It seems big companies can't catch a break. A recent Harris poll suggests that consumers don't trust a lot of big businesses and less than 20% of people trust companies in the banking, pharmaceutical and health insurance industries. The movement to buy local is arguably one factor, but large corporations and their actions may have brought about some negative attitudes. Listed below are just a few issues that some consumers hold against big businesses:

Poor Net Job Creators

In terms of numbers, the vast majority of businesses in Australia are considered small businesses. The Australian Bureau of Statistics (ABS) reports that of the 2.1 million businesses in our country 96% are considered to be small businesses. In June 2011, the ABS found that:

Over 2 million businesses employed less than 20 staff (including 1.3 million businesses who did not employ any staff) and;

Over 2 million businesses had an annual turnover of less than $2 million.

Of course, these small businesses employ the lion’s share of the Australian workforce and create the most new jobs. The reason for this is that new or growing companies (which tend to be small at first) hire more employees over time as they grow. Large, established companies are in the business of making money for their shareholders. Most are focused on making more profits more efficiently. A common way to accomplish that is downsizing and increasing prices - two practices generally unpopular with consumers.

The Power to Affect Legislation

Large companies have deep pockets. Frequently, that means that they can have full-time lobbyists on the payroll making sure that any pending legislation is favourable to their industry and their company. Large corporations can have a huge impact on the law and on elected government officials who rely on their money at election time. Sometimes, corporations can even enter government agencies. This kind of cosiness between big business and the government can make people mistrustful.

Crushing Small Businesses

In industries where economy of scale makes a huge difference in profit margins, big businesses can, and do, squeeze smaller ones out of the market. This can happen through predatory pricing strategies, exclusive distributorship arrangements and even through lobbying state and federal governments to increase the barriers to entry in the industry. Big businesses are the Goliath to the small business David. In the Australian business world, David rarely wins.

Taking Profits out of the Economy

A corporation's main goal is to provide a profit to its shareholders. In a small company's growth cycle, profits are often ploughed back into company coffers to fund expansion, but a large, mature company siphons profits off to pay dividends to shareholders. Most shareholders retain those dividends in investment portfolios rather than spend them, so they don't have a stimulative effect on the economy. Local communities often do not benefit from having large corporations operate in their area, especially when top management is helicoptered in from elsewhere. Consumer sentiment can turn especially negative when large corporations receive government grants and loans to prop up operations.

The Bottom Line

Large corporations have a reputation for being untrustworthy and a drag on the economy. Some of this reputation has been earned fair and square; however, many big companies try to soften their image to appear more local and community-oriented, but jaded consumers are difficult to convince.


Facile synthesis of 3,4-dihalofurans via electrophilic iodocyclization.
A facile, efficient, and general synthetic method for 3,4-dihalofurans has been developed via the electrophilic iodocyclization of various 4-hydroxy-2-but-2-yn-1-ones. The use of MeOH as a solvent is crucial for the efficient chemoselective synthesis of the corresponding 3,4-dihalofurans.


Despite tosh spouted by idiots, losing a loved one to cancer, being made redundant, or finding oneself stuck in a lift with Piers Morgan aren’t made worse by the event’s proximity to 25th December, research has found.

“Any of those is a bugger” agreed project lead Dr Rachel Guest “though Morgan would be especially unwelcome, particularly in the run up to … no forget that”.

Guest found other evidence-free folk beliefs were common amongst those surveyed.

“One man’s mum had died the day before and he insisted ‘there’s a new star in the firmament today’ whilst pointing at Eridanus-Capricon vii, a massive ball Continue reading →

The Daily Mail’s Editor, Paul Dacre has been detained under the Mental Health Act, after MPs voted to have the final say on Brexit.

“He lasted an hour once the news broke.” said Mail journalist and physical embodiment of the argument for banning public schools, Quentin Letts, a man who might bum your cat and then expect you to thank him.

“When Paul’s dribble turned to foam we contacted emergency social services, which was ironic as we’d just made up a story about all social workers being Continue reading →

Couldn’t Glenn Close have played the part just as well? Or Bette Midler.

The UK premiere of The Darkest Hour, the latest biopic of Winston Churchill, brings with it fresh calls for a woman to play the part of the legendary British wartime leader.

“Gary Oldman is certainly a great actor” says Evening Harold film critic, Mariella Buss-Stop “but you can’t escape the fact that he’s still another middle-aged white man. And how they let him onto Air Force One Continue reading →

England’s pub brawlers are facing another crisis, as yet another member of the squad has been suspended, pending an inquiry into an alleged incident of cricketing.

Earlier in the troubled tour, Jonny Bairstow was accused of ‘wicket-keeping’ when he should have been head-butting one of the Australian team. However, even before the team left the UK England’s talismanic all-rounder Ben Stokes, was captured by security cameras, playing French-cricket in Continue reading →

Following a frantic last 48 hours of shuttle-diplomacy, Theresa May has finally managed to concede to almost all of the EU negotiators’ demands.

“It wasn’t easy and at any moment there was a danger I might not give in.” explained an obviously tired Prime Minister “Of course I could have agreed these terms months ago but I’m no pushover, so I held out to the last minute before caving Continue reading →

Theresa May says there’s no story behind the mass resignation of the only team within government that has even a pretence of caring.

“Rather than criticising imperceptible progress toward a fairer society,” said Mrs May “why not just replay YouTube clips of my first speech as PM, when I vowed to tackle social injustice and inequality. ‘Where there is hope may we bring … no, not that. Err Continue reading →

Philip Hammond’s budget played nug-a-nug with the UK yesterday but those unfamiliar with the detail of economic theory are struggling to know if this means everyone has been given a nice low down tingle, or a right royal seeing to, so thorough it’s left them feeling they’ve reached out and touched the face of God.

Professor of Economics Julia Hogsburn of Dunstable University explained that sexual innuendo and metaphor, though popular in tabloid journalism, were actually unhelpful when assessing economic stability. “No, what we’re looking at here is more akin to being Ramsay Boltoned” said Hogsburn “I hope Continue reading →

Speaking outside the 20th century (at the other end), Rees-Mogg, an expert on laws spiritual and temporal, explained that his God hates divorce, contraception, and menstrual cycles. And socialists – “not just the women socialists though.”

The MP says that although he is prepared to compromise his beliefs, as far as the divorce itself is concerned, actually paying for it is a step too far. “I would never do so, of course, but if I ever did leave my wife I Continue reading →

It hasn’t lost all humanity and will still throw your parcels over the fence

With funding for expanding driverless car use in the budget, Philip Hammond says the Tories have already piloted the idea, using entirely rudderless government.

“It uses very much the same principles.” said the Chancellor, dancing around and waving a torch so as to be seen “You swap a human driver, who is susceptible to being distracted by thoughts, feelings, and suchlike, for an emotionless robot making choices on Continue reading →

Explorer Benedict Allen has said sorry to his wife for the indignity of being rescued in Papua New Guinea by the Daily Mail.

Appalling hate-mongers at the Daily Mail had hired a helicopter to cash-in on the disappearance of Benedict Allen, hoping that it’s appalling editor Paul Dacre might yet sneak into the New Year’s Honours list.

Popular International Development Secretary Priti Patel was ordered back from an official trip in Africa by the PM, summoned to Downing Street and then by sheer coincidence decided to resign. “I wasn’t sacked” said Ms Patel.

In her resignation letter, which was in no way prepared in advance by the PM, Ms Patel said her actions “fell below the standards of transparency and openness that I have advocated for other people. I just didn’t realise they might apply to me. So I’ve resigned”.

With yet another hapless minister being shown the door, Larry the Downing Street cat is standing by, in the expectation that he’ll get a Cabinet post later this week.

The PM hopes that Larry will help dispose of some of the larger rats before they abandon the sinking ship. “He’s not actually very good at it” admitted press secretary James Slack “but then again David Davis and Jeremy Hunt haven’t set the bar very high.”

“Larry’s a safe pair of paws though,” insists Slack “used to shitting in public, then half-heartedly trying to cover it up, so he should fit in well with Boris Continue reading →

Chris managed to beat off rivals to secure a post with the family firm.

Tory MP, whip and all-round know-it-all Chris Heaton-Harris, has written to all home-schooling parents, asking them to send him copies of their lesson plans, with particular reference to Brexit.

“There’s no hurry,” says Heaton-Harris “but shall we say next Monday at the latest? As half-term actually ends on Friday afternoon.”

The popular government whip likes people to justify their position in society and has written to all the nation’s educators, partly because time hangs heavy on his hands as an MP but mostly because Continue reading →

Ukippers and other idiots are still keen on giving the UK a damned hard brexit, often waking early, drenched in various bodily fluids, after a night spent fantasising about it.

With the referendum won, right-wingers are managing their otherwise empty internal worlds by dreaming of giving us all a really good brexiting. “The UK may say be saying ‘no’ but I know better,” explained Continue reading →


Observation of amplitude and phase in ridge and photonic crystal waveguides operating at 1.55 microm by use of heterodyne scanning near-field optical microscopy.
We apply heterodyne scanning near-field optical microscopy (SNOM) to observe with subwavelength resolution the amplitude and phase of optical fields propagating in several microfabricated waveguide devices operating around the 1.55 microm wavelength. Good agreement between the SNOM measurements and predicted optical mode propagation characteristics in standard ridge waveguides demonstrates the validity of the method. In situ observation of the subwavelength-scale distribution and propagation of optical fields in straight and 90 degrees bend photonic crystal waveguides facilitates a more detailed understanding of the optical performance characteristics of these devices and illustrates the usefulness of the technique for investigating nanostructured photonic devices.


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// DupRemove.cpp : 定义控制台应用程序的入口点。
//

#include "../LJRedupRemover.h"

#include <string>
#include <vector>
#include <list>
#include <fstream>
#include <stdio.h>
#ifdef OS_LINUX
#include <dirent.h>
#include <unistd.h>
#else
#include <direct.h>
#include <io.h>

#endif
#include <sys/stat.h>
#include <ctype.h>
using namespace std;
typedef  std::string  tstring;
//support subtree
bool gfn_vScanFiles(const char* sFolderName, std::vector<std::string>& vsFileName,const char* sFilter)
{//sFilter: "*.txt"
	tstring sDirFiles = sFolderName;
	sDirFiles += "/";
	tstring sNoSuffixDir = sDirFiles;
	sDirFiles+="*.*";
	//sDirFiles +=sFilter;
#ifndef OS_LINUX
	intptr_t iNoFile, hFoundFile=-1;
	struct _finddata_t stFileStat;

	hFoundFile = _findfirst(sDirFiles.c_str(), &stFileStat);
	iNoFile =  (hFoundFile == -1);

	while (!iNoFile)
	{
		if (stFileStat.name[0] == '.')
		{//break;
			//iNoFile = _findnext(hFoundFile, &stFileStat);
		}
		else if(stFileStat.attrib & _A_SUBDIR)
		{//	滤掉"."和".."	子目录
			tstring newPath=sFolderName;
			newPath+="/";
			newPath+=stFileStat.name;
			gfn_vScanFiles(newPath.c_str(),vsFileName,sFilter);
		}
		else if (stricmp(stFileStat.name+strlen(stFileStat.name)-strlen(sFilter),sFilter)==0)
		{
			tstring sFullFilePath =  sNoSuffixDir + stFileStat.name;
			vsFileName.push_back(sFullFilePath);
		}
		iNoFile = _findnext(hFoundFile, &stFileStat);
	};
	if (hFoundFile!=-1)
		_findclose(hFoundFile);

#else

	DIR * dirp;  //目录指针
	char sFileName[2048];
	char sFilterExt[1024]=".";
	strcpy(sFilterExt,sFilter);
	dirp = opendir(sFolderName);
	if(dirp==NULL) {
		//cerr<<" Failure to open the directory " << lpszDir<<endl;
		return false;
	}

	struct dirent* direntp;                //指向所有找到的文件的指针
	struct stat st;                        //取回的文件的状态

	while((direntp = readdir(dirp)) != NULL)   //循环读取一个文件,每读取一次dirp指针往后移动
	{
		if((strcmp(direntp->d_name,".")!=0) && (strcmp(direntp->d_name,"..")!=0))
		{
			strcpy(sFileName, sNoSuffixDir.c_str());
			strcat(sFileName, direntp->d_name);
			if(stat(sFileName,&st) == -1) {
				//cerr<<"Error:stat " <<sFileName<<endl;
				continue;
			}
			if((st.st_mode& S_IFMT) == S_IFDIR)
			{//判断是不是一个目录
				tstring newPath=sFolderName;
				newPath+="/";
				newPath+=direntp->d_name;
				gfn_vScanFiles(newPath.c_str(),vsFileName,sFilter);
			}
			else
			{
				tstring sFullFilePath =  sNoSuffixDir + direntp->d_name;
				if(sFullFilePath.rfind(sFilterExt) == sFullFilePath.size()-strlen(sFilterExt))
					vsFileName.push_back(sFullFilePath);
			}

		}//if
	}//while
	if(dirp != NULL) closedir(dirp);
#endif
	return true;

}

bool gfn_bReadFile(const char* lpszFilename, string& sFileText) {

	if(!lpszFilename || (strlen(lpszFilename)==0)) {
		return false;
	}

	sFileText = "";

	FILE* fp = fopen(lpszFilename, "rb");

	try{
		if(!fp) {
			return false;
		}//if

		fseek(fp, 0L, SEEK_END);
		long lSize = ftell(fp);
		fseek(fp, 0L, SEEK_SET);

		if(lSize>0){
			char* lpszFileText = (char*)calloc(lSize+1, sizeof(char));
			if(!lpszFilename) {
				fclose(fp);
				return false;
			}

			fread(lpszFileText, sizeof(char), lSize,fp);

			sFileText = lpszFileText;
			free(lpszFileText);
		}//if

		fclose(fp);

	}catch(...) {
		if(fp)
			fclose(fp);
	}//try

	return true;
}//gfn_bReadFile

int main(int argc, char* argv[])
{
	/*
	FILE *fp = fopen("Data.txt", "wb");
	if (fp!=NULL)
	{
		fwrite("", 0, 0, fp);
		fclose(fp);
	}
	*/
	if (!RR_Init("Data.txt", "./",false,0,UTF8_CODE))
	{
		printf("%s\r\n", RR_GetLastErrMsg());
		printf("去重组件初始化失败，请退出并检查！该联系www.nlpir.org/或者新浪微博 @ICTCLAS张华平博士 ！\n");
		return-1;
	}

	vector<string> fileDir;
	string path = argv[1];
	string sContent = "";
	if(!gfn_vScanFiles(path.c_str(),fileDir,".txt"))
	{
		printf("获取文件夹中文件失败......\n");
		system("pause");
		return -1;
	}
	string sFilename;
	char *pcFindAll = new char[65565];
	pcFindAll[0]=0;
	char sID[100];
	for (int i = 0; i < fileDir.size();i++)
	//for (int i = 0; i < 10;i++)
	{
		sFilename = fileDir.at(i);
		gfn_bReadFile(sFilename.c_str(), sContent);
		/*
		if (i<5)
		{
			sContent="局申请绿皮车预算公开11人被困电梯求救无效后在墙上挖洞自救(图)新闻视频：桥下彻与右翼分子会谈 拍案对骂险动手专栏 | 农民的房子为何不计入GDP 揭开外逃贪官保护层国际 | 日本女大臣:去不去参拜不该由他国说三道四法国道达尔公司总裁深夜在莫斯科遇空难身亡财经 | 多地社保现运动式征缴扩面:任务不完成不收队院士反思塔里木油田会战：急于求成 造成极大资源浪费";
		}
		else
		{
			sContent="大众新速腾车主不接受召回方案 在美受损车辆国考最热职位竞争比达1300:1 有700余职位零报冯仑隐退江湖还是投身理想城 实惠走进校园免费送福利科技 |[第一线]苍井空做内衣电商：半数买家为男性苹果发布iOS 8.1 升级指南 iPad销量连续三个季度下滑丛林偶遇世界最大蜘蛛似幼犬 英一家人养145只动物同住时尚 | 抢镜必备“一抹蚊子血” 高圆圆周迅新婚娇美热点 | 听军事家解析时局热点 体育赛事一网打尽关注 | 协力找马航失联客机 昌平苹果甜蜜的选择";
		}*/
		sprintf(sID,"%d",i);
		sContent += "\r\n";
		if (RR_FileProcess(sContent.c_str(), sFilename.c_str()) == 1)
		//if (RR_FileProcess(sContent.c_str(), sFilename.c_str()) == 1)
		//if (RR_FileProcessE(sFilename.c_str()) == 1)
		{
			//memset(pcFindAll, 0, 65565);
			RR_FindRepeat(pcFindAll, true);//可不输出中间过程
			printf("sID=%s FindAllRepeat are : %s \n",sFilename.c_str(),pcFindAll);
		}
	}

	if (pcFindAll != NULL)
	{
		delete[] pcFindAll;
		pcFindAll = NULL;
	}

	RR_Output("RepeatFile.txt");
	RR_SaveHistoryData("Data.txt");
	RR_Exit();
	return 0;
}


1. Field of the Invention
This invention relates to electromagnetic drive devices of the moving coil type of which the direction of action is made to differ depending upon the direction of current flow, and more particularly to cameras with such a moving coil rendering it possible to control the operation of a focus adjusting mechanism and an exposure mechanism.
2. Description of the Prior Art
At the present time, state-of-the-art cameras are provided with a coil drivingly connected to the shutter blades and positioned in a magnetic field so that upon current supply to this coil, it is driven to move by electromagnetic force according to Fleming's left hand law so that the shutter blades are opened and closed. This is the so-called moving coil type electromagnetic drive device. However, there is not yet known a device which is made to also serve to control the initiation and termination of an operation of an automatic focus adjusting mechanism (hereinafter described as an "AF" mechanism). This is because in the moving coil type electromatic drive device, it is a prerequisite that the ordinary penlight (size AA) battery be used as the common electrical energy source. Thus, the device built into the camera cannot provide a driving torque large enough to effect functions other than opening and closing of the shutter blades, for example, actuation of an AF mechanism, while still preserving the reliability and accuracy of shutter control. Thus, if at the time of opening and closing of the shutter blades, the coil is subjected to an external interference, motion of the coil will become unstable, thereby creating a problem in that the accuracy of exposure control is reduced.
On the other hand, it is known to provide other types of electromagnetic drive devices different from the moving coil type, for example, one in which the operation of the focus adjusting mechanism and the opening and closing operation of the shutter blades is controlled by using only one solenoid as disclosed in U.S. Pat. No. 4,167,316, issued Sept. 11, 1979. This device operates in such a manner that, as the plunger of the solenoid is drivingly connected to the shutter blades, when the solenoid is first energized, the plunger is attracted to move from the initial position, whereby operation of the focus adjusting mechanism is initiated. Then when the aforesaid energization is terminated, as the plunger moves under the action of a return spring, the operation of the focus adjusting mechanism is terminated, and the shutter blades start to open. After that when the solenoid is energized again, as the plunger is attracted, the shutter blades are closed.
Since, however, the electromagnetic drive device in the form of the solenoid when energized only moves the plunger in one direction, the use of the common solenoid in selectively controlling the operations of the focus adjusting mechanism and the shutter mechanism leads to the existence of the drawback that its arrangement becomes very complicated. Also, in the aforesaid example of the prior art arrangement in which when the solenoid is de-energized, the plunger moves by spring forces to effect simultaneous stopping of the focus adjusting operation and an initiation of the opening of the shutter blades, it is impossible to control the individual operations independently of each other. Therefore, there is no opportunity for permitting a timer mechanism to be operated as the necessity arises after the completion of the focus adjusting, and thereby the initiation of the shutter operation cannot be deferred, and an exposure with a self-timer cannot be made.
In short, where the electromagnetic drive device for controlling both the focus adjusting operation and the shutter operation is constructed in the form of a solenoid arranged upon energization to move the plunger in only one direction, the complexity of the structure of the camera is increased, and the capabilities of the camera are reduced.


 is the derivative of d(n) wrt n?
10*n
Let d(l) be the first derivative of 125*l**6/2 + 165*l**3 - 713. Find the third derivative of d(c) wrt c.
22500*c**2
Suppose -5*q + 0*q = -10. Let p be q/3 + (-14)/(-6). Differentiate 4*v**3 + 4 - 5*v**p - v**3 wrt v.
-6*v**2
Let g = -2 - -6. Suppose -g*a = -d + 6, 10 = 4*d - 4*a - 14. What is the first derivative of 6 - 2 + z**4 + d - 5 wrt z?
4*z**3
Let c(h) be the second derivative of -4*h**5/15 - h**4/8 - 11*h**2/2 + 5*h. Let b(g) be the first derivative of c(g). Find the second derivative of b(y) wrt y.
-32
Suppose -3*d - 17 = -32. Suppose 0 = 5*z - 5*l - 680, 4*z + d*l - 528 = l. Find the third derivative of -9*f**2 + z - 12*f**3 - 134 wrt f.
-72
Let s(c) be the third derivative of c**7/210 + c**6/120 - 5*c**4/24 - 5*c**3/6 + 2*c**2 - 84. Find the second derivative of s(y) wrt y.
12*y**2 + 6*y
Let y(n) = -178*n**2 - 16*n + 8. Let d(m) = -178*m**2 - 17*m + 8. Let h(l) = 5*d(l) - 4*y(l). What is the second derivative of h(f) wrt f?
-356
Let d(g) be the first derivative of -40*g + 15 - 8/3*g**3 + 0*g**2. Differentiate d(l) wrt l.
-16*l
Find the second derivative of -136*v + 4*v**2 - 15*v**2 + 23*v wrt v.
-22
Let m(p) be the first derivative of p**6/120 + 3*p**4/8 - 4*p**3 + 8. Let x(u) be the third derivative of m(u). What is the first derivative of x(t) wrt t?
6*t
Let h(o) = -9*o + 4. Let k(c) = 2*c - 1. Let y = 31 - 53. Let v(b) = y*k(b) - 6*h(b). Differentiate v(w) wrt w.
10
What is the second derivative of -76*j + 7*j**2 - 91*j + 218*j**4 - 7*j**2 wrt j?
2616*j**2
Let t(p) = -p**3 - 8*p**2 - 3*p - 20. Let d be t(-8). What is the second derivative of -j - 11*j**d + 13 - 13 wrt j?
-132*j**2
Let u(r) be the first derivative of r**3/3 + 185*r**2/2 + 370*r - 197. Differentiate u(h) wrt h.
2*h + 185
Let o(m) be the second derivative of -m**8/2240 - m**5/12 - 5*m**4/12 - 17*m. Let t(h) be the third derivative of o(h). Find the first derivative of t(z) wrt z.
-9*z**2
Let w(t) be the second derivative of t**4/4 - t**3/3 - 15*t**2/2 - 3*t - 13. Differentiate w(x) wrt x.
6*x - 2
Suppose -14*c = -9*c - 20. Differentiate -26*h**4 - 9*h**4 + 10*h**c + 0 + 4 with respect to h.
-100*h**3
Find the second derivative of -168*n**2 - 5520*n + 2615*n + 2328*n wrt n.
-336
Let k(j) = 304*j**2 - 32*j - 71. Let m(n) = 61*n**2 - 6*n - 14. Let p(s) = -2*k(s) + 11*m(s). Find the second derivative of p(b) wrt b.
126
What is the third derivative of -204*p + 2*p**3 + 32*p**2 + 100*p + 104*p wrt p?
12
Let j(f) = 1247*f**2 + 10*f - 609. Let r(d) = -416*d**2 - 3*d + 202. Let x(v) = -2*j(v) - 7*r(v). Find the second derivative of x(h) wrt h.
836
What is the second derivative of 4*n**2 - 2*n + 33*n + 35*n**2 + 2*n**3 + 2 wrt n?
12*n + 78
Let x be (48/9)/((-10)/(-15)) + 0. Differentiate -13 - 13*q**4 - x - 6*q**4 - 3 wrt q.
-76*q**3
Let z(g) = 2*g**2 + 7*g + 9. Let m be z(-4). Find the second derivative of 2*h**5 - 12*h - m*h**5 + 23*h wrt h.
-220*h**3
What is the first derivative of -3247 + 1064 + 1083 + 1026 + b**2 - 83*b wrt b?
2*b - 83
Let w(j) = -12*j**4 + 5*j**3 + 2*j**2 - 5*j - 39. Let x(s) = -s**4 - s**3 + s + 1. Let m(a) = -w(a) - 5*x(a). Differentiate m(o) with respect to o.
68*o**3 - 4*o
What is the second derivative of -38*h + 4*h**3 + 0 + 21*h**3 + 1 - 2 + h**5 wrt h?
20*h**3 + 150*h
Suppose -5*u + 8 = -3*u. Let l be u + -3 + (2 - -2). Find the second derivative of 0 + 34*b + 0 + 6*b**l - 35*b wrt b.
120*b**3
Let n(w) be the first derivative of 0*w + 5/6*w**6 + 0*w**5 - w**2 + 0*w**4 + 7 + 0*w**3. Find the second derivative of n(c) wrt c.
100*c**3
Let z(o) = 74*o**2 - 4*o - 15. Let u(g) = 149*g**2 - 7*g - 28. Let l(b) = 3*u(b) - 5*z(b). Find the second derivative of l(n) wrt n.
154
Let c(l) be the second derivative of -221*l**7/42 + l**4/6 - 49*l**2/2 + l + 14. Find the third derivative of c(g) wrt g.
-13260*g**2
Let m = -37 - -39. Find the third derivative of 18*f**6 + 6*f**2 + 0*f**m - 2*f**6 wrt f.
1920*f**3
Suppose 0 = -5*s - 0*s. Suppose s = g - 5*g + 16. Find the third derivative of -2*w - 7*w**2 - 2*w**5 + g*w**2 + 2*w wrt w.
-120*w**2
What is the derivative of -7 + 16*t - 13*t - 2 + 23*t + 10*t wrt t?
36
Let t(c) be the second derivative of -c**5/20 + 13*c**4/12 + 94*c**2 - 19*c - 1. What is the first derivative of t(m) wrt m?
-3*m**2 + 26*m
Let n(t) = -t**2 + 1. Let j(b) = b**3 + 3*b**2 + 74*b + 16. Let i(k) = 2*j(k) + 6*n(k). Find the first derivative of i(o) wrt o.
6*o**2 + 148
Let y be (-4)/((-24)/(-18)) - 4*-20. Differentiate 194 - 31*d**3 - 91 - y wrt d.
-93*d**2
Let y(r) be the first derivative of 6 - 11/2*r**2 - 11*r. What is the first derivative of y(o) wrt o?
-11
Let j = 93 - 90. What is the second derivative of 5*c - 16*c**5 + j*c**5 + 16*c**5 wrt c?
60*c**3
Let c(q) be the second derivative of 31*q**8/28 - 59*q**4/12 + q**3/6 - 33*q. Find the third derivative of c(i) wrt i.
7440*i**3
Let o(q) be the second derivative of -389*q**4/6 - 365*q**3/3 - 5*q - 35. What is the second derivative of o(g) wrt g?
-1556
Let y = -77 - -79. Let j(m) be the second derivative of 6*m + 0*m**3 + 0*m**y - 1/2*m**4 + 0 - 1/30*m**6 + 0*m**5. What is the third derivative of j(d) wrt d?
-24*d
Let x(q) be the third derivative of 13*q**7/70 + q**4/12 - 13*q**3/6 + 170*q**2. What is the second derivative of x(b) wrt b?
468*b**2
Suppose 4*s + 3*f - 9 = 0, s + 5*f = 2*f. Find the third derivative of 396*l + s*l**3 - 396*l + 9*l**2 wrt l.
18
Let v(d) be the second derivative of -d**8/48 + d**4/3 - 2*d**2 + 4*d. Let h(o) be the first derivative of v(o). What is the second derivative of h(l) wrt l?
-140*l**3
Suppose 0*z = -3*z + 15. Suppose 0 = 2*d - z + 1. Find the second derivative of q**3 - 8*q**3 - d*q + 4*q**3 wrt q.
-18*q
Let n(w) be the first derivative of w**2 + 14*w + 6. Let y be n(-6). What is the third derivative of -2*p + 3*p**y + 2*p**3 + 2*p + 2*p**2 wrt p?
12
Suppose -2*i + 30 = 3*h, -2*i + 5*i + 2*h = 45. Find the second derivative of 3*c - 23*c**4 + i*c + 6*c wrt c.
-276*c**2
Differentiate -j + 4*j**3 + 44 + 2*j**3 + 248 - 23*j**3 wrt j.
-51*j**2 - 1
Let a(m) be the second derivative of -9*m**4/4 - 13*m**3 - 8*m + 4. What is the second derivative of a(y) wrt y?
-54
What is the derivative of -132*m + 128 + 101 - 56 + 59 wrt m?
-132
Let a(l) = l**4 - 2*l + 2. Let v(w) = 2*w**4 - 7*w**2 + 5*w - 12. Let s(r) = 3*a(r) + v(r). Find the second derivative of s(t) wrt t.
60*t**2 - 14
Let p = -17/27 + 115/54. Let u(l) be the second derivative of 13/20*l**5 + 0*l**3 + 0*l**4 + 0 - p*l**2 + 7*l. Differentiate u(c) wrt c.
39*c**2
Let d be 6*3/6 - (-30)/(-10). Let q(m) be the first derivative of 0*m**4 - 1/5*m**5 - 2 + 0*m**2 + 4/3*m**3 + d*m. What is the third derivative of q(x) wrt x?
-24*x
Let z(n) be the first derivative of 0*n**5 + 0*n**2 - 1 + 11/7*n**7 + 7/3*n**3 + 0*n**6 + 0*n**4 + 0*n. What is the third derivative of z(b) wrt b?
1320*b**3
Let t(q) = q**2 - 8*q - 11. Let s be t(8). Let a = 18 + s. Differentiate -4*j**2 + 3*j - 3*j + a + 0*j with respect to j.
-8*j
What is the third derivative of -384*s**3 - 8*s**2 + 7*s**2 + 299*s**3 + 3*s - s wrt s?
-510
What is the third derivative of 8 + 95*g**4 + 10 - g**2 - 18*g**6 - 91*g**4 - 3 wrt g?
-2160*g**3 + 96*g
Let x be -1 + ((-32)/2)/4 + 8. Let c(g) = 1 + 4 + 5 + 15*g. Let d(r) = -14*r - 9. Let s(w) = x*c(w) + 4*d(w). What is the first derivative of s(v) wrt v?
-11
Suppose 2*j - 5*h + 5 = 27, -26 = -2*j + 4*h. Suppose 4 = 4*a - 0*a, 5*k - j = -a. What is the first derivative of -8*o + 5*o**k + 4 + 8*o + 1 wrt o?
20*o**3
Differentiate 180*s**4 - 43 - 8 - 106 + 12 with respect to s.
720*s**3
Let n(f) be the first derivative of -23/2*f**2 + 0*f + 29 + 0*f**3 - 9/4*f**4. Find the second derivative of n(m) wrt m.
-54*m
Suppose -5*v - 2 = -2*b, -6*v + 4*v + 2 = 2*b. Suppose 5 + b = 3*m. Find the first derivative of -3 + 0 - 2 + o**m + 0*o**2 wrt o.
2*o
Suppose -2*m - 6 = 0, u - m = 4*u - 3. Suppose -16 - 8 = -2*x. What is the third derivative of -2*t**u - 4*t**2 + 3*t**2 + 4*t**2 - x*t**3 wrt t?
-72
Let a(u) be the third derivative of 59*u**7/210 + 37*u**3/3 - 52*u**2 + 1. What is the first derivative of a(n) wrt n?
236*n**3
Find the second derivative of 95*a - 44400*a**2 + 44400*a**2 + 178*a**3 wrt a.
1068*a
Find the first derivative of 129*s + 102*s - 87 + 46*s + 241 + 113*s


Dejan Jović

Dejan Jović (born 12 April 1968) is a full-time professor at the Faculty of Political Science at the University of Zagreb.

Biography
He completed undergraduate studies in Zagreb (1990), master level studies in Ljubljana (Slovenia) and Manchester (England) (1994) and PHD studies at the London School of Economics and Political Science (1999). In the period of 2010-2014 Jović was the main political analyst for the President of Croatia Ivo Josipović. Jović has been a Jean Monnet Fellow at the European University Institute in Florence and a lecturer at the Scottish University of Stirling. Since 2015 he is guest professor at the University of Belgrade. In an interview he explicitly described himself as being both Croat and Serb, acknowledging that such a complex self-determination may cause shock among both communities exposed to totalitarian nationalism and unaccustomed to liberal political tendencies.

Dejan Jović is the main editor of the Croatian Political Science Review journal since 2013. In 2017, he has signed the Declaration on the Common Language of the Croats, Serbs, Bosniaks and Montenegrins.

Controversies
In 2014, when serving as senior advisor to president Ivo Josipović, in his book review for the Croatian Political Science Review he highly praised the book "First Do No Harm: Humanitarian Intervention and the Destruction of Yugoslavia" written by David N. Gibbs and published by Vanderbilt University Press in 2009. The book is considered controversial for denying the genocide in Srebrenica and glorifying Croatia's territorial dismemberment, among other things. He was thus accused by the North American Congress Of Bosniaks of "silently denying Serbian aggression and genocide". British historian Marko Attila Hoare accused Jović of being an apologist of Slobodan Milošević and the JNA during the war in the 1990s. Jović defended himself by stating that the accusations are "completely tendentious and incorrect, and the campaign itself has political rather than academic motives", he also defended Gibbs by claiming he had never denied genocide in Srebrenica, that he is a distinguished professor of history at the University of Arizona whose book had a number of positive reviews in academic journals, and that the same people who are now accusing him as a genocide denier for a book review have previously accused many, including the Washington Times and The Guardian that they are genocide deniers. His claims were, however, disputed by Hoare in a subsequent response to his defense, concluding "It is dangerous to both Croatia and Bosnia-Hercegovina for someone holding such views, and with such poor analytical judgement and grasp of reality, to occupy the position that he does.".

During the same year, he was sacked by president Ivo Josipović after Jović claimed in his article that 1991 Croatian independence referendum was "highly illiberal" and that it can not be compared with Scottish independence referendum arguing that, unlike the Croatian one, every opinion was considered legitimate and was equally present in public debate. This statement was described by president Josipović as "malicious and false". President sacked him shortly before Croatian presidential election, 2014–15. The left-leaning British political website openDemocracy opined that sacking of Jović was the result of "(re)establishment of a certain dogmatism in interpreting or discussing about the past".

References

Category:1968 births
Category:Living people
Category:University of Zagreb faculty
Category:Academics of the University of Stirling
Category:Alumni of the London School of Economics
Category:University of Ljubljana alumni
Category:Alumni of the University of Manchester
Category:University of Belgrade faculty
Category:Signatories of the Declaration on the Common Language
Category:Serbs of Croatia


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A writer and an NBA junkie, Karan has worked for the Basketball Federation of India (BFI) and written for publications such as SLAM Magazine. He's also the writer of the blog Hoopistani, your source for Basketball, India, Philosophy, and everything else in between. Follow him on Facebook or Twitter.

All season long, Karan will provide a weekly look at the NBA, touching on everything we've missed and filling you in on everything you need to know.

Super Mario

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Mike Ehrmann/NBAE/Getty Images

For three games of the Finals, and for most of the playoff run before that, and for the first few years of his short career, he took their abuse, he took their perceived lack of respect, and he handled their angry stares. And he responded to it all the only way he best could: with an explosive performance on the court.

With the keys to help orchestrate one of the most devastating trios in NBA history, Mario Chalmers fell into international spotlight, a light that shone on him with doubt, disrespect, and disregard. He was supposed to be the weak link of a team that ran LeBron James, Dwyane Wade, and Chris Bosh together. His every mistake was magnified, he survived Wade’s angry stares, he survived LeBron’s curses, he survived distrust by his own fans when he scored just 17 points total in the first three games making only an unflattering seven of 22 shots.

In his own confident mind, there was never any doubt about his ability.

“He actually thinks he’s the best player on the team, and that’s a gift and a curse,” said Dwyane Wade of Chalmers – and Chalmers morphed into ‘Super Mario’ in Game 4, scoring 25 crucial points for the Heat. Many of these points came over the outstretched wingspan of Thunder superstar Kevin Durant, who was deputised to defend him for the game to stay out of foul trouble. Chalmers made 9-of-15 shots to finish with a single-game total higher than the previous three games combined. He carried the team’s load when the bigger superstars couldn’t get going. He made four of five clutch baskets in the final quarter and hit the game-sealing free throws to help Miami get just one win away from an NBA title. He saw three-time MVP LeBron James crash on court, limp back, and then crash away again, yet he kept his head up to close the game.

A year ago, he started the NBA Finals as backup to the aging Mike Bibby. Now, Mario Chalmers is back on the same stage enjoying the biggest moment of his career.

‘Super Mario’ has appeared at a big basketball stage before, too. Four years ago, in the NCAA Championship game, Chalmers hit a 3-pointer with 2.1 seconds on the clock to help his side – Kansas – tie the game with Derrick Rose’s Memphis squad. Kansas went on to win the championship in overtime.

You’d be right to think that there is something oddly familiar in Chalmers’ story. A bad team with one superstar brings in two more superstars to form a big three, but the point guard of that team remains an unheralded, unknown commodity. The point guard is treated to both encouragement and abuse from the big stars and survives his doubting fans. He remains so confident of himself that, despite being teammates with three All-Star players, there are moments like this when he rises to match or even outperform them.

The previous story belongs to Rajon Rondo of the Boston Celtics, who was the young star between Paul Pierce, Kevin Garnett, and Ray Allen, and as the ‘Big 3’ aged, he morphed into the team’s best player. With LeBron James in his prime (and Wade and Bosh not too far from theirs), Chalmers will never rise above his superstar teammates like Rondo did. He's just not that good. But if he continues to improve and offer big time moments like he did in Game 4, then Miami’s opponents will have one more name to fear.

And they can be sure that, no matter the situation, the past shooting slumps, the doubts, stares, and abuses, Mario Chalmers will remain fearless.


Serotonergic innervation in the brain originates from the raphe nuclei. Both, the medial and the dorsal raphe nucleus (DRN), project to common areas implicated in motor control, such as the thalamus. Nevertheless, the basal ganglia (BG) nuclei receive serotonergic afferences coming prevalently from the DRN (reviewed in Di Matteo et al., [@B40]). The BG contain serotonin (5-HT) and its metabolite 5-hydroxy-indolacetic acid (5-HIAA) (Palkovits et al., [@B107]; Saavedra, [@B127]; Lavoie and Parent, [@B85]), 5-HT transporter (SERT) and serotonergic receptors (from 5-HT~1~ to 5-HT~7~). These serotonergic receptors are unevenly expressed along the BG, and their distribution also differs between species. Here, we will review the evidences supporting the serotonergic system as a modulator of the BG functionality. Both physiological and pathological conditions will be analyzed from the basic and clinical point of view.

Physiological serotonergic modulation of the basal ganglia
==========================================================

In accordance with its neuroanatomical distribution (as summarized in Table [1](#T1){ref-type="table"}), 5-HT physiologically modulates BG nuclei activity by acting on serotonergic receptors.

######

**Localization and expression density of serotonergic receptors in the basal ganglia of healthy brains of rodents, monkeys and humans**.

             **GPe/GPi(EP)**   **Striatum**       **STN**   **SNc/SNr**   **References**
  ---------- ----------------- ------------------ --------- ------------- ----------------------------------------------------------------------------------------------------------------
  5-HT~1A~   \+^r^             \+^r^              \+^r^     \+^r^         ^r^Lanfumey and Hamon, [@B84]
             \+^m^             \+^m^(matrix)      \+^m^     \+^m^         ^m^Frechilla et al., [@B52]; ^m^Huot et al., [@B66]
             \+^h^             ++^m^(striosome)
                               \+^h^                                      ^h^Huot et al., [@B67]
  5-HT~1B~   +++^r^            ++^r^              +++^r^    +++^r^        ^r^Bruinvels et al., [@B22]
             +++^h^            ++^h^                        +++^h^        ^h^Varnas et al., [@B141]
  5-HT~2A~   ++^r^             ++^r^              \+^h^     \+^r^         ^r^Pazos et al., [@B109]
             \+^m^             \+^m^                        \+^m^         ^m^Huot et al., [@B68]
             ++/+^h^           ++^h^                        ++/+^h^       ^h^Hoyer et al., [@B65]; ^h^Pazos et al., [@B110]; ^h^Hall et al., [@B61]; ^h^Varnas et al., [@B141]
  5-HT~2C~   ++^r^             ++^r^              +++^r^    +++^r^(c)     ^r^Mengod et al., [@B91]; ^r^Pompeiano et al., [@B112]; ^r^Abramowski et al., [@B1]; ^r^Clemett et al., [@B30]
             +++^h^            +++^h^                       +++^h^        ^h^Pazos et al., [@B110]; ^h^Lopez-Gimenez et al., [@B87]
  5-HT~3~                      \+^r^                        \+^r^         ^r^Kilpatrick et al., [@B77]; ^r^Gehlert et al., [@B53]
                               +++^h^                       ++^h^         ^h^Bufton et al., [@B23]
  5-HT~4~    +++^r^            +++^r^                       +++^r^        ^r,m^Jakeman et al., [@B71]; ^r^Nirogi et al., [@B103]
             +++^m^            +++^m^                       +++^m^
             +++^h^            +++^h^                       +++^h^        ^h^Bonaventure et al., [@B17]; ^h^Varnas et al., [@B143], [@B141]
  5-HT~5A~   \+^r^             \+^r^              ++^r^     +++^r^        ^r^Oliver et al., [@B105]
  5-HT~6~                      +++^r^                       ++^r^         ^r^Gerard et al., [@B54]
                               +++^h^                       ++^h^         ^h^Kohen et al., [@B82]
  5-HT~7~    \+^r^             \+^r^              \+^h^     \+^r^         ^r^Horisawa et al., [@B64]
                               \+^h^                        \+^h^         ^r,h^Martin-Cora and Pazos, [@B90]
                                                                          ^h^Varnas et al., [@B142]

*+++, strong; ++, moderate; +, weak/r, rodent; m, monkey; h, human. EP, entopeduncular nucleus; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata*.

Striatum
--------

The striatum is the main input nucleus of the BG and a key neural substrate for motor function. Several studies have shown that 5-HT affects striatal function. In fact, both DRN stimulation and local administration of 5-HT into the striatum inhibit the vast majority of the striatal cells (Olpe and Koella, [@B106]; Davies and Tongroach, [@B37]; Yakel et al., [@B149]). However, by performing intracellular recordings, some researchers have reported striatal excitatory postsynaptic potentials after DRN stimulation, as well as a 5-HT-induced increase in firing rate of medium spiny neurons (MSN) (Vandermaelen et al., [@B139]; Park et al., [@B108]; Stefani et al., [@B134]; Wilms et al., [@B146]). Stimulation of presynaptic 5-HT~1A~ and 5-HT~1B~ receptors inhibits striatal 5-HT release (Gerber et al., [@B55]; Knobelman et al., [@B81]), and these receptors also control the release of other neurotransmitters in the striatum. Accordingly, 5-HT~1A~ receptor activation decreases glutamate release from corticostriatal projections (Antonelli et al., [@B4]; Mignon and Wolf, [@B93]; Dupre et al., [@B44], [@B45]). On the other hand, activation of 5-HT~1B~ receptors indirectly stimulates the *substantia nigra pars compacta* (SNc) by decreasing GABA release from the *substantia nigra pars reticulata* (SNr), what consequently leads to increasing striatal dopamine levels (Gerber et al., [@B55]).

The 5-HT~2~ receptor family produces an inhibitory action on striatal neuron activity, mainly by modulating MSN (el Mansari et al., [@B47]; el Mansari and Blier, [@B46]). Moreover, Rueter et al. ([@B125]) have shown that 5-HT~2C~ receptors exert tonic inhibitory control over MSN membrane excitability. Other *in vivo* studies, however, have shown contradictory results suggesting that the effect of serotonergic drugs depends on the area of the striatum analyzed (Wilms et al., [@B146]). 5-HT~2~ receptor activation indirectly reduces the activity of striatal MSN by enhancing the inhibitory tone of cholinergic interneurons over these output neurons. The increased release of acetylcholine is due to activation of cholinergic interneurons mainly through 5-HT~2C~ receptors, although the involvement of 5-HT~6~ and 5-HT~7~ receptors has also been demonstrated (Bonsi et al., [@B19]; Blomeley and Bracci, [@B16]). In addition, the activation of 5-HT~2C~ receptors located on fast-spiking interneurons increases their excitability, causing an enhancement of GABAergic postsynaptic inhibition that also decreases the activity of striatal projecting neurons (Blomeley and Bracci, [@B16]).

Subthalamic nucleus
-------------------

5-HT exerts a complex effect in the *subthalamic nucleus* (STN) that is considered to be a powerful excitatory drive in the BG motor circuit. Both pharmacological lesion of the DRN and 5-HT depletion increase STN firing frequency and burst activity *in vivo* (Liu et al., [@B86]; Aristieta et al., [@B7]). Decreased and increased excitability have been reported with the activation of 5-HT~1A~ and 5-HT~2C~, and 5-HT~4~ receptors, respectively (Flores et al., [@B50]; Stanford et al., [@B132]; Xiang et al., [@B148]; Shen et al., [@B130]; Aristieta et al., [@B7]). In addition, activation of 5-HT~1B~ receptors inhibits synaptic activity of STN neurons (Barwick et al., [@B12]; Shen and Johnson, [@B129]).

Globus pallidus
---------------

The *globus pallidus* (GP) has two segments, the external GP (GPe), which has a central position in the BG loop, and the internal GP (GPi/EP), which, together with the SNr, form the output structures of the BG. In the GPe, 5-HT depletion decreases the firing frequency and increases the proportion of bursty and irregular neurons (Delaville et al., [@B39]). In contrast, local application of 5-HT or selective serotonin reuptake inhibitor (SSRI) administration excites most of GPe neurons (Querejeta et al., [@B115]; Zhang et al., [@B153]; Wang et al., [@B144]). These findings have been further confirmed by a patch-clamp recording study in which 5-HT perfusion produced a reversible depolarization of the GP neuron membrane potential, thereby increasing the firing rate of these neurons (Chen et al., [@B28]). *In vivo* studies indicate that the stimulatory effect of 5-HT on GPe neurons is mediated by the activation of 5-HT~4~ or 5-HT~7~ postsynaptic receptors, but not 5-HT~2C~ and 5-HT~3~ receptors (Bengtson et al., [@B13]; Kita et al., [@B79]; Chen et al., [@B28]; Hashimoto and Kita, [@B63]). In contrast, 5-HT can decrease the presynaptic release of glutamate and GABA from the subthalamopallidal and striatopallidal terminals, respectively, through 5-HT~1B~ receptors (Querejeta et al., [@B115]). In addition, 5-HT has been proposed to modulate the inhibitory and excitatory responses in GPe electrical stimulation of the motor cortex in awake monkeys (Kita et al., [@B79]). In fact, 5-HT suppresses GABAergic inhibitory responses to cortical stimulation through presynaptic 5-HT~1B~ receptors and glutamatergic excitatory responses involving presynaptic or postsynaptic 5-HT~1A~ receptors (Kita et al., [@B79]).

Few studies have been conducted to investigate the effects of 5-HT on the GPi/EP nucleus. Recently, it has been shown that intra-EP administration of a 5-HT~2~ receptor agonist promotes oral movements and inhibits EP neuronal activity in dopamine-depleted rats (Lagiere et al., [@B83]).

Substantia nigra
----------------

Together with the GPi, the SNr constitutes the principal output nucleus of the BG and plays a relevant role in movement initiation. In this nucleus, 5-HT induces mostly an inhibitory effect *in vivo* (Dray et al., [@B42]; Collingridge and Davies, [@B31]), while 5-HT depletion decreases firing rate and increases burst activity of SNr neurons (Delaville et al., [@B38]). Electrophysiological studies carried out in brain slices indicate that 5-HT not only excites SNr neurons acting directly on 5-HT~2C~ receptors (Rick et al., [@B123]; Stanford and Lacey, [@B133]; Stanford et al., [@B132]) but also disinhibits SNr neurons by reducing GABA release from striatonigral terminals via presynaptic 5-HT~1B~ receptor stimulation (Stanford and Lacey, [@B133]). A recent electrophysiological study reveals that presynaptic 5-HT~1B~ receptor activation gates STN excitatory inputs to the SNr and reduces burst firing activity of the SNr, and therefore may be critically involved in movement control (Ding et al., [@B41]).

The role of 5-HT transmission in modulating the activity of dopaminergic SNc neurons is still unclear. Although the effect of 5-HT input seems to be inhibitory (Sinton and Fallon, [@B131]; Arborelius et al., [@B6]), chemical lesion of the DRN does not significantly alter SNc activity and DRN electrical stimulation only inhibits spontaneous activity in a subset of neurons (Kelland et al., [@B75]). Further, SSRI administration does not modulate SNc activity (Prisco and Esposito, [@B114]), and 5-HT depletion has been shown to either decrease or have no significant effect on SNc neuron excitability (Kelland et al., [@B75]; Minabe et al., [@B96]). Non-selective 5-HT~2~ receptor antagonists stimulate SNc neurons (Ugedo et al., [@B138]), whereas 5-HT~4~ receptors selectively prevents the stimulatory effect induced by haloperidol in this brain area (Lucas et al., [@B88]).

Implication of the serotonergic system in Parkinson\'s disease
==============================================================

In the parkinsonian state and subsequent replacement therapy with L-DOPA, the serotonergic system adapts to the lack of dopamine by adopting anatomical and functional transformations.

Serotonergic system in Parkinson\'s disease and parkinsonian animal models
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Parkinson\'s disease (PD) is a neurodegenerative disease typified by loss of dopaminergic neurons in the SNc and subsequent dopamine depletion in the striatum. In patients with PD, it is generally supported that serotonergic neurotransmission decreases in advanced stages of the disease (Haapaniemi et al., [@B60]; Kerenyi et al., [@B76]) since the DRN, in addition to other nuclei, undergoes degeneration (Halliday et al., [@B62]; Jellinger, [@B72]). Moreover, 5-HT and 5-HIAA concentrations, as well as SERT expression, are reduced in several BG nuclei (Scatton et al., [@B128]; Raisman et al., [@B117]; D\'Amato et al., [@B36]; Chinaglia et al., [@B29]; Kerenyi et al., [@B76]; Guttman et al., [@B59]; Kish et al., [@B78]; Rylander et al., [@B126]). Regarding receptor expression, 5-HT~1A~ is decreased and 5-HT~2C~ is increased in some BG nuclei (Fox and Brotchie, [@B51]; Ballanger et al., [@B10]) (Figure [1](#F1){ref-type="fig"}). Other serotonergic receptor (5-HT~1B/D~, 5-HT~3~, and 5-HT~4~) densities are however not modified by the dopaminergic loss (Steward et al., [@B135]; Reynolds et al., [@B119]; Wong et al., [@B147]; Castro et al., [@B27]). Overall, this dysfunctional serotonergic neurotransmission can indeed be linked to the high prevalence of depressive symptoms in parkinsonian patients (Reijnders et al., [@B118]).

![**Simplified diagram of the basal ganglia circuits and altered serotonergic receptor expression in pathological states**. Changes found in serotonergic receptor density in parkinsonian (left boxes) and dyskinetic (right boxes) patients or animals models compared to control conditions. Each nucleus and its modifications in receptor expression are encoded with the same color. GABAergic inhibitory pathways are represented in dark blue and glutamatergic excitatory pathways in red. Modulatory dopaminergic connections are indicated in green and serotonergic pathways in brown. DRN, *dorsal raphe nucleus*; GPi (EP), internal segment of the *globus pallidus (entopeduncular nucleus)*; GPe, external segment of the *globus pallidus*; STN, *subthalamic nucleus*; SNc, *substantia nigra pars compacta*; SNr, *substantia nigra pars reticulata*. r, rodent; m, monkey; h, human.](fncir-08-00021-g0001){#F1}

In animal models of parkinsonism, the changes occurring after dopaminergic lesion have not been equally reproduced by different research groups. The discrepancies between these studies may be due to different protocol paradigms used for inducing the parkinsonian state, including the age of the animals, site of injection, concentration of the toxin, and the time between surgery and performing the studies. Several researchers have reported hyperinnervation (Zhou et al., [@B155]; Rozas et al., [@B124]; Balcioglu et al., [@B9]; Maeda et al., [@B89]), while others found no sprouting (Prinz et al., [@B113]), or even a decrease in striatal serotonergic fibers after dopaminergic damage (Takeuchi et al., [@B136]; Rylander et al., [@B126]). Along the same lines, striatal 5-HT levels have been found to be increased (Commins et al., [@B32]; Zhou et al., [@B155]; Karstaedt et al., [@B73]; Balcioglu et al., [@B9]), unchanged (Breese et al., [@B21]; Carta et al., [@B26]), or decreased (Frechilla et al., [@B52]; Aguiar et al., [@B3], [@B2]). As detailed in Figure [1](#F1){ref-type="fig"}, studies performed in different animal models report unequal modification in serotonergic receptor expression along the BG nuclei. On the other hand, the DRN also suffers adaptative changes after the dopaminergic degeneration, such as increased 5-HT~1A~ expression in MPTP monkeys (Frechilla et al., [@B52]) or weaker inhibitory effects of 5-HT~1A~ agonists on neuron activity in rats (Wang et al., [@B145]). Electrophysiological studies using different 6-hydroxydopamine (6-OHDA) lesion models have shown increased basal firing rate of serotonergic cells in the parkinsonian state (Zhang et al., [@B151]; Kaya et al., [@B74]; Wang et al., [@B145]; Prinz et al., [@B113]), while others show decreases (Guiard et al., [@B58]) or no changes (Miguelez et al., [@B95]).

In spite of the disparity of results, it seems clear that to varying extents, the serotonergic system is affected in parkinsonian conditions. More clinical and preclinical studies using the same experimental models and a greater amount of samples would help to clarify the role of the serotonergic system in each stage of PD.

Serotonergic system in L-DOPA induced dyskinesia
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The dopamine precursor L-DOPA is the most effective pharmacological treatment for PD, but it does not stop the progression of the disease. Moreover, long-term administration of L-DOPA induces motor complications, known as L-DOPA induced dyskinesias (LID), which have been related to adaptive changes of the serotonergic system. For example, a recent publication revealed that patients who had developed dyskinetic movements showed significant serotonergic hyperinnervation in the GPe and caudate, in comparison to non-dyskinetic individuals (Rylander et al., [@B126]). Such sprouting was directly correlated with the severity of motor complications. In contrast, other studies have shown that striatal *postmortem* content of 5-HT and SERT levels did not differ significantly between dyskinetic and non-dyskinetic cases (Calon et al., [@B24]; Kish et al., [@B78]), and chronic L-DOPA treatment did not influence SERT expression (Politis et al., [@B111]). As for serotonergic receptors, a study performed in PD patients that followed L-DOPA treatment showed increased 5-HT~1A~ expression in several cortical areas, while no modification in the striatum, GP, SN, or thalamus was reported (Huot et al., [@B67]). In the SNr, 5-HT~2C~ expression has also been observed to be raised in those patients (Fox and Brotchie, [@B51]).

The use of animal models has provided valuable data to better understand the physiopathological mechanisms of LID. The most used models include non-human primates injected with MPTP and rodent-models with hemilateral dopaminergic loss chronically treated with L-DOPA. Although differences may arise from the methodological protocols, such models are considered to reproduce resembling symptoms and molecular changes to those observed in PD patients and efficiently respond to antidyskinetic therapy (Iderberg et al., [@B69]). It is now well known that exogenously administered L-DOPA can be stored, transformed into dopamine, and released from serotonergic terminals to multiple brain regions, including the striatum, in an uncontrolled manner, producing a non-physiological stimulation of sensitized dopaminergic receptors (Arai et al., [@B5]; Carta et al., [@B25]; Yamada et al., [@B150]; Navailles et al., [@B100], [@B101]). Lesions of the DRN consistently prevent the expression of dyskinesia (Carta et al., [@B25]; Eskow et al., [@B48]) or dopamine release after an acute L-DOPA injection (Navailles et al., [@B100]). This interaction between serotonergic and dopaminergic systems is reciprocal, as 5-HT levels also decrease after L-DOPA administration, and L-DOPA itself can antagonize the effect of serotonergic agents (Bartholini et al., [@B11]; Everett and Borcherding, [@B49]; Commissiong and Sedgwick, [@B33]; Borah and Mohanakumar, [@B20]; Navailles et al., [@B99]; Riahi et al., [@B121]; Miguelez et al., [@B94]). In dyskinetic animals, SERT expression has been found to be up-regulated (Rylander et al., [@B126]), not modified (Prinz et al., [@B113]), or decreased (Nevalainen et al., [@B102]). Serotonergic receptor expression in the BG is unevenly modified with L-DOPA treatment: 5-HT~2A~ and 5-HT~1B~ receptor expression is increased (Zhang et al., [@B154]; Riahi et al., [@B121], [@B122]; Huot et al., [@B68]), while 5-HT~1A~ receptor expression is increased (Huot et al., [@B66]) or does not change (Riahi et al., [@B120]) (Figure [1](#F1){ref-type="fig"}). The primary modifications occurring in the serotonergic system are thought to take place at terminal levels because no changes in the number of serotonergic neurons (Rylander et al., [@B126]; Inden et al., [@B70]) or 5-HT or dopamine levels in the DRN of dyskinetic rats have been reported (Bishop et al., [@B15]).

Clinical relevance
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Although motor complications appear in the majority of the patients that receive chronic treatment with L-DOPA, an effective pharmacological tool for avoiding or treating LID expression is still missing. In this sense, 5-HT~1A/1C~ receptors, which are involved in the regulation of the ectopic dopamine release, are envisaged as promising targets. In 6-OHDA-lesioned rats and MPTP monkeys chronically treated with L-DOPA, 5-HT~1A/1C~ receptor agonists reduce expression of LID without impairing L-DOPA improvement in motor performance (Bibbiani et al., [@B14]; Ba et al., [@B8]; Dupre et al., [@B43]). Furthermore, administration of the 5-HT~1A~ agonist, 8-OH-DPAT, also prevents L-DOPA-induced increment of extracellular dopamine (Nahimi et al., [@B98]). Other drugs that modulate 5-HT neurotransmission have shown efficacy over LID. Thus, a recent study has revealed that the treatment with the precursor of 5-HT, 5-hydroxytryptophan reduces the appearance of LID in L-DOPA-primed rats (Tronci et al., [@B137]). The 5-HT~2A~ receptor inverse agonist ACP-103 reduces tremor in rodents and LID in MPTP monkeys (Vanover et al., [@B140]). Acute and prolonged SSRI treatment attenuates the severity and development of LID in L-DOPA-primed and naive rats without interfering with motor improvement, which may be mediated in part by 5-HT~1A~ receptors (Bishop et al., [@B15]; Conti et al., [@B35]). In contrast, in PD patients, while buspirone, a partial 5-HT~1A~ agonist, ameliorates dyskinesia (Kleedorfer et al., [@B80]; Bonifati et al., [@B18]), sarizotan, another 5-HT~1A~ receptor agonist, failed to improve it compared with placebo (Goetz et al., [@B57]) and significantly increased *off* time (Goetz et al., [@B56]).

Concluding remarks
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The effects of 5-HT in the BG depend on the specific nucleus and its receptor distribution. 5-HT induces an inhibition of MSN in the striatum using either direct or indirect activation of serotonergic receptors, as well as in the STN and SNr *in vivo*. In contrast, in the GPe the overall effect of 5-HT is excitatory. In other nuclei such as the EP or SNc the net effect is still not well understood.

The serotonergic physiological modulation may be modified in pathological conditions where the BG nuclei are highly affected. Here, we provide data regarding the alteration of the serotonergic system in PD, pointing out important discrepancies about the relationship between the serotonergic and dopaminergic systems in pathological states. In this concern, key methodological differences such as the use of different animal species and models, pharmacological treatments or stage of the disease in PD patients may explain these inconsistencies.

In summary, the serotonergic system is implicated in the modulation of the BG activity and in the etiopathology of PD and LID. However, although in preclinical studies results indicate that serotonergic drugs may be suitable for treating LID, this fact has yet to be supported by clinical trials. Accordingly, further investigation is required to determine the most suitable serotonergic target to treat these motor disturbances.

Conflict of interest statement
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This study was supported by the grants IT747-13, PI12/00613, UPV/EHU UFI11/32.

[^1]: Edited by: M. Victoria Puig, Massachusetts Institute of Technology, USA

[^2]: Reviewed by: Bruno Pierre Guiard, University of Paris XI, France; Karen Jaunarajs, University of Alabama, USA; Kristin Briana Dupre, National Institutes of Health, USA

[^3]: This article was submitted to the journal Frontiers in Neural Circuits.