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03 March 1916 – International Trench
When the Western Front sank into being, it formed a great salient around the city of Ypres that ran up against the Yser Canal just north of Boezinge in Flanders. French and Algerian troops manned the trenches around Boezinge until May of 1915, when they were relieved by British troops. The above photo, which is taken from the vantage point of a place known as the International Trench, shows a spoil-pit that has become a vital observation post; you can see a small lake shining before it. The area is known to the Germans as the Südspitze, or southern tip, for its prominence at the top of the Ypres bulge.
The area was hit hard during the opening poison gas attack of the Second Battle of Ypres last April, when the 1st Canadian Division fought the Germans to a standstill near here. Taking heavy casualties from the intense preparatory bombardment and the abysmal state of their shelter, the Canadians withdrew to the secondary trenches to huddle for cover. When the Germans reached the first line and found no resistance, they continued their advance right into a double-set of Canadians armed with new Lee Enfield rifles, who then put up a withering fire. The Canadians stopped the German attack cold and then charged their abandoned saps, reclaiming the lost ground. After another unsuccessful struggle against British troops in June, the Germans dug circumvaling lines of their own and stopped attacking the International Trench.
The scene has gotten its name as dark humor. The characteristic churn of ever-putrescing trench warfare, attack and counterattack, have produced a diversity of blooming corpses in the wet, fetid mud. No matter the weather, puddles and ponds adorn the land and the lines. Drainage is a dream, while the festering rot and unspeakable pungency of the situation are made worse by the impossibility of sanitation.
Two maps of the International Trench. Note the ever-vulnerable bridges over the Yser Canal. Via Mausershooters.org
The Canadians were here again on February 15th when an 800-meter section of trench came under assault during a series of attacks on the Ypres salient. The International Trench was lost, but yesterday morning they returned with a vengeance. The 3rd Battalion's war diary reads:
Entry: 4:30 am – Field guns, heavies & hows [edit: howitzers] all opened up. MGs opening indirect fire on approaches appalling now. Germans contributed a splendid display of rockets & flares. The strafe lasted violently for 30 minutes, then gradually died down. It was a demonstration to cover attack on International Trench in YPRES salient. Attack was successful. Little reply to our bombardment. Draft of 26 O.R. reported. Bathing & working parties. Gas Alert. Weather – snow.
Teasing the message apart: an artillery bombardment pummeled the International Trench first, and for a half-hour, German machine guns opened up from behind the low undulations of the landscape, where they are safe from direct observation, hosing down the areas where the 3rd Battalion would have advanced, had they actually been attacking. 'Strafe' is the German word for 'punish,' and while it has been used to describe plastering an area with fire for some time before the war, by the end of the conflict it will be more exclusively associated with aircraft firing on ground targets. The gas alert is a product of the weather report that follows it, for both sides have developed a system of meteorology stations to monitor wind speed and pressure, warning units in the line when conditions are right for an enemy gas attack.
This morning's newspapers carry word of the small victory. Mere blurbs based on military public relations information, they are another instance of the limited offensive operations which characterize most fighting in France and Belgium, forming a daily drumbeat of 'news' that never changes. Because of the headlines, English language war chronicles record this as the day the International Trench was won, and the error lives on in cyberspace. Today, the 3rd Battalion war diary reads only: "Bathing and working parties. Weather – cold, snow." The Western Front is never peaceful, but here, at least, it is all quiet.
'The Brooding Soldier,' a nearby Canadian war monument to the 2,000 men who died in the Second Battle of Ypres
23 April 1915 - Altar Of The Earth
Advancing in the wake of the first poison gas attack on the Western Front yesterday, the 46th Reserve Division managed to cross the Yser Canal at two points, while the 51st and 52nd Reserve Divisions made it all the way to Mauser Ridge…
19 October 1914 - First Ypres
The British Expeditionary Force (BEF) has just finished redeploying from the Aisne to Flanders, and they are just in time for a fight. Seven and a half battle-weakened divisions occupy a bulging thirty-six mile front as a German attack begins today near…
15 October 1914 - River Yser
Joined by French Marines and reservists, the remaining Belgian army stops their week-long retreat from Antwerp today and digs in on the western bank of the River Yser. Just twenty feet wide with low embankments, it is hardly the perfect obstacle behind which…
artillery, Belgium, Britain, Canada, France, Germany, infantry, machine guns, trenches, Ypres
1916 - Brave New World, 21 - March Lions, Western Front
02 March 1916 – De Gaulle
04 March 1916 – Unrestricted


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Reparation case examples and legal advice for claiming reparation in the UK.
A. v. N. [2008] CSOH 165
Debate:- In this action the pursuer sought damages for a period of sexual abuse from when she was a child until the age of thirty by the defender. The abuse ended in 1997 and the pursuer's loss was known in 1998. The triennium expired in 2001 with this action raised three years later. At debate t......
Categories: Reparation | Costs & Damages
Court Date: Wednesday, 10 December 2008
Court: Court of Session
Alan Law v. Frank Ronald & Motor Insurers? Bureau [2010] CSOH 53
In this action the pursuer sought damages from the first defender for injuries which he sustained as a result of a road accident on 30 May 2004. In addition the pursuer sought from the second defender declarator that they were liable to satisfy any decree awarded against the first defender if any d......
Court Date: Wednesday, 21 April 2010
Judgement Address: http://www.scotcourts.gov.uk/opinions/2010CSOH53.html
Alan Pearson v. Ray McDermott Diving International Inc [2008] CSIH NUMBER 39
Reclaiming Motion:- On 6 May 1997 in the course of his employment with the defenders the pursuer suffered injury whilst working on a barge in assistance of two divers. An action was raised in May 2000 and, following a proof in 2003, on 18 February 2004 the Lord Ordinary assoilzied the defenders. ......
Court Date: Tuesday, 17 June 2008
Judgement Address: http://www.scotcourts.gov.uk/opinions/2008CSIH39.html
Alyson King v. Advocate General for Scotland [2008] CSOH 166
Debate:- The pursuer breeds and rears horses and in 2000 purchased a property in south-west Scotland with the intention to operate stables there. In March 2001, the pursuer was aware of aircraft flying at low altitudes over the stables in an area where operational low flying was allowed. The purs......
Andrew Young v. The Advocate General for Scotland [2009] CSOH NUMBER102A
Proof:- The pursuer, a 60 year old man, worked in the employment of the Ministry of Defence at Rosyth Dockyard as a fitter from 1968 until 1976. He worked on vessels undergoing refit and repair and worked in the vicinity of laggers who were stripping and applying asbestos lagging. From 1976 until......
Court Date: Wednesday, 15 July 2009
Judgement Address: http://www.scotcourts.gov.uk/opinions/2009CSOH102A.html
Angus Campbell v. Robert Downie [2010] CSOH 37
Proof:- On 7 October 2007 the pursuer was driving his car on the M8 towards the Kingston Bridge in Glasgow. The pursuer slowed down to take heed of queuing traffic, and was close to stopping, when he was hit from behind by a van driven by the defender. The pursuer came to a halt and was again struc......
Court Date: Wednesday, 17 March 2010
Angus Joinery Limited v. James and Valerie McKay, Sheriff Davidson, Dundee Sheriff Court, 16 November 2010
The pursuers and defenders entered into a contract for the supply and installation by the pursuers of six hardwood traditional sash and case windows, at the defenders' home. The defenders had attended at the pursuer's premises and had selected the particular windows which they wished installed conf......
Court Date: Tuesday, 16 November 2010
Anne Mitchell & Karin Mitchell (Aps) v. Glasgow City Council [2008] CSIH 19
Reclaiming Motion:- On 10 August 2001 James Mitchell, aged 72, died as a result of an assault by his neighbour James Drummond. On 12 July 2002 Drummond pled guilty to culpable homicide. In 2003, the deceased's widow and daughter raised this civil action of damages against Glasgow City Council in ......
Anthony Brookes v. First Aberdeen Limited [2010] CSOH 16
Proof:- On 27 January 2006, the pursuer, a 45 year old man at the time of the incident, was driving his scooter in Aberdeen when he lost control, fell and was injured. It was the pursuer's contention that the accident was caused by a bus operated by the defenders, and driven by one of their employe......
Court Date: Wednesday, 24 February 2010
Arthur Clelland v. Quinn Direct, Sheriff C.N.R. Stein, Arbroath Sheriff Court, 22 October 2010
On 27th September 2007, the pursuer's TVR Tuscan Mark 1 fibre-glass motor vehicle was parked and unattended, when the defender's insured collided with it while attempting to reverse park. The collision caused damage to the pursuer's vehicle, specifically its paint and bodywork. At the time of the a......
Court Date: Saturday, 04 December 2010
Axa General Insurance Limited and Others v. The Right Honourable Elish Angiolini QC and others [2010] CSOH 36
Here a motion was made on behalf of eleven individuals who claimed to have been diagnosed with bilateral pleural plaques caused by negligent exposure to asbestos and who had actions for loss, injury and damage in process or in immediate contemplation for leave to enter the process in terms of Rule ......
Benjamin Monteith v. Scot Tech Furniture Services Limited [2009] CSOH 21
Proof:- On 25 August 2005 the pursuer was injured in an accident sustained by him during the course of his employment with the defenders as a delivery driver. Liability was admitted by the defenders and the only issue at proof was whether the injury had rendered the pursuer unfit for heavy work t......
Billy McGhee v. Diageo plc [2008] CSOH 74
Proof - Reparation:- In this action the pursuer, a 20 year old trainee service engineer employed by Stilcan Industrial Conveyors Ltd, attended at the defenders' premises at Glen Ord Distillery to carry out maintenance work on scrapers on two conveyor belts. Whilst carrying out the repair work his......
Court Date: Friday, 23 May 2008
Brenda Downie v. Fife Council [2008] CSOH 47
Reparation - Proof:- The pursuer was employed by the defenders as a social worker. The pursuer had a desk bound job in which she claimed that she developed a pain in her neck from stretching and twisting to use a computer that she shared with a colleague and which was situated on an adjacent desk......
Court Date: Thursday, 20 March 2008
Brian Kelly v Shetland Health Board [2008] CSIH 7
Court Date: Thursday, 17 January 2008
Cameron Don v Eastern Holdings Limited ? Edinburgh Sheriff Court, 18 June 2008
This action concerned liability for a road accident involving the Pursuer's car and a car being driven by the Defenders' employee, M. Quantum was agreed and a Proof on liability took place at which the Pursuer and M were the only witnesses. The accident occurred on a road which had four lanes, two ......
Judgement Address: http://www.scotcourts.gov.uk/opinions/A574207.html
Caroline Jarrett as legal Representative of Megan Jarrett v Kirkcaldy Ice Rink - Kirkcaldy Sheriff Court, 2nd July 2009
The Pursuer's daughter suffered an accident at Kirkcaldy Ice Rink in October 2007 when she was 12 years old. As she left the ice and stepped onto a walkway, her right skate became caught in some netting that was trailing on the ground. She fell and twisted her ankle. The netting was there to protec......
Court Date: Thursday, 20 August 2009
Caroline Spencer v Miss E Baron ? Edinburgh Sheriff Court, 4 February 2008
Action for Damages – Solatium - Road traffic accident – Causation - Pursuer having suffered whiplash type injury, although vehicles she was in The Pursuer was a passenger in a private hire vehicle, which was stationery at a junction when it was struck on the rear bumper by the......
Chalmers v Aberdeenshire Council ? Aberdeen Sheriff Court, 28 November 2008
The Pursuer sought damages for alleged negligence on the part of the Defenders and also damages for alleged nuisance. A drainage ditch at the side of a public road ran alongside the Pursuer's fields. The Defenders were the local authority responsible for the management and maintenance of the road a......
Christine Robertson (AP) v. The Scottish Ministers [2007] CSOH 186
Reparation - Debate:- In this action the pursuer sought damages in respect of alleged bullying and harassment at her work between early 2000 and late 2001. During that period the pursuer was employed as a prison guard by the Scottish Prison Service and her claim comprised solatium for anxiety, dist......
Court Date: Wednesday, 28 November 2007
Craig McIntosh v. First Glasgow Limited [2009] CSOH NUMBER117
Motion to remit to Sheriff Court:- In this ordinary action the pursuer sought damages of £9,000 in respect of damage caused to his motor vehicle following a collision with a bus driven by an employee of the defenders. Liability was not disputed by the defenders and the only issue related to th......
Court Date: Wednesday, 12 August 2009
Crolla v Hussain and Ascension Construction Limited, Edinburgh Sheriff Court, 8 October 2008
The Pursuers/Appellants were heritable proprietors of a first floor tenement flat. The Defender/Respondent was the proprietor of the property below. He had arranged for Ascension Construction Limited to carry out works to his property and they were convened as third parties to the action. The Pur......
Judgement Address: http://www.scotcourts.gov.uk/opinions/A601_05_.html
Dale McFarlane v. Barry Thain & James Campbell & The Motor Insurers Bureau [2009] CSIH 64
Reclaiming motion:- On 17 July 1999 the pursuer was riding as a pillion passenger a on a motorcycle which was driven by the first defender. The pursuer was seriously injured when the motorcycle collided with a car driven by the second defender. The pursuer thereafter raised an action against both a......
Court: Court of Session (Inner House)
David & Doreen Stewart v Aftab Ahmed Malik ? Ayr Sheriff Court, 29 April 2008
The Pursuers and Appellants were the joint proprietors of a first floor flat. The Defender and Respondent was the heritable proprietor of the shop which was located directly below the flat. The Defender had arranged for alteration works to be carried out to the shop. The works were subject to a......
Court Date: Wednesday, 28 May 2008
David Lyons v Wm Morrisons Supermarkets PLC [2010] CSOH 50
The pursuer was employed by the defenders at a supermarket in St. Andrews. During the course of his employment the pursuer stacked shelves. On two separate occasions in December 2005 and a month later, the pursuer injured his back whilst lifting heavy goods within the supermarket. Following the sec......
Diana Cheesman v. International Travel Service Limited [2008] CSOH 58
Contract:- In September 2001 the pursuer and her husband went on a coach holiday in Switzerland and Italy. On the last day of her holiday the pursuer tripped on a carpet in the coach and injured her ankle. The pursuer raised an action against the defenders with whom she had entered into a contract ......
Donal Toner v. Kean Construction (Scotland) Limited & CRGP Architects and Surveyors and Partners Thereof [2009] CSOH 105
Procedure Roll:- In this action the pursuer, an architect, sought damages from the first and second defenders, developers and architects respectively, for breach of copyright. The pursuer was instructed by the first defenders predecessor in title as an architect in relation to the development of ......
Donald Bremner v. Kevin Bartlett [2008] CSOH 03
Donald Ross v. PGS Production A.S. [2009] CSOH45
On 2 June 2000 the pursuer was injured whilst employed as a deck foreman on an off-shore installation. The action was settled by extra judicial agreement. In this opposed motion enrolled on behalf of the pursuer, the pursuer sought the certification of two engineers as skilled witnesses for the p......
Douglas Robert Porter v. Scottish Borders Council [2008] CSOH163
Proof:- In this action the pursuer sought damages in respect of injuries sustained as a result of an accident occurring on 2 September 2005. That afternoon the pursuer had finished work for the week and visited the public toilet of the town. The pursuer worked as a joiner and was wearing his work......
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redpajama_set_name: RedPajamaCommonCrawl


It's an old game: blame the innocent and make the innocent look guilty.
What Israel built was not a border, but a barrier against death and destruction. What Israel built was protection, not apartheid.
The separation wall between North and South Korea is armed and mined. Yet, the UN remains largely silent as to North Korea's terrorism of its own people.
As the world mourns the passing of Nelson Mandela and reflects upon his lifelong fight against racial injustice, his lengthy imprisonment and his ultimate defeat of apartheid as President of South Africa, it is quite appropriate to examine the origins, concepts, applications and misapplications of apartheid.
Much will be written about President Mandela's bold stands, deep commitment to truth and justice, his legacy and lessons learned. Much less will be said about the ugly and wrongheaded accusation that Israel is an apartheid racist criminal state.
Such an accusation, equating Israel with the racist criminal state against which Mandela heroically fought, not only maligns Nelson Mandela, but ignores Israel's rich history as a defender of human rights for all peoples. This slander does nothing to promote truth or justice.
In this context, let us remember that exactly ten years ago on December 9th, 2003 the United Nations General Assembly ("UNGA") adopted a resolution referring the question of the "legal consequences" of the Israeli-constructed security fence to the International Court of Justice ("ICJ"). This resolution, preceded by decades of maligning Israel at the United Nations, was contrary to any semblance of objectivity and in violation of the UN Charter.
The apartheid accusation campaign against Israel has indeed hijacked the very concept and illegality of apartheid in a concerted effort to deceptively tell the world that Israel is today, like South Africa was before Mandela, an apartheid racist criminal state. This propaganda war seeks to expose Israel to liability at the International Criminal Court.
This devious plot is in the same nature as the ploy to drag Israel before the International Court of Justice for an advisory opinion relating to Israel's construction of the terrorism prevention security fence/barrier. Moreover, the attempt to equate Israel's security actions as an act of apartheid completely disregards the reality of the raging Second Intifada which was ongoing ten years ago. Fencing out the terrorists served as a legitimate exercise of meeting Israel's right and obligation to defend and protect her people.
It's an old game: blame the innocent and make the innocent look guilty. After the commencement of the Second Intifada campaign of orchestrated terrorist bombings and heinous suicide attacks across Israel in late September of 2000, Israel took the necessary steps to route, design and construct a security line to keep out terrorists, suicide-homicide-bombers, and munitions and to guard against grenade and missile attacks from the Palestinian territories.
In 2001, 2002 and 2003, these activities conducted by Palestinian terrorist organizations continued to threaten lives and security across Israel. No one was spared the fear inflicted by these murderous attacks upon schools, buses, restaurants, nightclubs, shopping malls, religious sites and family gatherings. In this climate of danger and with a commitment to protect innocent human life and achieve a lasting peace through security, construction of the fence ensued.
The response was an outcry that Israel was interfering with the lives and livelihood of the Palestinians near the fence line and was taking steps to separate the Israelis and Palestinians. Misguided opponents accused Israel of unilaterally establishing a border.
In truth, what Israel built was a security barrier, movable upon the cessation of terrorism, an integral part of achieving an everlasting peace between Israel and the Palestinians. In fact, approximately 95% of this "wall" is merely a fence; the remaining five-six percent is composed of concrete akin to expressway Jersey walls. Of necessity, these concrete portions guard against rocks, boulders, grenades and munitions. What Israel built was not a border, but a barrier against death and destruction. What Israel built was protection, not apartheid.
Central to the necessity of the security fence was the fact that the vast majority of weaponry and terrorists originated from within the portions of Judea and Samaria, the West Bank of the Jordan River, controlled by the Palestinian Authority (PA). Indeed, the fence guaranteed that terrorists and weapons could no longer avoid detection by exiting PA controlled regions of Judea and Samaria through the wilderness or unguarded border crossings. As a result, the number of suicide bombings and terrorist attacks in Israel dropped significantly.
However, the threat of even one event, the killing of even one person, is intolerable for any nation-state; and intolerable for Israel.
After the UN Security Council refused to adopt a resolution in 2003 condemning Israel's construction of the security fence, those opposed to Israel's very existence bypassed the UN Security Council and introduced in the UN General Assembly the resolution referring the matter of the fence to the ICJ. In a display of unbridled bias, the resolution suggested that the fence was tantamount to Israel, the "Occupying Power" acquiring territory by force and thus acting violative of the principle of equal rights and self-determination of peoples.
Under the guise of fighting a non-existent apartheid, the prejudiced opponents of Israel deceptively attempted to divert the focus away from terrorism and toward their own biased aims.. In a hijacking of truth and miscarriage of justice, the world forgives the terrorists and forgets the victims. Such has been the case regarding Israel, as those who committed the terrorism seem to have been forgiven, while those who have suffered have been forgotten; and Israel, standing up for her people against the terrorists, has been mercilessly maligned.
Ironically, among the supporters of the UNGA resolution referring the matter to the International Court of Justice was North Korea. This brutal dictatorship hardly possesses the moral credibility to render a judgment on a security fence, as it has long refused to allow its starving citizens to freely travel into prosperous South Korea. The separation wall between North and South Korea is armed and mined. Yet, the UN remains largely silent as to North Korea's terrorism of its own people, while castigating Israel year after year, session after session..
Moreover, in 2004, the ICJ issued its Advisory Opinion on the security fence. The opinion gave no credence to the necessity of the State of Israel to construct the barrier as a preventative measure against terrorist attacks nor did it provide any deference to the decision of the Israeli High Court of Justice ordering rerouting of portions of the security barrier.
Notwithstanding world pressure, principled Israeli leadership has refused to cave in to both the biased UN General Assembly and an ICJ operating without lawful jurisdiction. Indeed, the Israeli government possesses a sacred obligation, and the absolute right, to defend and protect her people and to assure security for Israel and her people.
Until the Palestinians choose to live side by side in peace and security with Israel as its neighbor, the fence will continue as an important part of meeting that duty.
For not only during the past ten years, but for decades, Israel has weathered the bigoted misrepresentation of her true intentions to attain peace through security and the constant attempt to blame her for acts not done. Ten years since the adoption of the UN General Assembly Resolution wrongly referring the issue of the security fence to the ICJ, one thing is clear: Israel has acted rightly and out of necessity in building the barrier. While Israel patiently awaits the day when the protections it affords will no longer be necessary, the maligning of Israel continues, with the accusation of apartheid as the mantra.
As the "heart of South Africa", Mandela's legacy of standing against apartheid in South Africa is legendary. Likewise, Israel and the Jewish people possess a legacy deserving of respect by the entire world: a proven dedication to the principles and watchword of the Jewish people thousands of years ago of "Justice, Justice Shalt Thou Pursue".
Israel's protection of human rights, care for the sick and downtrodden, respect for the dignity of each person and commitment to the rule of law, bear testament to this pursuit. Indeed , Israel and the Jewish people deserve both respect and admiration—not the unjust and untrue accusation of having committed apartheid.
*Richard D. Heideman serves as Senior Counsel of the Washington, DC law firm Heideman Nudelman & Kalik, PC, representing victims of terrorism and international human rights violations and is the author of The Hague Odyssey: Israel's Struggle for Security on the Front Lines of Terrorism and Her Battle for Justice at the United Nations (Bartleby Press, 2013; see thehagueodyssey.com). Contact: info@thehagueodyssey.com.
Copyright © 2013 · Richard D. Heideman. All Rights Reserved.


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Long-Circulation and Brain Targeted Isoliquiritigenin Micelle Nanoparticles: Formation, Characterization, Tissue Distribution, Pharmacokinetics and Effects for Ischemic Stroke
Weitong Song,1 Lu Bai,1 Yuya Yang,1 Yongchao Wang,2 Pingxiang Xu,1,3 Yuming Zhao,1 Xuelin Zhou,1,3 Xiaorong Li,1,3 Ming Xue1,3 1Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China; 2CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, People's Republic of China; 3Beijing Laboratory for Biomedical Detection Technology and Instrument, Beijing, People's Republic of China Correspondence: Ming Xue, Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Youanmen, Beijing, 100069, People's Republic of China, Tel +8610-83950416, Fax +8610-83911520, Email [email protected] Purpose: We designed a novel isoliquiritigenin (ISL) loaded micelle prepared with DSPE-PEG2000 as the drug carrier modified with the brain-targeting polypeptide angiopep-2 to improve the poor water solubility and low bioavailability of ISL for the treatment of acute ischemic stroke. Methods: Thin film evaporation was used to synthesize the ISL micelles (ISL-M) modified with angiopep-2 as the brain targeted ligands. The morphology of the micelles was observed by the TEM. The particle size and zeta potential were measured via the nanometer particle size analyzer. The drug loading, encapsulation and in vitro release rates of micelles were detected by the HPLC. The UPLC-ESI-MS/MS methods were used to measure the ISL concentrations of ISL in plasma and main tissues after intravenous administration, and compared the pharmacokinetics and tissue distributions between ISL and ISL-M. In the MCAO mice model, the protective effects of ISL and ISL-M were confirmed via the behavioral and molecular biology experiments. Results: The results showed that the drug loading of ISL-M was 7.63 ± 2.62%, the encapsulation efficiency was 68.17 ± 6.23%, the particle size was 40.87 ± 4.82 nm, and the zeta potential was − 34.23 ± 3.35 mV. The in vitro release experiments showed that ISL-M had good sustained-release effect and pH sensitivity. Compared with ISL monomers, the ISL-M could significantly prolong the in vivo circulation time of ISL and enhance the accumulation in the brain tissues. The ISL-M could ameliorate the brain injury induced by the MCAO mice via inhibition of cellular autophagy and neuronal apoptosis. There were no the cellular structural damages and other adverse effects for ISL-M on the main tissues and organs. Conclusion: The ISL-M could serve as a promising and ideal drug candidate for the clinical application of ISL in the treatment of acute ischemic stroke. Keywords: isoliquiritigenin, micelle, brain distribution, pharmacokinetics, ischemic stroke, MCAO Introduction Cerebral stroke was defined as the formation of thrombus or blood clots on basis of the pathological changes in the brain arteries, while the blood flow was slow, the blood composition changed or the blood viscosity increased, which caused the lesion and blockage in the blood vessels. 1 Approximately 87% of strokes have been accounted for the ischemic strokes, and it was the second most common cause of mortality and permanent disability worldwide. 2 Up to now, intravenous thrombolysis and thrombectomy are the major therapeutic strategies and methods, and this procedure is often accompanied by cerebral ischemia-reperfusion injury, which results in aggravating brain damage with very few effective treatments. Thus, it is very important and urgent to develop the novel drugs or new methods to prevent and treat ischemic stroke in early phase. 3 Isoliquiritigenin (ISL) is one of the major active flavonoid glycosides extracted from Glycyrrhiza uralensis, which has shown the markedly pharmacological activities, such as anti-inflammatory, anti-oxidant and anti-tumor. 4–6 The results also showed that ISL had a good protective effect on cerebral ischemia-reperfusion injury. 7 However, the pharmacokinetic studies had found that there were the poor oral absorption, low bioavailability and brain tissue distribution, and short half-life for ISL compound in vivo. These weakness of in vivo disposition for ISL largely limited the effective application of the drug in clinical practice. In order to effectively increase the exposure and circulation levels of ISL in the targeted tissue, the polymeric micelle system was successfully designed and used to improve the physicochemical and structural properties of drug such as solubility resulting in that the circulation time was prolonged and the immunogenicity was reduced. 8–11 DSPE-PEG2000 is an amphiphilic polymer which could be formed into the core-shell structured nanoparticles by self-assembly methods. In this study, we designed and prepared the ISL loaded micelles made of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000), which was proved safe, biocompatible and relatively nontoxic, and had been approved by the Food and Drug Administration of United States of American (FDA, USA). 12 , 13 The hydrophobic groups formed by the long fatty acyl chains could load the fat soluble drug molecules, which efficiently restricted the mobility of drugs at the same time, leading to a sustained drug release. Furthermore, a polyethylene glycol (PEG) surface-modified nanoparticles could enhance the circulation time in blood, reduce the clearance rate by the reticuloendothelial system (RES), and prolong the circulation time of the drug-loaded micelles. 14 , 15 The existence of blood–brain barrier (BBB) could effectively prevent some drugs from penetrating into the brain. To overcome this barrier, it was an effective method to modify the nano micelles with the specific brain targeted ligands binding to the endogenous receptors on the BBB, resulting in drugs across the BBB more easily. 16–18 Angiopep-2 (Ang) was a novel polypeptide composed of nineteen amino acids, it could enter the brain tissue via the low-density lipoprotein receptor-related protein 1 (LRP-1) receptor mediated endocytosis, which expressed on the BBB. 19 In addition, the nano drug modified with angiopep-2 could significantly improve the accumulation of drugs in the brains. Compared with lactoferrin (LF) and transferrin (TF) which were the major brain targeted modification ligands with endogenous competition, 20 the BBB penetration efficiency of angiopep-2 was several times higher than that in LF and TF. 21 Based on these considerations, the DSPE-PEG2000 modified with the brain-targeting peptide angiopep-2 was used as the effective carrier to prepare the ISL micelles (ISL-M) for treatment of brain injury induced by acute ischemic stroke. In this study, the ISL nano micelles were designed and prepared to improve pharmacokinetic characteristics, increase the accumulation level of ISL in the brain, ameliorate the neuronal damage and reverse the behavioral deficits cause by ischemic stroke. In addition, there was no any obvious toxicity in main tissues and organs after intravenous administration of ISL-M. The data from our present experiments showed that the ISL-M was a novel, effective and safe drug candidate for the treatment of ischemic stroke. Materials and Methods Materials Isoliquiritigenin (MW=256.25, Purity>95%) [(e)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl) −2-propen-1-one] was purchased from the Tokyo Chemical Industry Co., Ltd (Tokyo, Japan). DSPE-mPEG2000 [1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-2000] was provided by the Lipoid GmbH (Ludwigshafen, Frigenstrasse, German). DSPE-PEG2000-Mal [1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-MaleiMide (polyethylene glycol)-2000] was obtained from the Shanghai Ponsure Biotechnology Co., Ltd (Shanghai, China). Angiopep-2 (CTFFYGGSRGKRNNFKTEEY) was synthesized by the Shanghai Top Biological Technology Co., Ltd (Shanghai, China). Tris (2-carboxyethyl) phosphine (TCEP) was obtained by the Beijing Solarbio Science and Technology Co., Ltd (Beijing, China). MCAO monofilaments were purchased from Beijing Cinotech Co., Ltd (Beijing, China). Hematoxylin-eosin staining was provided by the Wuhan Service Bio-technology Co., Ltd (Wuhan, Hubei, China). TUNEL staining was obtained from the Beyotime Biotechnology (Nantong, Jiangsu, China). Antibodies were purchased from Cell Signaling Technology (Beverly, Massachusetts, USA). Acetonitrile was supported as HPLC grade by the Fisher Scientific (Fair Lawn, NJ, USA). All other chemicals and solvent were of analytical grade. Synthesis of DSPE-PEG2000-Angiopep-2 Maleimide-functionalized copolymer DSPE-PEG2000-Angiopep-2 was synthesized by linking DSPE-PEG2000-Mal to angiopep-2 through a carbodiimide-mediated coupling reaction. 6 mg of DSPE-PEG2000-Mal, 5 mg of angiopep-2 and 5 mg of TCEP were weighed accurately and dissolved with 50 mM HEPES buffer (pH = 7) in pear shaped bottle. After ultrasonic mixing for 20 min, the mixture was stirred magnetically under the protection of nitrogen for 4 h at room temperature. Then the solution was dialyzed in a dialysis bag (MWCO = 3500) for 24 h, freeze-dried and stored for use in a refrigerator at −20 ℃. Preparation of ISL-M ISL micelle was prepared by the methods of thin-film rotary evaporation. First, the ISL was fully dissolved in methanol, DSPE-PEG2000 was dissolved in dichloromethane, DSPE-PEG2000-Angiopep-2 dissolved in chloroform, respectively, and then these compounds were mixed. Subsequently, the organic solvent was removed via vacuum rotary evaporation at a temperature of 45 ℃, the rotating speed was 130 rpm for 20 min. After hydration with normal saline, the suspension was sonicated for 20 min and filtered by a nylon filter (0.22 μm) to obtain the ISL micelles. Characterization of ISL-M UV-Visible Spectroscopy DSPE-PEG2000-Mal, DSPE-PEG2000-Angiopep-2 and angiopep-2 were dissolved in deionized water, respectively, and detected by the UV-2600 spectrophotometer (Shimadzu, Kyoto, Japan). Fourier Transform Infrared Spectrometer (FT-IR) The chemical structures of DSPE-PEG2000-Mal, DSPE-PEG2000-Angiopep-2 and angiopep-2 were measured by attenuated total reflection (ATR) with a Nicolet iS5 Fourier transform infrared spectrometer (Thermo Fisher Scientific, MA, USA). 1H-NMR Spectrometer 5 mg of DSPE-PEG2000-Mal, DSPE-PEG2000-Angiopep-2 and angiopep-2 were dissolved in 1 mL of DMSO-d6, respectively, and analyzed in the 400 MHz NMR spectrometer (Bruker Daltonics Lnc., Blairika, Massachusetts, USA). Particle Size, Polydispersity Index, and Zeta Potential The freshly made micelles were diluted appropriately with distilled water. The particle size, particle dispersion index (PDI) and zeta potential (ZP) of ISL micelles were measured by the Zeta-sizer Nano S90 (Malvern Instruments, U.K.). Morphology of ISL-M The micromorphology of the ISL micelles was observed by 120 kV HT7700 transmission electron microscope (Hitachi, Tokyo, Japan). Encapsulation Efficiency and Drug Loading Capacity of ISL-M The concentrations of ISL were detected by the high-performance liquid chromatography (HPLC) system (Agilent Technologies, Santa Clara, USA), the sample separation was performed on the ZORBAX SB-C18 column (5 μm, 4.6 × 150 mm, Agilent) with a flow rate of 1.0 mL/min. The isocratic mobile phase was consisted of 0.1% formic acid aqueous solution and acetonitrile (50:50, v/v), and the detection wavelength of ISL was set at 367 nm. The ISL micelles were dissolved in methanol and sonicated for 20 min. After centrifuging at 13,000 rpm for 10 min, the supernatant was filtered through a nylon filter (0.22 μm) and 20 μL was injected into HPLC. The encapsulation efficiency (EE) of ISL micelles was calculated as the following formula: EE (%) = Weight of loaded drug / Weight of drug in feeding× 100% The drug loading capacity (DLC) of ISL micelles was calculated as the following formula: DLC (%) = Weight of loaded drug / Weight of micelles× 100% In vitro Release Studies As described similarly in the previous study, 22 the ISL-loaded micelles were transferred into a pre-soaked dialysis bag (MWCO = 500), immersed in 50 mL of release medium (PBS buffer with 1% SDS), and shaken with speed of 200 rpm at 37 ℃. 0.2 mL of the outside PBS was withdrawn for measurements at predetermined time intervals (0.5, 1, 2, 4, 6, 8, 12, 24 and 48 h) and an equal volume of the fresh PBS was supplemented. The accumulative release amounts of ISL were analyzed and calculated using the HPLC system as described above. LC-MS/MS Determination for ISL and ISL-M in vivo The UPLC-MS/MS system consisted of Agilent 1290 series with LC pump and auto-sampler (Agilent, Santa Clara, USA), coupled with an Agilent 6490 triple quadrupole mass spectrometer (Agilent Technologies, Santa Clara, USA) equipped with the electrospray ionization (ESI). Chromatographic separation was implemented by the Eclipse Plus C18 column (100 × 2.1 mm i.d., 1.8 μm, Agilent Technologies, USA) under isocratic mobile phase compositions using 0.1% formic acid aqueous solution and acetonitrile (60:40, v/v) with a flow rate of 0.3 mL/min. The column temperature was set at 25 ℃ and the autosampler temperature was 4 ℃. The MS/MS system was operated under the negative mode with an optimized condition as follows: ion spray voltage at +5.5 kV, nitrogen as nebulizer gas, auxiliary gas and curtain gas was at 30, 60 and 10 psi, respectively. The auxiliary gas temperature was at 225 ℃ and interface heater temperature at 110℃. The multiple reaction monitoring (MRM) analyses were conducted by monitoring the precursor ion to production transitions, including the m/z 255 → 119 for ISL and the m/z 268 → 133 for genistein (the internal standard, IS). 100 μL of plasma sample was spiked with 300 μL of acetonitrile and 100 μL of IS (1 μg/mL). After vortexing, the mixture was centrifuged 13,000 rpm for 10 min at 4 ℃. The supernatant (400 μL) was collected followed by being evaporated to dryness under nitrogen at room temperature. The residue was reconstituted with 200 μL of methanol, filtered through a nylon filter (0.22 μm) and 5 μL aliquot was injected into the UPLC-MS/MS system for analyses. The LC-ESI-MS/MS method for quantification of ISL in plasma and tissue was validated for accuracy, precision, selectivity, linearity, recovery and matrix effect according to the guidelines of US FDA bioanalytical method. Pharmacokinetics and Tissue Distribution of ISL-M and ISL Sprague Dawley (SD) male rats (aging 7-9 weeks, 240-260 g) were purchased from the Beijing Animal Science Biotechnology Co., Ltd (Beijing, China). All animal procedures were performed in accordance with the guidelines for Care and Use of Laboratory Animals for Capital Medical University and approved by the Animal Ethics Committee of Capital Medical University. The rats were randomly divided into two groups, with six rats in each group and fasted overnight before the experiment. ISL (dissolved in physiological saline containing 30% propylene glycol) and ISL micelles were injected via the tail vein at a dose of 2 mg/kg, respectively. The blood samples (100 μL) were obtained from the jugular vein and collected in the heparin pretreated polypropylene centrifuge tubes at each time point (0.03, 0.08, 0.17, 0.33, 0.5, 1, 2, 4 and 8 h) over a period of 8 h after the administration. The plasma was isolated by centrifuging at 13,000 rpm for 10 min at 4 ℃ and then stored at −80 ℃ for further analysis. The pharmacokinetic analysis was processed with the program DAS 2.0 Pharmacokinetics Software (Chinese Pharmacological Society, Beijing, China). ICR male mice (aging 6-8 weeks, 27-28 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd (Beijing, China). The mice were randomly divided into two groups and these two formulations of ISL at a dose of 2.8 mg/kg were administered via intravenous route. At each predetermined time point (0.17, 0.5, 1 and 2 h) after dosing, four mice for each test point were sacrificed for collection of heart, liver, lung, kidney, and brain, respectively. The tissues were rinsed with normal saline, weighed and homogenized with cold saline (w/v=1:2). Subsequently, the tissue homogenates were centrifuged at 13,000 rpm for 10 min. The supernatant was transferred into the tube, and stored at −80 ℃ until analysis. The maximum concentration (Cmax) in tissues was obtained from the observed data, and the values of area under the curve (AUC) for the drug concentration with time were calculated by the linear trapezoidal method. 23 The relative rate of uptake (Re) of each tissue was the ratio of AUC for ISL-M to AUC for ISL in this tissue, and the ratio of peak concentration (Cp) of each tissue was the ratio of Cmax of ISL-M to Cmax of ISL in the tissue. The Middle Cerebral Artery Ischemia (MCAO) Model C57BL/6 mice (male, aging 6-8 weeks, 24-26 g) were purchased from the Beijing Vital River Laboratory Animal Technology Co., Ltd (Beijing, China), which were randomly divided into six groups, with four mice each group. The groups were the group for the sham, MCAO model, 3 mg/kg dose of ISL, 1 mg/kg dose of ISL micelles, 3 mg/kg dose of ISL micelles, and 3 mg/kg dose of edaravone (EDA). The MCAO model in mice was used for experiments as previously described. 24 The mice were anesthetized with 5% chloral hydrate by intraperitoneal injection before the experiment. The suitable incision in neck was conducted to fully expose the field of view for operation, and the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA) from the peripheral connective tissues were separated. The surgical monofilament (1620-A4, Beijing Cinotech Co., Ltd) was slowly inserted into ICA via the ECA stump until the resistance occurred, indicating that it had blocked the starting point of the middle cerebral artery (MCA). Then the surgical monofilament was fixed, the wound was covered with cotton moistened with normal saline and the mice were housed in an incubator at 37 ℃. One hour later, the monofilament was removed to restore blood flow. Sham-operated mice underwent the same procedures without insertion of the monofilament. After the operation, the mice in different groups were intravenously injected for 7 days with corresponding drugs. Then the mice were sacrificed and perfused with PBS (pH = 7) and 4% paraformaldehyde. The brain tissue was collected to slice into frozen sections with a thickness of 20 μm and stored at −80 ℃ refrigerator. The Effects of Drug on the MCAO Model Mice Longa Scores The neurological examination was used to assess the neurological deficits of MCAO mice. 24 The test was conducted by the investigator who was blinded to treat the tested groups. The neurologic findings were scored on a 5-point scale as follows: a score of 0, with no neurologic deficit; a score of 1, failure to extend left forepaw fully; a score of 2, walking in a circle to the left; a score of 3, falling to the left; and a score of 4, unable to walk spontaneously and a depression in consciousness. Adhesive Removal Test The sensorimotor function in animals was evaluated by using adhesive removal test after stroke, as described in the previous studies. 25 Patches of adhesive tape (3 mm × 4 mm) were attached to the right front paws of mice with equal pressure by the experimenter before each trial. The mice were placed in a test box, and the times to contact and to remove adhesive tape were recorded with a maximum of 120 s, respectively. The mice were trained for three days, and tested for three times on the seventh day after operation conducted. Rotarod Experiments The rotarod experiment was used to evaluate the neurological function of mice. 26 The mice were trained on the rotarod (DXP-2, Institute of Materia Medica, Chinese Academy of Medical Sciences) for three days after surgery. The speed on the first day was 6 rpm, the speed on the second day and the third day was 14 rpm. The latency to fall was recorded as the time before mice fell off the rotarod with the beginning speed for 14 rpm. Hematoxylin-Eosin Staining of Tissue for Toxicity Study The C57BL/6 mice in each group were intravenously injected with ISL and different doses of ISL-M, respectively, the unloaded micelles or the ISL micelles for the in vivo toxicity study. The organs in mice including the heart, liver, spleen, lung and kidney, were all collected and fixed in 4% paraformaldehyde. The frozen tissue sections were used for hematoxylin and eosin (H&E) staining, and the tissue toxicity was observed by a brightfield microscope. Nissl Staining of Tissue for Neuronal Injury The frozen sections of brains in mice were immersed in the Nissl staining solution (Sigma) at room temperature for 20 min. The slides were then sealed with neutral balsam after dehydration with different concentrations of ethanol, and washing with xylene for 5 min. Observations of neuronal injury were performed using a brightfield microscope. TUNEL Staining for Apoptosis of Nerve Cell The TUNEL assay was employed to observe the apoptosis of nerve cells in the MCAO model. According to the instructions of the TUNEL kit (Beyotime Biotechnology), the frozen sections of brain tissues for each group in mice were fluorescently stained to observe the broken nuclear DNA fragments. The number of cells with significant fluorescence in different fields of view were recorded by the image J software. Immunofluorescence Staining for Autophagy of Nerve Cell The frozen slides were baked in a 37 ℃ oven for 10–20 min and fixed in paraformaldehyde for 30 min. After washing three times with PBS (pH = 7.4) for 5 min, the sections were immersed in EDTA antigen retrieval buffer (pH = 8.0), and maintained at a sub-boiling temperature for 8 min, standing for 8 min, and then followed by another sub-boiling temperature for 7 min. Wash three times with PBS (pH = 7.4), 5 min each time, and add 3% BSA to cover the marked tissue to block non-specific binding for 30 min. The immunostaining was performed by incubating with primary antibody rabbit Anti-LC3 (1:100, Cell Signaling Technology) overnight at 4 ℃ followed by secondary antibody Cy3 conjugated goat anti-rabbit IgG H&L (1:300, Wuhan Servicebio Technology Co., Ltd) at room temperature for 50 min. The brain sections were rinsed three times in PBS (pH = 7.4) for 5 min each, and then incubated with DAPI solution (Wuhan Servicebio Technology Co., Ltd) at room temperature for 10 min in order to observe the cell nuclei by a laser confocal fluorescence microscope. The images from the junction of infarction and intact areas were randomly captured and processed for counting the number of cells with significant fluorescence by the image J. Statistical Analysis The data of the experiments were summarized as the mean ± standard deviation (SD). The image processing and image analyses were performed using the Image J software, version 1.43 for Windows. The statistical analysis was performed by one-way ANOVA or unpaired t-test and followed by SPSS 19.0 statistical software. The differences were considered statistically significant at P < 0.05. Results and Discussion Design and Preparation of ISL-M Scheme 1 showed the design and synthetic routes of DSPE-PEG2000-Angiopep-2 under the protection condition of nitrogen and the reduction of TCEP. The DSPE-PEG2000-Angiopep-2, DSPE-PEG2000 and ISL were mixed in a distillation flask to prepare the ISL nano micelles by thin film evaporation. The prepared micelles were successfully injected into the MCAO mice by intravenous administration, uptaken across the blood-brain barrier via the blood circulation. The transport mechanism of the micelles was investigated and recognized, indicating that the LRP-1 receptor mediated endocytosis into the blood-brain barrier. 19 Scheme 1 Preparation of ISL micelles and its mechanism of LRP-1 receptor-mediated penetration of the blood-brain barrier. Abbreviations: LRP-1, low-density lipoprotein receptor-related protein 1; ISL, isoliquiritigenin; ISL-M, isoliquiritigenin micelles. Characterization of DSPE-PEG2000-Angiopep-2 The spectra of UV, FT-IR and 1H-NMR were used to characterize the compounds of DSPE-PEG2000-Angiopep-2 by linking DSPE-PEG2000-Mal to the thiol moiety of angiopep-2. Compared with the UV absorption nature of DSPE-PEG2000-Mal, the UV absorption of DSPE-PEG2000-Angiopep-2 was significantly shifted to the blue wave side, and coincided with the UV characteristic absorption of angiopep-2 near 270 nm ( Figure 1A ). As shown in Figure 1B , there was obvious enhancement of the peak near 3300 cm−1 in the infrared spectra of DSPE-PEG2000-Angiopep-2 due to the hydroxyl group existed in angiopep-2. The peaks existed at 1650–1690 cm−1 and 1500–1600 cm−1 were ascribed to stretching vibration of the amide bond and benzene ring. Figure 1C1 showed the 1H-NMR spectrum of Angiopep-2 had a large number of H peaks from benzene ring and amide bond in chemical shifts 6.5 to 8.5 ppm. Compared with DSPE-PEG2000-Mal that had a characteristic peak of maleimide group at the chemical shift of 6.5 ppm, shown in Figure 1C2 , the Mal peak disappeared in the 1H-NMR spectra of DSPE-PEG2000-Angiopep-2 and was replaced by lots of H peaks around chemical shifts 6.5 to 8.0 ppm (see the Figure 1C3 ). The results of three kinds of spectra confirmed that the Mal group had reacted with the thiol moiety of angiopep-2. Figure 1 Characterization of the DSPE-PEG2000-Ang. The UV (A) and FT-IR spectra (B) of angiopep-2, DSPE-PEG2000-Mal and DSPE-PEG2000-Ang; 1H-NMR spectra of angiopep-2 (C1), DSPE-PEG2000-Mal (C2) and DSPE-PEG2000-Ang (C3). Abbreviations: UV, ultraviolet; FT-IR, fourier transform infrared spectroscopy; 1H NMR, nuclear magnetic resonance H spectrum. Characterization of ISL-M DSPE-PEG2000, as an amphiphilic molecule, could self-assemble to form the polymer micelles composed of a hydrophobic core formed by DSPE and a hydrophilic shell formed by PEG2000 in aqueous solution via filming-rehydration method. 27 Our results that the encapsulation efficiency and drug loading of ISL-M were 68.17 ± 6.23% and 7.63 ± 2.62%, respectively. The average particle size of ISL-M was 40.87 ± 4.82 nm with a good distribution (PDI, 0.26 ± 0.01) (see the Figure 2A ). Previous studies had shown that the nanoparticles with a particle size of less than 10 nm were easy to be quickly removed by the kidney, 28 , 29 and nanoparticles with a particle size of greater than 200 nm would be rapidly eliminated by activating the complement system from the blood stream. 30–32 Further, most in vitro studies had shown that the uptake of nanoparticles by cells was mainly in the particle size range of 10~60 nm. 33–37 Based on these studies, it would be inferred that ISL-M could prolong the circulation time in vivo and be better uptaken by cells. 28–37 Figure 2 The physicochemical properties of ISL-M. (A) Particle size distribution of ISL-M; (B) TEM image of ISL-M; (C) zeta potential of ISL-M; (D) in vitro release profile of ISL and ISL-M in PBS at pH = 7.4 and 5. Abbreviations: TEM, transmission electron microscope; PBS, phosphate buffer saline. Note: Data was presented as the mean ± SD, n = 3. The observation via the TEM ( Figure 2B ) showed that the micelles were spherical and well-dispersed in the aqueous solution, which could be uptaken by cells more easily than non-spherical nanoparticles. 38 Generally, the absolute value of zeta potential above 30 mV could be considered as relatively stable for the dispersion system and it was difficult to agglomerate. The higher the absolute value of zeta potential, the greater the repulsive force among the charges on surface of nanoparticles, and the better the dispersion of nanoparticles. 39 In our study, the zeta potential of ISL-M was −34.23 ± 3.35 mV (shown in Figure 2C ), indicating that ISL-M had good dispersion. The in vitro release profiles of the free ISL and ISL-M were investigated at simulated in vivo conditions using phosphate-buffered saline (pH = 7.4 and pH = 5, 37 ℃) containing 1% (w/v) sodium dodecyl sulfate ( Figure 2D ). More than 60% of free ISL in PBS buffer (pH = 7.4 and pH = 5) was rapidly released within the first four hours, and the cumulative release was close to 90% in eight hours. Whereas, the cumulative release rate of ISL-M slowed down significantly at pH of 5 and reached more than 90% after 48 h dialysis. Under the condition of pH of 7.4, the release rate of ISL-M was the slowest, and only about 60% of ISL was released within 48 hours. These results suggested that of this nano-micelle had good slow-release effect and pH sensitivity, which prevented drugs from being released as fast as possible during blood circulation (pH = 7.4) so that it could maintain a sustained higher drug concentration in an environment of cerebral ischemia and hypoxia. In addition, the nano micelles uptaken by nerve cells could quickly release drugs in lysosomes (pH = 4.5~5.0) and take effects as follow. In general, excellent physicochemical properties and biological effects would help nano micelles play a better role in drug delivery. 40 Validation of Analytical Method In order to determine the concentration of ISL in plasma and tissue, the LC-MS/MS methods were established for this study. The retention times of IS and ISL in plasma were 2.4 min and 3 min, respectively, while those in tissues were 1.7 min and 2.1 min, respectively ( Supporting Information Figure S1A and S1B ). There were no endogenous substances interfered in plasma and tissue matrix ( Supporting Information Figure S1C and S1D ), indicating that there was good specificity of these methods. After intravenous injection of ISL-M, there was no significant shift in the retention time of ISL and IS in rat plasma and mixed tissue homogenate ( Supporting Information Figure S1E and S1F ), indicating that the method has good stability. The regression equation of standard curve in plasma for the low concentration range (5–2000 ng/mL) was y = 0.004391x + 0.004727 (R2 = 0.9998) and for the high concentration range (2–100 μg/mL) was y = 3.867x + 0.7097 (R2 = 0.9999). In addition, the calibration curve for the tissues was also identified within the range of 5–1000 ng/mL (y = 0.001869x - 0.007118, R2 = 0.9990). Therefore, the linearity of these methods was excellent. The lower limit of quantification (LLOQ) in plasma and in tissue was 5 ng/mL, shown in Supporting Information Table S1 . The intra-day and inter-day precision (RSD %) of quality control (QC) samples in both matrices were all less than 13.78%, while the accuracy (RE %) ranged from −6.57% to 7.32% for ISL in two matrices ( Supporting Information Table S2 ). The recovery of ISL was between 88.08% to 104.73%, and the results of the matrix effect were in the range of 86.31-107.82% for all the QC samples ( Supporting Information Table S3 ). These data indicated that the precision, accuracy and extraction recovery of QC samples with three different concentrations were within an acceptable range according to the FDA guidelines, and no significantly matrix effect was found for the plasma and tissue homogenate. Pharmacokinetics Profiles of ISL and ISL-M The plasma concentration-time profile of ISL and ISL-M after single intravenous administration of 2 mg/kg in rats was shown in Figure 3 . The concentration of ISL in plasma for the ISL group was low, and could not be detected after 2 hours of administration, while the ISL-M group could be detected within 4 hours. The data in Table 1 summarized the pharmacokinetic parameters of ISL and ISL-M, which were calculated according to the compartment model and statistical moment theory. The results showed that the plasma elimination half-life (t1/2β) of ISL-M was markedly prolonged by 2.6 times compared with that of ISL. The AUC of ISL-M was significantly higher than that of ISL, suggesting that the in vivo exposure of ISL from ISL-M notably increased, and the mean residence time (MRT) of ISL-M had also been obviously prolonged. The clearance rate of ISL and ISL-M was 5.78 L/h.kg and 3.64 L/h.kg, respectively, indicating that the elimination speed of ISL-M was slower than that of ISL in rat. ISL-M has high relative bioavailability of 148.96%. Our results indicating that ISL-M could effectively prolonged the circulation time of ISL, markedly increased the in vivo exposure amount and significantly improved the pharmacokinetic properties of ISL. Table 1 Pharmacokinetic Parameters of ISL After Single I.V. Administration of ISL and ISL-M (2 Mg/Kg) to Rats Figure 3 The mean plasma concentration-time curve of ISL and ISL-M after a single intravenous injection (2 mg/kg) to rats. Note: Data was presented as the mean ± SD, n = 6. Tissue Distribution and Targeting Evaluation of ISL-M The results in tissue distribution of ISL and ISL-M at different times following an i.v. administration at a dosage of 2.8 mg/kg were shown in Figure 4A–E . The ISL concentration in ISL-M was higher than that of ISL at all time points and in the most of tested tissues. It should be noted that ISL in ISL-M could be measured 1 h after administration, but ISL itself could not be detected at this time in mice. The data in Table 2 illustrated that the values of AUC and Cmax of ISL from ISL-M were significantly increased compared with that of ISL in all tissues except the heart. In terms of the targeting parameters, the relative rate of uptake (Re) and the ratio of peak concentration (Cp) of the mouse brain from ISL-M in all tissues were higher than that of ISL, there were significant alteration for the values of Re and Cp in brain targeted, indicating that ISL-M prepared in our study obviously altered the brain exposure of ISL, increased and prolonged the accumulation in the brain tissue (shown in Figure 4E ). Table 2 Targeting Tissue Evaluation of ISL-M Figure 4 The tissue distribution of ISL in (A) heart, (B) liver, (C) lung, (D) kidney and (E) brain after single i.v. administration of ISL and ISL-M (2.8 mg/kg) to mice. Notes: Data was presented as the mean ± SD, n = 4. ISL-M Could Decrease Behavioral Impairment in MCAO Mice The results in Figure 5A showed that there was no significant difference in the longa scores from the MCAO mice in other groups except the sham operation group, indicating that the injury of experimental mice in each group before administration was the same. As shown in Figure 5B , the neurological scores of mice injected with ISL and ISL-M were significantly decreased compared with the MCAO model group. In addition, the weight of mice after MCAO modeling was obviously reduced and the weight recovery rate was also slowed down compared with the sham operation group (see Figure 5C ). After treatment with ISL-M, the improvement of perception and motor function in mice was significantly better than that in these mice treated with ISL via the results from the rotarod experiments (see Figure 5D ) and the adhesive removal test (shown in Figure 5E and F ), suggesting that ISL-M had a more effective protection effect on MCAO brain damage. Figure 5 Neuroprotection by the treatment of ISL-M in MCAO-induced ischemic and reperfusion injury. Longa scores of mice in different groups on (A) the first and (B) seventh days after the operation. (C) The weight of mice in different groups in seven days. Behavioral manifestation of MCAO in mice in the rotarod experiments (D) and tape removal test (E and F). Notes: Data was presented as mean ± SD, n = 4; vs MCAO: *P < 0.05, **P < 0.01, ***P < 0.001; vs MCAO + 3 mg/kg ISL: # P < 0.05, ### P < 0.001. Inhibition of Apoptosis and Autophagy of ISL-M in MCAO Mice It was found that there were some vacuolar in the neurons from the ISL group, and the Nissl bodies were partially disappeared, which was not significantly different from that in the model group ( Figure 6A ). After ISL-M administration, the dark blue granular Nissl bodies could be clearly seen, and the color was relatively uniform. The number of positive cells stained with the TUNEL ( Figure 6C and E ) and positive cells expressing the LC3 protein ( Figure 6B and D ) in the ISL group were both less than that in the model group and more than that in the ISL-M group, which showed that ISL-M had a better effect on inhibiting neuronal apoptosis. The presence of LC3 protein was an effective marker for cell autophagy, 41 and the level of autophagy in normal tissue and organism was low. When the homeostasis was destroyed (such as brain injury, ischemia and hypoxia), the autophagy would be induced to remove the excess or damaged organelles and intracellular components. 42–44 Our data indicated that ISL-M could better protect and alleviate the brain injury induced by stroke via inhibition of occurrence or level of autophagy and neuronal apoptosis. Figure 6 Inhibitory effect on apoptosis and autophagy of ISL-M in MCAO mice model was proved by Nissl staining (A) and immunofluorescence staining of LC3 (B) and TUNEL (C). Record the number of cells in the same fields of view stained with LC3 (D) and TUNEL (E) by image J. Notes: Data was presented as mean ± SD, n = 3; vs MCAO: **P < 0.01, ***P < 0.001; vs MCAO + 3 mg/kg ISL: ## P < 0.01, ### P < 0.001. Biocompatibility of Nanoparticles in Major Organs In order to evaluate the biocompatibility and toxicity of this nanoparticles, the main tissues in mice were paraffin sectioned and stained with the HE in the different tested groups. The results showed that the myocardial cells had the good morphology and complete tissue structures (see Figure 7 ). In the liver, hepatocytes were also arranged neatly, and the structures of hepatic lobules were not affected by ISL-M. Spleen tissue was also intact, and nanoparticles had no significant effect on the spleen. The structures of lung parenchyma and lung stroma were complete, there was no obvious inflammatory cell infiltration and the lung function was good. We also examined the effect of nanoparticles on the kidney, and found that there were no obviously changes in the structures of glomerulus. In general, the ISL nanoparticles have good biocompatibility in these main tissues and organs. Figure 7 Hematoxylin-eosin staining of heart, liver, spleen, lung and kidney from control, MCAO, MCAO + ISL, MCAO + M, MCAO + ISL-M group of mice (Scale bar: 50 μm). Abbreviations: MCAO, middle cerebral artery occlusion; M, blank micelles. Conclusions In this study, we designed a novel ISL loaded nano micelle prepared with DSPE-PEG2000 as the drug carrier modified with the brain targeting polypeptide angiopep-2, which have small particle size, good dispersibility, high drug loading and encapsulation efficiency, sustained release effect and pH sensitivity. Compared with the ISL monomers, the ISL nano-micelles could significantly prolong the in vivo circulation time of ISL and enhance the accumulation in the brain tissues via regulating the physicochemical properties of ISL, improving its pharmacokinetic disposition and increasing brain intake. The ISL-M could ameliorate the brain injury induced by the MCAO mice via inhibition of occurrence or level of cellular autophagy and neuronal apoptosis. There were no cellular structural damages and other adverse effects for ISL-M on the main tissues and organs. Our data further confirmed that the ISL-M could improve the ischemic stroke effect. In conclusion, our ISL-M could serve as a promising, ideal and effective candidate for the clinical application of ISL in the treatment of acute ischemic stroke. Acknowledgments This study was supported by the National Foundation of Natural Sciences of China (Grant No. 82073925 and 81773803). Disclosure
Yongchao Wang Investments
Yongchao Wang has made 1 investments. Their latest investment was in Mr. Mark as part of their Series A on December 12, 2018.
Yongchao Wang Investments Activity
Undisclosed Investors, and Yongchao Wang


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    name = models.CharField(max_length = 255)
    width = models.IntegerField(default = 0)
    height = models.IntegerField(default = 0)
    created = models.DateTimeField(auto_now_add = True)
    image = models.ImageField(upload_to = 'images/%Y/%m/%d')
    image_post = models.ForeignKey('Post')

    def get_image(self):
        return self.image.url

class Post(models.Model):
    title = models.CharField(max_length = 255)
    slug = models.SlugField(unique = True, max_length = 255)
    description = models.CharField(max_length = 255)
    content = models.TextField()
    published = models.BooleanField(default = True)
    created = models.DateTimeField(auto_now_add = True)
    post_image = models.ForeignKey(Image, null = True)

    def image_tag(self):
        return u'' % self.post_image.url

    image_tag.short_description = 'Image'
    image_tag.allow_tags = True

in admin.py, I've defined as inlines:
class ImageInline(admin.TabularInline):
    model = Image
    extra = 3

class PostAdmin(admin.ModelAdmin):
    list_display = ('title', 'description')
    readonly_fields = ('image_tag',)
    exclude = ('post_image', )
    inlines = [ImageInline, ]
    list_filter = ('published', 'created')
    search_fields = ('title', 'description', 'content')
    date_hierarchy = 'created'
    save_on_top = True
    prepopulated_fieldes = {"slug" : ("title",)}

In the admin page, when I upload an image in the Post admin page, the image is stored. But it's not hooked up with the Post. How to hook the image with the post when I upload in admin? I mean let the inline image uploaded become post's post_image.
Thanks!

A: As far as I understand thee is 1-to-1 relation between Image and Post models.  So you should use the OneToOneField instead of two ForteignKeys.
class Image(models.Model):
    ...
    post = models.OneToOneField('Post')

And the delete the post_image field from the Post model.
To access the image instance from the Post just write:
def image_tag(self):
    return u'' % self.image.get_image()

redpajama_set_name: RedPajamaStackExchange


text:
Is It Sometimes Best To Say Nothing?
Sometimes. But only sometimes. Other times, it's important to stand up for yourself and what you believe in.
Keith Old commented
True Brising.
Michael Regenauer answered
I would like to answer but my lips are sealed..LOL. OK but sometimes saying nothing can
get you in trouble such as when your sweetie asks- do these pants make my but look big?
Being silent gets you in trouble, so in this case it's better to fudge the truth a little by saying
No honey your but wouldn't look big no matter what you wore.Silence = couch
fudgeing truth = hugs and kisses. Trust me I have been doing this for almost 50 years and
have never slept on the couch.OOPS I have to go now my wife has been standing behind me
reading this with a blanket and a pillow. Keithold this is all your fault.
Sorry Galaxie.
Your Worst Nightmare Ever answered
It is best to keep your mouth shut sometimes , indeed.
Thanks V-mar.
Shanna Graves answered
Like the saying says 'If you can't say something nice, don't say anything at all.'
Indeed Soulalone.
Better to be silent and thought a fool than to open one's mouth and remove all doubt...It is definately better to keep quite sometimes.....Especially when your not sure what to say or have not thought things out enough...And there is always the fifth amendment
Indeed Socrates.
That would depend on whose courtroom in which you find yourself being forced to testify.
Each judge is different.
True Mensan.
emma loveees youuu xo answered
Well...yeah i suppose...but make sure you only shut up when it's absolutely necessary or you'll regret it :)
Quite possibly. Coldplace.
If you have nothing good to say or something that is going to make matters worse...well then yes keep it your self.
Good advice Xbella.
Only if it is to teach a life lesson.some people will not learn unless they have to experience the effects of their decisions.
Thanks Nomad
Gene wright answered
Proverbs 29.11 is only one verse, there's more
Thanks Genew.
It depends on what the topic is.
Unless, you wanna get screamed at.
Brooke Mundy answered
Yeah, sometimes, but other times you should say something.
If your mind can also move on and not dwell on it.
Yes, especially when u r talking to the boss; but, I can't until I have had my say and that's NOT always good.
suman kumar answered
If you are in a troublesome situation, where you neither can say yes nor no, then it is best loll.
HKP hkp answered
No doubt about that. Sometimes it works like a medicine...
Glenn Greenwood answered
Sometimes? Absolutely!!!
Joseph Cutrone answered
Sometimes silence is golden
james caison answered
If you have a tendency to go to far by running your mouth, then it is best to back off and become mute. But it is very doubtful that will happen.
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Pam Pam Pam Pizza in Renens is finally available on Smood !
At the Pam Pam Pizza restaurant in Renens, you will have the pleasure of tasting the best pizzas in the area! A wide choice of pizzas just to satisfy your taste buds. If you are more of a salad type, you can also enjoy our fresh salads of the day. To finish this magnificent meal, a little sweetness for dessert awaits you. So don't hesitate any longer and order on Smood.ch or by phone on 0840 004 004 004.


I wish to commend the Finance Committee of the Otsego County Board of Commissioners for its courage in recommending specific budget cuts in order to alleviate our county's present financial crisis.
Of particular interest to me and many others in our community is the budget of the Otsego County prosecutor's office. After analyzing this office's budget and personnel needs, the committee courageously recommended several staff positions be cut; this despite being publicly threatened by our present prosecuting attorney Kevin Hesselink, that he intends to sue the county if his department is not spared from any loss of revenue.
Mr. Hesselink's opposition to any cuts is based upon his own interpretation of state law regarding "mandated functions," yet, he does not bring forth other members of the legal community who can likewise give such an interpretation. He bases his opinion almost exclusively upon a Wayne County case many years ago. His legal interpretation of this present situation may or may not be legally accurate, yet merely because of his position and his view, he threatens other publicly elected officials with suit if they don't conform to his view of the law.
This has the appearance of intimidation and is not, in my personal opinion, conduct becoming a county prosecutor, an elected official, or an officer of the court. Instead of showing true courage and willingness to share some of the burdens of this community, Mr. Hesselink chooses to place himself and his office above other departments.
I ask the voters of Otsego County to remember Mr. Hesselink's shameful and heavy handed conduct during this crisis. Mr. Hesselink is not at all deserving of a renomination by the local Republican party during its August 2004 primary and should he follow suit and take legal action against his own county, local residents would be well advised to take up a recall campaign against him.
By forcing our county commissioners to give him what he wants (under threat of suit), Mr. Hesselink would force the commissioners to either back down, or hire at county expense another attorney to defend Otsego County against its own prosecutor. Should this actually occur, in my opinion, Mr. Hesselink would be well deserving of a recall election and removal from office.
Let's all stand behind the difficult but courageous actions of the Finance Committee, particularly Paul Beachnau, one of the finest public servants this community has ever produced, and demand that Mr. Hesselink act like he is on our side in this matter and not merely an advocate for the interests of his own department.


Parents and a former coach complained about the annual cheerleading awards.
KENOSHA, Wis. (AP) — A Wisconsin high school is ending cheerleading awards given annually to girls with the largest breasts or buttocks after district officials received repeated complaints from parents and a former coach.
Coaches at Tremper High School in the Kenosha Unified School District give out awards each year recognizing the most improved or hardest working cheerleaders, but they have also given gag awards, called "Big Booty," ''Big Boobie," and "String Bean." The last award has gone to the thinnest team member.
"I'm disgusted with the cheer coaches and with the Kenosha parents that sat there and said and did nothing," former track coach Patti Hupp told the Kenosha News . Hupp emailed Tremper principal Steve Knecht last year to express her concerns after a parent notified her of the awards.
Knecht told cheerleading coaches in an April 28 email that he would launch an investigation into the awards after receiving complaints from four people. He later told a parent who followed up that he had found no evidence of wrongdoing. When the parent asked for justification, he wrote in a letter that the awards "were meant to be funny" and the coaches were "just joking around."
District spokeswoman Tanya Ruder said "a clear expectation has been set that awards of this nature are not acceptable and are not to be given at Tremper cheerleading banquets going forward."
"The last thing these high school girls need is a fellow woman in their lives communicating to them that they are objects or that their appearance is something to be gawked at, demeaned, laughed at, or even awarded for that matter," Hupp said in the email.


text:
Q: How can I get access to or replace LINQ to SQL's IdentityManager? I need to find out if an object with a particular primary key is already attached to a DataContext and get the entity from the DataContext if it is attached.  Is there any way at all to do this that doesn't require Reflection with full trust?
Ideally, I would like to call GetCachedObject(), but I'd have to use reflection to get at that, and I'm pretty sure I'd have to be in full trust mode, which won't work in a hosted environment.
I'm open to thinking outside the box here.  Also, I can fully control the generated LinqToSql code, so that's not a problem either.  I can rewrite my DataContext class.  Is there any way to get access to the IdentityManager, replace the IdentityManager with my own abstraction, etc?  Any and all ideas are welcome.

A: One potential 'workaround'. I haven't tried it, so don't know if it will work... ...but since you said 'out of the box': Assign a bad connection or bad connection string to the DC, or mess up the sqlconnection it already has. Next query for the object by PK. If it is in the cache, there's a good chance that L2S won't notice that the connection is bad, so you should get the object back. If it is not in the cache, L2S should try a db roundtrip and you'll get an exception.
As I said, dirty and untested, but worth trying if you really want to avoid using reflection to get access to the identity manager / change tracker. Not sure if it will save you any CPU cycles though... :)

A: If you control the generated code, why not let the ctor of every entity register itself in a per-thread dictionary. That way you have all existing entities of the current thread. If you have one datacontext per thread, you now have a list of all loaded (but not necessarily attached) entities.


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text:
Hotel deals North America United States California Los Altos
Hotels in Los Altos
Find the best deals on 11 hotels in Los Altos, CA
Top Hotels in Los Altos
Find the perfect Los Altos hotel for business or leisure
Things to do in Los Altos
Los Altos History Museum
Chinese Fine Arts Gallery
What is the average price of a hotel near Los Altos History Museum?
The average price for hotels near Los Altos History Museum is $160 per night. Of those hotels, momondo users recommend the 12 hotels below for those looking to stay in the area. Since Los Altos History Museum is more popular at some times of year than others, prices may vary depending on when you plan your trip. Hotels near Los Altos History Museum are typically 30% less expensive than the average hotel in Los Altos, which is $230.
Hotels near Los Altos History Museum
Wild Palms, a JDV by Hyatt Hotel
910 East Fremont Avenue, Sunnyvale, CA
Courtyard Palo Alto Los Altos
4320 El Camino Real, Los Altos, CA
Residence Inn Marriott Palo Alto Los Altos
Enchante Boutique Hotel
1 Main Street, Los Altos, CA
Charming Home In The Heart Of Silicon Valley
Juniper Hotel Cupertino, Curio Collection by Hilton
10050 South De Anza Boulevard, Cupertino, CA
Hyatt Regency Santa Clara
5101 Great America Parkway, Santa Clara, CA
The Nest Hotel Palo Alto
3901 El Camino Real, Palo Alto, CA
Hayes Mansion San Jose, Curio Collection by Hilton
200 Edenvale Avenue, San Jose, CA
Hotel Parmani
Crowne Plaza Palo Alto
Maple Tree Inn
711 East El Camino Real, Sunnyvale, CA
What is the average price of a hotel near Chinese Fine Arts Gallery?
The average price for hotels near Chinese Fine Arts Gallery is $160 per night. Of those hotels, momondo users recommend the 12 hotels below for those looking to stay in the area. Since Chinese Fine Arts Gallery is more popular at some times of year than others, prices may vary depending on when you plan your trip. Hotels near Chinese Fine Arts Gallery are typically 30% less expensive than the average hotel in Los Altos, which is $230.
Hotels near Chinese Fine Arts Gallery
When to book a hotel in Los Altos
Check out the information below to find the best deal on a Los Altos hotel room
How much does a hotel in Los Altos cost per night?
Use the information below to find quality Los Altos hotel rooms for low prices
4 stars +
Best prices found by momondo users in the past 24 hours.
Hostels and cheap hotels in Los Altos
These hotels and hostels usually make for a cheap way to stay in Los Altos
Get the best value hotel in Los Altos
Los Altos travel information
How long do people stay in Los Altos?
When visiting Los Altos the average booking length is 2 nights.
How much does a hotel cost in Los Altos?
Hotels in Los Altos show a range of prices for their rooms. These are determined by factors such as availability, locale and amenities. On average, rooms will be around $222 per night.
When is the best time to book a hotel in Los Altos?
Room prices for hotels in Los Altos can be as much as 50% lower in the month of December. So this is a great time to book and save money.
Which day is cheapest to stay in Los Altos?
The cost of a Los Altos hotel room will vary for each day but generally Friday works out the most economical, with Sunday proving the least economical.
momondo's favorite hotels
Learn more about these user-preferred hotels in Los Altos
4460 El Camino Real 94022
1 Main Street 94022
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interface - City products - hotels interface - POI interface - map Star