting on the global queue while waiting
for other requests to process.
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As previously reported, Tremors 5 has been shooting in South Africa and the first picture and plot details have been revealed.
As per the official press release: “The theatrical release of the original Tremorsin 1990 combined suspense-filled action, sci-fi imagination and witty humor in the tale of a tiny Nevada town terrorized by giant man-eating worms known as Graboids. The Graboids eventually morphed into even more deadly creatures known as Ass Blasters. In this all-new adventure that travels halfway around the world to South Africa, the Graboids and the Ass Blasters are not only bigger and badder but Tremors 5 introduces an additional unexpected surprise that raises the stakes in the battle for survival.”
Naturally, the brilliant Michael Gross is back as weapons expert and one-liner-machine Burt Gummer, and he’s joined by Screamstar Jamie Kennedy “as his new right hand man, tech-savvy Travis. The pair are joined by an international cast as they mount a battle against the deadly creatures that turns out to be far more than they bargained for.”
Any Tremorsnews is good (actually, amazing) news, and we can’t wait to see how this turns out. Stay tuned for more news on Tremors 5.
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Croix Scaille
The Croix Scaille is the plateau of a forested massif in the Ardennes bounded to the north by the valley of the Semois and to the east by the Meuse. It is the highest point of the southern Ardennes, with a height of 504 metres above sea level and is located exactly on the Franco-Belgian border on the edge of the French département of Ardennes (commune of Hautes-Rivières), and the Belgian province of Namur (Gedinne commune).
The wooded plateau is covered by the bois de Saint-Jean on the Belgian side, named after the stream that crosses the border from south to north, and by the bois des Haies on the French side, probably taking its name from the beech trees (French: hêtres) which are one of the dominant species here together with oak and spruce.
During the Second World War, the wooded area of Croix Scaille was a hotbed of maquis resistance in the Ardennes.
The spectacular Tour du Millénaire, which was erected in 2001, has 243 steps and enables a panoramic view of the Belgian and French Ardennes. The original wooden structure rotted and was dismantled in 2008 before being rebuilt in metal in 2012.
Category:Plateaus of Europe
Category:Mountains under 1000 metres
Category:Mountains and hills of the Ardennes (Belgium)
Category:Mountains and hills of the Ardennes (France)
Category:Landforms of Namur (province)
Category:Landforms of Ardennes (department)
Category:Belgium–France border
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Telecommunications systems are used to provide telecommunications services between two or more user interfaces. User interfaces may include telephone handsets, facsimile machines, computers and other equipment, and may be connected to the switching system by fixed land-based conductors or wireless services. Telecommunications services are provided by establishing a telecommunications channel between two user interfaces, such that encoded analog or digital data may be transmitted between the user interfaces until a state of completion is reached.
An undesired characteristic of telecommunications channels is the generation of echo. Echo may be inadvertently created, and is usually a function of the physical parameters of a telecommunications channel. For example, when a telecommunications channel includes a two wire conductor in series with a four wire conductor, echo may be generated at the interface between the two wire conductor and the four wire conductor. Other sources of echo are also known. Echo is one of the primary factors affecting the perceived quality of voice connections. Echo canceller devices are routinely used to prevent echo from degrading telecommunications channels.
Although echo cancellation is a useful technique in processing telecommunications, echo cancellation is not always required. If an echo canceller is enabled on a given telecommunications channel when echo cancellation is not required, the resulting signal may have degraded quality such that voice data is unintelligible. Moreover, enabling an echo canceller typically consumes resources that may be better utilized to carry out other functions rather than unneeded echo cancellation. Accordingly, it is highly desirable to not enable, or disable if already enabled, echo cancellation with respect to a telecommunications channel that does not require echo cancellation, such as when a call is directed to a radio based subscriber unit, such as a hand held mobile telephone.
One method of simulating the activation of an echo canceller is to increase the rate of attack of an echo canceller upon detection of off-hook signaling. This method has the drawback of requiring the echo canceller to remain active, even though echo cancellation is not performed. Thus, increasing the rate of attack of echo cancellation upon detection of off-hook signaling may still result in allocation of system resources to perform echo cancellation when not required. Increasing the rate of attack of echo cancellation to simulate turning the echo canceller on may also result in additional processing delay if the echo canceller is located in an external bank and the signal is routed to the echo canceller regardless of the rate of attack of echo cancellation.
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{
"pile_set_name": "USPTO Backgrounds"
}
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"Hey!" "What's the matter with you?" "Johnny, you got a call on line two." "You're in early." "I like the beard, but the mustache isn't working for me." "Want me to do it?" " I nailed him cold." " All right." "A stolen-car ring was smashed during..." "Come on, you guys." "It was nothing, really." "I still can't believe they thought you were a boy." "The mustache helped." "And thanks for teaching me how to boost a car." "To Lois Lane." "Still going where no reporter has gone before." "Hey!" "Turn that thing off." "Jimmy, don't encourage her." "She's got a head as big as the Metrodome as it is." "It's nice to know I'm appreciated around here, Chief." "What do you expect?" " Garlands thrown at your feet?" " No." "But I would like a raise." "I'd like 145-foot, triple-masted schooner with a teak interior... but, Lois, times are tough." "What's everybody standing around for?" "This is a newspaper... not happy hour at Buckingham Palace." "Chief, I got an angle on the mini-mall murders." "I figure there was blood on the burritos because... check this out, they were eating, and the perpetrators..." "Did you finish those obituary updates?" "Jimmy, never underestimate... the need for a good obituary." "I can think of one right now." "I guess you finally hit the big time." "This time, Lex Luthor's personal assistant returned your call." "Give it up, Lois." "Luthor never gives one-on-one interviews." "He's never met Lois Lane before, either." "Watch the doors." "Hey, that's my stop!" "He stopped it!" "He..." "Lois Lane?" " It's going to explode!" " He's got a bomb." " No, it's not a bomb." " It's my credentials." " I'm sorry, sir." "He ran right past reception." " You don't understand!" "Ms. Lane, the Messenger is going to explode." "Please, Ms. Lane, you must tell my story." " We've had trouble with him before." " Wait a minute." "Don't!" " He's a buck short of a variety pack." " Please, believe me." "The space program is doomed!" "Please!" "The transport vehicle Messenger, piloted by Cdr." "Jack Laderman... and carrying the final propulsion module for Space Station Prometheus... is scheduled for lift-off Friday at 9:00 a.m." "Dr. Toni Baines reminds us that timing is crucial." "Unless all the modules are in place within the next few weeks..." "Space Station Prometheus will lose its orbit... and fall back into the Earth's atmosphere." "That kind of an occurrence... will surely spell the end to any future projects... and the space program as a whole." "A series of delays and launch failures have already put EPRAD's back to the wall." "Morning, Lois." "On your hands and knees again, I see." "Isn't it a little early for you to be in, Cat?" "I thought ladies like you only worked nights." " Part of my job as society columnist..." " Mudslinging rumor-monger." "...is to maintain an active social life." "You remember what that's like." "Or do you?" "What do men see in her, anyway?" "Don't they know she's just looking for another notch on her garter belt?" "Pathetic." "Have you actually... seen this garter belt?" " So, you are Mister..." " Kent." "Clark Kent." "Yes, Kent." "Prof. Carlton called me about you." "Boy, I haven't seen him in I don't know..." "Let's see here." " Editor, Smallville Press." "Where is that?" " Kansas." "Just a minute." "Yeah?" "Tell him to keep his pants on." "If Carlini's can't deliver on time, just find a place who can." "You believe I had to buy a blood-pressure monitor last week?" "Paava leaves." "I beg your pardon?" "The Yolngu tribe in New Guinea eat paava leaves to relieve stress." "It puts them in a meditative state." "Maybe you should try it." "I see you've done some traveling." "This is my first trip to Metropolis." " I have some samples of my work." " Good." "Let's take a look." "The Borneo Gazette." ""Mating rituals of the knob-tailed gecko."" "Kent, I'm sure that these are fascinating stories... but you see, son, this is The Daily Planet." "We're the greatest newspaper in the whole world." "Now, our people are dedicated servants of the fourth estate... who routinely handle matters of international significance." " Chief, I fixed the horn on your golf cart." " Not now, Jimmy." " The tone's still off..." " Jimmy!" "Not now!" "Now, as I was saying, you just can't walk in here with those kind of..." "I think there's a story here." "We should have this guy checked out." "The crazy one from this morning?" "He was an engineer at EPRAD..." "Lois, can't you see I'm in the middle of something here?" " Lois Lane." "Clark Kent." " Nice to meet you." "Anyway, he worked on the Messenger..." "Wait a minute." "What happened to that mood piece I gave you... about the razing of that old theater on 42nd Street?" " I wasn't in the mood." " You weren't in the mood." "You can't come in here and tell me you're not..." "I've gotta go." "I'll catch you later." "I tell you... if that woman wasn't the best damn investigative reporter I've ever seen..." "Look, Kent, I'm sure that you're an intelligent guy... but you just can't walk in here with this kind of resume... and expect to get a job." "Mr. White, I know I lack experience, but I'm a good writer and a hard worker." "I just don't have anything for you, son." "Thank you, sir." "I appreciate your taking the time to see me." "Yeah." "Thank you." " You want me to wire you some cash?" " No, I'm fine." "How did the interview go?" "Not so good." "But something will turn up." "I'm sure." " I think I better wire you some cash." " I'm fine, Dad." " Still gonna make it home on Friday?" " I'd miss your home cooking?" "What home cooking?" "I haven't had a home-cooked meal in..." "Clark, you're being careful, aren't you?" "Sure." "Other than the bus incident this morning, but..." " Bus incident?" " Metropolis isn't the outback." "People in the city are always looking to make a quick buck." "If they find out about you, they'll put you in a laboratory..." ""And dissect you like a frog." I know, Dad." "Believe me, I'm trying my best to be like everybody else here." "I'll get that cash out to you tonight." "I'll pay you back." "I promise." " Okay." "I'll talk to you guys soon." " Bye, honey." "Lucy?" " Are you home?" " Hi, sis." " I thought you were going out tonight." " I've got to work." "I can't." "Don't start." "Did you find an escort to Lex Luthor's White Orchid Ball yet?" " No, I did not." " Lois, it's tomorrow night." "What about Mitchell?" "I thought you liked him?" "Mitchell is a hypochondriac." "They can't all be bad, Lois." "They can't all be boring or stupid." " What're you waiting for?" " Fine." "I'll ask Mitchell to take me." "I'm not just talking about the ball." "You've got to get out more." "Will you stop?" "Jesus, you sound like Dad." " I'm only 26." " Twenty-six today, 36 tomorrow." "And I know why that dentist, Alan, never called you back." "Dragging him to that Women in Journalism seminar?" ""Weak Men, and the Wise Women who Love Them"?" "You've gotta stop scaring them off." "You've gotta stop being so smart all the time, so intense." "Look, I'm just being myself." "If they're not man enough to handle it... then I guess I'll just wait for someone who is." " I just hate to see you sitting at home." " I get out plenty." "I have dates." "You have interviews." "It's not the same thing." "I just want you to meet a super guy." "Gwendolyn, have you made your decision?" "All right." "You win." "I'll keep my promise." "Tonight, my body is yours... but my heart... my heart beats only for one man." "Keep the theater on the spot." "We don't need a parking lot." "What is this?" "Bea?" "Come on." ""After the dark death of autumn, and the cold barren winter..." ""how I wish this rock might be taken from my heart."" "Okay, Bill." "Start her up." "...destroying the neighborhood!" ""For the days of my childhood..." ""back when my soul was pure." ""I slept right here in this nursery..." ""looking out at the orchard from this very room." ""And every morning I awoke with such joy in my heart." ""My orchard is just the same as it was then, nothing different." ""All of it, all of it dressed in white." ""My lovely orchard."" " Who's there?" " Just a fan." "I'm not leaving." "Not until I finish." "All right." "Mind if I watch?" "I always loved this play." " You know it?" " The Cherry Orchard." "Anton Chekhov." " His finest, don't you think?" " Definitely." "They don't understand." "Theater is more than bricks and mortar." "It's drama, and passion... and mystery, and comedy, and life." "Don't make me go." "I'm not ready." "We have some time." "You understand." "I just want to say goodbye." ""All of it dressed in white." ""My lovely orchard."" "Beatrice was 18 when she made her debut." "Warren G. Harding was President... the Unknown Soldier was interred at Arlington... and Babe Ruth was sold to the Yankees." "She came to say goodbye, as we all must, to the past..." ""...and to a life and a place that soon would exist..." " "only in a bittersweet memory."" " Smooth." "Yeah." "If you like that sort of thing." "There's only one attribute I value more than experience... and that's initiative." "Clark Kent, welcome to The Daily Planet." "Oh, no, the space shuttle's on fire!" " It's on the TV now!" " Quick, turn it up!" " Let's take a look." " Lois, get over here." "Fast-breaking story." "We have a reporter on the scene... and we're trying to establish contact with a Carmen Alvarado." "Can you hear me?" "She's on the launching pad right now." "Carmen?" "You've just seen what we've seen here." "A terrible tragedy is unfolding." "There seems to be..." "I knew there was something to Platt's story." "Lois, just because one madman's prediction came true... doesn't mean that there's a conspiracy to sabotage the entire space program." "With more than a hundred colonists going up in the next launch... are you willing to take that chance?" "I'll need a task force." "I can't cover this story alone." "You can have Jimmy." " We're talking about the space program." " Okay." "Take Kent." " Kent?" " Kent." " What about Myerson?" " He's busy." " Burns?" " Budapest." "Forget Kent." "He's a good man." "Kent is a hack from Smallville." "I couldn't make that name up." "Kent or nobody." "Fine." "Don't ever say that I am not a team player." "Let's hit it." "Just get on it, will you?" " Mind if I ask where we're going?" " To interview Samuel Platt." "He's convinced the Messenger was sabotaged." "I'll brief you." "And get something straight." "I didn't work my buns off... to become an investigative reporter for The Daily Planet... just to baby-sit some hack from Nowheresville." "And one other thing." "You are not working with me." "You're working for me." "I call the shots." "I ask the questions." "You are low man." "I am top banana." "And that's the way I like it." " Comprende?" " You like to be on top." "Got it." "Don't push me, Kent." "You are way out of your league." "Dr. Platt?" "Dr. Platt, it's Lois Lane." "And they said that I was crazy." "But wouldn't you be, after the drugs?" "You know they drugged me after I submitted my report to Dr. Baines." "Dr. Platt, how could the Messenger have been sabotaged?" "In order to bypass security..." "Unless the orders came from high up." "Under extreme temperature conditions... the particle isolators were in danger of shutting down." "So, in order to prevent this, we installed heating devices." "But, when I broke into one of the off-limit labs..." "I discovered that the heating devices had been replaced by coolant systems." " To freeze the ion particles?" " Of course." "Then it'd fuse... and the Messenger would blow up." "It's all in my report." " What report?" " The report that I gave to Dr. Baines." "Do you have a copy of this report?" "What kind of a scientist would I be if I didn't keep reports?" "Dr. Platt, perhaps you could gather your report together some other time." "I'll have somebody come by and pick it up." "My wife." "We planned to live together on Prometheus." " Where's your family now?" " Gone." "They left me..." "It's all for the best." "Dr. Platt, who would want to sabotage Space Station Prometheus?" "I don't know." "See, the microgravity laboratory on the Prometheus... could be the key for curing hundreds of diseases here on Earth." "In a zero-gravity environment... we can actually separate the proteins that form viruses." "So many children with crippling diseases..." "My daughter." "We could cure them." "I think you and I should pay Dr. Baines a visit." "...to report to room 135." "Naturally, we're all still in a state of shock." "I don't suppose I have to tell you what a catastrophe this explosion was." "Capt. Laderman was one of our best." "His three kids, his wife, Anna..." "Dr. Baines, what's being done to investigate the cause of the explosion?" "We won't know anything until we've examined the burnt wreckage." "We're in the process of moving it to a hangar for inspection." "Can we take a look at it?" "Sorry, no press allowed." "No exceptions?" " I'll see what I can do." " Great." "On the subject of Dr. Samuel Platt..." "I have his file right here." "A real waste of talent." "Seems building the space station and his divorce finally got to him." "Started drinking, taking drugs." "He went from bad to worse." "We kept him on as long as we could... but when he set fire to one of the laboratories... we had to let him go." "Dr. Platt said he submitted a report to you." "Something about coolant devices installed to..." "Coolants?" "No, I don't recall any report." " I could check my records." " Could you..." " and give us a call?" " Certainly." "Be glad to help." "Let me know if I can be of any further assistance." "Thank you." " She seemed cooperative." " I don't trust her." "Very attractive." " Young for a woman in her position..." " Typical." " What?" " That's a typical male response." "Trust me on this, I am not a typical male." "No?" " Just because she's okay-looking..." " Very okay-looking." "...you automatically assume she's telling the truth." "And you assume she's not?" "Does everyone have an angle?" "No honest people left in the whole world?" " That's pretty cynical, Lois." " It's realistic, Clark." "At least, I don't go through life disappointed." "We have different sections, just like the paper does." "Society, Sports, Entertainment." "Come here." "Who's the new tight end?" "Why don't you throw your usual forward pass and find out?" " Excuse me, I..." " Catherine Grant." "Cat's Corner?" "Oh, yeah, I've read your column." "Then my reputation precedes me." "Among other things." "I know what it's like to be new in town." "Lonely." "I'd be happy to show you around." "That's very nice of you, Ms. Grant." "Cat." "Cat." "Maybe when I get settled in." "It's a date." "Cat." "No, Mitchell, I'm not mad." "If you've got the sniffles, then you've got the sniffles." "Yeah, that could lead to complications." "No, don't call me." "I'll call you." "I don't suppose that you own a tuxedo?" "I could get one." "Why?" "The man that I was going to Lex Luthor's ball with has the flu." "Yes?" "Well, I was just wondering if you wanted to..." "Do you want to take his place or not?" "Thanks anyway, Lois." "But I thought I'd go to bed early tonight." "Are you crazy?" "This is the social event of the season." "Everyone who is anyone is gonna be there." "And you want to go to bed early?" " So, is this a date?" " Date?" "You mean like in Kansas, where you meet my parents... and then you try to give me a hickey in the vacant lot behind the Dairy Freeze." "No, this is not a date." "This is business." "I am going to land the first one-on-one Lex Luthor interview, if it kills me." "Okay." "Good." "I'll see you there." "9:00." "Okay." "Buddy, you got a buck?" "You must be some kind of angel, brother." "Some kind of angel." "Dinner was great, Mom." "Thanks." "Thanks, honey." "More than I get these days." "You're mother is now an artiste." "I call it Too Much, Too Soon, Tortured Heart, Waning Moon." "What do you think?" "Too cerebral?" "No, it's... very imaginative." "So, now, tell me more about this woman you're going to Lex Luthor's ball with." "Lois is..." "Well, she's complicated." "Domineering, uncompromising, pigheaded... brilliant." "And we're not really going out." "It's business." " Thanks for sewing my jacket, Mom." " You're welcome, honey." "That electrical storm over Cleveland was brutal." "Maybe you should take another route." "See you next week, honey." "I love you." "Take care." "I forget how beautiful it is here." "The only stars you see in Metropolis are riding around in limos." "You're the one who wanted the rat race." "I couldn't live there." "Not for a minute." "There's something about the city." "The pace." "Everyone going somewhere." "Impatient." "Like you." "I guess you finally found your niche... and stopped living out of that old suitcase." "I hope so, Dad." "Being in Metropolis, working at the Planet... it's a dream come true, but..." "But you still feel like you don't fit in." "Because I don't." "I don't fit in." "I have to control myself all the time." "Never use my powers." "Because I don't want to jeopardize my chance to lead a normal life." "Whatever that means." "Just being human, like you and Mom." "Living, working, meeting someone." "Having a family." "We don't know if that's possible." "You can't risk anyone finding out about you." "If they knew you came from another planet..." "But I can't hide forever, Dad." "There has to be a way that I can be Clark Kent... and still use what I've been given to do some good." "You'll find a way, boy." "You'll find a way." "Have you ever met him?" "Lex Luthor?" "No, but I read all five of his unauthorized autobiographies." "Rags to riches." "Wrong side of the tracks." "Self-made billionaire." "Owns dozens of companies, employs thousands of people." "Man of the Year, every year." "Has his finger in every pie." "But rarely appears in public." "He won't give personal interviews." "There he is!" "Good evening." "Nice to see you." "Hi." "Good evening." " Good evening." " How are you?" "You're on my phone list, Margaret." "Harry, congratulations on the bio." "I liked that editorial on the ozone." "Sen. Washington." "Hi, how are you?" "Nice to come." "Gentlemen, Sen. Morales." "Lex Luthor." "Why haven't you returned my calls?" "Gentlemen." "Lois Lane, Daily Planet." "I assure you that I'll never make that mistake again." "She's something, isn't she?" "Clark?" "Yeah." "She is something." "I hope you'll forgive me for being so bold." "But boldness is a trait I find very attractive in a woman, Ms. Lane." "Thank you." " Anyway, Mr. Luthor, I..." " Lex." "I know that you're hesitant to give interviews." "You can understand a man in my position." "I wouldn't want to be... misinterpreted." "And I have had one or two bad experiences with the media." "But not with me." "So, why don't we make it... tonight?" "Yeah, mind if I cut in?" "Lex, this is Clark Kent." "Clark works at the Planet." "A pleasure." "Later." "Clark, you idiot!" "It's taken me a year to get this close." "What, this close?" "I would have thought square dancing was more your style." "Actually, I learned from a Nigerian princess... who studied ballroom dancing in England." " Really?" "How fascinating." " Where are you going?" "Lois, what are you doing?" "Being a reporter." "You should try it sometime." "Lois." "You can't come in." "It's..." "Just look around." "Macedonian." "Belonged to Alexander the Great." "A brilliant tactician." "Alexander's strategy was simple." "Always seize the high ground." "It was with this sword that he defeated Darius..." "Darius III, and was proclaimed King of Asia." "You surprise me, Mr. Kent." "I'm not often surprised." "I hope you don't mind us looking around." "You have a beautiful home, Lex." "Have you seen the view from here?" "The tallest building in Metropolis." "I must confess that I love the fact... that everyone in the city has to look up in order to see me." "Let's get back to the party." "I think you'll find my announcement will interest you." "After you." "Ladies and gentlemen, honored guests... my friends." "We've come here tonight for a good cause." "Thanks to your generosity, the Luthor House for Homeless Children... will soon be a reality." "Thank you." "As you know, I've dedicated myself... to improving the quality of the lives of the citizens of Metropolis." "Tonight, I'd like to go further." "Now, it is my sad understanding... that the Congress of Nations intends to cancel the Space Station Prometheus." "Profit aside, the potential benefits... that a zero-gravity laboratory could bring... most importantly, pharmaceuticals... that could end many crippling diseases here on Earth... must not be lost to the citizens of this planet." "So, therefore, I have decided to commit my total financial support... toward the building of a privately-owned space laboratory." "I've submitted my proposal to the Congress of Nations... and I'm awaiting their outcome." "Ladies and gentlemen, I give you Space Station Luthor." "Now, step right up." "Don't be shy." "Feast your eyes on an engineering marvel." "A signpost to a new age of scientific advancement." "A flagship, cruising into the new century." "My gift to the future of mankind... the children of Earth." "Will that be all for this evening, sir?" "Yes, Asabi, thank you." "That will be all." "Pleasure, sir." "Good morning, Lois." "Maybe for you." "I've been at it for hours." "I went back to EPRAD." "I followed the truck with the wreckage of the Messenger inside." "They brought it into this hangar." "I tried to get in, but your friend Dr. Baines threw me out." "There's a man down there!" "Call the fire department!" "We need help!" "Back off, all right?" "Call the fire department!" "People, get back." "There's a man down here." "Ten-five." "There's a man down, here." "Back off." "Get these people back." "Okay." "I got you." "You're all right." "You okay?" "That man saved me!" "He pulled me out." " He's delirious." " Obviously." "Look at you." "You're a mess." "From now on, do what I do." "Bring a change of clothes to work." "Hey, C.K." " Hold that elevator." " Where are you off to?" "Lois sent me to pick up that report from Platt." "He called this morning, said he hoped we can read it." "She also told me to take a copy over to my friends at STAR Labs to analyze." " What happened to your suit?" " Don't ask." "See you later." "Morning, handsome." "Hi, Cat." "If you'll excuse me, I..." "No, I don't think I will excuse you." "I've asked you to have dinner with me two times." "That's two times more than I've ever had to ask any man to do... anything." "I'm sorry, I've been really swamped." "Lois and I..." "Poor Lois." "All work and no personality." "Well, if I can take a rain check on that dinner..." "Sure." "But don't wait too long." "Okay." "I love it when they play hard to get." "Catnapping?" "Anything?" "I must have called 50 ex-employees... that worked at EPRAD the same time Platt did." "None of them are talking." "I don't know." "Maybe there's nothing to talk about." "So, what do we do now?" "First, we piece together Platt's report." "If that's possible." "Then we try and figure out a way to prove that Dr. Baines got a copy of it." "If there's any written evidence... that Platt found coolant devices and Baines ignored it..." "I hope you didn't make dinner plans." "I am all yours." "It's done." "The Messenger is at the hangar." "I knew that I could leave everything in your capable hands." "What's he doing here?" "I have an errand for him to run." "Platt has to be silenced... and those reporters, Clark Kent and Lois Lane... are also becoming a problem." "Lois Lane was there this morning." "Followed the truck to the hangar." "All right, do what you want with Platt." "You leave the reporters to me." "Tell me, Lex, do you have some special interest in those reporters?" " Clark Kent, for example?" " Kent's nothing." "He's a giblet." "And Lois Lane?" "She's a very talented young woman." "I may have use for her." "Unfortunately, she may not be so easily seduced." "As me?" "Have I seduced you?" "I thought it was you who seduced me." "I'm warning you." "Stay away from her." "Antoinette, you know me." "Perhaps a little too well." "You know I don't like threats." "I don't care." "Everything we've worked for, we are so close... and I will not let her interfere." "You do know what I'm capable of." "Yes, I do." "And that is part of the appeal." "This is impossible." "Nothing matches." "No dates." "We're never going to get through this." "I'm starving!" "I wish I knew some good Chinese takeout." "I know a place." "I'll be right back." " Don't you want to know what I want?" " I'll bring an assortment." "That was quick." "I took a shortcut." "It's still hot." "This is out of this world." "It's in Chinese." "Don't tell me that you read..." ""A good horse is like a member of the family."" "I hate that." "That is not a fortune." "You are a strange one, Clark Kent." " Am I?" " Yeah." "But I think I got you figured out." "Really?" "It didn't take you very long." "It's my business, looking beyond the external." "Don't fall for me, farm boy." "I don't have time for it." "Come on, let's go find Platt." "Maybe he can help us decipher this." "Lois, let me look first." "Don't be silly." "I've seen it all." "War, crime, famine." "Dr. Platt?" "Wait." "The water." " Suicide?" "That's ridiculous." " He's tried it before." "No sign of forced entry." "No sign of struggle." "Nobody saw anybody come in or out." "But we were on the verge of proving his theory..." "That something he was working on was right." "There's no way..." "If the man's gonna barbecue himself, he ought to use sauce." "The man's name was Samuel Platt." "He was brilliant." "A scientist, and someone who cared about others." "Under the circumstances, I don't believe that kind of humor is appropriate." "Sorry, buddy." "Really, I'm sorry." " Are you okay?" " We should have known." " We should have protected him." " How?" "I don't know, but we should've done something." "Look, Clark, all we can do now is try and prove him right." "We have a lot of work to do." "It's only 5:30." "Why don't we try and get a few hours sleep... and I'll come by for you about 9:00, okay?" "I can't help it, Mom, I feel responsible." "If you could have helped him, you would have." "Clark, what's this about a worker caught in an explosion down a manhole?" "Your mother told me he recognized you." "Dad, the workman was really out of it." "I mean, nobody believed him when he pointed to me." "One of these days, you'll pull one of your stunts..." " and a nut with a video camera..." " What did you want him to do?" "Did you just want him to let the man die?" " How are your clothes holding out?" " Don't change the damn subject." "I have been thinking about this." "Maybe it's a crazy idea, but, Mom, how's your sewing machine?" " Is it still working?" " I think so." "I have a favor to ask." "I think I need some kind of outfit." "Outfit?" "Like a disguise I could wear, when things like that explosion happen." "I could..." "Mom, I gotta go." "Lois is here." "Lois again, huh?" "Bye." "I said 9:00." "I thought you'd be naked." "Ready." "I was on the phone." "I'll be out in a jiff." "We'd better be going." "Explain something to me." "You eat like an eight-year-old, and you look like Mr. Hardbody." "What's your secret?" "And can I have it?" "But, Henderson, if there were contusions on Dr. Platt's head..." " then he could've..." " Inconclusive." "He could have gotten them last week." "I'm sorry, but the autopsy result is gonna read: "suicide."" "This isn't over." "I'll call you back." "Who's that?" "That's Mrs. Platt, and her daughter, Amy." "Mom, I was supposed to be at Susan's by now." "Okay, honey." "Take my coat, and just wait over there by the elevator for me, okay?" " Bye." " Excuse me." "I haven't told her yet." "You see, everything we worked for was for Amy." "The space lab Prometheus was the only hope, and now..." "Mrs. Platt, when you and Amy left your husband..." "No, we never left him." "He made us leave." "He was sure that they were going to come after him." "He was afraid that Amy and I would get hurt... so he sent us away." "Do you have any idea who might have..." "All I know is..." "Samuel knew that Prometheus was being sabotaged... and that knowledge got him killed." "Please, help me." "Don't let his daughter grow up believing her father committed suicide." "We'll try." "We promise." "Thank you." "We interrupt our regularly scheduled program... to bring you this special report from the Congress of Nations." "I am pleased to announce that we have unanimously decided... that the Space Station Prometheus will proceed." "What about Lex Luthor's proposal?" "This body would like to extend our deepest gratitude to Mr. Lex Luthor... for his generous offer... but it is our firm belief... that the space station should go forward as originally planned." "A project dedicated to global cooperation... for the advancement of the sciences." "The colonist launch, scheduled for next week... will proceed as planned." "The rocket will also carry an auxiliary propulsion module." "Should any serious problems arise... we shall be forced to cancel the mission." "We don't anticipate that happening, we anticipate success." "So, I gave STAR Labs Dr. Platt's report." "They recreated the launch in a hologram." "It was really smooth." "Anyway, they concluded that Platt's theory was right on." "There was deliberate sabotage... and the transport explosion was no accident." "Congrats." "He was right." "Platt was right." " Now we can write the story." " I can write it." " With my help." " With your help." "And if we can convince people there was sabotage..." " and who was behind it..." " We can stop him." "Why don't we have dinner?" " I don't know." " We should celebrate." "Okay." "Dinner." "Great." "Wait a second, what am I talking about?" "I can't." "I have plans tonight." "Luthor?" "Yeah." "Tell me something." "How far are you willing to go to get this interview?" "Not that it's any of you concern, but as I told you before, this is business." "What is your problem, anyway?" "You've had a chip on your shoulder since the day I met you." " You resented the fact..." " Perry foisted an inexperienced..." " Snob." " What?" "You are a snob, Lois." "Coming from Mr. Green Jeans, that's really..." "I live by three rules." "I never get involved with my stories, I never let anyone else get there first... and I never sleep with anyone I work with." "This is business." "Your mother and father both died when you were 14, correct?" "Why don't I just have my office send you a biography?" "Because I don't want the standard line." "I wanna know the real Lex Luthor." "What makes you tick, what you strive for... what you want." "Pleasure." "The pursuit of pleasure." " Does that surprise you?" " I would have guessed you'd say power." "Power is a means, not an end." "You took over your first big company when you were 21." "There were rumors that that buyout was coerced." "Is it true that the board of directors were..." " Now, was the food not to your liking?" " It was delicious." " It's just that when I work, I..." " All work and no play." "Is that your credo, Lois Lane?" "I think that we should..." "Why don't we just enjoy the evening... enjoy each other... let down your hair, loosen the tie." "I'm not wearing a tie." "But you're so tense." "Why don't you just let your defenses down?" "I think you've gotten the wrong idea about this dinner, Lex." "I hope you don't think that we're here... merely because you're a beautiful young woman." "That wouldn't speak very well, for either of us." "Look, you want an interview, right?" "A scoop." "I understand that." "Quid quo pro." "Let me tell you what I want." "My talent in life is not making money." "It's not juggling companies." "It's character assessment." "And I sense things about you." "Possibilities, potentials." "You have the intelligence, the spirit, and the vision... to transcend the mundane." "And, just so there are no misunderstandings... you are beautiful." "Lex, I have a story to write tonight." "I should get going." "No dessert?" "No." "I never have dessert." "Really?" "You don't know what you're missing." "Good night." "Well?" "I blew it." "I didn't get the interview." "No, did he ask you out again?" "I don't know." "I guess so." "You guess so?" "I hope you said yes." "Lex Luthor is the world's most eligible bachelor." "Mr. Right could be right out there." "Come back to Earth, Lucy." "This is reality we're talking about." "All right, let me see if I've got this straight." "You want me to publish a story... that says that the Prometheus project is being sabotaged... that the space transport Messenger exploded... and that the transport carrying the habitation module... to Space Station Prometheus... scheduled to be launched in less than three days... is probably also going to blow up." "And all of this information... you got from interviewing Samuel Platt... a man who was banned from the scientific community... underwent psychiatric treatment, and committed suicide... although he was "probably" murdered." "Now, does that about sum it up?" " Chief..." " Hard facts." "That's the name of this game." "Now go out there and get me some." " What we need is physical evidence." " I'll call Dr. Baines... and try to get permission to set up an independent examination." "Baines will not let you do that." "She could be involved." "Besides, we don't have time to play by the rules." "The colonist transport goes up in two days." "I'm calling." "Maybe someone else at EPRAD will authorize it." "You do that." "Where are you going?" " Nowhere." " I'm coming, too." "I guess I don't need to point this out to you, Lois... but this is dangerous." "Fine, you go back to writing obituaries..." "I'll grab the scoop of the century all by myself." "How do we get inside?" " We don't have to." " What?" "I watched them load the Messenger wreckage onto the truck." "The whole left side of the shuttle was bashed in." "That one isn't." "They're working on a phony shell." "Dr. Langley, contact the main gate." "Dr. Langley, main gate, please." "You're amazing." "Where'd you learn to do that?" "Reform school." "It was a bum rap." "Your friend Lois Lane is here." " Lois, this is so cool." " I think it's time we eliminated her." "Kill off The Daily Planet's star reporter?" "I'm surprised at the suggestion, Antoinette." "She suspects me, Lex." "You said I would never be implicated." "She lacks evidence." "Evidence is sometimes all that separates the criminal... from the successful businessman." "Or woman." "I told you I'd take care of her." "I did this for you, Lex." "And you've been paid very well." "In fact, your final installment is waiting in the helicopter." "Proceed as planned." "I promise, there will be no loose ends." "Lois, what do you expect to find here?" "Do you know what particle isolators even look like?" "Wow, smooth." "Take pictures of every inch of this wreck." "We'll have them analyzed later." "Then we'll have to break into Dr. Baines' office." "I am positive she's lying about that report." "I never trusted that woman, not from the very first time I met her." "The way she looked at Clark, very unprofessional." "Jimmy?" "Jimmy, get up." "Very impressive, Lois." "These days, a woman has to know self defense." "Okay, sorry about the late hour, folks." "Just doesn't seem to be enough time in a day." "Where are Lois and Jimmy?" "Clark?" "I assumed they'd be here." "All right, we're going to just start without them." "Okay, now... the piece on the recent sex-change operation in the royal family." "I kind of have mixed feelings about this." "L..." "Kent, the meeting's not over." "It's not like Lois or Jimmy to miss a staff meeting, sir." "I thought I'd go call around, if that's okay." "Hell of a way to run a railroad." "All right, let's see, where was I?" "Yeah, okay." "Kent?" " Kent, there you are." " Yes, sir." "They told me you were in here." "Yes, sir." "Did you make your call?" "I was just about to, sir." "Are you looking for something?" "No, sir." "Not really." "I guess I'd better be getting back." "Yes, sir." "When are you coming?" "Out of the closet..." "Soon, sir." "Very soon." "You'll never get away with this." "Everyone at the Planet knows where I am." "Let her go." "Put down those guns or I'll..." "Or you'll what?" "Nothing." "I told Perry I needed a task force." "A task force!" "What do I get?" "Amateurs." "I still can't believe you came barreling in here like some 500-pound gorilla." "If you thought we were in trouble, why didn't you bring the police?" " Look..." " Don't tell me, I already know." "Because you're like every other man in Metropolis." "You've got this testosterone surplus that says, "I can do it myself."" "Baines has got to kill us now." "I don't know why she hasn't done it already." " Lois, I've somehow managed to..." " Mess everything up?" "No kidding!" "Now hold on a second." "I'm not the one who snuck in here..." "What are you saying?" "Are you saying that this is my fault?" "At least I have the guts to come in here and..." "What am I saying?" "This probably is my fault." "Oh, God." "I sometimes do things." "You know, like jump into the pool without checking the water level first." "But, Clark, it's the only way I know how to do it." "How to get the job done, to get the respect that I want... that I deserve." "Do you remember when I told you about my three rules?" "I've broken every one of them." "I somehow manage to always get involved with my stories." "You slept with someone at work?" "Yeah." "It wasn't Jimmy, was it?" "Don't be ridiculous." "It was a long time ago, when I first started at The Daily Planet." "Claude." "He was French." "I must have been in love with him, or thought I was, anyway." "One night I told him about my story... and the next morning when I woke up, he was gone." "So was my story." "He won an award for that." "Didn't even thank me for my input." "I guess when you're in love with somebody... it doesn't matter how smart you are or how many rules you set for yourself... you're still vulnerable." "We're only human." "And what difference does it make now, anyway?" "We're just gonna die." "You know what you said about respect?" "I just want you to know that everybody on the Planet... everyone, thinks you're just about the best reporter they've every met." "Perry told me that the day I interviewed." " He did?" " Yeah." "And not that it really means anything coming from a hack from Nowheresville... but I think you're pretty terrific, too." "I'm sorry... about everything." "I know it's too late for apologies, but I never meant..." "I hope you'll forgive the accommodations." "But then again, I never was much of a hostess." "Answer one question." " Why?" " It's simple, Lois." "Profit." "Outer space is no different than any other new frontier." "It'll belong to those who get there first and seize the high ground." "Sorry you won't be around to enjoy the rest of the evening... but accidents do happen." " Accidents?" " Yes." "You see, while dismantling the orbital maneuvering system... the monomethylhydrazine leaked... and mixed with the nitrogen hydroxide." "Unfortunately, the blast killed three nosey reporters... who didn't bother to read the sign." " Clark, how did you..." " A missing link." "Come on." "What happened?" "I don't know." "I guess the force from the explosion must have carried us here." "Look." "Good night, Antoinette." "Sweet dreams." " Were you scared, Jimmy?" " Scared?" "No!" "No, ladies, not at all." "I was more concerned with the larger issue... unless we got out of there alive, the colonist launch could blow up as well." "I just spoke to ground control over at EPRAD." "They went back over the colonist launch vehicle... with a fine-tooth comb." "Found the same coolant problem in the protective bands, and fixed it." "Launch is all set for tomorrow morning." "It's a no-go for you, Lois." "No reporters allowed." "Imagine The Daily Planet getting an exclusive personal account... of being on the colonist transport." "No can do, Lois." "All right." "Another time, maybe." "Clark, you're gonna be pleased to know... that Platt's widow and his daughter are back on board." "Thank you very much, sir." "I appreciate that." "Clark, I just..." "I wanted to thank you for all your help getting us out of there." "I'm glad it all worked out." "And one other thing." "If you ever breathe a word of anything I told you in there..." " I will deny it and I will..." " You can trust me, Lois." "Right." "Heard that one before." "Hey, Lois, good luck!" "Mobile logical monitoring devices should be self-activated." "I'm still showing a red light in Sector 7." "We will advise." "Attention, all ground personnel." "All service vehicles depart the gantry area." "I don't know about this costume thing, Clark." "It'll work." "It has to." "If I have an effective disguise..." "I won't have to worry about people finding out about me." "Come on, let's get started." " What about that one?" " I don't know." "What do you think?" "One thing's for sure, nobody's gonna be looking at your face." "Mom!" "They don't call them tights for nothing." "I don't know." "There's something missing." "Something..." "What's that?" "The baby blanket we found you in, so long ago." "And this." "Your folks would be proud of you." "We sure are." "Thanks, Mom." "I'm not so sure about the cape, though." "Really?" "I love it." "It'll be great when you're flying." "Hey, you two, come on in here." "Launch vehicle's about ready to go up." "...preparation for the upcoming launch." "All have undergone a series of examinations..." "The colonists are just about all on board." "...to function in an off-Earth environment." "This will be the first time that a group this large... drawn from the general population, will..." "Historic occasion." "Remember when you were a kid, Clark, and we watched the first moon landing?" "On a more personal note, head columnist..." "What do you think?" "That's my boy." "That's right." "What if somebody recognizes you?" "I don't think they will, Mom, because it won't be me." "Yeah." "Attention, all personnel, we have reached and cleared..." "Booster, set on my mark." "Prepare to synchronize all information processing... and data retrieval systems at this time." "Main computer panel control transfer to redundant computer sequence." ""T"minus three minutes." "All technical personnel should deplane at this time." "Mission Control advises ground crew that the system check is on." "Panel is now green in all sectors." "All bio-monitoring systems are go." "The umbilical cord attached to the liquid-fuel booster... has been disengaged." "One minute and counting." "Almost ready to go." "Section 8, please double-check your indicators." " Roger." " Confirmed, no problems." "Forty-five seconds and counting." "Go back to BOCS again." "Pick up 255.66..." "Cabin temperature is 60 degrees, cabin heat exchange is 48 degrees." "Oh, my God, it's a bomb." "Baines." "It's a bomb!" "Someone, help!" "There's a bomb!" "Help!" "Perfect ignition." "There she blows." "Thirty seconds and counting." "Circuit failure in the main panel." "Due to a mechanical failure... we are suspending the countdown at 29 seconds." "We will advise." "I don't believe it." "Something's gone wrong." "...there has been a launch termination." " Clark." "Seemingly, the computers have sensed some sort of a problem..." "What the hell is that?" " Is that a bird?" " Is it a plane?" "Nope." "Just a guy in a pair of tights and a cape." "Are we scrubbing the mission?" "Get away from that!" "What kind of a lunatic are you?" "That's a bomb, and you're..." "Excuse me." "What the hell are you?" "Yes, sir, due to equipment problems and an unexplained occurrence..." "There was a bomb." "He... ate it." " Hi." " Hi, I like your costume." "Thank you." "My mother made it for me." " What's your name?" " Amy." "Amy Platt." " Who are you?" " I'm a friend." " Can you teach me how to fly?" " Not fly." "But once this lab is operational, walk." "That's very possible." "Attention, colonists." "The mission has been scrubbed." "Prepare to disembark." "That's it, then." "It's all over." "Why?" "Once the thrusters have been fired, they have to be replaced." " We lose our launch window." " Yes." "We just have to forget about Space Station Prometheus." "No, you don't." "There's nothing wrong with this transport vehicle, or the station." "You only need to get there." "How are they supposed to do that?" "Easy." "I'll give them a boost." "I want security tech teams over every inch of that transport." " Lift-off." " What?" "That's impossible!" "Lift-off." "All Prometheus personnel, prepare for docking." " I still don't believe it." "A man who flies." " It's all over the TV." "Jimmy, don't believe everything you see on TV." "I'll tell you one thing, though." "Whoever pulled off a hoax like this is..." "Great shades of Elvis!" "I see it, but I don't believe it." "What, a man who flies?" "No, Lois Lane finally, literally, swept off her feet." "Too bad he's an alien." "I think, considering the fact that I saw you first... you owe me an exclusive." "Is that the rule?" "Well, no, but I'd appreciate it very much." "Wait a minute!" " How do I find you?" " I'll be around." "Real smooth." "Did you find out what the "S" stands for?" "Super..." "Superman." "Let's get back to work." "We've got a newspaper to run." "An astonishing debut, Superman." "Haven't you heard?" "That's what they're calling you." "It's international news." "So, to what do I owe this honor?" "I came to tell you that I know who you are." "Who you really are." "I suppose, on its face, it was a good plan." "Destroy Prometheus, so that you could put your own space station in its place." "Then, not only would you make billions... from the patents of the vaccines developed... but you would also be the supposed savior of the space program." "Well, it's an interesting theory, Superman, but I'm afraid that's all it is." "You were also responsible for the deaths of at least three people." "Cdr." "Laderman, Samuel Platt, Dr. Baines." "Those probably aren't the only skeletons in your closet." "So you've become both my judge and executioner?" "Like any other citizen of the planet, I must obey the law." "I am not above it." "You, it seems, believe you are." " I hold a certain position in this city." " Yes." "And there is nothing that would please me more than to see you dethroned... and behind bars like any common criminal." " That day will come." " Well, I trust not." "But, as they say, let the games begin." "One more thing." "If you ever need to find me... all you have to do is look up." "Morning, Lois." " Clark, where have you been?" " Around." "Not that it's anywhere near as exciting... as the stories you covered on The Smallville Press... but Superman was in the newsroom, and I just about nailed down the exclusive." "Well, congratulations." "Clark, you should have seen him." "Up close, he is the most magnificent figure of a man that I have ever..." "Sounds like he made quite an impression on you." "He did." "Why, are you jealous?" " Of Superman?" "Should I be?" " Please." " Where are we going?" " Terrorist shootout on Sixth." "And, Kent, I'll ask the questions." "English"
|
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"pile_set_name": "OpenSubtitles"
}
|
Superior cleaning with twice the suction of any robot vacuum . Schedule cleaning time from your smartphone with the Dyson Link App . Built for carpets and hard floors, the 360eye picks up dirt from almost anywhere in your home using its powerful V2 spin...
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{
"pile_set_name": "Pile-CC"
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|
Q:
Replace textbox lines contains 2 digit replace with Vbcrlf (VB.Net)
if I have a textbox1.lines > how can i somehow do where there is a single digit, to be replaced with vbcrlf? (Visual Studio)
2
77,48
1,3
7
9
11,90
Output:
77,48
1,3
11,90
A:
Something like:
Dim NewLines As List(Of String) = New List(Of String)
For Each Line As String In TextBox1.Lines
If (Line.Contains(",")) Then
NewLines.Add(Line)
Else
NewLines.Add("")
End If
Next
TextBox1.Lines = NewLines.ToArray()
Outputs:
(blank line)
77,48
1,3
(blank line)
(blank line)
11,90
This iterates through each line in the Lines collection. If the line contains a comma (which indicates there is more than one letter), it adds the line to the output list. If it does not contain a comma, it adds an empty string.
Finally, the contents of the output list are assigned to the Lines property of the TextBox.
Also: There could likely be a neater Linq solution but I'm not an expert
|
{
"pile_set_name": "StackExchange"
}
|
Pro-Team Cleaning & Janitorial is a privately owned company. We are not brokers nor a referral service or a franchise. When you contact us, you are interacting with the people that own the company. You will always receive personalized service and an immediate response to your needs.
Be certain that all our cleaners receive the most rigorous training in the industry and are decent, honest human beings dedicated to providing solutions to all our customers' cleaning needs.
We provide all cleaning supplies so you can concentrate on relaxing and enjoying a clean, sanitized beautiful smelling house. Always choosing the right cleaning agents that are less of a health risk for your children as well as your pets and use organic cleaners whenever we can without compromising the quality of our work.
|
{
"pile_set_name": "OpenWebText2"
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|
#UniteInSpeed
Collect all of the other Trophies.
0.5%
Ultra Rare 5.15%
Very Rare
Clubman
Join a Club, or have someone join a Club that you have created.
16.4%
Rare 32.98%
Uncommon
First Of Many
Beat your first Face-Off.
78.4%
Common 81.93%
Common
Contender
When the timer expires on a Driver Challenge, be at the top of the leaderboard.
1.6%
Ultra Rare 9.00%
Very Rare
And So It Begins!
Send a Challenge to another player.
6.9%
Very Rare 16.99%
Rare
Level Up!
Reach Driver Level 2.
68.4%
Common 70.35%
Common
5 and Counting
Reach Driver Level 5.
47.8%
Rare 50.91%
Common
Progress
Reach Level 2 with one Accolade.
56.5%
Common 58.48%
Common
Tonnage
Complete a point to point Event with an average speed of 100mph or 161 km/h.
14.1%
Very Rare 20.49%
Uncommon
Face-Off
Complete 50 Face-Offs.
37.8%
Rare 44.29%
Uncommon
On The Podium
Place in any of the top 3 positions during a 12 player race.
61.6%
Common 67.80%
Common
Nose To Tail
Draft another vehicle for at least 2000 metres (2187 yards) in a single event.
37.7%
Rare 43.13%
Uncommon
Team Work
Be a member of a Club that is Club Level 10 or above.
10.7%
Very Rare 24.17%
Uncommon
Rack 'em Up, Knock 'em Down
Beat 3 Target Times in a single Time Trial event.
11.8%
Very Rare 16.76%
Rare
Long Distance
Drive for at least 300 miles (483 km).
19.7%
Rare 25.33%
Uncommon
Making Waves
Reach Driver Level 15.
24.6%
Rare 30.74%
Uncommon
Life Begins
Reach Driver Level 30.
8.5%
Very Rare 15.19%
Rare
Full House
Win a Race in each class of vehicle: Hot Hatch, Performance, Sports, Super and Hyper.
9.6%
Very Rare 17.16%
Rare
Unbeatable
Win 5 of your own Solo Challenges after sending them to at least one other player.
0.7%
Ultra Rare 6.58%
Very Rare
Mastery
Reach Level 6 with one Accolade.
11.4%
Very Rare 17.08%
Rare
Hoon-a-tic
Rack up 1 million Drift Points in total.
3.6%
Ultra Rare 9.29%
Very Rare
Cleanup
In a 12 player race, finish on the podium without losing any Fame due to collisions with other competitors.
11.3%
Very Rare 18.67%
Rare
Lifer
Drive at least 1000 miles (1610 km) as a Club Member.
2.6%
Ultra Rare 9.41%
Very Rare
Welcome To The Limit
Reach Driver Level 50.
2.1%
Ultra Rare 7.40%
Very Rare
|
{
"pile_set_name": "OpenWebText2"
}
|
Tomas Kalas: Set for Cologne loan move
Newly promoted Cologne are close to concluding a loan deal for Chelsea defender Tomas Kalas, the club have confirmed.
The highly-rated 21-year-old central defender made his Premier League debut at the end of last season, starting in Chelsea's 2-0 win at Liverpool in April, but Jose Mourinho is ready to sanction a loan deal.
Cologne are understood to be looking to clinch a two-year loan for Kalas, similar to a spell he had with Dutch outfit Vitesse Arnhem from 2011 to 2013.
Cologne general manager Jorg Schmadtke confirmed that talks are ongoing.
Schmadtke told BILD: "Nothing has been signed just yet. But I am expecting the (loan) deal (of Tomas Kalas) to go through."
|
{
"pile_set_name": "OpenWebText2"
}
|
BBC refuses to show emergency relief appeal for Gaza
By
Niall Green
28 January 2009
There has been broad condemnation of the decision by the British public service broadcaster the BBC to refuse to show an appeal for humanitarian aid for the people of Gaza organised by the Disasters Emergency Committee (DEC) of aid charities. The corporation is the only terrestrial broadcaster in the United Kingdom to refuse to air the appeal, which aims to raise funds to provide emergency relief to the thousands of Palestinians facing a humanitarian catastrophe in the war-torn Gaza Strip.
The DEC is a blanket organisation representing many aid charities, including the Red Cross, Christian Aid, Islamic Relief, Oxfam and Save the Children. Their appeal requested support from the British public to buy food, medicine and blankets for the tens of thousands of Gazans left hungry and homeless by the Israeli assault on territory.
BBC Director General Mark Thompson claimed that airing the DEC appeal would put the corporation's impartiality at risk by giving the impression the BBC was "backing one side" over the other.
"The public wants us to be very strict about our impartiality, and it is my job to protect that impartiality," said Thompson, who denied claims that the decision had been made to appease pro-Israel lobbyists. The director general also offered the unsubstantiated suggestion that the BBC could not guarantee that aid would reach the victims.
According to the Guardian newspaper, Brendan Gormley, the DEC's chief executive, had informed the BBC that the appeal would raise money "for all those affected by the recent conflict," indicating that they would provide aid to people in southern Israel if needed.
Veteran Labour MP Gerald Kaufman claimed the BBC had responded to "nasty pressure" from "very active and not very pleasant Israeli diplomatic representation in Britain."
Over 11,000 viewers have contacted the BBC to complain about its refusal to air the appeal. The other main television broadcasters ITV, Channel 4 and Five aired the DEC message Monday evening.
The decision is widely opposed within the BBC itself. Former BBC journalist and independent MP Martin Bell wrote in the Guardian: "The refusal to transmit the Disasters Emergency Committee appeal has left it isolated and exposed. Its senior journalists feel betrayed, but dare not speak out because of their terms of service."
One unnamed BBC news sources stated: "Feelings are running extremely high and there is widespread disgust at the BBC's top management. There is widespread anger and frustration at the BBC's refusal to allow people to speak out about it."
In a joint statement journalists' union the NUJ and the broadcaster's union BECTU said the BBC's choice was "cowardly and in danger of being seen as politically motivated." Several artists and broadcasters have criticised the BBC, including actress Samantha Morton, who claimed she would never work for the corporation again due to its "horrific" and "disgusting" decision.
Mohammed Shafiq, head of the Ramadhan Foundation, a British Muslim youth organisation, condemned the BBC. "Whatever our positions or views on the Gaza crisis the innocent victims in Gaza need our help and support and the BBC has a public duty to broadcast this appeal," Shafiq said.
The Sky News channel, part of the media empire of the staunchly pro-Zionist billionaire Rupert Murdoch, has also refused to show the DEC message, insisting that it would be "incompatible" with its objectivity. Sky News announced its decision a few hours before the appeal was due to be broadcast on the other main channels.
Despite the BBC's claim that it is only interested in defending its "impartiality," the corporation has broadcast DEC appeals for aid in other war zones. For example, it showed DEC films requesting aid for the victims of the conflicts in the Democratic Republic of Congo and the Darfur region of Sudan. Last year the BBC showed an appeal for victims of the cyclone that hit Burma, despite the politicisation of aid by the Western powers and widespread criticism of the Burmese junta's commitment to distributing supplies.
The BBC has form when it comes to refusing to air public appeals on the grounds of "impartiality." The BBC used this justification regarding an appeal for aid to Lebanon in 2006 following the Israeli war against Hezbollah and its supporters, in which hundreds of civilians died and much of the country's infrastructure was targeted for destruction.
When it comes to charitable appeals, the BBC are quite prepared to show them if the plight of the victims can readily be attributed to regimes such as those of Sudan or Burma, which are subject to the threats of London and Washington. But when the victims are civilians slaughtered and made destitute by a key ally of British imperialism such as Israel it seems that Broadcasting House cannot seek to raise the flag of impartiality quickly enough.
In fact, the claims of "objectivity" and "impartiality" that Thompson and the BBC are using to justify their decision not to show the charity appeal stand in contrast to the actual content of their news reportage on the Gaza conflict. Despite the overwhelming devastation that was rained down on the almost completely defenceless and impoverished population of Gaza, BBC news reports insisted on giving roughly equal coverage to the few homemade rockets being fired by Hamas militants into southern Israel. At the end of Israel's assault on Gaza the Palestinian death toll stood at over a thousand, the majority civilians, including hundreds of women and children. Israel suffered 13 fatalities, ten of them soldiers.
Throughout the conflict, the corporation treated Israel's claim that it was acting in self-defence as good coin. It provided Israeli military spokespeople with ample opportunity to state their case, usually with few or no probing follow-up questions from journalists. Opposing statements by Hamas or Palestinian Authority representatives were rarely shown.
Nor did the BBC seriously take up the Israeli government's refusal to allow international journalists into Gaza in an effort to cover-up the scale of IDF atrocities.
Around 120 Members of Parliament have backed a parliamentary motion criticising the BBC and Sky for not showing the appeal. Cabinet ministers Douglas Alexander and Hazel Blears weighed in. Alexander, the International Development Secretary, called on the BBC to consider that "People are suffering right now; many hundreds of thousands of people are without the basic necessities of life." The prime minister's website posts a link to the DEC appeal.
All this is sheer hypocrisy. Alexander, like the rest of the Labour government of Gordon Brown, has refused to condemn Israel's war crimes in Gaza or its blockade of the territory since Hamas came to power in 2006. The British government fully endorsed the Israeli claims that it acted in "self-defence" against "terrorist" Hamas, despite Israel's bombardment of civilian targets including United Nations run schools and hospitals.
The government's criticism of the BBC effectively sealed the corporation's decision regarding the DEC appeal. BBC Trust Chairman Sir Michael Lyons warned that such comments from government ministers came "close to constituting undue interference in the editorial independence of the BBC." Thus, Thompson could not reverse his decision, even if he wanted to, as it would appear he had bowed to political demands.
The publicly-owned broadcaster is an anathema to a substantial section of the British bourgeoisie, who resent it as a limitation on its ability to make profit and for its supposedly "pinko liberal" editorial views. While issuing crocodile tears for the civilians in Gaza, most of the British press has used the issue as a stick to beat the BBC with.
Melanie Phillips, commentator for the right-wing tabloid the Daily Mail supported Thompson's refusal to show the appeal but said this was nonetheless an indicator of how the BBC had "lost its way." Attacking the BBC news for being pro-Hamas and directed by "left-wing" executives, Phillips insisted that "licence-fee payers are increasingly questioning its very existence as a publicly financed broadcaster."
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