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A simple and fast electrophoretic method for elution of nucleic acids from gels.
MedLine Citation:
PMID:
530273
Owner:
NLM
Status:
MEDLINE
Abstract/OtherAbstract:
A very convenient electrophoretic procedure for DNA or RNA elution from agarose or polyacrylamide gels is described. The gel piece with nucleic acid to be eluted is contained in a dialysis bag filled with buffer and elution is carried out in a horizontal electrophoresis apparatus. The nucleic acid is recovered with a high yield and can be used, without prior treatment, in further enzymatic or chemical reactions. Results obtained with DNA are presented here. | 2023-10-25T01:26:35.434368 | https://example.com/article/5998 |
Market Scenario, Ring main unit (RMU) is used in a secondary distribution system. It is basically used for an uninterrupted power supply. It is used for medium voltage distribution in compact substations, small buildings, residential housing complex etc. Increase in demand of electricity across the globe, is the primary driving factor of ring main unit market. Additionally, rising demand for renewable energy is also fueling the demand of ring main unit (RMU). However, the cost of ring main units being higher than conventional switchgears is the restraining factor that may hamper the growth of global ring main unit market. , The global ring main unit market is projected to grow at a CAGR of 8.4% from 2017 to 2023, to reach the market size of USD 2.65 billion by 2023., Study Objectives of Global Ring Main Unit Market, , To provide detailed analysis of the market structure along with forecast for the next five years of various segments and sub-segments of the global ring main unit market , To provide insights about factors affecting the market growth, To analyze the global ring main unit market based on various tools such as Price Analysis, Supply Chain Analysis, Porter’s Five Forces Analysis, To provide historical and forecast revenue of the market segments and sub-segments with respect to four main geographies and their countries- North America, Europe, APAC, and Rest of the World (ROW), To provide country level analysis of the market with respect to the current market size and future prospective, To provide country level analysis of the market segmented, by types, by installation, by applications, and by regions, To provide strategic profiling of the key players in the market, comprehensively analyzing their core competencies, and drawing a competitive landscape for the market, To track and analyze competitive developments such as joint ventures, strategic alliances, mergers and acquisitions, new product developments, and research and developments in the ring main unit market, , Segmentation, , , Regional Analysis of Global Ring Main Unit Market, Asia-Pacific dominates the global ring main unit market followed by Europe. Rapid expansions in industrialization as well as the growing renewable sector in this re
Market Scenario
Ring main unit (RMU) is used in a secondary distribution system. It is basically used for an uninterrupted power supply. It is used for medium voltage distribution in compact substations, small buildings, residential housing complex etc. Increase in demand of electricity across the globe, is the primary driving factor of ring main unit market. Additionally, rising demand for renewable energy is also fueling the demand of ring main unit (RMU). However, the cost of ring main units being higher than conventional switchgears is the restraining factor that may hamper the growth of global ring main unit market.
The global ring main unit market is projected to grow at a CAGR of 8.4% from 2017 to 2023, to reach the market size of USD 2.65 billion by 2023.
Study Objectives of Global Ring Main Unit Market
To provide detailed analysis of the market structure along with forecast for the next five years of various segments and sub-segments of the global ring main unit market
To provide insights about factors affecting the market growth
To analyze the global ring main unit market based on various tools such as Price Analysis, Supply Chain Analysis, Porter’s Five Forces Analysis
To provide historical and forecast revenue of the market segments and sub-segments with respect to four main geographies and their countries- North America, Europe, APAC, and Rest of the World (ROW)
To provide country level analysis of the market with respect to the current market size and future prospective
To provide country level analysis of the market segmented, by types, by installation, by applications, and by regions
To provide strategic profiling of the key players in the market, comprehensively analyzing their core competencies, and drawing a competitive landscape for the market
To track and analyze competitive developments such as joint ventures, strategic alliances, mergers and acquisitions, new product developments, and research and developments in the ring main unit market
Segmentation
Regional Analysis of Global Ring Main Unit Market
Asia-Pacific dominates the global ring main unit market followed by Europe. Rapid expansions in industrialization as well as the growing renewable sector in this region, increase the demand of ring main unit market. This region is expected to grow at the fastest pace during the forecast period. Europe is another important market and is expected to contribute significantly during the forecast period mainly due to upgrading the existing infrastructure.
Key Players
The key players of global ring main unit market are ABB Ltd. (Switzerland), Schneider Electric SE (France), Eaton Corporation, PLC (Ireland), Siemens AG (Germany), General Electric Company (U.S.), Lucy Electric Limited (U.K.), L&T (India), Yokogawa Electric Corporation (Japan), SwitchGear Company (Belgium) and EPE Switchgear (M) Sdn. Bhd. (Malaysia).
Target Audience
Manufacturing Organizations
Distributors & Suppliers
Environmental Associations
Government as well as Independent Regulatory Authorities
Research Institute / Education Institute
Potential Investors
Product Analysis
Product matrix which gives a detailed comparison of the market for different recycled product types
Additional Information
Regulatory Landscape
Pricing Analysis
Macroeconomic Indicators
Geographic Analysis
Geographical analysis across 15 countries
Company Information
Profiling of 10 key market players
In-depth analysis including SWOT analysis, and strategy information of related to report title
Competitive landscape including emerging trends adopted by major companies
The report for Global Ring Main Unit Market of Market Research Future comprises of extensive primary research along with the detailed analysis of qualitative as well as quantitative aspects by various industry experts, key opinion leaders to gain the deeper insight of the market and industry performance. The report gives the clear picture of current market scenario which includes historical and projected market size in terms of value and volume, technological advancement, macro economical and governing factors in the market. The report provides details information and strategies of the top key players in the industry. The report also gives a broad study of the different market segments and regions. | 2024-02-01T01:26:35.434368 | https://example.com/article/4865 |
After World War II, with the onset of the Cold War, the constant technological development of new weapons was institutionalised, as participants engaged in a constant 'arms race' in capability development. This constant state of weapons development continues into the present, and remains a constant drain on national resources, which some[who?] blame on the military-industrial complex.
A military brat is a colloquial term for a child with at least one parent who served as an active duty member (vice reserve) in the armed forces. Children of armed forces members may move around to different military bases or international postings, which gives them a childhood differing from the norm. Unlike common usage of the term brat, when it is used in this context, it is not necessarily a derogatory term.
The United States has the world's largest military budget. In the fiscal year 2016, $580.3 billion in funding were enacted for the DoD and for "Overseas Contingency Operations" in the War on Terrorism.[4] Outside of direct DoD spending, the United States spends another $218 to $262 billion each year on other defense-related programs, such as Veterans Affairs, Homeland Security, nuclear weapons maintenance and DoD.
I don’t mean just being present. I’m talking about large-scale military deployments — the sort that would be necessary to respond to North Korean or Iranian aggression, or to fight alongside our NATO allies should one of them invoke Article 5. The threat of an overwhelming American force is the deterrent that keeps many of our foes from pushing the envelope as far as they’d like.
Including U.S. territories and ships afloat within territorial waters As of 31 December 2009, a total of 1,137,568 personnel were on active duty within the United States and its territories (including 84,461 afloat).[29] The vast majority (941,629 personnel) were stationed at bases within the contiguous United States. There were an additional 37,245 in Hawaii and 20,450 in Alaska while 84,461 were at sea, 2,972 in Guam and 179 in Puerto Rico.
Militaries often function as societies within societies, by having their own military communities, economies, education, medicine, and other aspects of a functioning civilian society. Although a 'military' is not limited to nations in of itself as many private military companies (or PMC's) can be used or 'hired' by organisations and figures as security, escort, or other means of protection; where police, agencies, or militaries are absent or not trusted.
Each of the five services employs a single Senior Enlisted Advisor at departmental level. This individual is the highest ranking enlisted member within that respective service and functions as the chief advisor to the service secretary, service chief and Congress on matters concerning the enlisted force. These individuals carry responsibilities and protocol requirements equivalent to three-star general or flag officers. They are as follows:
As in most militaries, members of the U.S. Armed Forces hold a rank, either that of officer, warrant officer or enlisted, to determine seniority and eligibility for promotion. Those who have served are known as veterans. Rank names may be different between services, but they are matched to each other by their corresponding paygrade.[21] Officers who hold the same rank or paygrade are distinguished by their date of rank to determine seniority, while officers who serve in certain positions of office of importance set by law, outrank all other officers in active duty of the same rank and paygrade, regardless of their date of rank.[22] In 2012, it was reported that only one in four persons in the United States of the proper age meet the moral, academic and physical standards for military service.[23]
As you go along, keep in mind that the ASVAB practice test is just that: practice. Memorizing these questions and answers will not be very helpful on the actual test because it is unlikely to have any of the same exact questions. If you only know the right answers to the sample questions, you won’t be prepared for the real thing. Study the concepts until you understand them fully, and then you’ll be able to answer any question that shows up on the test.
Just as the President, the Secretary of Defense, and the Secretary of Homeland Security, are in charge of the entire military establishment, maintaining civilian control of the military, so too are each of the Defense Department's constitutive military departments headed by civilians. The four DoD branches are organized into three departments, each with civilian heads. The Department of the Army is headed by the Secretary of the Army, the Department of the Navy is headed by the Secretary of the Navy and the Department of the Air Force is headed by the Secretary of the Air Force. The Marine Corps is organized under the Department of the Navy, however it is still considered a separate and equal service. The Coast Guard is under the Department of Homeland Security and receives its operational orders from the Secretary of Homeland Security. However, the Coast Guard may be transferred to the Department of the Navy by the President or Congress during a time of war, thereby placing it within the DoD.[17]
As in most militaries, members of the U.S. Armed Forces hold a rank, either that of officer, warrant officer or enlisted, to determine seniority and eligibility for promotion. Those who have served are known as veterans. Rank names may be different between services, but they are matched to each other by their corresponding paygrade.[21] Officers who hold the same rank or paygrade are distinguished by their date of rank to determine seniority, while officers who serve in certain positions of office of importance set by law, outrank all other officers in active duty of the same rank and paygrade, regardless of their date of rank.[22] In 2012, it was reported that only one in four persons in the United States of the proper age meet the moral, academic and physical standards for military service.[23]
International protocols restrict the use, or have even created international bans on weapons, notably weapons of mass destruction (WMD). International conventions define what constitutes a war crime, and provides for war crimes prosecution. Individual countries also have elaborate codes of military justice, an example being the United States' Uniform Code of Military Justice that can lead to court martial for military personnel found guilty of war crimes.
Taken together, this shortage of ships and qualified mariners is “threaten[ing] our ability to meet national security requirements,” as the outgoing U.S. Transportation Command commander, Gen. Darren McDew, told the Senate Armed Services Committee. Our enemies know that, as capable as our military is, it is a paper tiger if it can’t get to the battlefield on time. The deterrent capability of our military is weakened by our inability to deploy combat-ready forces quickly.
In Medieval Europe, tales of knighthood and chivalry, the officer class of the period captured the popular imagination. Writers and poets like Taliesin, Chrétien de Troyes and Thomas Malory wrote tales of derring-do, featuring Arthur, Guinevere, Lancelot and Galahad. Even in the 21st century, books and films about the Arthurian legend and the Holy Grail continue to appear.
Note: While the U.S. Navy is older than the Marine Corps,[50] the Marine Corps takes precedence due to previous inconsistencies in the Navy's birth date. The Marine Corps has recognized its observed birth date on a more consistent basis. The Second Continental Congress is considered to have established the Navy on 13 October 1775 by authorizing the purchase of ships, but did not actually pass the "Rules for the Regulation of the Navy of the United Colonies" until 27 November 1775.[51] The Marine Corps was established by act of said Congress on 10 November 1775. The Navy did not officially recognize 13 October 1775 as its birth date until 1972, when then–Chief of Naval Operations Admiral Elmo Zumwalt authorized it to be observed as such.[50]
The IRT model underlying ASVAB scoring is the three-parameter logistic (3PL) model. The 3PL model represents the probability that an examinee at a given level of ability will respond correctly to an individual item with given characteristics. Specifically, the item characteristics represented in the 3PL model are difficulty, discrimination (i.e., how well the item discriminates among examinees of differing levels of ability), and guessing (i.e., the likelihood that a very low ability examinee would respond correctly simply by guessing). | 2023-09-26T01:26:35.434368 | https://example.com/article/9392 |
NBA Inside Stuff
NBA Inside Stuff is a television program airing on NBA TV and previously aired on NBC for many years, then on ABC, featuring behind the scenes activities of NBA players. The program also includes features on fitness and fundamentals of basketball. Previously hosted by Ahmad Rashād (and once co-hosted by Julie Moran, and then Willow Bay) and Summer Sanders, the show is now hosted by former NBA star Grant Hill and Kristen Ledlow.
Overview
NBA Inside Stuff served as a sort of recap and analysis show reviewing the week's previous games in the NBA, complete with top plays and special moments. The hosts would also interview top NBA players outside of game situations, often discussing issues relevant to them.
The show first aired on October 27, 1990 and ended on August 28, 2004. After an nine-year hiatus, NBA TV brought back Inside Stuff with new hosts and a new look. The revamped show began airing on November 2, 2013 on NBA TV.
Broadcast history
NBA Inside Stuff was usually the bridge program for NBC between TNBC (or, in its first two seasons, its Saturday morning cartoon lineup) and Saturday afternoon programming, usually sports. In the late 1990s the program received some adaptation in order to meet the FCC's educational and informational requirements. When it moved to ABC in 2002, it aired between that network's ABC Kids morning lineup and afternoon sports programming (occasionally being moved to Sundays during college football season). ABC replaced NBA Inside Stuff with the similarly themed NBA Access with Ahmad Rashad (which ran until the ABC Kids block was discontinued in 2011). As its name implies, Rashad was the host. NBA Inside Stuff was moved at that time to NBA TV.
As previously mentioned, NBA TV announced that after an nine-year hiatus, NBA Inside Stuff would return with Grant Hill and Kristen Ledlow as hosts. The commercial for the then-newly resurrected NBA Inside Stuff later aired on NBA TV.
Hosts
Current hosts
Grant Hill: Retired in 2013 following an 19-year NBA career, he is a seven-time NBA All-Star, five-time All-NBA selection, three-time winner of the NBA Sportsmanship Award and NBA co-Rookie of the Year in 1995. A small forward and the third overall pick in the 1994 NBA draft, played for the Detroit Pistons, Orlando Magic, Phoenix Suns and Los Angeles Clippers during his NBA career. He won two NCAA Division I Men’s Basketball Championships (1991 and 1992) at Duke University, where his No. 33 jersey is retired. He also is an analyst on NBA TV and occasionally on Inside the NBA.
Kristen Ledlow: Co-host of The Morning Drive, the morning show of Atlanta sports radio station 92.9 FM The Game, and also a reporter for NBA TV's Game Time. She’s previously served as a field reporter for Fox Sports and Scout.com covering Southeast Conference and Atlantic Coast Conference football and basketball. Additionally, Ledlow has anchored WTXL-TV 27 News and has been a sideline reporter for 97.9 ESPN Radio in Tallahassee, Florida.
Shaquille O'Neal (fill-in host): Also a rapper and actor, he retired in 2011 after an NBA career that included the 2000 Most Valuable Player award and four NBA championships and was inducted into the Naismith Memorial Basketball Hall of Fame in 2016. A center drafted first overall by the Magic in 1992, he also played for the Phoenix Suns, Los Angeles Lakers (where his #34 is retired), Miami Heat, Cleveland Cavaliers and Boston Celtics. He joined TNT/NBA TV following his retirement and currently is an analyst on Inside the NBA and the presenter of popular blooper segment Shaqtin' a Fool.
Former hosts
Ahmad Rashād (1990–2004)
Julie Moran (1990–1991)
Willow Bay (1991–1998)
Summer Sanders (1998-2004)
See also
Run It Back – a show related to Inside Stuff, aired on Cartoon Network.
References
External links
Category:TNBC
Category:ABC Kids
Category:1990 American television series debuts
Category:2004 American television series endings
Category:2013 American television series debuts
Category:1990s American television series
Category:2000s American television series
Category:2010s American television series
Category:American Broadcasting Company original programming
Category:English-language television programs
Category:NBC original programming
Inside Stuff
Category:NBA TV original programming
Category:American sports television series
Category:American television series revived after cancellation | 2023-09-09T01:26:35.434368 | https://example.com/article/3862 |
Q:
Creating product/Service in Quickbooks Online in an Invoice line item
I'm trying to create the service/product type in the invoice line item. It returns an error saying bad request, is my ItemRef phrased correctly. My service/product is created in qbo already, its called Subscription Fee, it's the 3rd in the dropdown list.
line.AnyIntuitObject = new Intuit.Ipp.Data.SalesItemLineDetail()
{
ItemRef = new Intuit.Ipp.Data.ReferenceType()
{
Value = "3",
type = "Item",
name = "Subscription Fee"
},
ItemElementName = Intuit.Ipp.Data.ItemChoiceType.UnitPrice,
AnyIntuitObject = (decimal)item.Rate, // Line item rate
Qty = (decimal)item.Quantity,
QtySpecified = true,
ServiceDate = DateTime.Now.Date,
ServiceDateSpecified = true,
TaxCodeRef = new Intuit.Ipp.Data.ReferenceType()
{
Value = taxCode0ZR.Id,
type = Enum.GetName(typeof(Intuit.Ipp.Data.objectNameEnumType), Intuit.Ipp.Data.objectNameEnumType.TaxRate),
name = taxCode0ZR.Name
},
};
What am i creating wrongly please help.
A:
You cannot create an Item within an invoice or rather any entity within an entity.
QBO v3 does not supports creating entities on the fly.
You first need to do a create Item.
Get the Id of that Item and refer it in your Invoice.
Also, enable request/response log to get the details of the errors in log files-
https://developer.intuit.com/docs/0025_quickbooksapi/0055_devkits/0150_ipp_.net_devkit_3.0/0002_configuration/override_configuration
| 2023-12-17T01:26:35.434368 | https://example.com/article/7513 |
Q:
How to echo random row from database?
Possible Duplicate:
MySQL: How to retrieve a random row or multiple random rows?
Pull 5 random records from mysql database
I have a large list of domains in my database in the table "list" under the column "website".
There are about 140 million rows and I just need to know how to echo a random one.
Basically like this:
<?php include('directory/database.php'); ?>
WHATEVER CODE WORKS FOR GETTING A RANDOM DOMAIN FROM THE DATABASE
<?php
echo $domain;
?>
There's just a huge amount of records so I need to know the quickest way to just have one of them randomly selected and displayed on a page. Thanks!
A:
You definitely don't want to use ORDER BY RAND(). MySQL has to build a temporary table. If your table has a unique id column, something like this is much better:
SELECT * FROM `table`
WHERE id >= (SELECT FLOOR( MAX(id) * RAND()) FROM `table` )
ORDER BY id LIMIT 1;
See this blog post for other approaches that work well in php.
Note: This simply repeats my answer on this thread.
| 2023-11-03T01:26:35.434368 | https://example.com/article/6483 |
The doe-eyed, soft-spoken performer looks nothing like a covert revolutionary or rebellious youth, but appearances in Qaddafi's Libya were often deceiving. Abu Sagar and a few of his friends decided to teach themselves the script, letter-by-letter and word-by-word. It was political dissent by alphabet. They swore one other to secrecy, fearing arrest. They began to hop from one internet café to the next, changing locations every hour and never signing in with their real names. "We were very scared," Abu Sagar remembered, "people were watching everywhere."
Abu Sagar said it took him two years to master the language. Eight years after that, he would hold clandestine classes for other Amazigh who wanted to learn it. For one month last summer, 25 students convened nightly in a cave in the Nafusa Mountains, a scraggly range west of Tripoli near the Tunisian border where many of Libya's Amazigh communities still reside. Abu Sagar taught his students what he knew and he shared the Amazigh poetry he'd composed. Like many before him, his goal was to keep the language alive, despite the risks.
From Carthaginian, Roman, Byzantine, Vandal, Arab-Muslim, and European conquerors to the policies of modern-day North African leaders, the Amazigh have been oppressed throughout their millennia-long history. This year's Arab Spring unleashed a lesser-known social movement: unprecedented Berber activism and an Amazigh cultural revival. Nowhere in the region has this new movement been more unique than in Libya, where after playing a vital role in the fight against Qaddafi, the Amazigh want their contribution to Libya's revolution acknowledged and their identity accepted. But despite the relative openness of post-Qaddafi Libya, the Amazigh face a difficult road ahead and their fate will become one of the true tests of Free Libya's freedom and its future.
Centuries of assimilation and decades of outright oppression have left the minority, which Berber scholar Bruce Maddy-Weitzman estimates today make up about 9 percent of Libya's 5.7 million people, marginalized. The Arab conquests in the seventh century promoted Arabic as the language of God and created a stigma against using Tamazight. Amazigh identity took an even harder hit from populist Arab-national sentiments promoted by the region's leaders against European colonialism, often denying Berber identity altogether. Past Amazigh cultural revivals in the region have ended with brutal repression. In a country whose future looks more and more tumultuous each day, some worry that history may repeat itself, especially if Libya's new government is hyper-nationalist.
"In the end, they kept their heads down during all the Qaddafi time. I just hope that having stuck them over the barricades they don't have them chopped off," says archaeologist and academic Elizabeth Fentress, who studies Amazigh communities and co-authored of one of the definitive books on the group's history, The Berbers. "There's a tremendous tendency in these countries for the Arab groups to say, 'Thank you very much for your help now would you shut up and start speaking Arabic again.' They [Arabs] really don't trust them or like them or want to know them." | 2024-01-22T01:26:35.434368 | https://example.com/article/1142 |
Q:
Balanced Partition in Haskell
In haskell, how can I generate a balanced partition of a set?
Assuming I have a set {1,3,4,6,9}, a balanced partition of that set would be s1{9,3} and s2{6,4,1}, seeing as s1-s2 is 1.
A:
Well, for brute force, we can generate all partitions recursively by generating partitions for the tail and then putting the head on the left list or the right:
partitions :: [a] -> [([a], [a])]
partitions [] = [([], [])]
partitions (x : xs) = let ps = partitions xs in
[(x : ys, zs) | (ys, zs) <- ps] ++ [(ys, x : zs) | (ys, zs) <- ps]
have a way to compute the unbalance:
unbalance :: Num a => ([a], [a]) -> a
unbalance (ys, zs) = abs (sum ys - sum zs)
and then put it all together:
balancedPartition :: (Num a, Ord a) => [a] -> ([a], [a])
balancedPartition = minimumBy (comparing unbalance) . partitions
Here's the complete module:
module Balance where
import Data.List(minimumBy)
import Data.Ord(comparing)
partitions :: [a] -> [([a], [a])]
partitions [] = [([], [])]
partitions (x : xs) = let ps = partitions xs in
[(x : ys, zs) | (ys, zs) <- ps] ++ [(ys, x : zs) | (ys, zs) <- ps]
unbalance :: Num a => ([a], [a]) -> a
unbalance (ys, zs) = abs (sum ys - sum zs)
balancedPartition :: (Num a, Ord a) => [a] -> ([a], [a])
balancedPartition = minimumBy (comparing unbalance) . partitions
| 2024-02-13T01:26:35.434368 | https://example.com/article/4721 |
Q:
Displaying YUV Image in Android
In my application, we need to display the Video frame receives from server to our android application,
Server is sending video data @ 50 frame per second, having encoded in WebM i.e. using libvpx to encode and decode the images,
Now after decoding from libvpx its getting YUV data, that we can displayed over the image layout,
the current implementation is something like this,
In JNI / Native C++ code, we are converting YUV data to RGB Data
In Android framework, calling
public Bitmap createImgae(byte[] bits, int width, int height, int scan) {
Bitmap bitmap=null;
System.out.println("video: creating bitmap");
//try{
bitmap = Bitmap.createBitmap(width, height,
Bitmap.Config.ARGB_8888);
bitmap.copyPixelsFromBuffer(ByteBuffer.wrap(bits));
//}catch(OutOfMemoryError ex){
//}
System.out.println("video: bitmap created");
return bitmap;
}
To create the bitmap image ,
to display the image over imageView using following code,
img = createImgae(imgRaw, imgInfo[0], imgInfo[1], 1);
if(img!=null && !img.isRecycled()){
iv.setImageBitmap(img);
//img.recycle();
img=null;
System.out.println("video: image displayed");
}
My query is, overall this function is taking approx 40 ms, is there any way to optimize it,
1 -- Is there any way to display YUV data to imageView ?
2 -- Is there any other way to create Image( Bitmap image) from RGB data ,
3 -- I believe i am always creating image, but i suppose i should create bitmap only once and do / supply new buffer always, as and when we received.
please share your views.
A:
Following code solve your problem and it may take less time on Yuv Format data because YuvImage class is provided with Android-SDK.
You can try this,
ByteArrayOutputStream out = new ByteArrayOutputStream();
YuvImage yuvImage = new YuvImage(data, ImageFormat.NV21, width, height, null);
yuvImage.compressToJpeg(new Rect(0, 0, width, height), 50, out);
byte[] imageBytes = out.toByteArray();
Bitmap image = BitmapFactory.decodeByteArray(imageBytes, 0, imageBytes.length);
iv.setImageBitmap(image);
or
void yourFunction(byte[] data, int mWidth, int mHeight)
{
int[] mIntArray = new int[mWidth*mHeight];
// Decode Yuv data to integer array
decodeYUV420SP(mIntArray, data, mWidth, mHeight);
//Initialize the bitmap, with the replaced color
Bitmap bmp = Bitmap.createBitmap(mIntArray, mWidth, mHeight, Bitmap.Config.ARGB_8888);
// Draw the bitmap with the replaced color
iv.setImageBitmap(bmp);
}
static public void decodeYUV420SP(int[] rgba, byte[] yuv420sp, int width,
int height) {
final int frameSize = width * height;
for (int j = 0, yp = 0; j < height; j++) {
int uvp = frameSize + (j >> 1) * width, u = 0, v = 0;
for (int i = 0; i < width; i++, yp++) {
int y = (0xff & ((int) yuv420sp[yp])) - 16;
if (y < 0)
y = 0;
if ((i & 1) == 0) {
v = (0xff & yuv420sp[uvp++]) - 128;
u = (0xff & yuv420sp[uvp++]) - 128;
}
int y1192 = 1192 * y;
int r = (y1192 + 1634 * v);
int g = (y1192 - 833 * v - 400 * u);
int b = (y1192 + 2066 * u);
if (r < 0)
r = 0;
else if (r > 262143)
r = 262143;
if (g < 0)
g = 0;
else if (g > 262143)
g = 262143;
if (b < 0)
b = 0;
else if (b > 262143)
b = 262143;
// rgb[yp] = 0xff000000 | ((r << 6) & 0xff0000) | ((g >> 2) &
// 0xff00) | ((b >> 10) & 0xff);
// rgba, divide 2^10 ( >> 10)
rgba[yp] = ((r << 14) & 0xff000000) | ((g << 6) & 0xff0000)
| ((b >> 2) | 0xff00);
}
}
}
| 2023-12-23T01:26:35.434368 | https://example.com/article/9054 |
I don’t give two flying rat behinds that this isn’t about gaming news. This is a rare moment where someone on network television dropped a few red pills for the perpetually blinded masses and their ideological hooded cloaks they wear to keep from facing reality. What am I talking about? I’m talking about the Sports Center segment that every uncultured snowflake, Liberal, and Social Justice Warrior needs to listen to in order to wake up from the slumber that keeps them asleep on Left’s political plantation fields.
Scott Van Pelt from SportsCenter dropped some truth bombs in a recent two minute tirade against the snowflake culture that is ruining the backbone of America’s stature and crushing the confidence we have in Western values. It’s two minutes of pure, unadulterated criticisms of this mollycoddle culture cultivated by the Cultural Marxists on the Left and the Social Justice Warrior-defending Centrists in the middle. Pelt lays it all on the line to ensure that no matter what field you’re in, what occupation you hold, or what political line you toe, you need to stop being a weak-minded, low-confidence, adversity-averse crybaby and man up!
The calmly spoken and intonational exposition was rolled out by Pelt in rebuttal to all the SJWs flooding social media to condemn college basketball coach Tom Izzo for verbally putting a player into place. Pelt explains that sometimes it’s through tough love and a correction for failure that we learn how to overcome the obstructions we encounter in life. You can view the clip below that was posted up on March 24th, 2019, which has almost garnered a million views.
“Stop being offended by things that don’t concern you.”@notthefakeSVP shared his thoughts on the conversation around Tom Izzo yelling at one of his players. pic.twitter.com/OavnFa3zKB — SportsCenter (@SportsCenter) March 24, 2019
If you’re unable to view the clip (or if it gets taken down for rolling out the truth), Scott Van Pelt says…
“This isn’t about snowflakes being soft. It is about a gigantic problem we’ve allowed to happen in society, but go out of our way to ensure it gets worse. People seem to have a real issue if they’re held accountable or if others are too harsh. We’re so concerned with how someone’s feelings might get hurt, we lose sight of this fact: Life is has a scoreboard, the world will be difficult, and we do nobody any favors when we coddle them to the point where they never hear criticism, or a harsh word, or have to face any adversity. Because when nobody in a job interview or negotiations stops to ask about your feelings and then you don’t get the job, or you don’t get the contract, what are you going to do? Demand the world stop being mean to you? “The college admission scandal is a great example of this. They say you should prepare your kids for the path, not the path for your kids. You cannot eliminate every challenge or adversity they might face. ‘Cause if you do, what have you accomplished? “We’re so concerned with safe spaces and not saying mean things that when a coach gets on a player it’s seen by some of you as out of bounds. And that is insane to me. Is that the only way to get your point across? No. You can go about it differently. But you notice who didn’t have a problem with it? Michigan State [University]. “Did you notice what [the players] did? They told Izzo, ‘We got this’. Because they have a voice. They’ve been empowered in a family dynamic that occasionally gets volatile – because there’s a scoreboard and they’re trying to win. “You know who else didn’t have a problem with [Tom Izzo’s yelling]? The freshman, who was getting the what for, Aaron Henry. His social media as well as the accounts of past Spartans, like Miles Bridges and Draymond Green, and countless other Spartans gave insights into why they didn’t and don’t have a problem with it. But that doesn’t matter to people who don’t really want context, they just want to be mad and be offended. “So, be good and mad about how Tom Izzo yelled at his players. His players, past and present, have a rare loyalty to him. He doesn’t have a transfer problem, he has the opposite – a bunch of four-year guys, the overwhelming majority of whom have gotten to final fours and in part because of being held accountable the way he holds them accountable. “You don’t like it? Fine. Don’t send your kid there. But stop being offended by things that don’t concern you. Because they’re not.”
You can also view the segment on YouTube in case you’re visually impaired and the tweet is no longer accessible.
Either which way, Pelt makes it clear that the culture of crybabies and the padding of opinions and expression done in consideration for snowflakes and safe-space dwellers isn’t helping anyone. In fact, it’s doing the opposite. It’s degrading America’s resolve to become hardened and steeled through the challenge of adversity.
Social Justice Warriors have run roughshod over nearly every aspect of Western culture, completely emasculating comic books and video games, and turning many testosterone-driven franchises in entertainment media into effeminate agitprop.
Thankfully, every once in a blue moon we’ll have someone in a position to speak to the masses rain down some much needed common sense and criticisms of the Leftist’s agenda to destroy our nation by turning everyone into weak, pitiful, crying sods and worthless cretins.
As many people pointed out in the comment section on the YouTube video, this looks especially bad when a converged Disney-owned network like ESPN – the same network that had Capcom tell players not to pick default outfits for certain female characters in Street Fighter V during the Top 8 at EVO because thongs were a huge no-go – has a host telling the masses that they’re too freaking soft. I doubt it will change many minds, but at least Social Justice Warriors are finally getting called out more frequently than before.
(Thanks for the news tip Reina Todoroki) | 2023-11-24T01:26:35.434368 | https://example.com/article/5857 |
Here is what was displayed on console::/var/www/owncloud$ sudo -u www-data php occ upgrade ownCloud or one of the apps require upgrade - only a limited number of commands are available You may use your browser or the occ upgrade command to do the upgrade Set log level to debug Exception: Updates between multiple major versions and downgrades are unsupported. Update failed Maintenance mode is kept activeReset log level | 2023-11-10T01:26:35.434368 | https://example.com/article/8178 |
North Denmark gears up to fight fake news
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How do fake news influence politics in all around the globe? What is the danger of fake news for the European Union? How is the future going to look like? And most importantly - how can we fight back? These questions and many more were asked at an event called The Danger of Fake News: How to Fight Back, organised by European Youth North Denmark (JEF North Denmark) in Aalborg.
At the beginning of the event, there was a presentation about DisinfoLab, an NGO working on analysis and prevention of spreading disinformation. Then, the audience tried to guess which headlines are fake or true in a short Kahoot! quiz and finally, two discussions - an informal moderated discussion among the audience, followed by a panel discussion with three experienced speakers:
Juuso Järviniemi - Editor-in-Chief of The New Federalist and President of Young European Movement UK (JEF-UK)
Ben Dorfman - associate professor of intellectual and cultural history, and head of the Language and International Studies programs at Aalborg University
Lasse Frimand Jensen - project manager at the International House North Denmark and also a member of the City Council in Aalborg
Fake news: Catalysts and remedies
In the discussion, Juuso pointed out that the European Union is a political system that continually fights for its existence, which makes fake news particularly damaging to it. In an established nation-state, fake news may dethrone the government of the day, but when false criticism is levelled against the European Commission, it is the institution rather than just Jean-Claude Juncker’s cabinet that is being criticised.
At the same time, the strongest defence mechanism against fake news isn’t at the EU’s disposal. Namely, the EU has no impartial, widely trusted public broadcaster. All that the EU as a system can rely on is national-level media giving it accurate and sufficiently extensive coverage. After all, fake news tap into existing public perceptions – if a made-up story doesn’t correspond with the reader’s worldview, it is particularly unlikely to make an impact. About the EU, citizens have no accurate image, but instead fake news may fill a tabula rasa in viewers’ heads.
Lasse Frimand Jensen spoke about the importance of admitting one’s mistakes. Fake news thrive in an environment where politicians are not trusted, and endless excuse-finding is one factor contributing to the erosion of trust in the political class. Would more relatable and ‘human’ politicians be more immune to fake news?
Ben Dorfman discussed the turbulent times that we are living in. Perhaps, despite technological change and the unprecedented rapidity of communication, fake news would not resonate if it weren’t for the social malaise across societies from Poland to the Philippines. Nordic countries haven’t struggled with fake news as much as some other places, and perhaps social equality and the relative lack of deprivation are to be thanked.
Time to act
The main aim of the Aalborg event, however, was to set up a permanent unit of volunteers called Anti-Troll Unit which will identify fake news and other disinformation in their respective countries or languages, write reports and then send them to the EU East Stratcom Task Force who will publish it in their weekly Disinformation Review. In this way, European Youth North Denmark, the majority of whose members come from Eastern Europe, want to contribute their share to the fight against disinformation in Europe.
However, volunteers from all over Europe are more than welcome to sign up. Every member will get an Anti-Troll Unit patch!
Last but not least, we had a small surprise: three members of The New Federalist editorial board met at the same place, so we had a tiny TNF get-together.
About the author
Editor-in-Chief of The New Federalist. Opinions presented in articles represent author’s personal views rather than a common view held by The New Federalist.
Originally from Finland, Juuso Järviniemi studies International Relations at the University of Edinburgh. He was the President of the British JEF section in 2017/18, and has been a member of JEF-Europe’s Federal Committee since 2017. In 2018/19, Juuso is on an Erasmus exchange at Sciences Po Paris.
Juuso’s interests include the democratic structures of the EU, the UK’s place in the European project, and European identity. | 2024-06-06T01:26:35.434368 | https://example.com/article/5751 |
That design wouldn't even be useful. If the player is standing on the platform, following the player would mean going up, because standing on the platform is above it. And if the player is to the right, it would push the player to the right constantly. Or if it was semi-solid, it would float around wherever Tux's origin is, and what use would that be? | 2023-12-06T01:26:35.434368 | https://example.com/article/5400 |
I will watch the games that I can. I love the Warriors, I dont like the way things are headed right now, but I like a lot of the players that are still on the team. I am curious to see if the Jack move improves chemistry and what effect it will have on Monta. I can not give up on my team, I will not support them financially, but I will continue to watch and root for them.
I understand, but have you seen the roster do the warriors even have enough players to suit up, and if so they will be mis-matched, but hey am a young guy and don't want to start balding, or pull my hair. Am still a fan always will be, but this is the breaking point. We deserve better, I like this team too much to even watch this train wreck, day after day.
I feel your pain, believe me! Im not a young guy and I have seen this team go through many ups and downs, mostly downs, but I have always continued to follow and support them. Everybody has been calling for Curry / Morrow and Randolph to get more minutes.....now there is no choice!!
and Bell's now going for surgery.
a few things confuse me here:
1) Why did Bell think "toughin' it out" was a good idea in the first place in CHA? I mean who wants to sign a vet guy who needs surgery?
2) Is Cha that much better than us?
and Bell's now going for surgery. a few things confuse me here:1) Why did Bell think "toughin' it out" was a good idea in the first place in CHA? I mean who wants to sign a vet guy who needs surgery?2) Is Cha that much better than us?
CHA doesnt have to be that much better, they are in the eastern conference. He also goes from playing for Larry Brown with Michael Jordan in the front office to Don Nelson and Rowell. His surgery would have definitely healed over the offseason, but its hard to blame the guy for going for it now.
and Bell's now going for surgery. a few things confuse me here:1) Why did Bell think "toughin' it out" was a good idea in the first place in CHA? I mean who wants to sign a vet guy who needs surgery?2) Is Cha that much better than us?
CHA doesnt have to be that much better, they are in the eastern conference. He also goes from playing for Larry Brown with Michael Jordan in the front office to Don Nelson and Rowell. His surgery would have definitely healed over the offseason, but its hard to blame the guy for going for it now.
MJ is just as bad of a front office person as Rowell. I would think the reason that Bell would stick it out while he was in Charlotte because that team lacks offense as much as we lack defense so, he was one of the featured offensive pieces there, here he would just be one of 5 or 6 other players that can do the same things that he can.
and Bell's now going for surgery. a few things confuse me here:1) Why did Bell think "toughin' it out" was a good idea in the first place in CHA? I mean who wants to sign a vet guy who needs surgery?2) Is Cha that much better than us?
CHA doesnt have to be that much better, they are in the eastern conference. He also goes from playing for Larry Brown with Michael Jordan in the front office to Don Nelson and Rowell. His surgery would have definitely healed over the offseason, but its hard to blame the guy for going for it now.
MJ is just as bad of a front office person as Rowell. I would think the reason that Bell would stick it out while he was in Charlotte because that team lacks offense as much as we lack defense so, he was one of the featured offensive pieces there, here he would just be one of 5 or 6 other players that can do the same things that he can.
beat me to it... MJ has been a below average GM... Oakafor and Morison, getting Sean May, They've been stuck with nazir Mohammed forever, they had that coach before Brown that insisted Felton play SG? I'm not trying to say we are better I'm not even saying were even, but they aren't THAT much better than us.
and Bell's now going for surgery. a few things confuse me here:1) Why did Bell think "toughin' it out" was a good idea in the first place in CHA? I mean who wants to sign a vet guy who needs surgery?2) Is Cha that much better than us?
CHA doesnt have to be that much better, they are in the eastern conference. He also goes from playing for Larry Brown with Michael Jordan in the front office to Don Nelson and Rowell. His surgery would have definitely healed over the offseason, but its hard to blame the guy for going for it now.
MJ is just as bad of a front office person as Rowell. I would think the reason that Bell would stick it out while he was in Charlotte because that team lacks offense as much as we lack defense so, he was one of the featured offensive pieces there, here he would just be one of 5 or 6 other players that can do the same things that he can.
beat me to it... MJ has been a below average GM... Oakafor and Morison, getting Sean May, They've been stuck with nazir Mohammed forever, they had that coach before Brown that insisted Felton play SG? I'm not trying to say we are better I'm not even saying were even, but they aren't THAT much better than us.
I wasnt talking about Jordans FO skills, I was simply stating that a situation where you are surrounded by Larry Brown and MJ is going to be for a player something more worth fighting for than Nellie and Rowell. | 2024-02-18T01:26:35.434368 | https://example.com/article/7719 |
Neil Dexter became Middlesex's first new signing for the 2009 season this week.
Chief-executive Vinny Codrington confirmed the new arrival in St John's Wood, after Dexter rejected a new three-year deal with Kent and the advances of several other suitors including Essex.
The South-African-born batsman had become frustrated at not gaining a regular place in the Spitfires' top six, despite an average of 41 in first-class cricket.
With doubts over the futures of Ed Joyce and Ed Smith, a Kent fringe player might not be every Middlesex fan's solution for a Crusaders' batting lineup likely to be without Andrew Strauss and Owais Shah for much of 2009 on England duties.
However, Codrington has backed the 24-year-old, along with Dawid Malan and Eoin Morgan - called up this week for the England Performance squad tour of India this winter - to fire a Middlesex promotion bid next summer.
"Neil is a good middle-order batsman and an excel-lent prospect, who will bolster our batting whether or not Joyce and Smith are still with us," he said.
"We could be without Strauss and Shah a lot next year but our young players like Malan and Morgan have bags of promise."
One man who might not be around next year is Dirk Nannes.
Only last week the giant left-arm pace bowler told your favourite local paper he'd love to stay at Lord's.
But a decision to return to Australia this winter to play Twenty20 cricket, may invalidate an affidavit signed by the Dutch passport holder's future here.
However, according to Codrington, Nannes' injury problems also put a question mark over his future.
"Dirk contributed brilliantly in his five Championships matches but because of injury didn't play enough," he said. | 2023-12-08T01:26:35.434368 | https://example.com/article/1381 |
Assembly elections: BJP’s West Bengal gap widens
With things not going well for the BJP and the TMC, people are eyeing the CPI(M)-Congress coalition as an alternative
TMC workers carry giant hoardings of West Bengal CM Mamata Banerjee for the upcoming assembly elections in Kolkata on March 18. (PTI )
New political equations in West Bengal have raised hopes for both the Trinamool Congress (TMC) and the BJP in the coming assembly elections. It is almost certain that the state is going to witness a triangular fight in most of the constituencies, now that there is an electoral alliance between the Left and the Congress even though in about a dozen seats they are contesting each other. As of now, the TMC has an edge over others. But a great deal depends on how these parties do their electioneering in the coming days. The stakes are high for the BJP; after losing in Delhi and Bihar, the party will now try hard to win as many seats as possible in West Bengal and Assam. But there are problems and the party has to address them.
The BJP lacks enough foot-soldiers to help it win a large number of seats. It controls only a handful of local-level political bodies such as gram panchayats, anchal panchyat and zilla parishad (village, block and district councils). In 2013 the TMC defeated the BJP in three-tier panchayat elections in all the districts. The BJP’s performance in the municipal elections was far from satisfactory. In the Kolkata municipal elections it lost to the TMC by wide margins. In the parliamentary elections in 2014, the BJP managed to secure 17.02% of the votes, as compared to 39.79% of the TMC. In the 2015 byelections in the Bangaon parliamentary and Krishanganj assembly constituencies, the BJP did relatively well and since then it has managed to put pressure on the ruling party. During the last one year it has organised a large number of rallies with prominent leaders of the party, with the turnout in each of these rallies being quite high.
In order to do well in the coming assembly elections, the party needs a cadre to mobilise support in different parts of the state. During the past four decades, the CPI(M) has spent a great deal of effort to build its local organisations, and the TMC has done the same thing since the 2011 assembly elections. It is difficult to deny that the tireless efforts of the foot-soldiers helped Mamata Banerjee to win polls over the past five years. The party’s defeat in the Delhi and Bihar assembly elections has demoralised the small group of BJP party workers in the state, and recruiting a cadre before the elections is not going to be easy.
The BJP has to leave behind its baahari (outsider) tag and for that it must project leaders who can speak in Bengali. Unfortunately, they do not have Bengali-speaking popular leaders. It seems they have lost an opportunity by not making an all-out effort to welcome the Trinamool’s much-maligned leader Mukul Roy, who is now back with the party. Also, the BJP has not yet succeeded in finding a stalwart who could be its chief ministerial candidate. As a result, it will be difficult for the party to convince the electorate that it can form the government under the leadership of a popular leader. In the Delhi assembly elections, the BJP paid the price of selecting its chief ministerial candidate late. The TMC has a chief ministerial candidate, and the CPI(M) too for quite some time is projecting one or two leaders who could be chief minister.
The BJP’s fault lines are in the Muslim-dominated districts such as Malda, North and South Dinajpur, Murshidabad and, to some extent, South 24 Parganas. According to the 2011 census, the Muslim population in the state has gone up to 27%. The lynching incident in Dadri, UP, and the anti-Muslim propaganda by the Sangh parivar will help other parties to grab this huge vote bank. The TMC took great care to keep the Muslim voters on its side by partially implementing the Sachar Committee Report (2006), including as many as 30 Muslim occupational categories in the state OBC list, and offering financial assistance and loans to the Muslim youth. The BJP, however, can expect some support from the 25% Dalits belonging to either the displaced Namasudra caste or the Rajbangshis in north Bengal. It depends a lot on how the Dalits vote in the border districts, where they are in a majority. The TMC and the CPI (M) have received the support of the Dalits from the border districts for many years by distributing fake voter cards and giving rations at a subsidised rate. The BJP is trying hard to get the support of a section of illegal migrants by calling them ‘Hindu refugees’.
All is not well with the TMC either. Besides the anti-incumbency factor, it is now struggling to deal with the crisis that emerged as a result of the Saradha chit fund scam. The party is still in damage control mode. The involvement of some high-profile TMC leaders in the scam raises questions about chief minister Mamata Banerjee’s commitment to root out corruption in the state. Similarly, questions are being raised about the TMC’s ability to offer good governance. The recent riots in Malda have exposed the ineffectiveness of the government machinery in dealing with law and order problems. As far as the economy is concerned, the TMC neither managed to attract investment for infrastructural growth nor created jobs. Against this backdrop, all eyes are now on the CPI(M)-Congress coalition. Is this a viable alternative? This seems to be the question that the people of West Bengal are asking now. | 2023-08-16T01:26:35.434368 | https://example.com/article/4039 |
Q:
Firebase function context.auth and context.authType undefined
I am diving into Firebase functions (server-side), and having trouble grabbing the authentication information from within the function. In it's simplest form, my index.ts that is getting deployed to Firebase functions looks like this :
import * as functions from 'firebase-functions';
import * as admin from 'firebase-admin';
admin.initializeApp();
export const createOrganization = functions.firestore.document("Organizations/{organizationId}").
onCreate((snap, context) => {
console.log(context)
});
I can see from Firebase's logging that this function is indeed getting called, and the context that gets logged looks something like this :
{ eventId: 'XXXXX-XXXX-XXXX',
timestamp: '2018-04-13T21:37:33.349247Z',
eventType: 'google.firestore.document.write',
resource:
{ service: 'firestore.googleapis.com',
name: 'projects/XXXX/databases/(default)/documents/Organizations/XXXXXXXXXXXX'
},
params: { organizationId: 'XXXXXXXXXXXX' }
}
I would expect from the documentation that the context parameter would also include properties called "authType" and "auth" that contain information about the user who is making the request. However, after trying all sorts of things, context.authType and context.auth are always undefined.
I have tried this both as an authorized user and unauthorized user with no changes.
Any help figuring out why context.authType and context.auth are not populated would be really helpful, thanks!
A:
Auth information is only given for Firebase products that provide auth information to Cloud Functions for each triggered event. Currently, only Realtime Database supports this. Firestore support is being worked on. In theory, Cloud Storage could provide support as well.
It's inconsistent because each event provider in Cloud Functions for Firebase is driven by different teams, each with different implementations and priorities.
| 2024-06-23T01:26:35.434368 | https://example.com/article/8934 |
Do you tend to use "God" or "god" online?
If I debate with theists, I tend to use "your god" or "the god of christianity". This way, I can avoid making them think that I acknowledge that their god "is THE God", but that I am just denying it. I de-throne their god and toss it into a clusterf*ck of other mythological beings.
I notice sometimes that other atheist debaters capitalize the word god, and I feel that the theists believe that this only confirms their gods' status. If we confirm their gods' status, then we are just rebels. How do you use the word "god"?
Replies to This Discussion
I think it would really depend upon the purpose of the discussion with the theists. Are you trying to persuade them to consider the atheistic PoV? If so, that words like "Jeebus" and "Sky-Daddy" probably aren't the way to go. A lot of theists feel antagonized by our very existence as atheists, so as far as a persuasive argument goes, we already are starting from a negative stance. It would be counterproductive to add coal to that particular fire.
If, however, there is either no desire on the atheist's end to persuade, or if it is completely obvious that rational argument is falling on deaf ears, then...meh...go for it.
I tend to go for neutral clinical terms most of the time, but if someone has pissed me off to the point that I don't care if they think I'm an asshole, I have been known to use words like "your mythology."
I would agree with you completely, except that I figure bigfoot is more of the individual, non-scientific name of a nonexistent animal. But if there can be only one, like Highlander, then I suppose Bigfoot is correct.
“ 'I am Duncan MacLeod, born four hundred years ago in the Highlands of Scotland. I am Immortal and I am not alone. For centuries we have waited for the time of the Gathering, when the stroke of a sword and the fall of a head will release the power of the Quickening. In the end, there can be only one.'
Good stuff. Good stuff. Nothing like "the fall of a head" to get MY attention! ha
I use the term "the supposed god". Thus it is a non-existent god which is merely, (by some people), supposed to exist. I use "God" in quotes as the name of the Abrahamic supposed god, and god to mean any old supposed god that one might like to consider.
When I describe my atheism, I say that: 'I hold no belief in a god, any god'. | 2024-01-15T01:26:35.434368 | https://example.com/article/2498 |
The use of ultrasonic guided waves and wavelets analysis in pipe inspection.
One of the main applications of guided waves is for pipe inspection, since its one-dimensional geometry allows inspecting long distances in a short time. As with most configurations (frequency, thickness) ultrasonic waves with many modes of propagation are generated, recent research focuses mostly on the generation and reception of specific modes, mainly by means of sophisticated arrays of transducers. In this paper this problem is addressed with a different approach, by processing ultrasonic signals with a low signal/noise ratio acquired with a single transducer in an pulse-echo configuration. In order to improve the evaluation of results, frequency bandpass filters and wavelet analysis were tested. Results showed that even when very noisy signals are utilized, signal processing improve the signal/noise (S/N) ratio up to 12 dB approximately and enhance the analysis of the results, thus demonstrating its usefulness. | 2024-02-06T01:26:35.434368 | https://example.com/article/6890 |
Q:
How to differentiate a programmatic delete from an application delete in crm 2011 plugins
I have an entity with a pre delete plugin. Is it possible to differentiate in the plugin if the delete request has been issued manually in crm or programmatically using the crmservice from the sdk?
A:
As far as I know is not possible to differentiate inside a plugin a request made by web interface from another made using the sdk.
| 2024-07-04T01:26:35.434368 | https://example.com/article/1894 |
text {
fill: #eee;
}
polyline {
stroke: #ccc;
}
path {
stroke: #ccc;
}
rect.module-background, .background-fill {
fill: #111;
}
polyline.module-border-inner {
stroke: #191919;
}
polyline.module-border-middle {
stroke: #111;
}
polyline.module-border-outer {
stroke: #000;
}
rect.input-background, rect.input-background-filler {
fill: #aaa;
}
rect.output-background, rect.output-background-filler {
fill: #666;
}
text.input-label {
fill: #222;
}
polyline.input-label, path.input-label {
stroke: #222;
}
text.output-label {
fill: #ddd;
}
polyline.output-label, path.output-label {
stroke: #ddd;
}
circle.port-rim {
stroke: #c0c0c0;
}
circle.port-barrel {
stroke: #222;
fill: #222;
}
circle.knob-center {
fill: #888;
}
circle.knob-rim {
fill: #444;
}
circle.knob-tick {
fill: #fff;
}
polyline.knob-tick {
stroke: #fff;
}
| 2024-06-07T01:26:35.434368 | https://example.com/article/7491 |
DatabaseMap
class DatabaseMap
DatabaseMap is used to model a database.
GENERAL NOTE
The propel.map classes are abstract building-block classes for modeling
the database at runtime. These classes are similar (a lite version) to the
propel.engine.database.model classes, which are build-time modeling classes.
These classes in themselves do not do any database metadata lookups. | 2024-04-20T01:26:35.434368 | https://example.com/article/6527 |
Quick Links
Solar Options
What Solar Options Are There?
Rooftop solar systems are common because they make sense in many ways. Aesthetically, solar panels on the rooftop can be out of sight. They also don’t take up space you would normally use.
Installing a rooftop solar array is a fairly common and quick practice these days as well. For many homeowners, rooftop solar is usually the way to go. But it isn’t practical for every home or situation. There are times you might need to look into other options.
Ready to get started?
Non-Rooftop Solar Options
Ground-Mounted Solar
Ground-mounted solar is an excellent option if you find yourself in a situation where rooftop doesn’t make sense.
There are a couple variations for ground-mounted solar. One option is a standard ground mount, where solar panels are secured to a stationary metal frame close to the ground. The other is pole mounting, which often incorporates solar tracking.
These are both great choices with the following advantages:
Optimal positioning towards the south (or even following the sun)
No space limitations, which means as many panels (and as much power) as you want
Easily avoid shading by picking an optimal location
No roof upgrade needed
If you own a lot of land, it might be worth looking into ground solar anyway. You have more control over positioning your panels or even purchasing a tracking system. These moveable ground mounts follow the sun’s position in the sky, which can significantly increase how much power your panels produce.
Better energy production means more energy savings sooner.
Of course, you’ll need to compare these benefits with the added cost of ground mounts. These systems require more hardware and labor, including trenching from the system to your inverter and panel box. Our Energy Advisors can help you easily figure out what is best for you.
Community Solar
Community solar allows people to go solar even if they do not own property on which to put their own system.
Through a community solar project, participants benefit from one shared system usually located on a piece of land that is not necessarily owned by any of the users. The electricity generated generally costs less than the price participants would ordinarily pay to their utility. Community solar allows people to go solar even if they do not own property. There are a number of different ways that shared renewable energy can operate, each falling under one of two categories: ownership or subscription.
The billing system that makes much of this possible is Virtual Net Metering (VNM). What Net Metering is to rooftop solar, VNM is to community solar. Through this system, which is currently operating in a number of states, consumers can receive the Net Metering credits associated with a renewable energy project even if they are not connected to its electricity meter.
These credits then offset their electricity usage as the credits are often worth equal or nearly equal to the cost of electricity from the utility company. This means that, if a participant’s share of a community solar farm is 10 kWh of electricity, it will reduce his or her power bill on a one-for-one basis by 10 kWh. VNM is a powerful system that encourages the use of these projects, but other models are emerging that allow both consumers and developers to get involved in community solar without it.
For Your Home
Determining whether or not your home is a good candidate for solar depends on a few factors.
Let’s take a look on what you should look out for when qualifying your home for solar.
What’s your monthly electric bill?
Your current electricity bill is the largest factor in determining how much you’ll save by installing solar. You pay your utility company for every kilowatt-hour (kWh) of electricity you use, and your rate varies significantly depending on where you live. In the Western New York region, customers pay usually 11 to 12 cents per kwh.
We base our solar system designs (how many solar panels you will need) on the past 12 months usage of your home. If the home is a new-build or you have just moved in, there is just a little more calculating we need to do with your help to come up with our projections.
These high-level production and economic analyses incorporate local electricity rate data and 30 years of local weather station data to give you a customized estimate of what you can expect to save, and just how quickly your investment will pay off.
Does your roof have southern exposure?
The ideal location for a solar panels on lightly pitched south-facing roof that doesn’t have obstructions such as a chimney, vents or antennas. East- and west-facing roofs are also a good option because they get a lot of sun in the morning and evening hours. If your only available roof area for solar panels are north-facing or you don’t have much unobstructed room for panels, then your home may not be a good candidate.
Space permitting, ground mounts may also be a viable solution. Ground mounts allow for optimal pitch and orientation for the solar array to capture the most sunlight.
Grants, Incentives, and Costs
Installation prices will vary depending on a number of factors. The type of installation choose and the equipment you choose are two large factors in price diffireciateors. Tier one modules are made by bankable companies that have been listed on Bloomberg and have been in 3 years or more. Typically these panels come standard with a 25 to 30 year production warranties carried by the manufacturer.
Between the 25% State Tax Credit, uncapped 30% Federal Investment Tax Credit, and NYSERDA (New York State Energy and Research Development Authority) grant, initial system costs can be drastically reduced by up to 60%. CIR advises all prospective buyer to confer with a tax professional to ensure how much of the State and Federal tax credits they are eligible for.
Net-Metering
A lot of customer wonder how solar works well in WNY, and the answer is simple: Net Metering. Net metering is a billing mechanism that credits customers on their utility bill with the production from their solar energy system. These credits roll over from month to month until their anniversary date which will be changed to April 1st. This method allows us to take advantage of the seasonality of WNY. Credits that you have have accumulated in June may roll over to when you have a deficit of credits in December.
The biggest installers typically don’t offer the best price
A recent report by the U.S. government found that large installers are $2,000 to $5,000 more expensive than smaller local solar companies.
For Your Business
Determining whether or not your business is a good candidate for solar depends on a few factors.
Let’s take a look on what you should look out for when qualifying your business for solar.
Own, rent, or lease?
Do you own, rent or lease the space in which your business runs out of? If you do not own the building the business operates out of, the Landlord’s permission will be needed in order to move forward with any type of solar project. If you lease or rent and you are unable to get permission from the Landlord, you may also consider opting into a Community Solar array if you are responsible for paying for your electricity.
For property owners who have land they are willing to commit to solar, a ground mounted array may be considered. Ground mounts allow for optimal pitch and orientation for the solar array to capture the most sunlight.
Flat roofs can also be considered when looking at solar for your business. A ballast mount
is a common alternative used on solar installations unable to penetrate either the roof or the ground. On low-sloped, flatter rooftops, many building owners don’t want to poke holes through the roof. Temperamental ground-mounts have some of the same concerns; solar arrays installed on top of landfill caps cannot penetrate that liner. Concrete blocks are placed throughout a project to secure an array to the ground or the roof and prevent wind lift or other movement, all without having to make any (or as many) penetrations.
How much are you paying in electric per month?
Your current electricity bill is the largest factor in determining how much you’ll save by installing solar. You pay your utility company for every kilowatt-hour (kWh) of electricity you use, and your rate varies significantly depending on where your located and how much electricity your business uses. In the Western New York region, customers pay between $0.03- $0.12/ kWh. Generally speaking, the larger the user, the lower the cost of supply. On the flip slide, once a customer reaches a certain threshold on 1-time electrical usage, they may be switched to a demand use account. These types of accounts can go back to traditional metering after a few consecutive months of lowered usage, which may come with the installation of a solar array. Demand meters can account for roughly 50% of a customer’s bills.
Businesses sometimes require a generator back up system. Depending on the equipment type, solar is able to work with existing generator systems without the use of batteries to keep costs low and return on investment high.
Incentives for Businesses to go Solar
The Federal government will provide a 30% tax credit, uncapped, on any system regardless of sizes. This offer will be decreased to 26% in 2019, 22% in 2021 and 10% for commercial systems or third-party-owned residential placed in service after 1/1/2022 and 0% for residential host-owned. Excess credits may be carried to the following five years after purchase. CIR advises business owners to confer with their tax professional to ensure that these incentives may be recaptured.
NYSERDA (New York State’s Research and Development Authority) under the umbrella of NY-Sun have designed a system of incentives to subsidize the cost of installation, making the prospect of going solar more attractive to customers. Project incentives will vary by region and current incentive rate. Incentive rates decrease as projects capacity increases.
As current capacity stands, projects under the 750 kW cap may fall under the Small Commercial and Non-residential structure subject to $0.45/watt installed. For commercial industrial projects over 200 kW, there is either a Performance Based Incentive (PBI) Monetary or Volumetric crediting method. Currently, Commercial & Industrial (C&I) incentive stands at $0.25/watt up to 7.5MW.
Qualifying solar energy equipment is eligible for a cost recovery period of five years. For equipment on which an Investment Tax Credit (ITC) grant is claimed, the owner must reduce the project’s depreciable basis by one-half the value of the 30% ITC. This means the owner is able to deduct 85 percent of his or her tax basis. “Depreciation” is the loss of value that occurs over time when the object purchased is used for a specific use. As a business owner, you are eligible to deduct this “loss in value” from your taxable income when used for your business. If you are running a profitable business, and you can show that the solar power you are generating is for business use (as opposed to personal use), then it may have a strong impact on reducing your bottom line.
Project Type
Given the space on the roof or ground, we may not always be able to cover 100% of a businesses usage. A cost-benefit analysis will be conducted to determine whether the site makes sense for solar given the businesses electrical use. Projects for businesses have a few more options when it comes to how they offset their electricity with solar.
Onsite vs. Offsite
If there is enough space on the roof or grounds of the facility, a business is most likely to have a ‘behind the meter’ project, meaning the the project is physically tied into one location and the production is fed back to the existing main service panel and excess eventually is sent to the grid. As the power is being generated by the business, not produced on the side of the grid, it is referred to as ‘behind the meter.’
If it is the case that there is not enough space onsite or that the customer owns additional land and is looking to utilize that for solar, they would most likely be a good candidate for a ‘remote net meter’ project.
Remote Net-Metering, sometimes referred to as “Virtual Net-Metering”, is an arrangement that allows for the kilowatt hours (kWh) generated from a solar system located at a specific site to be credited towards kWh consumption at a different location. The host meter is where the credits are being produced whereas the satellite meters are where the excess generation is being sent to. These accounts all have to be with the same utility and within the same utility load zone to be eligible for this type of crediting.
Community Solar
Community solar allows people to go solar even if their property does not qualify.
According to data from the National Renewable Energy Laboratory, the primary US research and development center for renewable energy, only a quarter of commercial and residential rooftops are suitable for solar panels. If that’s the case, it provides an opportunity for community solar projects to drive the initiative of shared solar energy.
What is community solar?
Community solar also known as Community Distributed Generation (CDG) is when a large solar array is built and hosted by a nearby landowner where interested customers can purchase a small percentage of the array. The array will be comprised a variety of different members.
Residential, commercial, and industrial energy users qualify to participate, renters and owners alike. All members must be located in the same utility territory where the project is located. Any member looking to patriciate must have at least an allocation of 1,000kWh annually on their electric bill.
Participating members can pre-purchase, lease, enter into a PPA to become a part of the community solar array. The members within the community array receive net metering credits from the array which are deducted from their current electric bill. Members are not required to have any physical equipment at their home or business. Everything is sent electronically via the accrued net metering credits.
In communities across the United States, people are seeking alternatives to conventional energy sources. There are 24 states and climbing that currently are participating in some sort of shared renewables program. The universality of shared renewables where the project is being pooled by investments from multiple members of a community to provide power and/or financial benefits can be seen all over the world.
How can I qualify?
Whether you aim to increase energy independence, hedge against rising fuel costs, cut carbon emissions, help increase local jobs, or are looking to community-scale renewable energy projects for solutions other than conventional energy sources, your local community can benefit too. Advances in solar technology, federal and state tax incentives, and creative new financing models have made solar projects including community solar projects, more financially feasible. We are currently seeking members for the WNY area in both National Grid and NYSEG territories. | 2023-11-30T01:26:35.434368 | https://example.com/article/8459 |
In performing various groundworking operations, if often is required to use different types tools to accomplish a particular task. The task may involve ripping or cutting a surface area and excavating, grading and compacting an area, splitting stumps and the like and excavating or raking debris and variety of other multiple operations to accomplish a particular task. Typically, it has been the conventional practice in performing such tasks to either utilize separate pieces of equipment or to change tools on a single piece of equipment which in either circumstance requires an increase in capital investment, unproductive downtime and/or increased operation costs. It thus has been desirable and the principal object of this invention to provide an attachment for a machine such as an excavator providing multiple tools capable of performing multiple operations in accomplishing a particular task.
The present invention generally provides for an excavating machine and like having a handle, operable to perform groundworking functions, consisting of an arm member pivotally connectable to the underside of the machine handle, an extendable strut pivotally connected to the arm member and pivotally connectable to the under side of the machine handle when the arm member is connected to such handle, and at least two tools, each detachably mountable on the arm member. Preferably, the extendable strut consists of a hydraulic cylinder assembly having a cylinder member pivotally connected to the machine handle and a rod member pivotally connected to the arm member when the attachment is connected to the machine handle, means intercommunicating the base and rod ends of the cylinder member, a valve disposed in the intercommunicating means, selectively operable to open the valve and prevent the free flow of fluid between the base and rod ends of the cylinder member, and correspondingly the angular displacement of the arm member relative to the handle upon maneuvering of the handle by an operator of the machine, and to close the valve and preclude the free flow of fluid between the base and rod ends of the cylinder member, and correspondingly the angular displacement of the arm member relative to the handle, and means for operating such control valve. The tools detachably mountable on the arm member are interchangeable and may include a ripping tooth, a ground compactor, circular cutter, a stump splitter, a rake and the like. Such detachably mountable tools may be operated independently or with another component of the handle such as an excavating bucket to permit multiple ground working functions in accomplishing a particular task. | 2023-12-11T01:26:35.434368 | https://example.com/article/2221 |
Background
==========
Resistance to expiratory flow is a concern for patients with obstructive lung disease. Thickening of airway walls, partial occlusion of lumen due to excessive mucus production, and airway narrowing associated with smooth muscle contraction can all contribute to increased airway resistance, which impedes expiratory flow and can lead to dynamic hyperinflation and dyspnea \[[@B1]-[@B4]\]. Previous studies have explored the hypothesis that breathing low-density helium/oxygen (He/O~2~) mixtures improves lung emptying in patients with obstructive lung disease \[[@B5]-[@B9]\]. From these investigations, coupled with analysis of the underlying respiratory fluid mechanics, it may be gathered that the potential for He/O~2~ to influence expiratory flow rates is highly dependent on the location of obstruction \[[@B5],[@B6]\]. Moving from the upper airways to the peripheral lung, as the gas Reynolds number decreases by several orders of magnitude, airway resistance becomes less influenced by flow inertia (which depends in turn on gas density) and more influenced by viscous effects \[[@B5],[@B10],[@B11]\].
In addition to their depth along the respiratory tract, airway obstructions may also vary in their severity across different airways at the same depth in the lung \[[@B12],[@B13]\]. Variation in airway resistance between lung regions leads to regional differences in ventilation, including differences in expiratory time constants. In such circumstances, end-expiratory volumes and pressures will also vary regionally \[[@B5],[@B14]\]. As noted recently by Diehl and colleagues \[[@B15]\], breathing He/O~2~ may hypothetically modify regional time constants so as to redistribute ventilation. Previously, we employed a dual chamber mechanical test lung to demonstrate that, in the presence of heterogeneous airway resistance representative of conducting airway obstruction, the ventilation distribution between chambers on inspiration was more homogeneous for He/O~2~ than for air \[[@B11]\]. In the present work, we used a similar approach to investigate the influence of He/O~2~ on expiratory flow, with attention paid to differences between the behavior of an individual, obstructed lung compartment and the lung as a whole. Additional measurements were made to assess the expiratory resistance imposed by the breathing circuit of the ventilator used to supply gas to the test lung, and these data were used as input in the development of an analytical model describing the test system.
Methods
=======
Bench experiments
-----------------
The bench apparatus was similar to that described previously by Katz et al. \[[@B11]\]. As displayed schematically in Figure [1](#F1){ref-type="fig"}, the two compartments of a dual adult test lung (Michigan Instruments, USA) were connected through a symmetric Y-piece to the patient end of a ventilator breathing circuit. Flows into and out of the compartments (Q~L~ and Q~R~) were measured using variable orifice flow sensors (PN 155362; Hamilton Medical AG, Switzerland) identical to that used by the ventilator itself to monitor the total flow (Q~TOT~). Differential pressure signals across the two compartmental flow sensors were obtained using low pressure transducers (PX277-05D5V; Omega Engineering Inc., USA) and processed using LabVIEW software (National Instruments Corp., USA) to produce flow versus time curves. Prior to the experiments, the left and right flow sensors were calibrated against known flow rates of medical air and He/O~2~ provided by a mass flow controller (EL-FLOW Select; Bronkhorst High-Tech, Netherlands). The ventilator flow sensor was calibrated with medical air or He/O~2~ prior to each experiment following the ventilator's standard calibration procedure.
{#F1}
The test lung was ventilated in volume-control mode with either dry medical air (78% N~2~/22% O~2~; Air Liquide, France) or He/O~2~ (78% He/22% O~2~; Air Liquide, France) using a Hamilton G5 ventilator (Hamilton Medical AG, Switzerland). Two breathing patterns were used: a 500 ml tidal volume at 12 breaths/min, producing a minute ventilation (V~E~) of 6 l/min, and a 1000 ml tidal volume at 20 breaths/min, producing a minute ventilation of 20 l/min. In either case, the inspiratory/expiratory ratio was ½, and flow was set as constant over the inspiratory phase (i.e., a square wave).
Parabolic resistors (PneuFlow; Michigan Instruments, USA) were placed in the two limbs of the test lung (R~L~ and R~R~). While R~L~ was held constant with an Rp5 resistor, R~R~ was varied between an Rp5, Rp20, or Rp50. These resistors obey the relationship
$$\Delta P = \frac{k}{2}\rho{\overline{U}}^{2}$$
where *ΔP* is the pressure loss across the resistor, *ρ* is the gas density, ${\overline{U}}^{}$is the gas velocity averaged over the cross-section of the entrance to the resistor, and k is a loss coefficient that, over the conditions tested, is a function of only the geometry of the resistor. Table [1](#T1){ref-type="table"} displays values of k for the parabolic resistors, along with equivalent values of the linear resistance R for air and He/O~2~ at two representative flow rates. The compliances of the left and right compartments (C~L~ and C~R~) were at all times equal to one another, but were varied between 0.02, 0.05, and 0.10 l/cm H~2~O over different experiments.
######
Loss Coefficients (k) and Equivalent Linear Resistances (R) for the Rp5, Rp20, and Rp50 Parabolic Resistors
**R\[cmH**~**2**~**OI**^**-1**^** s\]**
-------------- ------- ---------------- ----------------------------------------- -----------------
**Resistor** **k** **Q\[I/min\]** **Air** **He/O**~**2**~
Rp5 3.3 20 0.9 0.3
60 2.7 0.9
Rp20 21.5 20 5.8 2.0
60 17.5 6.1
Rp50 132.9 20 36.1 12.7
60 108.4 38.0
Finally, in order to provide input data for the analytical model, additional measurements were performed to assess the resistance imposed by the flow sensors and the expiratory limb of the breathing circuit. The pressure drop across either a single flow sensor, from inlet to outlet, or the entire expiratory circuit, from the patient end of the ventilator's proximal flow sensor through the expiratory valve, was measured using a digital manometer (PR-201; Eurolec, Ireland) over a range of steady flow rates of medical air or He/O~2~ supplied by the mass flow controller.
Calculation of time constants
-----------------------------
The single-compartment linear model of the respiratory system has been widely employed as a conceptual framework through which to discuss and explain various observed phenomena related to breathing mechanics. This model reduces the respiratory system to a single compliant compartment supplied by a single airway of a specified resistance. For the single-compartment linear model, the driving pressure across the system is given by Otis et al. \[[@B16]\]:
$$\Delta P = \frac{1}{C}V + RQ$$
where Δ*P* is the driving pressure, *V* is the volume of the compartment, *Q* is the volumetric flow rate into or out of the system, and *R* and *C* are constants representing, respectively, the resistance and compliance of the system. The resistance is specified as the pressure drop across the airway per unit flow rate, whereas the compliance is the change in compartment volume per unit pressure.
For a single-compartment linear model of the respiratory system, the time-dependence of the expiratory flow rate can be described as purely monoexponential \[[@B17]\]:
$$Q_{e}\left( t \right) = Q_{e,p}e^{\frac{- t}{\tau}}$$
where *Q*~*e*~(*t*) is the expiratory flow rate at time *t*, *Q*~*e,p*~ is the peak expiratory flow rate, and the time constant:
$$\tau = RC$$
is the product of the resistance and compliance of the system. This time constant also describes the time-dependence of the volume response of such as system:
$$V_{e}\left( t \right) = \tau Q_{e,p}\left( {1 - e^{\frac{- t}{\tau}}} \right)$$
where *V*~*e*~(*t*) is the exhaled volume at time t.
In the present work, a two-compartment model with non-linear resistance was employed, for which expiratory flow did not follow the idealized exponential form of Equation 3. Nevertheless, *apparent*, or representative, time constants were calculated for each compartment, and for the test lung as a whole, following the iterative method described by Brunner et al. \[[@B18]\]. Equation (5) can be evaluated at the end of expiration and rearranged to yield:
$$\tau = \frac{V_{e,tot}}{Q_{e,p}}\left( {1 - e^{\frac{- t_{e}}{\tau}}} \right)^{- 1}$$
where *V*~*e,tot*~ is the total exhaled volume, and *t*~*e*~ is the exhalation time.
Equation (6) is an implicit equation for the time constant, which was solved iteratively with an initial estimate of:
$$\tau_{0} = \frac{V_{e,tot}}{Q_{e,p}}$$
followed by iterations of the form:
$$\tau^{k + 1} = \tau_{0}\left( {1 - e^{- t_{e}/\tau^{k}}} \right)^{- 1}$$
The solution described in Equations (7) and (8) was implemented in Microsoft Excel, with input values of *V*~*e,tot*~, *Q*~*e,p*~, and *t*~*e*~ obtained from flow versus time data acquired for each compartment, and the whole lung, as described above. It was found that the time constant calculated in this manner typically varied between iterations by less than 1% after no more than 3 or 4 iterations.
Under the controlled experimental conditions described above, there was only very small variation in the calculated time constant between repetitions performed with all parameters held constant; therefore, for the experimental time constants reported below, uncertainty in measurement was estimated as the maximum difference between values determined for the right and left compartment when an Rp5 was inserted in both limbs (in which cases the time constants for the left and right compartments should ideally have been identical, and differences were attributed mainly to experimental uncertainties in the set left and right chamber compliances).
Analytical model
----------------
In contrast to the idealized single-compartment linear model, a closed form solution of exhalation for the two-compartment lung model with nonlinear resistance is not possible. Therefore, the problem was solved numerically using MATLAB (Mathworks, United States). The analysis followed the engineering pressure loss model presented previously by Katz et al. \[[@B11]\], where in the present case the energy balance was made between each chamber and the atmosphere after accounting for losses through the complete expiratory path including the parabolic resistors, flow meters, Y-piece, breathing circuit, and the ventilator's expiratory valve (Figure [1](#F1){ref-type="fig"}). Accordingly, with the atmospheric pressure equal to zero, the governing equation for either the left or right chamber was:
$$\frac{P_{i}}{\rho} = \frac{V_{i}}{\rho C_{i}} = \frac{\left( {k_{i} + k_{\mathit{fs}}} \right)}{2}\left( \frac{Q_{i}}{A} \right)^{2} + \frac{k_{\mathit{cct}}}{2}\left( \frac{Q_{i} + Q_{j}}{A} \right)^{2}$$
where the subscript *i* indicates the left or right chamber, the subscript *j* indicates the opposite chamber, *P* is the chamber pressure, *V* is the volume of gas in the chamber, *C* is the chamber compliance, *Q* is the volumetric flow rate out of the chamber, *A* is the cross-sectional area of the airway, and *k*~*i*~, *k*~*fs*~, and *k*~*cct*~ represent loss coefficients for the parabolic resistor, the flow sensor, and the expiratory circuit, respectively. Of note, unlike the loss coefficients for the parabolic resistors provided in Table [1](#T1){ref-type="table"}, loss coefficients for the flow sensors and expiratory limb of the breathing circuit depended on gas density and flow rate. Therefore, the measurements described above in Section 2.1 for the resistances imposed by these components were fit with second order polynomials for use in the analytical model.
Equation (9) was solved for either chamber with the initial chamber volume and pressure at the start of exhalation calculated using the inhalation model of Katz et al. \[[@B11]\]. The analysis consisted of a quasi-steady solution for the flow rates at each time step, progressing until the expiratory time limit was reached. Time constants for the left and right chambers were again determined according to equations (7) and (8), in this case using the peak flow and exhaled volume determined by the model.
Results and discussion
======================
Time constants determined experimentally
----------------------------------------
For each set of experimental conditions, expiratory time constants were determined for the left and right chambers of the test lung from measured expiratory flow versus time data. In addition, a whole-lung time constant was determined from the total expiratory flow out of the test lung. Figures [2](#F2){ref-type="fig"} and [3](#F3){ref-type="fig"} display, for the two breathing patterns studied, changes in compartmental and whole lung time constants as the right chamber was increasingly obstructed. For a given breathing pattern and gas, the time constant of the right chamber increased as the severity of obstruction in the right branch of the test lung was increased. However, the increase in the whole lung time constant was much less pronounced, and coincided with a slight decrease in the time constant of the left chamber. The latter effect was unexpected, but we speculate that it resulted from the pendelluft phenomenon described by Otis et al. \[[@B16]\]. As the severity of obstruction in the right lung increased, cycling between inspiration and expiration in the right and left compartments was observed to become increasingly out of phase, such that the relatively unobstructed left lung began to expire gas while the right lung was still inspiring. This presented a flow path (from the left to the right compartment) for a small portion of gas expired from the left lung that had lower resistance than the normal flow path through the ventilator's expiratory circuitry, and therefore may explain the influence of right chamber obstruction on left chamber time constants observed in Figures [2](#F2){ref-type="fig"} and [3](#F3){ref-type="fig"}.
{#F2}
{#F3}
Comparing Figure [2](#F2){ref-type="fig"} and Figure [3](#F3){ref-type="fig"} further, it is clear that, all else being equal, measured time constants were greater at higher minute ventilation, and lower for He/O~2~ than for air. The former effect is no doubt due to the flow-dependence of resistance exhibited by the parabolic resistors used in the present study, as evidenced above in Table [1](#T1){ref-type="table"}. Regarding the effect of He/O~2~, the pressure drop across these resistors results from phenomena that are inertial in nature, and therefore density-dependant \[[@B11]\]. By substituting He/O~2~ in place of air, the low density of the mixture reduces resistance, in turn reducing expiratory time constants. The applicability of these results to the human respiratory tract, where airway resistance contains both inertial and viscous components, will clearly depend on the nature and severity of airway disease, with obstructions occurring in more proximal airways favoring inertial effects, and those in the distal airways favoring viscous effects. However, as discussed below, it should be noted that the resistances imposed by healthy, conducting airways, and by common components of external breathing circuits, are both flow- and density-dependent.
The relative effects of breathing pattern and gas density on expiratory time constants are further explored in Figure [4](#F4){ref-type="fig"}, in which the time constant of the right chamber is plotted against varying chamber compliance. As both the loss coefficient and the compliance of the two chambers were equal during these measurements, no heterogeneity in ventilation between the two chambers was observed, and the reported right chamber time constants are also representative of the left chamber and whole lung time constants. Referring again to Figure [4](#F4){ref-type="fig"}, for a given breathing pattern and gas, the time constant increased linearly, or close to linearly, with compliance. Furthermore, despite the fact that these measurements were made with relatively low resistance (one Rp5, representative of healthy airways \[[@B11]\]), time constants were still strongly affected by the breathing pattern and gas density. This is in part a reflection of the added flow- and density-dependent resistance imposed by the breathing circuit, as will be discussed in the following section. However, even when resistance is small, a further reduction caused by decreasing flow rates or decreasing gas density can have a strong influence on the time constant because the time constant arises from the multiplicative influences of resistance and compliance (as in Equation 4 for the idealized single compartment linear model). That is to say, time constants that become large due to loss of pulmonary elasticity that increases compliance (e.g. caused by emphysema) may be reduced by decreasing airway resistance, thereby facilitating lung emptying during exhalation. Given that the resistance of normal, healthy airways is density-dependant \[[@B11],[@B19]\], breathing He/O~2~ may, rather counter-intuitively, improve expiratory flows in cases where elasticity is reduced, but airway resistance is essentially normal. It is also worth noting that the compliances of the left and right chambers were kept equal to one another throughout the present experiments, whereas variation in compliance between lung regions is not uncommon in obstructed patients. While the arguments made above are expected to hold on the regional or compartmental level, heterogeneity in compliance has not been directly studied here.
{#F4}
Finally, the measured right, left, and whole lung time constants across the full range of experimental parameters studied are plotted in Figure [5](#F5){ref-type="fig"} against the expiratory time constant (RC) reported by the ventilator, which is calculated by the ventilator used in the present study as the ratio between the expiratory tidal volume and the expiratory flow rate at 75% of the tidal volume \[[@B20]\]. While the time constant reported by the ventilator is in reasonable agreement with those of the left chamber and the whole lung, it is poorly correlated with the time constant of the right (obstructed) chamber. This result is anticipated given that the ventilator is designed to monitor the total flow into and out of the lung. As the right chamber became more and more obstructed, it received a smaller and smaller fraction of the total tidal volume, and therefore its behavior had increasingly little influence on flows measured at the central airway. Accordingly, changes to the time constant, and associated end-expiratory gas trapping, of poorly ventilated lung compartments may go unnoticed when monitoring flows at the ventilator level. This is similar to the findings of Kurahashi et al. \[[@B14]\], who concluded that the intrinsic positive end-expiratory pressure (PEEPi) of an individual lung compartment can be much greater than that measured at the central airway. In such circumstances, potential effects of He/O~2~ on ventilation heterogeneity are difficult to assess in the clinic. While efforts have been made using the ratio of dynamic to static intrinsic PEEP as an indicator of heterogeneity, this ratio is influenced both by regional variation in time constants and by viscoelastic relaxation of tissue, such that the relative contribution of either factor is not clear \[[@B15]\].
{#F5}
Resistance imposed by the external breathing circuit
----------------------------------------------------
Figures [6](#F6){ref-type="fig"}a and [6](#F6){ref-type="fig"}b show the pressure drop measured across the flow sensor, and across the total expiratory circuit (including the flow sensor), as a function of flow rate of air or He/O~2~, respectively. For comparison, the pressure-flow relationships for the Rp5, Rp20, and Rp50 resistors are also indicated for both gases. The expiratory circuit consisted of the ventilator flow sensor, y-piece, standard 22 mm tubing, and an expiratory valve. Pressure losses across this circuit were dominated by the flow sensor and the expiratory valve. For both these components, the gas passageway grows larger with increasing flow rate (though for the expiratory valve PEEP applied by the ventilator can have an opposing effect), so that the increase in pressure drop with flow is less pronounced than for the rigid parabolic resistors. Nevertheless, as indicated in Figure [7](#F7){ref-type="fig"}, the pressure losses across both the flow sensor and the expiratory circuit taken as a whole remain dominated by inertial effects, and therefore vary with gas density and with the square of the flow rate. Such a result indicates that the resistance imposed by the breathing circuit at a given expiratory flow rate will be reduced with He/O~2~ compared to air. This reduction would be even more significant with the inclusion of an endotracheal tube for invasive ventilation, as the endotracheal tube would impose an additional flow- and density-dependent resistance \[[@B21]-[@B23]\].
{#F6}
{#F7}
Comparison with analytical model
--------------------------------
Figure [8](#F8){ref-type="fig"} compares regional time constants predicted analytically for the left and right chambers with those measured experimentally, in both cases following the solution described in Equations (7) and (8). As seen, a reasonable correlation was found between the predicted and measured values. This is an encouraging result, as future versions of the model could include features such as additional lung compartments (e.g., 5 lobes), mixed viscous-inertial airway resistance, and volume-dependant lung compliance that are pertinent to lung mechanics but are more difficult to implement using a mechanical test system. For example, we have previously reported on the extension of the engineering pressure loss model to a multi-generation airway tree by incorporating generation-specific loss coefficients derived from computational fluid dynamics simulation \[[@B11]\]. Further, it is important to note that the present experiments were conducted with dry, room temperature, normoxic gases, whereas gases administered in the clinic are regularly heated and humidified, and often delivered at higher oxygen concentration. While temperature and humidity will have only small influence on gas properties, increasing the oxygen concentration in a He/O~2~ mixture will of course strongly influence its properties \[[@B24]\]. In contrast to repeated experiments on the bench, mathematical modeling offers the potential to rapidly estimate the influence of gas properties on ventilation across a large range of mixture concentrations.
{#F8}
Differences between predicted and measured time constants observed in Figure [8](#F8){ref-type="fig"} may be attributed in part to the omission of inertia and friction of the test lung components (e.g. bellows, chamber top plates, hinges) in the model. This can be observed in the curves displayed in Figure [9](#F9){ref-type="fig"}, where, for example, cycling between inspiratory and expiratory phases is instantaneous for the model, but comparatively delayed for the experiments. Also, for many cases with longer experimental time constants, expiratory flow behavior was clearly not well described by a single exponential function. The case displayed in Figure [9](#F9){ref-type="fig"}d serves as an example. The modeled and experimental time constants were 0.74 and 1.27 s, respectively. In this case, the experimental curve in particular differs considerably from a single exponential function, to the extent that one might question the applicability of describing such an irregular expiratory curve using a single time constant, at least when determined following the methodology employed herein. Here, it is best to consider the calculated time constant as an index related to expiratory flow from the lung compartment rather than as a mathematical parameter that precisely describes the flow behavior.
{#F9}
Conclusions
===========
In summary, where inertial phenomena contribute to airway resistance, He/O~2~ reduces expiratory time constants compared to air. Regional variation in resistance leads to regional variation in expiratory flow, and the behavior of obstructed lung compartments has only minor influence on the time constant derived from flow data collected by the ventilator. Accordingly, such measurements may not permit a full appreciation of the effects of He/O~2~ on regional lung ventilation. Finally, results of experiments performed using a mechanical test lung were reproduced by a mathematical model that can be readily extended to include further physiological and pathophysiological phenomena pertinent to the assessment of He/O~2~ therapy for specific diseases and phenotypes.
Competing interests
===================
All authors are present or past employees of Air Liquide, which has conducted and is presently conducting clinical trials to evaluate helium/oxygen therapies.
Authors' contributions
======================
AM conceived of the experimental study, participated in its design, carried out analysis of experimental and analytical data, and drafted the manuscript. IK participated in the design of the study, conceived of and participated in the development of the analytical model, carried out analysis of experimental and analytical data, and edited the manuscript. KT participated in the experimental study design and conducted the experiments. LG participated in the development of the analytical model, and carried out the calculations. GC participated in the design of the study. JT participated in the design of the study and edited the manuscript.
| 2024-01-18T01:26:35.434368 | https://example.com/article/4934 |
226 F.2d 100
THE DALLES CITY, a municipal corporation, Appellant,v.RIVER TERMINALS COMPANY, Appellee.
No. 14287.
United States Court of Appeals Ninth Circuit.
Sept. 21, 1955.
Phillips, Coughlin, Buell & Phillips, James K. Buell, Portland, Or., Charles A. Phipps, Phipps & Phipps, The Dalles, Or., for appellant.
Harold E. Patterson, Hickson & Dent, Portland, Or., for appellee.
Before STEPHENS, HEALY and POPE, Circuit Judges.
POPE, Circuit Judge.
1
The Dalles City, although a municipal corporation of the State of Oregon, owned and operated a municipal airport across the Columbia River at Dallesport, Washington, as the Oregon law permitted it to do. The City made a lease to S & M Flying Service, a corporation, whereby it leased and let to the latter the privilege of using the airport in common with others, and also the exclusive use of the hangar and shop buildings on the airport grounds. The appellee River Terminals Company, plaintiff below, made an arrangement with S & M Flying Service, whereby the latter agreed to store an airplane belonging to plaintiff within the hangar building in the possession of the Flying Service. This airplane was in that hangar during the month of January, 1950, when a very heavy snowfall occurred piling snow to a considerable depth upon the roof of the hangar building.
2
The lease to the Flying Service contained the following provision: 'The Lessor reserves the right, but shall not be obligated to the Lessee, to maintain and keep in repair the landing area of the airport and all publicly owned facilities of the airport, together with the right to direct and control all activities of the Lessee in this regard.'
3
DeWald, airport manager employed by the City, and Moore, president of Flying Service, were in conference each day following the heavy snowfall with respect to the snow conditions. The president testified: 'Mr. DeWald and I were inside of the building on the 19th and looked for any signs of disturbances that might indicate to us any danger and we decided that there was none and went on about our other work.' He also testified: 'Q. Did you ever ask him to take the matter up with the City Engineer? A. No. We didn't feel that there was any danger at that time. That was the purpose of our discussion-- that was the outcome of our discussion that we didn't feel that there was any immediate danger then.'
4
The roof of the hangar in which the airplane was stored collapsed on January 20, 1950, and damaged the plaintiff's plane. This collapse was due to the weight of the snow upon the roof. Plaintiff's expert witness, an architect, testified that in his opinion the collapse came about because the snow load upon the roof was uneven in that the weight was more heavy on some portions of the roof than upon others. This the witness called 'eccentric loading', which in his opinion caused a strain for which the roof was not designed.
5
The plaintiff brought this action against both the S & M Flying Service and the City to recover the damages to its airplane. The cause was tried to the court sitting without a jury and judgment was granted against both defendants. The City appeals and here urges among other things the contention made by it in the court below stated in the pretrial order as follows: 'Defendant The Dalles City contends that the admitted facts and the statement of factual contentions contained in the foregoing pre-trial order are not sufficient to constitute a cause of action against this defendant for the reason that plaintiff has not shown any duty on the part of this defendant toward plaintiff or its property and for the further reason that the admitted facts affirmatively disclose that this defendant owed no affirmative duty toward plaintiff or its property.'
6
The point so made and again urged upon this appeal is well taken. The ordinary rule is that where premises are let to a tenant the landlord owes no general duty of repair. Clarke v. Yukon Inv. Co., 83 Wash. 485, 487, 145 P. 624, 625; Miles v. Spokane P. & S. Railway Co., 176 Or. 118, 126, 155 F.2d 938, 941. Here in the paragraph of the lease quoted above, the City reserves the right to intervene and repair, but it assumed no duty to do so, and hence, the day before the accident, it was in the position of the ordinary landlord. All that the City did thereafter was through the action of its airport manager as above noted in going inside the building and looking for signs of disturbances indicating danger. The only testimony upon this matter was as shown in the portions quoted above.
7
The grounds on which the trial court held the City liable are set forth in the court's opinion, as follows: 'I find the defendant, The Dalles City, liable because, shortly before the roof collapsed, one of its employees made an examination of the hangar and particularly the roof. Therefore, even though The City was not required, under its lease, to exercise control over the facilities on the airfield, it in fact did so. Having done so, its conduct in failing to order the snow removed or take other precautions constituted negligence.' It is plain that the district court thought that this was a case for the application of the general rule that one who although not under legal obligation to repair, nevertheless undertakes to make repairs and then fails to exercise ordinary care in that undertaking, becomes responsible for the results of his negligence. Generally the law distinguishes between the failure or refusal of the landlord to do what he has not promised to do or is not legally bound to do and his doing it in a negligent manner.1 While the rule which the trial court undertook to apply has wide and general application,2 we think that it would not extend so far as to attach liability to a landlord who did no more than inspect a building. Here, where the lessor reserved the right to make repairs, while expressly negativing any obligation to do so, it must be conceded that the landlord had the right merely to look at the premises for the purpose of seeing whether it would or would not choose to make repairs. Cf. Nash v. Goritson, 174 Or. 368, 372, 149 P.2d 325, 326. The City had the absolute right to 'have a look' without thereupon assuming a larger duty.
8
For that reason the judgment made and entered against The Dalles City must be reversed, and it is so ordered.
9
HEALY, Circuit Judge (dissenting).
10
In my opinion the evidence supports the trial court's finding relative to the City's exercise of its reserved right of control over the airfield facilities. Accordingly, I would affirm the judgment.
1
This distinction has sometimes been referred to as a distinction between 'nonfeasance' and 'misfeasance'. See also Prosser on Torts, p. 195
2
'Notwithstanding that plaintiff was not legally bound to repair the roof, yet, having undertaken so to do, he is liable for the damage sustained on account of a failure to make said repairs in a proper and skillful manner. The principle that governs in such cases being that, although the landlord is not bound to repair in the absence of an express covenant to repair, where no controlling statute interferes, and though his promise to repair, made subsequent to the execution of the lease, is without consideration, and hence is unenforceable, yet if he shall voluntarily and gratuitously undertake, during the term, to repair the demised premises, he is bound in so doing to use ordinary care and diligence. He may be held responsible for his negligence or lack of care and skill, or the negligence of his servants, or those employed by him in doing what, in the first instance, he was not bound to do. The distinction is made by the authorities between nonfeasance and misfeasance of the landlord. In other words, the law distinguishes between the failure or refusal of the landlord to do what he has not promised to do, or is not legally bound to do, and his doing it in a negligent manner. But if the landlord voluntarily repairs and actually enters upon the carrying out of his scheme of repair, he will be responsible for the want of due care in the execution of the work, upon the principle of liability for negligence, without reference to any question of implied contract to repair, or implied consideration.' Horton v. Early, 39 Okl. 99, 134 P. 436, 438, 47 L.R.A., N.S., 314
| 2024-01-28T01:26:35.434368 | https://example.com/article/2790 |
Mehmed IV
Mehmed IV (Ottoman Turkish: محمد رابع Meḥmed-i rābiʿ; Modern Turkish: IV. Mehmet; also known as Avcı Mehmet, Mehmed the Hunter; 2 January 1642 – 6 January 1693) was the Sultan of the Ottoman Empire from 1648 to 1687. He came to the throne at the age of six after his father was overthrown in a coup. Mehmed went on to become the second longest reigning sultan in Ottoman history after Suleiman the Magnificent. While the first and last years of his reign were characterized by military defeat and political instability, during his middle years he oversaw the revival of the empire's fortunes associated with the Köprülü era. Mehmed IV was known by contemporaries as a particularly pious ruler, and was referred to as gazi, or "holy warrior" for his role in the many conquests carried out during his long reign.
Under his reign the empire reached the height of its territorial expansion in Europe. From a young age he developed a keen interest in hunting, for which he is known as avcı (translated as "the Hunter"). In 1687 Mehmed was overthrown by soldiers disenchanted by the course of the ongoing War of the Holy League. He subsequently retired to Edirne, where he resided until his natural death in 1693.
Biography
Early life
Born at Topkapı Palace, Constantinople, in 1642, Mehmed was the son of Sultan Ibrahim (r. 1640–48) by Turhan Sultan, a concubine of Ukrainian origin, and the grandson of Kösem Sultan of Greek origin. Soon after his birth, his father and mother quarreled, and Ibrahim was so enraged that he tore Mehmed from his mother's arms and flung the infant into a cistern. Mehmed was rescued by the harem servants. However, this left Mehmed with a lifelong scar on his head.
Mehmed ascended to the throne in 1648 at the age of six, during a very volatile time for the Ottoman dynasty. On 21 October 1649, Mehmed along with his brothers Suleiman and Ahmed were circumcised. The empire faced palace intrigues as well as uprisings in Anatolia, the defeat of the Ottoman navy by the Venetians outside the Dardanelles, and food shortages leading to riots in Constantinople. It was under these circumstances that Mehmed's mother granted Köprülü Mehmed Pasha full executive powers as Grand Vizier. Köprülü took office on 14 September 1656. Mehmed IV presided over the Köprülü era, an exceptionally stable period of Ottoman history. Mehmed is known as Avcı, "the Hunter", as this outdoor exercise took up much of his time.
Reign
Mehmed's reign is notable for a revival of Ottoman fortunes led by the Grand Vizier Köprülü Mehmed and his son Fazıl Ahmed. They regained the Aegean islands from Venice, and Crete, during the Cretan War (1645–1669). They also fought successful campaigns against Transylvania (1660) and Poland (1670–1674). When Mehmed IV accepted the vassalage of Petro Doroshenko, Ottoman rule extended into Podolia and Right-bank Ukraine. His next vizier, Köprülü Mehmed's adopted son Merzifonlu Kara Mustafa, led campaigns against Russia, conquering Chyhyryn in 1678. He next supported the 1683 Hungarian uprising of Imre Thököly against Austrian rule, marching a vast army through Hungary and besieged Vienna. At the Battle of Vienna on the Kahlenberg Heights, the Ottomans suffered a catastrophic rout by Polish-Lithuanian forces famously led by King John III Sobieski (1674–96), and his allies, notably the Imperial army.
In 1672 and 1673, the sultan, who embarked on two Polish campaigns with serdar-ı ekrem and Grand Vizier Fazıl Ahmed Pasha, and the acquisition of the Kamaniçi Castle, returned to Edirne after the signing of the Bucaş Treaty.
Fire of 1660
The fire that spread from Unkapanı to Süleymaniye in the fire that broke out at the Ayazma gate in Istanbul on 4 July 1660, turned the city into a destiny. 2700 people died. 120 palaces and mansions, 100 cellars, 360 mosques, 40 baths. The house burned down with madrasahs, inns, hankah and thousands. After the fire, a famine and plague epidemic started in the city.
Great Turkish War
On 12 September 1683 the Austrians and their Polish allies under King John III Sobieski won the Battle of Vienna with a devastating flank attack led by Sobieski's Polish cavalry. The Turks retreated into Hungary, however this was only the beginning of the Great Turkish War, as the armies of the Holy League began their successful campaign to push the Ottomans back to the Balkans.
Later life and death
In May 1675 his sons Mustafa II and Ahmed III were circumcised and her daughter Hatice Sultan was married. The empire celebrated it with Famous Edirne Festival to mark the occasion. Silahdar Findikli Mehmed Aga, He described Mehmed as a medium-sized, stocky, white-skinned, sun-burnt face, sparse beard, leaning forward from the waist up because he rides a lot.
After the second Battle of Mohács (1687), the Ottoman Empire fell into deep crisis. There was a mutiny among the Ottoman troops. The commander and Grand Vizier, Sarı Süleyman Pasha, became frightened that he would be killed by his own troops and fled from his command, first to Belgrade and then to Istanbul. When the news of the defeat and the mutiny arrived in Istanbul in early September, Abaza Siyavuş Pasha was appointed as the commander and soon afterward as the Grand Vizier. However, before he could take over his command, the whole Ottoman Army had disintegrated and the Ottoman household troops (Janissaries and sipahis) started to return to their base in Istanbul under their own lower-rank officers. Sarı Süleyman Pasha was executed, and Sultan Mehmed IV appointed the commander of Istanbul Straits, Köprülü Fazıl Mustafa Pasha, as the Grand Vizier's regent in Istanbul. Fazıl Mustafa made consultations with the leaders of the army that existed and the other leading Ottoman statesmen.
After these, on 8 November 1687 it was decided to depose Sultan Mehmed IV and to enthrone his brother Suleiman II as the new Sultan. Mehmed was deposed by the combined forces of Yeğen Osman and the Janissaries. Mehmed was then imprisoned in Topkapı Palace. However, he was permitted to leave the Palace from time to time, as he died in Edirne Palace in 1693. He was buried in Turhan Sultan's tomb, near his mother's mosque in Constantinople. In 1691, a couple of years before his death, a plot was discovered in which the senior clerics of the empire planned to reinstate Mehmed on the throne in response to the ill health and imminent death of his successor, Suleiman II.
His favourite harem girl was Gülnuş Sultan, a slave girl and later his wife. She was taken prisoner at Rethymno (Turkish Resmo) on the island of Crete. Their two sons, Mustafa II and Ahmed III, became Ottoman Sultans during 1695–1703 and 1703–1730 respectively.
Family
Consorts
Mehmed had two consorts:
Gülnuş Sultan;
Afife Kadın;
Sons
Mustafa II (6 February 1664 – 30 December 1703) – son with Gülnuş Sultan;
Ahmed III (30 December 1673 – 1 July 1736) – son with Gülnuş Sultan;
Şehzade Bayezid (15 December 1678 – 18 December 1678, buried in Sultan Mustafa I Mausoleum, Hagia Sophia);
Daughters
Hatice Sultan (1668 – Edirne, 5 July 1743, buried in New Mosque, Istanbul), daughter with Gülnuş Sultan, married firstly on 9 July 1675 to Musahip Mustafa Pasha, married secondly on 13 March 1691 to Moralı Hasan Pasha;
Fatma Sultan (1672 – Eyüp Palace, 5 December 1700, buried in New Mosque, Istanbul), daughter with Gülnuş Sultan, married firstly on 9 July 1675 to Kara Mustafa Pasha, married secondly on 19 January 1696 to Tırnakçı Çerkes Ibrahim Pasha, married thirdly to Vezir Mısırlı Mehmed Pasha;
Ümmi Sultan (died of smallpox, 21 December 1700, buried in New Mosque, Istanbul), married on 13 January 1694 in the Edirne Palace to Silahdar Çerkes Osman Pasha;
See also
Transformation of the Ottoman Empire
Köprülü era
Great Turkish War
Kösem Sultan
Çınar incident
Notes
References
External links
[aged 51]
Category:1642 births
Category:1693 deaths
Category:Modern child rulers
Category:Ottoman people of the Great Turkish War
Category:People of the Ottoman Empire of Ukrainian descent
Category:17th-century Ottoman sultans
Category:Turks of the Ottoman Empire
Category:Custodian of the Two Holy Mosques
Category:Ottoman dynasty | 2024-05-13T01:26:35.434368 | https://example.com/article/9973 |
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| 2023-08-09T01:26:35.434368 | https://example.com/article/3662 |
Image copyright Reuters Image caption The choreographed New Year display actually happened a few days earlier
A spectacular drone display in Shanghai to mark the start of the new year did not actually happen at New Year, it has emerged.
The display of thousands of drones flying in formation over the city was widely covered by global media.
But people who were at the event on New Year's Eve have said they saw nothing.
The company behind the display has confirmed to the BBC that the footage broadcast around the world was actually from a practice run on 28 December.
Footage of the impressive display was released to the world's media by China's state-run media.
It shows 2,000 drones taking off against the dramatic skyline of Shanghai's Pudong district, then creating firework shapes, an animated running man figures and then spelling out 2020 and Chinese characters in the sky.
The video was picked up by the world's media and widely hailed as a futuristic and low-pollution alternative to traditional fireworks.
But as local English news site The Shanghaiist reported, people who were watching from the riverside area The Bund across from Pudong "say they didn't see anything in the night sky. No drones. No nothing".
"This blows my mind because it's 100% Chinese fake news. We stood outside last night for a show that never happened," one person, Patrick Cox, said on Twitter.
Shanghaiist noted that one video posted on 29 December appeared to show exactly the same display.
One video purportedly of midnight on New Year's Eve shows the lights over the Pudong district going out, only to come back on again a few moments later with no drones appearing.
The BBC contacted the company behind the display, Yihang Bailu, whose media manager admitted that it was filmed on 28 December.
The manager said it had been arranged by local TV station Shanghai Dragon Television "to ensure the global live broadcasting effect".
It also emerged that local authorities had also posted on their official social media accounts on 30 December that there would be "no New Year Eve celebration activity" on The Bund this year.
Media playback is unsupported on your device Media caption New Year Fireworks: The world welcomes 2020
However some people appeared not to mind that the Shanghai footage was not entirely as advertised.
Comments defending the move on the China's CCTV news agency's YouTube page said it did not matter when it took place, it was still an impressive show.
Others said it was a responsible move, to prevent possible injuries or overcrowding.
Shanghai has held muted New Year events ever since a stampede in 2014 left nearly 40 people dead in crushes.
Pre-recording highly choreographed drones is not entirely new.
In 2018, it was confirmed that TV viewers of the opening ceremony of the Winter Olympics in South Korea were shown a "secretly pre-recorded" drone display, because of the risk of freezing weather and winds causing disruption on the night.
And a dramatic sequence of fireworks crossing Beijing like footsteps during the 2008 Olympics was also faked for TV audiences. | 2024-02-29T01:26:35.434368 | https://example.com/article/8903 |
In interview, Trump contradicts Pence on Comey Pence has said this week that Trump fired the FBI director following the recommendation of the DOJ, but the president himself said Thursday that wasn't the case.
Vice President Mike Pence has once again delivered the White House line, in the face of growing contradictory evidence, on a charged topic related to Russia’s possible connections to the Trump campaign.
In meetings on Capitol Hill and in interviews, Pence has said this week that Trump fired FBI Director James Comey on the recommendation of Deputy Attorney General Rod Rosenstein.
“Let me be very clear that the president’s decision to accept the recommendation of the deputy attorney general and the attorney general to remove Director Comey as the head of the FBI was based solely and exclusively on his commitment to the best interests of the American people and to ensuring that the FBI has the trust and confidence of the people this nation,” Pence told reporters Wednesday.
But Trump said in an interview with NBC on Thursday that he’d planned to fire Comey no matter what Rosenstein told him. “I was gonna fire regardless of recommendation,” Trump told Lester Holt. “Regardless of recommendation I was going to fire Comey.”
People close to the White House say Pence knew the president was thinking about firing Comey before he met with Rosenstein on Monday. Trump, these people said, was frustrated with Comey’s testimony and the growing Russia investigation scrutiny into his campaign. He also disliked Comey’s testimony last week on Capitol Hill, particularly the FBI director’s use of the word “nauseous” to describe his reaction to the idea that he may have influenced the election.
Pence, who hasn't assumed the traditional role of power player in the White House but is liked by many, signaled support for the decision, said one adviser to the president.
“Pence knew this wasn’t about Rosenstein writing a memo, the president seeing it and suddenly deciding to fire Comey,” said this person. “He knows better than that.”
Pence allies on Wednesday said the vice president was merely pointing to the factual turn of events: Rosenstein sent a memo on Tuesday recommending Comey’s dismissal, Attorney General Jeff Sessions seconded the opinion and Trump made the move. Pence had not specifically addressed who initiated the whole process, one noted.
“As any new manager would come in, you’re going to review the operations,” said Pence press secretary Marc Lotter.
On Thursday, Lotter acknowledged that Pence may have been privy to previous conversations about Trump’s desire to fire Comey.
“He meets with the president, consults with the president, multiple times a day,” Lotter told POLITICO. His involvement on the Comey issue was “no different,” he said.
“I’m not going to get into the timeline,” Lotter said, when asked when Pence was made aware of the president’s decision.
But Lotter defended the remarks Pence gave on Wednesday.
“The vice president and the White House laid out how the actions took place,” he said. “And the vice president was speaking yesterday to the events that led to the president’s decision.”
Breaking News Alerts Get breaking news when it happens — in your inbox. Email Sign Up By signing up you agree to receive email newsletters or alerts from POLITICO. You can unsubscribe at any time. This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
The firing again put the mild-mannered vice president in a difficult position of defending the president amid uncomfortable facts and fallout. Pence, who often wears his Christian faith on his sleeve and has said he doesn’t drink around women unless his wife is present, had to defend Trump after the president said he grabbed women by the genitals.
In February, Pence assured the American people that, contrary to news reports, national security adviser Michael Flynn had not discussed sanctions during phone calls with Russian Ambassador Sergey Kislyak during the transition. The White House said Flynn was fired for misleading Pence. | 2023-08-24T01:26:35.434368 | https://example.com/article/2134 |
Independent game-makers are hoping to inundate Apple's App Store with "candy" games in a demonstration against Candy Crush Saga-maker King for its trademark of the word CANDY.
In a rather pointed protest, the developers have launched a game jam to try to get as many app-makers as possible to come up with games using candy, with the word CANDY in the title - with bonus points for using words like SAGA and APPLE.
The "Candy Jam" says it is mounting the protest against King "because trademarking common words is ridiculous, because ethics matter and because it gives us an occasion to make another game jam", according to its website.
The jam has had 113 games submitted so far, with titles like Super Candy Handy Mandy Saga and The Candy Apple Crusher Saga.
King's trademark of the word CANDY in Europe and its pursuit of the same trademark in the US and trademarks on SAGA have been met with outrage and derision. One of the first developers to feel King's wrath was Benny Hsu, whose game All Candy Casino Slots - Jewels Craze Connect: Big Blast Mania Land was listed in the App Store as Candy Slots.
Although the app had only been out for around a week and Hsu insists gameplay is different, it was pulled off the store when King complained about the name. King claimed that Hsu was intentionally stepping on its toes.
"We don't enforce against all uses of CANDY - some are legitimate and of course, we would not ask app developers who use the term legitimately to stop doing so," the firm said last week.
"We believe this app name was a calculated attempt to use other companies' intellectual property to enhance its own games through means such as search rankings."
But Hsu told The Reg that he had never wanted there to be any confusion.
"My intent was not to infringe their intellectual property," he said. "Candy is something we have all loved since we were children. I just wanted to create a game with a fun theme.
"If anyone saw my icon or played my game, they would know that there was nothing in it that tried to copy Candy Crush. Also there are so many games in the App Store that have a candy theme. Candy Crush was not the first candy-themed game to be created and it won't be the last. So I don't understand why they feel like they own the word CANDY."
Candy Jam's website said it wasn't just protesting about King's actions towards Benny Hsu and the makers of The Banner Saga, but also against King as a company for allegedly copying other games.
The site points out that Candy Crush Saga has a lot in common with Bejewelled and Bubble Witch Saga, which is a type of bubble-bursting game similar to Bust-A-Move.
"The Candy Jam is a protest against both the system and those abusing it: King," the site said.
We have contacted King for comment, but it did not respond. We'll update if we hear more. ® | 2024-05-14T01:26:35.434368 | https://example.com/article/2866 |
Anybody that pays hydro in Ontario has certainly felt the squeeze with recent skyrocketing rates. Is there relief in sight?
According to a new study by the Fraser Institute, Ontario electricity prices increased twice as fast as the national average over the past decade, and the average Toronto resident now pays $60 more per month than the average Canadian for electricity.
“Electricity is a necessity, and Ontario’s high prices pose a serious burden for many families who, after paying their hydro bills, have significantly less money to spend on other important priorities,” said Kenneth Green, Fraser Institute senior director of energy and natural resource studies and co-author of Evaluating Electricity Price Growth in Ontario.
The study also finds that electricity prices in Ontario increased 2.5 times faster than Ontario income levels between 2008 and 2015 (the latest year of income data).
In fact, electricity prices rose a staggering 71 per cent (from 2008 to 2016), more than double the national average increase of 34 per cent over the same time.
Consequently, Ontario cities have some of the highest monthly electricity bills in Canada.
For example, residents in Toronto (the city with the highest price anywhere in Canada) pay, on average, $201 per month (including taxes) — an increase of $77.09 over the past six years. Ottawa residents pay $183 per month.
The study finds that Ontario’s high prices are directly tied to the provincial government’s phase-out of coal energy, poorly structured long-term renewable energy generation contracts and other policy choices.
What’s more, to address the high costs faced by residents, Queen’s Park has recently announced a plan to use debt-financing to artificially lower current electricity prices. However, this plan will result in new charges being added to future bills.
“The Ontario government and its energy policy decisions share a lot of blame for the current crisis in electricity prices,” Green said.
“Ontario residents need real policy reform to help make electricity affordable again, not just short-sighted shell games that borrow from future ratepayers to subsidize current bills.”
The Fraser Institute is an independent Canadian public policy research and educational organization with offices in Vancouver, Calgary, Toronto, and Montreal and ties to a global network of think-tanks in 87 countries. Its mission is to improve the quality of life for Canadians, their families and future generations by studying, measuring and broadly communicating the effects of government policies, entrepreneurship and choice on their well-being. To protect the Institute’s independence, it does not accept grants from governments or contracts for research. Visit www.fraserinstitute.org | 2024-05-05T01:26:35.434368 | https://example.com/article/7439 |
Q:
How can I delete a calendar from a PST that is no longer accessible in Outlook 2010?
I have a user that loaded a PST into Outlook 2010. The PST file had several calendars, which were loaded to the user's calendars. He has since deleted the PST file as he no longer needed access to it. The calendars are stuck in his calendar list, and the 'Delete Calendar' option is greyed out. This wouldn't be a problem, but each time he newly opens Outlook and goes to his calendar, he's notified that the PST file cannot be found and is then prompted to select it. There were five calendars, so it's a bit annoying to go through ten dialogs. How could these calendars be removed from Outlook?
A:
Can you restore the .pst? It needs unloading from outlook before just deleting it.
If not:
You can solve the errors rather easily - just remove the data links in 'Control Panel'/'Mail'/[Data Files]. Don't do this yet.
See if you have options to remove the calendars there (probably not - now would be a good time to backup/export the working PST+calendar) and do so.
If you can still expand the contents of the deleted .pst in the Navigation pane then goto the folder view and right click and delete the offending calendar. More than likely you won't have this option so just remove the data files from the Account window (as mentioned above).
If the calendars are still showing, do you have the option of unselecting them from the Calendar window?
| 2023-08-15T01:26:35.434368 | https://example.com/article/5005 |
Background {#Sec1}
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Licensed, seasonal influenza vaccines available in the United States include trivalent and quadrivalent inactivated vaccines and a live attenuated influenza vaccine produced in embryonated chicken eggs \[[@CR1],[@CR2]\], a cell culture based trivalent vaccine produced in Madin Darby Canine Kidney (MDCK) cells \[[@CR3],[@CR4]\], and most recently a recombinant trivalent vaccine (Flublok) produced using the baculovirus-insect cell system \[[@CR5]-[@CR7]\]. Flublok vaccine has several distinct advantages over other flu vaccines including high purity of the HA protein, and absence of antibiotics, preservatives, gelatin, and egg proteins.
HA, the most abundant and immunogenic surface antigen of the influenza virus, is responsible for mediating viral attachment by binding to sialic acid residues on the host cell surface, and for fusing the viral envelope to the host cell membrane \[[@CR8]\]. The HA protein is a homotrimer extending 135 Å from the viral membrane, and consists of a stem-like region formed by three helices, one from each monomer, and a globular head domain containing antigenic epitopes. These two domains form the ectodomain which has previously been solubilized by bromelain cleavage to determine its crystal structure \[[@CR9]-[@CR11]\]. The TM domain sequence has a propensity to form alpha-helical oligomers in model systems \[[@CR12]-[@CR14]\] and this tendency may extend to the alpha-helices of the stem region \[[@CR15]\]; however, the structure of this domain, as well as the conformation of C-terminal amino acids of the CT, has not been determined.
Flublok includes three rHA proteins (full length without signal peptide) that are highly purified (≥90%) using our universal purification process, and are updated according to the annual influenza strain selection process \[[@CR5]\]. By comparison, the whole virus vaccines produced using the traditional egg based system are chemically inactivated with either formaldehyde or beta-propiolactone (BPL) and partially purified by either column chromatography or sucrose gradient ultracentrifugation and filtration \[[@CR16]-[@CR18]\]. Split and subunit vaccines produced using both the egg and cell culture systems include a detergent extraction step, as well as an additional sucrose gradient or alternative purification step, to further reduce the lipid and contaminating protein content \[[@CR16]-[@CR18]\]. Despite considerable variation in the manufacturing processes and purity, the quantification or potency of the HA proteins produced either in eggs or in BEVS is determined using the SRID assay \[[@CR19],[@CR20]\]. The SRID based potency assay, in use since 1978, is required to standardize HA content in inactivated licensed flu vaccines by the FDA. The SRID assay uses strain specific anti-HA antibodies to quantify HA trimer in the presence of the surfactant Zwittergent 3--14.
Purified wild-type rHA proteins, particularly H3 rHAs, show an apparent initial loss of potency in the SRID assay before leveling off within typically four weeks after production. In the case of H3 rHA from the A/Perth/16/2009 influenza strain included in the 2010--2011, and 2011--2012 Flublok vaccines, this apparent initial loss of potency is as high as 40% and is correlated with an increase in disulfide bond cross-linking, and the oxidation of at least one conserved cysteine residue at position 549 of the primary sequence in the CT domain \[[@CR21]\]. HA proteins derived from human influenza viruses can contain 2--5 cysteine residues in the TM and CT domains depending on the subtype (Figure [1](#Fig1){ref-type="fig"}A) in addition to twelve conserved cysteine residues located in the ectodomain which form six sets of disulfide bonds based on X-ray crystal structure analysis and are required for proper folding \[[@CR22]-[@CR24]\]. These cysteine residues have been implicated in membrane fusion, viral assembly and replication \[[@CR25]-[@CR28]\]. More recent studies have examined the importance of the TM and CT cysteine residues on thermal stability, heterotypic protection in mice, and other virological features \[[@CR29]-[@CR32]\]. In the context of influenza viruses, these cysteines in HA proteins are modified with palmitic acid which may be important for biological function. While the baculovirus-insect cell system supports palmitoylation \[[@CR33],[@CR34]\], such reversible, post-translational modifications may be incomplete, as the available data indicate that at least one of the two C-terminal cysteine is partially free and undergoes oxidation \[[@CR21]\].Figure 1**A and B Amino acid sequence of the TM and CT domains. A**. Shown is a sequence alignment of the transmembrane (TM) and cytoplasmic tail (CT) domains in the hemagglutinin protein. Protein sequences from different human influenza strains belonging to the H1, B, and H3 subtypes have been included and the cysteine residues highlighted. **B**. The amino acid sequences of the wild-type and site directed variants of H3 A/Perth and H3 A/Texas rHA are shown. The position of the cysteine residues and the modifications are indicated. The sequences for the TM and CT domains are underlined and double underlined, respectively.
In this study, we evaluated the role of the TM and CT cysteine residues on the thermal stability as determined by DSF, functional stability as determined by potency, antigenicity, and tertiary and quaternary structure of the H3 rHA protein from the A/Perth/16/2011(H3 A/Perth) influenza strain. All or a portion of the TM and CT cysteine residues were substituted with either serine or alanine to produce SDV rHA proteins. Our results demonstrate that this cysteine substitution strategy can prevent an apparent potency loss associated with disulfide mediated cross-linking, but does not impact the expression, purification, folding, or thermal stability of the molecule. Hemagglutination inhibition, an assay used to determine the antigenic identity of the vaccine viruses, has been used to show that the SDV rHAs are antigenically similar to wild type rHA, and that the cysteine substitution strategy does not impact the antigen specific antibody responses in mice upon immunization. The SDV rHAs are presented to the immune system in the same quaternary structural form as the wild-type rHA based on the comparability of the rosette structure as determined by negative stain electron microscopy data. Finally, the cysteine substitution strategy has been applied to another H3 rHA derived from the A/Texas/50/2012 (H3 A/Texas) influenza strain with comparable results demonstrating that the approach can be applied to address in vitro potency loss in H3 rHAs caused by the formation of non-native disulfide bonds.
Results {#Sec2}
=======
Comparable expression and purification of the wild-type and site directed variants {#Sec3}
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To examine the role of the cysteine residues located in the TM and CT of the H3 A/Perth rHA protein, alanine or serine substitutions were introduced into the wild-type gene by site directed mutagenesis. Three different SDVs were produced having two, three, and five cysteine substitutions. They are referred to by the number of cysteine substitutions or as 2Cys, 3Cys and 5Cys, respectively (Figure [1](#Fig1){ref-type="fig"}B). Alanine was selected based on its small size, similar hydrophobicity, and lack of chemistry including hydrogen bonding. A cysteine to serine substitution was made at position 523 in the 2Cys SDV based on amino acid sequence alignments consistently showing a serine at the equivalent position of HA proteins from H1 and B subtypes (Figure [1](#Fig1){ref-type="fig"}A). As a control in this study, a pair of conserved cysteine residues in the ectodomain known to form a disulfide bond, C64 and C76, was disrupted by substitution with serine residues. Finally, to verify the relative potency findings obtained with the H3 A/Perth 5Cys SDV rHA in this study, the same strategy was used to replace all five TM/CT cysteine residues with alanine residues in the H3 A/Texas rHA protein (Figure [1](#Fig1){ref-type="fig"}A and B).
The universal purification process for the wild-type rHA was applied to the SDV rHA proteins without modification. The expression level for the control SDV replacing the two conserved and paired cysteines in the ectodomain was too low to purify (Table [1](#Tab1){ref-type="table"}). The potency of the soluble rHA in the supernatant fraction was determined in the SRID assay and was used to establish the starting yield. The final yield after purification was determined using the total protein results obtained by the BCA assay corrected for the rHA purity determined by SDS-PAGE. The results provided in Table [1](#Tab1){ref-type="table"} show that the starting and purified yields for the 2Cys, 3Cys, and 5Cys SDV rHA proteins relative to the wild-type rHA were equivalent or better compared to the wild-type rHA protein.Table 1**Starting and final purified yields for rHA proteinsrHAStarting yieldPurified yield% of wild-type% of wild-type**Wild-type100100Control SDV\*13Not Done2Cys971203Cys1181995Cys138136\*SDV contains modifications C64S, C76S in the ectodomain of the protein.
Purity of rHA was determined by reducing SDS-PAGE. The full length rHA proteins migrates as monomers (HA0) having an approximate molecular weight of 62 kDa (Figure [2](#Fig2){ref-type="fig"}A) under denaturing and reducing conditions. The purity of the rHA proteins exceeds 99%.Figure 2**A and B SDS-PAGE purity and trypsin resistance gels for the H3 rHA proteins. A**. Each rHA protein was loaded in duplicate to give 1 μg total protein per lane. The samples were separated using 4-12% gradient Nu-PAGE gels and stained with Coomassie Blue. Molecular weights of the proteins standards are shown. **B**. Shown are the reducing SDS-PAGE gels from the trypsin resistance assay. Each H3 rHA protein was analyzed neat (Lane 1), after trypsin treatment (Lane 2), after heat treatment (Lane 3), and after heat and trypsin treatment (Lane 4). The trypsin enzyme is loaded as a control and molecular weights of the protein standards are shown. HA1 and HA2 are indicated by arrows.
rHA folding and activity were unaffected by substitutions of the TM/CT cysteines {#Sec4}
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The trypsin resistance assay provides a qualitative assessment of the folded state of the rHA protein. All the trypsin recognition sites are masked in the correctly folded full-length, HA trimer with the exception of one site located toward the end of the stem region. As a result, properly folded rHA protein is cleaved by trypsin into HA1 and HA2, while denatured or mis-folded rHA degrades in the presence of trypsin. Each rHA was trypsin treated with and without heat denaturation and analyzed by reducing SDS-PAGE alongside the untreated rHA with and without heat denaturation (Figure [2](#Fig2){ref-type="fig"}B). All rHAs were resistant to trypsin digestion and the trypsin resistance profiles obtained for the SDV rHAs were comparable to that of the wild-type rHA. In the presence of trypsin, the monomeric rHA band (\~60 kDa) was cleaved into HA1 and HA2 that migrated as \~55 kDa and \~25 kDa proteins, respectively (Figure [2](#Fig2){ref-type="fig"}B, lane 2). Boiling the rHA sample prior to trypsin treatment denatured the protein and resulted in digestion of the rHA by trypsin (Figure [2](#Fig2){ref-type="fig"}B, lane 4).
To determine whether the SDV rHAs contain functionally active forms of the protein, they were evaluated in a hemagglutination assay using the wild-type H3 rHA protein as control. Agglutination of red blood cells requires the HA trimers to be organized in higher order (rosette) structures. The globular head of the rHA trimer forms a receptor binding site for terminal sialic acids on red blood cells. The arrangement of trimers in a rosette structure results in a lattice like structure of the bound cells which do not settle out. Unbound cells settle out and produce a button like or halo pattern of cells as observed in negative controls (Figure [3](#Fig3){ref-type="fig"}A). The HA activity of the H3 SDV rHAs were within 2--4 -fold of the HA activity of the wild-type H3 rHA (Table [2](#Tab2){ref-type="table"}).Figure 3**A and B Hemagglutination activity and negative stain electron microscopy of the H3 rHA proteins. A**. The hemagglutination assay was performed in 96-well u-bottom plates. The rHA proteins were assayed in triplicate at an initial concentration of 1 μg/mL loaded in the left-most lane. Two-fold serially dilutions were performed across the plate in PBS, and equal volume 0.5% guinea pig red blood cells added. Endpoints are denoted by dotted lines. **B**. The rHA proteins were stored at 25°C for 2.5 month at the time of EM analysis. The bar represents 100 nm.Table 2**Hemagglutination activity results for wild-type and SDV rHAsrHA proteinHA activityUnits/μg**Wild-Type1602Cys403Cys805Cys160
Particle size is unaffected by cysteine substitutions {#Sec5}
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The particle size of the H3 rHA proteins was determined by dynamic light scattering (DLS), and the results for the volume mean diameter are provided in Table [3](#Tab3){ref-type="table"}. The mean volume diameter for the wild-type H3 rHA, and the 5Cys and 3Cys SDV H3 rHAs are comparable (average 37.2 ± 2.1). In contrast, the mean volume diameter of the 2Cys SDV H3 rHA was consistently larger in size (average 50.5 ± 1.8) and may be due to the alternative cysteine to serine substitution in this SDV. Despite this difference, the mean volume diameter of the particles observed for the wild-type and SDV H3 rHAs by DLS (range 30--50 nm) was consistent with the size of rosettes visible by EM \[[@CR35],[@CR36]\].Table 3**Volume mean diameter by DLS for wild-type and Cys SDV H3 rHAsSample nameVolume mean diameter (nm)Day 0Day 7Day 28Average**Wild-type38.939.239.639.2 ± 0.45Cys36.536.338.837.2 ± 1.43Cys35.533.536.335.1 ± 1.42Cys52.649.749.350.5 ± 1.8
The morphology of the rosettes was determined by electron microscopy (EM). For this analysis, aliquots of rHA protein samples stored for 2.5 month at 25°C were submitted to Paragon Bioservices for electron microscopy. Representative EM images are shown in Figure [3](#Fig3){ref-type="fig"}B. Rosette size, estimated to be approximately 30--50 nm, and spike densities were similar in the EM images for the wild-type H3 rHA and the SDVs.
SEC was performed to determine the homogeneity of the preparations. The SEC elution profiles were similar for the rHAs (Figure [4](#Fig4){ref-type="fig"}A). The retention time of the primary peak (average 29.39 ± 0.26) and the extrapolated MWs (average 2,505 kDa ± 113 kDa) were similar for all the rHAs. In addition, the extrapolated numbers of trimers per rosette for the wild-type rHA and SDV rHAs remained constant \[[@CR11],[@CR12]\] suggesting that the cysteine substitution did not affect the assembly of the trimers into rosettes.Figure 4**A**-**4C SEC-HPLC elution profiles, SEC-UPLC elution profiles, and thermal denaturation curves using DSF for the rHA proteins. A**. The SEC-HPLC elution profiles for the wild-type and SDV rHA proteins overlay. The retention times and extrapolated MWs are similar for the rHA proteins. The \# of trimers per rosette was estimated using the extrapolated MW and a trimer MW of \~210 kDa. **B**. The SEC-UPLC elution profiles before (solid lines) and after (dotted lines) Zwittergent 3--14 pre-treatment are shown in for the wild-type (left) and 5Cys SDV rHA (right). **C**. The melting temperature (T~m~) was determined by DSF, and the second derivative thermal denaturation curves are shown for each rHA.
Both the wild type H3 rHA and 5 Cys SDV rHA were analyzed by SEC UPLC before and after treatment with 1% Zwittergent 3--14, a surfactant which converts rHA rosettes into the trimeric form. In the absence of Zwittergent treatment, the wild-type and 5Cys SDV rHAs gave a single broad peak by SEC with a retention time of approximately 3 minutes (Figure [4](#Fig4){ref-type="fig"}B). Pre-treatment of a 5Cys SDV rHA with 1% Zwittergent 3--14 prior to SEC-UPLC analysis shifted the broad peak to a narrower peak having a retention time of 3.8 minutes. In contrast, the SEC-UPLC profile for the wild-type rHA pre-treated with 1% Zwittergent 3--14 resulted in multiple peaks with retention times between 3 and 3.8 minutes. These results support the presence of disulfide cross-linked multimers that are not disrupted by the Zwittergent treatment in the wild-type rHA. In contrast, the 5Cys SDV rHA does not have disulfide mediated cross-linked structures and completely shifts to a trimeric conformation upon treatment with 1% Zwittergent 3--14.
Thermal stability of rHA is unaffected by cysteine substitutions in the TM and CT domains {#Sec6}
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The wild-type H3 rHA and Cys SDV H3 rHAs were analyzed from 25°C to 99°C by DSF in the presence of a molecular rotor dye (ProteoStat, Enzo Life Sciences) to determine thermal stability. Fluorescence intensity was monitored as a function of temperature and a single, large cooperative unfolding was observed for each protein (Figure [4](#Fig4){ref-type="fig"}C). These data showed that T~m~s of SDV rHA were all similar to the wild-type H3 rHA (Table [4](#Tab4){ref-type="table"}), and these differences in the T~m~s are not statistically significant. Since the thermal stability of the SDVs as determined by DSF was quite similar to the wild-type rHA, this data further supports that the effect of cysteine substitutions on the overall structure of the rHA is minimal.Table 4**Melting temperatures for wild-type and Cys SDV H3 rHAs using DSFProteinTM mean (n = 5)Standard deviation**Wild-type55.0805Cys55.8203Cys56.270.172Cys56.710.20
Cysteine modifications affect potency loss, cross-linking, and hydrophobicity {#Sec7}
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The wild-type H3 rHA and Cys SDV H3 rHAs were stored at 25°C and potency by SRID and cross-linking by SDS-PAGE were monitored. The potency was determined by SRID on the day of final purification (day 0), day 7, day 14 or 21, and day 28, and after approximately 2.5, 6, 9, and 12 months. The results were plotted relative to the day 0 results for wild-type rHA, as well as, for each H3 SDV rHA (Figure [5](#Fig5){ref-type="fig"}). The relative potencies of the 5Cys and 3Cys SDV H3 rHAs showed little change over time and were significantly improved compared to the wild-type and 2Cys SDV H3 rHA proteins. Based on the results, the loss in potency decreases with the number of cysteine substitutions in the order WT \> 2Cys \> 3Cys \> 5Cys.Figure 5**Potency determined by SRID for the wild-type and SDV rHA proteins stored at 25°C.** The rHA proteins were placed at 25°C storage and the potency measured at different time points by SRID. Shown are the potency results plotted relative to the day 0 value for each H3 A/Perth rHA in the study.
Figure [6](#Fig6){ref-type="fig"}A shows the reducing and non-reducing SDS-PAGE data obtained on days 0 and 28 of the study. Under non-reducing conditions, rHA proteins typically migrate as monomers and cross-linked oligomers which form a ladder of higher molecular weight bands. The primary full-length HA0 migrates at approximately 62 kDa, and dimer and trimer migrate at approximately 120 and 180 kDa, respectively. rHA proteins migrating above the 210 kDa marker are due to the formation of higher order cross-linked structures. The cross-linking is disulfide mediated based on the SDS-PAGE profiles obtained under reducing conditions which show predominantly monomeric rHA (Figure [2](#Fig2){ref-type="fig"}A,B and Figure [6](#Fig6){ref-type="fig"}A).Figure 6**A and B Non-reducing and reducing SDS-PAGE gels and densitometry for rHA proteins on days 0 and 28. A**. Each rHA (\~2.5 μg) was analyzed by SDS-PAGE under non-reducing (N-R) and reducing (Red) conditions on days 0, 7, 14 or 21, and 28. Shown are gels obtained on day 0 (top) and on day 28 (bottom). Densitometry was performed on the non-reducing lanes on the left-hand-side of each gel using the Carestream software program, and the corresponding intensity profiles are shown on the right. **B**. The intensities of individual bands in the non-reducing SDS-PAGE gel profiles were measured using the Carestream software program. The ratio of intensities for cross-linked bands migrating above the 70 kDa marker to the un-cross-linked monomeric band migrating at \~70 kDa was calculated for each rHA and time point and plotted as function of storage time below.
The day 0 results show essentially no disulfide mediated cross-linking by non-reducing SDS-PAGE for the 5Cys and 3Cys variants, while the wild-type and the 2Cys SDV show evidence of cross-linked dimer, trimer and higher order oligomers. After 1 month at 25°C, the 5Cys SDV shows no sign of cross-linking, and the 3Cys SDV shows a relatively small amount (approximately 15%) of cross-linked dimer and trimer compared to an extensive increase in cross-linking for the 2Cys SDV (approximately 63%) and the wild-type rHA (approximately 72%) during the same time period. A loss of intensity of HA0 (\~60 kDa) is observed for both the 2Cys and the wild-type rHA as a result of the cross-linking, while the intensity of HA0 protein remains comparable on days 0 and 28 for the 3Cys and 5Cys SDVs. Thus, the decrease in cross-linking observed with the number of cysteine substitutions in the TM/CT correlates with the corresponding increase in the relative potency for these SDVs.
The intensities of the individual bands in the SDS-PAGE gels were measured at each time point in the study, and the ratio of intensities of the cross-linked forms to the un-cross-linked rHA (HA0) was determined for each rHA. These ratios were plotted as a function of time (Figure [6](#Fig6){ref-type="fig"}B). It is evident that cross-linking steadily increased for the wild-type H3 rHA and the 2Cys SDV for up to 14 days and then stabilized. A slight increase in cross-linking was observed for the 3Cys SDV on day 28, while no cross-linking was observed for the 5Cys SDV during the study period.
The RP-HPLC profiles for the wild-type and 2Cys SDV H3 rHAs are comparable, but different from the RP-HPLC profiles for the 3Cys and 5Cys H3 SDV rHAs (Figure [7](#Fig7){ref-type="fig"}). The 3Cys and 5Cys SDV H3 rHAs elute as a single peak between 5.7-5.9 minutes, while the wild-type and 2Cys SDV H3 rHAs elute in three separate peaks (labeled 1--3) between 6--9 minutes. The elution time for the first peak is very similar for all the three SDVs (5.7-5.9 minutes), while the first peak for the wild-type elutes slightly later (6.2 minutes). Additionally, retention times for peaks 2 and 3 are slightly shorter for the 2Cys compared to the wild-type rHA. By day 28, the three peaks decrease in intensity and broaden for both the wild-type and 2Cys SDV rHA suggesting a change in the conformation of the rHA. In contrast, the profiles for the 3Cys and 5Cys SDVs showing a single peak are similar at the beginning and end of the study with one exception. A leading tail on the elution peak for the 3Cys rHA is observed on day 28, and coincides with the appearance of cross-linked rHA by SDS-PAGE on day 28 for the 3Cys SDV. These results suggest that 3Cys SDV is effective in reducing the disulfide mediated cross-linking, but all five cysteine substitutions of the 5Cys SDV are required to completely eliminate disulfide mediated cross-linking and prevent potency loss.Figure 7**RP-HPLC profiles for the H3 rHA proteins.** Each H3 rHA was analyzed in duplicate. Representative chromatograms from the day 0 and 28 time points are provided. rHAs were incubated with 25 mM DTT for at least 30 minutes prior to analysis. \~25 μg of each rHA was injected onto a Poros R1 column and an acetonitrile gradient applied.
The marked improvement in relative potency and the lack of disulfide mediated cross-linking for the 5Cys SDV in this study was confirmed for another 5Cys SDV rHA and corresponding wild-type rHA derived from the H3 A/Texas influenza strain. These rHA proteins were purified and stored at two temperatures, 5°C and 25°C. Potency by SRID, cross-linking by SDS-PAGE, and hydrophobicity by RP-HPLC were monitored monthly up to 12 months (Figure [8](#Fig8){ref-type="fig"}).Figure 8**A-C Experimental data for H3 A/Texas 5Cys SDV and wild-type rHA stored at 5°C and 25°C.** Potency by SRID, cross-linking by SDS-PAGE, and hydrophobicity by RP-HPLC were monitored monthly for 12 months. **A**. Shown are the potency results obtained at each time point for the rHA proteins stored at 5°C (top graph) and 25°C (bottom graph). For each rHA, the potency results are plotted relative to the day 0 value. **B**. Shown are the non-reducing and reducing SDS-PAGE results obtained on day 0 and after 12 months for the sets of wild-type and 5Cys SDV rHA proteins stored at 5°C and 25°C. **C**. Shown are the RP-HPLC profiles obtained on day 0 and 12 months for the sets of wild-type and 5Cys SDV rHA proteins stored at 5°C and 25°C.
Antigenicity is unaffected by cysteine substitutions in the TM and CT domains {#Sec8}
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To determine the antigenicity of the rHA proteins, the hemagglutination inhibition (HAI) assay was performed using two different polyclonal antisera. In addition, the CBER reference antigen for H3 A/Perth/16/2009 HA (lot\# 70) was also included in the assay for comparison with rHA proteins. Specific binding of the antibodies to different antigenic sites in the HA proteins interferes with the ability of the HA protein to agglutinate red blood cells and forms the basis of the HAI assay. The HAI endpoint or titer, the reciprocal of the last dilution of antiserum that completely inhibits hemagglutination, was determined for each rHA protein using both antisera and compared to the CBER reference HA antigen in Table [5](#Tab5){ref-type="table"}. Using both antisera, the HAI endpoints of the Cys SDV H3 rHA were equivalent or within 2-fold of the wild-type H3 rHA and the CBER reference antigen for H3 A/Perth HA. The results confirm that cysteine substitutions introduced into the TM and CT domain of H3 rHA did not alter the presentation of the antigenic sites.Table 5**HAI titers for wild-type and Cys SDV H3 rHAsH3 HA proteinHAI titerRabbit poly clonal anti-H3 rHA AbSheep polyclonal anti-H3 HA Ab**Wild-type1024025602Cys512025603Cys512012805Cys102402560\#70 H3 HA CBER51202560
Antigen-specific antibody production is unaffected by cysteine substitutions in the TM and CT domains {#Sec9}
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A comparative study was performed in mice using the 5Cys SDV rHA and corresponding wild-type rHA from the H3 A/Texas strain. The mouse study was performed by Josman LLC and included 7 cohorts, three for each rHA antigen and one for a placebo, with 10 acclimated Balb/c mice in each cohort. On day 0 and day 21 of the study, mice were administered a 25 μL intramuscular injection of either the wild-type rHA antigen at one of three doses (1 μg, 3 μg, or 10 μg) or the corresponding 5Cys SDV antigen at one of three doses (1 μg, 3 μg, or 10 μg). The placebo group received an equal volume dose of the formulation buffer. Pre-immune serum samples collected on day 0 were tested alongside serum samples collected on day 42 in the HAI assay (see above) using both the wild-type rHA and SDV rHA as the test antigens. The number of responders having at least a 4-fold change in geometric titer on day 42 compared to day 0 were similar for all test groups receiving the two different rHA antigens regardless of the antigen used in the assay (wild-type or 5Cys SDV). Further, the average geometric mean titers for all groups were comparable regardless of the antigen and dose delivered to the mice (Figure [9](#Fig9){ref-type="fig"}). Based on the results, C-terminal cysteine substitutions and the degree of disulfide cross-linking do not impact the levels of antigen-specific antibody responses upon immunization.Figure 9**A and B Pre-clinical mouse immunogenicity study results.** Sera samples from mice immunized with the H3 A/Texas 5Cys SDV rHA antigen (B1-B3) and with the H3 A/Texas wild-type rHA antigen (A1-A3) were tested in the HAI assay using both antigens, the H3 A/Texas 5Cys rHA antigen (Panel **A**, left) and the H3 A/Texas wild-type rHA antigen (Panel **B**, right). In each plot, the dotted line represents 4× the mean value for the day 0 titer.
Discussion {#Sec10}
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The influenza HA protein is an integral membrane protein and the primary target for inducing neutralizing antibodies to influenza virus. When purified to homogeneity, the protein forms a rosette structure which exposes the immunogenic, trimeric ectodomain, while the transmembrane domains and short cytoplasmic tails are most likely buried inside the rosette structure \[[@CR37]\]. It has long been demonstrated that formation of trimeric HA is not dependent on the TM or CT domains \[[@CR38]\], though it has been suggested that the TM domain may contribute to the stability of the trimer \[[@CR37]\]. Similarly, the early stages of HA mediated membrane fusion are unaffected by deletion of the TM and CT domains and replacement by a non-proteinaceous GPI anchor \[[@CR39]-[@CR42]\]. Therefore, the wild-type rHA and the TM and CT cysteine SDVs in this study are expected to form similar trimers and rosettes.
An evaluation of the human influenza strains which fall into 3 subtypes, H1N1 (H1), H3N2 (H3) and, B, shows that the H3 rHAs have five cysteine residues in the TM and CT domains (Figure [1](#Fig1){ref-type="fig"}A). The two cysteine residues in the CT domain are highly conserved and are found in all human influenza strains. The cysteine residue positioned at the interface between the TM and CT is found in H3 and H1 HAs, but not in B HAs. The biological role of these cysteine residues has been the subject of several studies which have identified them as sites of palmitoylation/acylation involved in membrane fusion and viral replication \[[@CR25]-[@CR28]\]. While these activities are indispensable for the virus, they are not required for expression and purification of the recombinant hemagglutinin protein during vaccine manufacture. In fact, replacing all five of the TM/CT cysteines in the 5Cys SDV or different subsets of them in the 3Cys and 2Cys SDVs (Figure [1](#Fig1){ref-type="fig"}B) result in rHA proteins having starting yields, final purities, and purified yields that are comparable to or better than the wild-type rHA protein (Table [1](#Tab1){ref-type="table"} and Figure [2](#Fig2){ref-type="fig"}A). In contrast, substitution of the two conserved cysteine residues in the globular head domain of the rHA protein, C64 and C76, with serine residues results in low expression further confirming that the cysteine residues in the globular head domain play a critical role in the folding of hemagglutinin protein, and cannot be substituted (Table [1](#Tab1){ref-type="table"}).
The folding and functional activity of the wild-type rHA and the TM/CT SDVs were compared by evaluating the trypsin resistance profiles, and hemagglutination activities. Trypsin resistance is a property of properly folded trimeric HA proteins, while hemagglutination requires the organization of these trimers into higher order rosette structures that can interact with red blood cells through their sialic acid and form a lattice like network. Trypsin treatment cleaves properly folded, full-length, trimeric HA into two fragments, an amino-terminal HA1 fragment and a carboxy-terminal HA2 fragment, while denatured or monomeric rHA is digested by the endoprotease. Trypsin treatment of the wild-type and SDV rHAs results in the same characteristic HA1 and HA2 cleavage with apparent molecular weights of \~50 kDa for HA1 and \~28 kDa for HA2 (Figure [2](#Fig2){ref-type="fig"}B). Hemagglutination occurs when the red blood cells interact via their sialic acid moiety with HA rosettes, and form a lattice like network that remains in suspension. In the absence of hemagglutination, the cells do not form the lattice like network, and a halo or circle of settled cells is observed. These results demonstrate that the hemagglutination activity of SDVs of rHA is comparable to the wild-type rHA (Table [2](#Tab2){ref-type="table"}). Further, these results suggest that the cysteine substitutions in the TM/CT domains do not impact the functional activity of H3 SDV rHAs.
Having established proper folding and function, the particle size and thermal stability of the wild-type and SDV rHA proteins were determined. The average particle size by DLS (Table [3](#Tab3){ref-type="table"}) for the wild-type rHA and the TM/CT SDVs is in the range expected for rosettes structures. The volume mean diameter of the 3Cys and 5Cys SDVs is 35 nm and 37 nm, respectively, compared to 39 nm for the wild-type H3 rHA protein. The diameter of the particles for the 2Cys SDV is consistently 10 nm larger than the wild-type, and may reflect that the replacement of cysteine to serine at position 523 is not optimal and leads to particles of larger size. By EM (Figure [3](#Fig3){ref-type="fig"}B), the rosettes of the wild-type and SDV rHAs are strikingly similar, and indistinguishable in terms of size and appearance. In addition to particle size and morphology, the thermal stability of the rosettes in the SDV rHAs as measured by DSF is similar to that of the wild-type rHA (Table [4](#Tab4){ref-type="table"}). The largest difference in T~m~, observed between the 5Cys SDV and the wild-type, is only 1.6°C. Decreased thermal stability has been reported previously for three H3 HA variants in which one or both of the two TM cysteine residues unique to this subtype were modified \[[@CR29]\]. However, the thermal stability in this study was determined in a fundamentally different way on crude extracts using the hemagglutination activity assay. Further, our thermal stability data are in close agreement with previously report TM values for rosettes suggesting that both the WT and Cys SDV rHAs are similarly highly stable \[[@CR43]\].
By SEC, all the rHA proteins have a single, primary peak with retention times differing by 0.5 minute or less. In addition, the wild-type and SDV rHAs elute before the largest standard, thyroglobulin, having an approximate molecular weight of 660 kDa (Figure [4](#Fig4){ref-type="fig"}A). These data also suggest that the rHA trimers assemble into rosettes structures, and the ability to form the rosettes is unaffected by the cysteine substitutions in the TM/CT domains. Differences in the homogeneity of the rosette population in the wild-type and 5Cys SDV rHAs are detected by UPLC SEC analysis of the Zwittergent 3--14 treated rHA (Figure [4](#Fig4){ref-type="fig"}B). The Zwittergent 3--14 surfactant efficiently converts the rosettes of the 5Cys SDV, but not of the wild-type rHA, to trimers. Due to its smaller size compared to the rosette, the rHA trimer elutes off the SEC column later and the peak is shifted. In contrast, Zwittergent 3--14 treatment of the wild-type rHA protein results in multiple peaks corresponding to rosette, trimer, and various species of intermediate sizes. Disulfide mediating cross-linking occurs readily in the wild-type rHA based on SDS-PAGE analysis (below), and the various cross-linked states of the protein result in multiple elution peaks as the Zwittergent 3--14 surfactant cannot disrupt the disulfide bonds.
Though the overall folding, thermal stability, size, and morphology are the same for the wild-type and TM/CT SDVs, differences in the formation of disulfide mediated cross-linked structures have been observed by SDS-PAGE (Figure [6](#Fig6){ref-type="fig"}A). Disulfide mediate cross-linking occurs readily at the C-terminus of the HA molecule through free cysteines located in the TM and CT domains. In the wild-type rHA and 2Cys SDV rHA, this cross-linking occurs during the purification process and is extensive. Cross-linked dimers, trimers, as well as higher order cross-linked oligomers are observed immediately following purification on day 0, albeit at a slightly reduced level in the 2Cys SDV. In the presence of reducing agent, the oligomers are converted to monomeric HA0 confirming that the cross-linking is disulfide mediated and due to the oxidation of free cysteine residues. Cross-linking of the 5Cys SDV rHA is not observed even after 28 days at room temperature, while cross-linked dimers and trimers of the 3Cys SDV rHA are first observed on the day 28 time point (SDS-PAGE gels for days 7 and 21 not shown). The non-reducing and reducing SDS-PAGE results for the 5Cys SDV and corresponding wild-type rHA from the H3 A/Texas strain further support the findings obtained with the H3 A/Perth SDVs (Figure [8](#Fig8){ref-type="fig"}). The formation of non-native disulfide bonds is prevented in H3 rHA proteins by replacing all five TM and CT cysteine residues.
Based on the SDS-PAGE results, the rHA protein is highly susceptible to oxidation through cysteines in both the TM and CT domain. The subset of cysteines modified in the 3Cys SDV (C539, C546, and C549) appears to be more susceptible to cross-linking than the subset of cysteines in the 2Cys SDV (C524 and C528). The latter two substitutions have little effect on the SDS-PAGE profile of the 2Cys SDV compared to the wild-type rHA, while the former three substitutions markedly reduce the formation of cross-linked rHA in 3Cys SDV. These results are not unexpected as the cysteines in the CT domain are more exposed at the C-terminus of the molecule. Free cysteine at this position may permit the cross-linking of monomers within a given trimer (intra-) and between monomers of different trimers (inter-).
The RP-HPLC profiles for H3 A/Perth rHAs (Figure [7](#Fig7){ref-type="fig"}) and the H3 A/Texas rHAs (Figure [8](#Fig8){ref-type="fig"}) are consistent with the non-reducing SDS-PAGE analyses. The multiple elution peaks observed for the wild-type rHAs and 2Cys SDV rHAs may be due to different cross-linked populations. Alternatively, they may due to the covalent attachment of fatty acids (palmitate and/or stearate) through thio-ester linkages involving the last three C-terminal cysteine residues present in both of these rHA molecules \[[@CR26],[@CR44]\], but absent in the 3Cys and 5Cys SDV rHA proteins. Both types of populations, cross-linked rHA and acylated rHA, are more likely to be retained on the column due the increased hydrophobic character and elute later in the gradient as observed here in the RP-HPLC profiles for the wild-type and 2Cys SDV rHA.
Concurrent with evaluation of the cross-linking, the potency of the wild-type and SDV rHA proteins from the H3 A/Perth and H3 A/Texas strains were measured by the SRID assay (Figures [5](#Fig5){ref-type="fig"} and [8](#Fig8){ref-type="fig"}). By this method, the relative potency is directly proportional to the number of TM/CT substitutions and inversely correlated with cross-linking. In the 5Cys SDV rHA in which all five TM/CT cysteines have been replaced, the potency relative to day 0 remains at 100% even after 12 months at room temperature for both the H3 A/Texas and H3 A/Perth 5Cys SDV rHAs, and no disulfide mediated cross-linking is observed. By comparison, the relative potency of the wild-type H3 rHAs drop approximately 75% after 4 weeks of storage at 25°C, and demonstrates extensive cross-linking. Compared to the wild-type rHAs, relative potency of the 2Cys SDV (two TM cysteine substitutions in H3 A/Perth rHA) drops to 50% during the same time (4 weeks at 25°C). Furthermore, the relative potency of the 3Cys SDV (three cysteine substitutions in the TM and CT domains of H3 A/Perth rHA), drops only 20% after 4 weeks storage at 25°C. While cross-linking is markedly reduced for the 3Cys SDV rHA, the 2Cys SDV shows only a marginal improvement over the wild-type rHA protein. These results clearly demonstrate that the substitution of cysteine residues in the CT domain has a significant impact on potency, but substituting cysteine residues in both the TM and CT domains has a synergistic effect on potency of the rHA.
While including a reducing agent and redox buffer, STG and Citrate, in the formulation buffer has been shown to prevent an apparent potency loss associated with the formation of non-native disulfide bonds and higher order cross-linked oligomers of the HA (manuscript in preparation), the results of this study clearly show that replacing the five cysteines in the TM and CT domains with an alternative amino acid has the same effect and is a highly effective alternative solution to address potency loss. The ability of these cysteines to cross-link appears to be a direct consequence of the production and purification process that releases the TM domain from the constrained environment of the membrane bilayer and the CT domain from the reducing environment of the cell. Since the three dimensional structure of the C-terminus (TM and CT domains) has not been solved by X-ray crystallography, a theoretical structural analysis of HA using a membrane protein topology prediction algorithm was performed assuming that the transmembrane region of the HA molecule adopts and continues the alpha- helical conformation of the proceeding HA2 domain \[[@CR15]\]. Using the program TMHMM \[[@CR45],[@CR46]\] and the HA sequence from H3 A/Perth, seven symmetrical alpha helical trimer configurations are possible (see Figure [10](#Fig10){ref-type="fig"}). Based on this model, the TM and CT cysteines are in the correct orientation and geometry to form both intra-molecular cross-links within a trimer and inter-molecular cross-links between different trimers. Amino acids with a spacing of three or four may be found on the same face of an alpha helix and cysteine residues in those positions can form disulfide bonds between two adjacent helices, thus covalently linking helices. Cysteine residues on the outside of the helices may participate in the covalent crosslinking of higher order oligomers. The association of HA trimers through their hydrophobic transmembrane domains in rosette structures also facilitates intermolecular cross-linking by positioning the C-terminal cysteines from different trimers in close proximity to each other.Figure 10**Modeling of the TM and CT domains in the HA trimer.** The top shows the amino acid sequence of the carboxy terminus (TM and CT domains) for H3 A/Perth HA with the TM and CT cysteines highlighted in yellow (top line), and the 7 possible orientations of that sequence in a helix with the interfacial positions highlighted in pink (A and D). The schematics depict the trimer configuration (each monomer is represented by a seven pointed helical wheel) with 7 positions labeled A through G on the bottom left and one possible configuration (orientation 2) on the bottom right.
While both intra- and inter-molecular cross-linking of the HA trimer are possible, the latter may reduce diffusion, and/or antibody recognition in the SRID assay. Prior to analysis in the SRID assay, the rHA proteins are pre-treated with Zwittergent 3--14 surfactant into order to dissociate non-covalently bound rHA rosettes structures into soluble trimers. SEC-UPLC analysis of rHA before and after Zwittergent 3--14 treatment clearly shows that only a portion of the wild-type rosettes are converted to trimers; in contrast, the rosettes of the 5Cys SDV are quantitatively converted to trimers. Due to their small size (\~12-14 nm in length, its longest dimension), rHA trimers can readily diffuse in to the agarose gel containing antibody and the size of the resulting precipitin ring is directly proportional to the antigen concentration. In contrast, trimers covalently bound together in rosettes through disulfide bonds are resistant to Zwittergent 3--14 pre-treatment. Depending on the extent of oxidation and/or the orientation of the cross-linked trimers, mobility of the particles through the gel may be hindered resulting in artificially small ring sizes. Alternatively, access to the epitopes may become increasingly hindered as the rosettes become covalently cross-linked through disulfide bonds resulting in a reduction in antibody binding and signal. Due to the inability of the SRID assay to accurately measure the rosette in a cross-linked state, an artificial or apparent potency loss is observed as the number of these oxidized species increases with storage of the rHA protein.
HA rosettes have been considered an indicator of immunogenicity because of their resemblance to the infectious influenza virions having HA trimeric spikes protruding from the viral envelope \[[@CR36]\]. Additionally, the antigenic sites on the HA molecule responsible for eliciting neutralizing antibodies are located in the globular head domain approximately 135 Å away from the cysteine substitutions located at the opposite end of the elongate molecule in the TM and CT domains \[[@CR9]-[@CR11]\]. Despite this wide physical separation, structural perturbations from side chain mutations have been shown to be propagated over long distances through the peptide backbone. For this reason, the antigenic and immunological affects of C-terminal substitutions on the rHA protein were determined. The hemagglutination inhibition assay was performed using the SDV and wild-type H3 A/Perth rHA proteins in order to determine and compare recognition and binding to antibodies in sera produced using the wild-type rHA antigen. The HAI titers for the SDVs were comparable to the wild-type rHA (Table [5](#Tab5){ref-type="table"}) indicating that the antigenic presentation of the epitopes on the SDVs has not been changed by the cysteine substitutions. Also, mice were immunized with either the H3 A/Texas 5Cys SDV or the corresponding wild-type rHA antigen. Based on similar HAI titers obtained in each group, the cysteine substitutions have no effect on the levels of rHA-specific antibody responses induced upon immunization. Thus, the cross-linked trimers in the wild-type rHA rosettes and the un-cross-linked trimers in the 5Cys SDV rHA rosettes induce comparable antibody responses in mice upon immunization. The results suggest that the potency loss observed for the wild-type rHA protein over time is largely due to the inability of the required potency assay to measure higher order cross-linked forms of the protein that retain their immunogenicity. Future work will include clinical trials to determine the impact on immunogenicity in human subjects.
In the manufacture of the rHA vaccine, the unique (non-biological) environment permits the formation of non-native disulfide bonds through free cysteines located in the TM and CT domains of the wild-type rHA protein. C-terminal cross-linking may occur to some extent in traditional split and subunit influenza vaccines as the purification process uses a detergent extraction step which may liberate the C terminus of the HA from the viral membrane. While both inter- and intra-molecular cross-linking can occur, only the latter results in cross-linked rosette structures that remain immunogenic, but are not accurately measured in the SRID assay. As a result, an apparent potency loss is observed with storage of the wid-type rHA vaccine. Cysteine mutagenesis is one way to overcome protein oxidation without the introduction of reducing agents in the formulation. However, the utility of this strategy is largely limited to the recombinant influenza vaccine since site specific mutagenesis of the virus prior to amplification in chicken cells or mammalian cells would represent a significant challenge.
Conclusions {#Sec11}
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rHA proteins form higher-order, defined oligomers (rosettes) that become covalently cross-linked through cysteine residues in the TM and CT domains. Replacement of these cysteine residues prevents disulfide bond formation at the C-terminus, but does not impact the expression, purification, or folding of the molecule based on our work as well as others \[[@CR28],[@CR29]\]. Moreover, the particle size and morphology, thermal stability, and antigenicity of the molecule are unaffected. Application of the cysteine mutagenesis strategy to rHA proteins derived from the other seasonal influenza subtypes (H1 and B), and pandemic strains (H5N1, H7N7) is currently underway, and a clinical trial is being planned. This technology may be extremely important for pandemic preparedness and would greatly enhance the value of the stock pile if the vaccine is not subject to potency loss at room temperature.
Methods {#Sec12}
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Generation of cysteine variants of rHA by site-directed substitution {#Sec13}
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The polymerase chain reaction (PCR) was used to construct three plasmid DNA constructs encoding different variants of the H3 A/Perth/16/2009 (H3 A/Perth) wild-type rHA protein. Amino acid residue changes were introduced by two complementary site directed mutagenesis (SDM) primers which contain sense mutations of the nucleotide(s). Table [6](#Tab6){ref-type="table"} provides the sequences of the SDM primers for the different variants with the nucleotides designed to introduce mutations in bold lower case type. The pPSC12 LIC transfer plasmid DNA, a proprietary transfer vector from PSC, containing the wild-type HA gene for the H3 A/Perth rHA protein was used as a template in the PCR for all constructs but one. The mutagenized DNA from the PCR for the triple mutation (C539A, C546A, and C549A) was used as a template in a subsequent PCR to generate the construct containing the TM and CT mutations, C539A, C546A, C549A, C524A, and C528A. The PCRs were treated with the restriction endonuclease DpnI to digest the template DNA, and transformed into *E. coli*. Plasmid DNA was isolated for sequencing. Sequencing analysis was performed using HA specific primers to confirm substitutions of the targeted amino acid residues. The PCR strategy described above was also used to substitute the five cysteine residues in the TM and CT domains of the H3 A/Texas rHA protein (C524A, C528A, C539A, C546A, C549A). The DNA containing corresponding H3 A/Texas triple cysteine substitutions (C539A, C546A, C549A) was used as the template in the PCR (Table [6](#Tab6){ref-type="table"}).Table 6**Primers for SDV rHA proteins of H3 A/Perth and 5Cys SDV rHA of H3 A/TexasSubstitutions (SDV)Primers (5′ to 3′)H3 A/Perth**C524S, C528A (Control SDV)forwardCCTTTGCCATATCAT**c**TTTTTTGCTT**gc**TGTTGCTTTGTTGGGGreverseCCCCAACAAAGCAACA**gc**AAGCAAAAAA**g**ATGATATGGCAAAGGC539A, C546A,C549A (3Cys)forwardGGGGTTCATCATGTGGGCC**gc**CCAAAAAGGCAACATTAGG**gc**CAACATT**gc**CATTTAAGTAAGTACCGreverseCGGTACTTACTTAAATG**gc**AATGTTG**gc**CCTAATGTTGCCTTTTTGG**gc**GGCCCACATGATGAACCCCC539A, C546A, C549A, C524A, C528A (5Cys)\*forwardCCTTTGCCATATCA**gc**TTTTTTGCTT**gc**TGTTGCTTTGTTGGGGreverseCCCCAACAAAGCAACA**gc**AAGCAAAAAA**gc**TGATATGGCAAAGGC64S,C76S (2Cys)forwardCCTCATCAGATCCTTGATGGAAAAAACT**ct**ACACTAATAGATGCTCTATTGGGAGACCCTCAGT**c**TGATGGCTTCCAAAATAAGAAATGGGreverseCCCATTTCTTATTTTGGAAGCCATCA**g**ACTGAGGGTCTCCCAATAGAGCATCTATTAGTGT**ag**AGTTTTTTCCATCAAGGATCTGATGAGG**H3 A/Texas**C539A, C546A, C549A (3Cys)forwardCATCATGTGGGCC**gc**CCAAAAGGGCAACATTAGG**gc**CAACATT**gc**CATTTGATAAGTAAreverseTTACTTATCAAATG**gc**AATGTTG**gc**CCTAATGTTGCCCTTTTGG**gc**GGCCCACATGATGC524A, C528A, C539A, C546A, C549A (5Cys)\*forwardTCCTTTGCCATATCAG**c**TTTTTTGCTT**gc**TGTTGCTTTGTTGGGGreverseCCCCAACAAA**gc**AACAGCAAGCAAAAAA**g**CTGATATGGCAAAGGA**\***DNA for the corresponding triple mutation (3Cys) was used as the template for the PCR reaction.
Baculovirus generation and scale-up {#Sec14}
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The parental AcMNPV baculovirus (AcB729.3) DNA was linearized to remove the polyhedrin gene and 3′ region of ORF1629, and subsequently co-transfected with the plasmid DNA containing the rHA gene of interest into *expres*SF+ (SF+) cells. The culture was incubated for \~5 days at 27°C with shaking prior to harvesting by centrifugation. The resulting viral supernatant post transfection was used to infect a monolayer of SF+ cells to purify and isolate recombinant plaques for further scale-up. Briefly, monolayers of SF+ cells in early to mid-log phase were inoculated with serial dilutions of the transfection supernatant. A 2× Protein Sciences Formulation Medium (PSFM)/Agarose overlay was applied to the plates. After 8 days at 27°C, well isolated recombinant baculovirus plaques were identified by microscopic evaluation under low magnification and by comparison with a control of wild-type baculovirus plaques with polyhedra. Recombinant baculovirus plaques were isolated and used to infect a culture of SF+ cells. The infected culture was incubated for at least 5 days at 27°C with shaking and was harvested by centrifugation. The supernatant containing the passage 1 (P1) virus was further amplified to passage 5 virus by propagation of P1 virus through P5 in SF+ cells serum-free PSFM. The viral supernatants were harvested by centrifugation to generate the virus stocks for infection.
Production and purification of rHA proteins {#Sec15}
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The recombinant P5 baculovirus stocks were used to produce the wild-type and variant rHA proteins. Cultures of SF+ cells (10 L) were seeded in PSFM media and maintained at 26-28°C with agitation in glass bioreactors equipped with an air overlay, and a desired dissolved oxygen concentration. After reaching a density of \~ 2.0-2.5 × 10^6^ cells/mL, the culture was infected by adding 2% (v/v) of the P5 working virus stock. The infected cultures were harvested approximately 56 hours post infection when the cell viability reached 40%-50%. The cell pellets were collected by centrifugation for further purification and analysis.
The rHA protein was solubilized from the SF+ cell membrane using Triton X-100 surfactant and released into a buffer for further purification. Cell debris and suspended solids were removed from the cell extract by depth filtration. The rHA in the filtrate stream was concentrated by ion exchange chromatography, and further purified from process related impurities using a hydrophobic interaction column followed by Q membrane filtration. Tangential flow filtration was used for final buffer exchange into phosphate buffered saline (PBS). The proteins were diluted, if necessary, to a final total protein concentration of 400--600 μg/mL. The purified rHA proteins were filtered through a 0.2 μm filter and stored at 4°C until further use.
Stability testing and biochemical and biophysical characterization of rHAs {#Sec16}
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The purified H3 A/Perth wild-type and SDV rHA proteins were stored under accelerated conditions by placing the samples at 25°C. Aliquots were removed on days 0, 7, 14 or 21, and 28 in order to determine potency by SRID, cross-linking by SDS-PAGE, and hydrophobicity by RP-HPLC. Additional potency measurements were made at approximately 2.5, 6, 9 and 12 months. Proper folding and functional activity were assessed by the trypsin resistance and hemagglutination assays (HA), respectively. Particle size was determined by Dynamic Light Scattering (DLS) and Size Exclusion Chromatography (SEC), thermal stability by Differential Scanning Fluorimetry (DSF), and antigenicity using the hemagglutination inhibition (HAI) assay.
The purified H3A/Texas 5Cys SDV and corresponding wild-type rHA proteins were stored under both accelerated (25°C) and real time (5°C) storage conditions. These rHA proteins were monitored for potency by SRID, cross-linking by SDS-PAGE, and hydrophobicity by RP-HPLC on a monthly basis for four months.
Total protein measurements {#Sec17}
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Total protein was determined by the bicinchoninic acid method (BCA) using the BCA protein assay kit (Cat\#23225, Thermo Scientific, Rockford, IL) following the manufacturer's recommendations.
Non-reducing and reducing SDS-PAGE {#Sec18}
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SDS-PAGE was performed under both reducing and non-reducing conditions. The rHA samples were mixed with 2× Laemmli buffer (Bio-Rad, 161--0737), and approximately 4-5 μgs of rHA was loaded per lane. For reducing conditions, a final concentration of 100 mM DTT was added to the Laemmli-rHA solution using a 500 mM DTT stock (Pierce, product\# 20291, lot\# ND170603) and incubated in a 100°C heat block for 3--5 min prior to loading on to the gel. Non-reduced and reduced samples were separated using either 3-8% Tris-Acetate gels (Life Technologies, EA03752BOX) and Tris-Acetate SDS Running Buffer (Invitrogen, LA0041) or 4-12% NuPAGE Bis-Tris Gels (Cat\# NP0323, Life Technologies Corporation, Carlsbad, CA) and 1× MES Running Buffer (50 mM MES, 50 mM Tris, 0.1% sodium dodecyl sulfate, 1 mM EDTA pH 7.3) at 150 volts for 1 hour. Protein bands were visualized by Coomassie staining (Bio-Rad, 161--0787). Gels were stained for 1 hour followed by a water wash until protein bands developed. Alternatively, purity and trypsin resistance gels were stained for 1 hour in 0.1% Brilliant Blue R, 7.7 M reagent alcohol, 1.75 M glacial acetic acid, and de-stained in 10% acetic acid. Gels were scanned using Gel Logic 212 Pro Imaging System, and densitometry was performed using the Carestream Molecular Imaging software (Carestream Health, Incorporated, New Haven, CT).
Trypsin resistance assay (TR) {#Sec19}
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Purified rHA proteins at a total protein concentration of 250 μg/mL were analyzed both with and without heat denaturation (5 minutes at 100°C) for trypsin resistance. The samples were incubated in the presence or absence of 50 μg/mL trypsin (Cat\#T1426, Sigma) for 30 min at 2-8°C. Digestion was stopped by incubating the samples in 2× disruption buffer (120 mM Tris pH 6.8, 20% glycerol, 4% sodium dodecyl sulfate, 0.2% bromophenol blue, 200 mM dithiothreitol) in a 100°C heat block for 3--5 minutes. Samples were analyzed by SDS-PAGE as described above.
Hemagglutination assay (HA) {#Sec20}
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The hemagglutination assay was performed in 96 well u-bottom microtiter plates (Corning Inc., Part\# 2797). Each monovalent bulk batch was loaded at a total protein concentration of 1 μg/mL in the first lane, and two-fold serial dilutions were performed in 1 × PBS across the plate. An equal volume of fresh, washed guinea pig red blood cells (RBCs) (Lampire Biological Labs, Cat\# 7243108) at a concentration of 0.5% in 1 × PBS was added to each well. After approximately 1 hour of incubation at room temperature, the plates were scored for agglutination of red blood cells in presence of rHA. The HA activity of the purified rHA is defined by the dilution at which partial agglutination was observed (i.e., 50% of the RBCs were agglutinated or the pellet appeared loose). If only fully agglutinated and/or tight pellets were observed, the endpoint was defined as the average of the dilutions at which agglutinated and tight pellets were observed.
Size exclusion chromatography (SEC) {#Sec21}
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Size exclusion chromatography (SEC) was performed on a Waters Alliance 2695 HPLC system (SEC-HPLC) with a PDA detector using a Biosuite 450, 8 μm HR SEC column (7.8 × 300 mm) (Waters; Cat\#186002166) or a Waters H-Class Bio UPLC system (SEC-UPLC) with PDA detector, using an acuity BEH 450 chromatography column. The latter system was used to analyze select rHAs including the wild-type and 5Cys SDV before and after pre-incubation with 1% Zwittergent 3--14, the surfactant used to pre-treat rHA samples for the SRID potency assay. For all SEC analyses, the mobile phase consisted of 1 × PBS pH 7.2 with 300 mM NaCl and a flow rate of 0.25 mL/min was used. Approximately 17.5 μg of rHA was injected per sample. Columns were calibrated by analyzing the proteins in a gel filtration HMW calibration kit (Cat\# 28-4038-42, GE Healthcare Piscataway, NJ), and a standard curve was generated. The data were analyzed using the Empower 2 Chromatography Data Software (Waters Corporation, Milford, MA).
Dynamic light scattering (DLS) {#Sec22}
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Dynamic Light Scattering was performed using a Malvern Zetasizer Nano-S (Malvern Instruments, Worcestershire, UK) according to the manufacturer's instructions. Zetasizer software (Version 6.20) was used for data analysis. Each purified rHA protein was analyzed undiluted at a total protein concentration between 400--600 μg/mL. A 70 μL aliquot of each rHA was dispensed into a micro-cuvette and measured in duplicate. Each measurement consisted of 12--14 individual scans. The volume-average size distributions from each set of scans were averaged for a given rHA.
Electron microscopy (EM) {#Sec23}
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Negative staining scanning electron microscopy was performed by Paragon Bioservices. Samples were prepared using a continuous carbon grid method, using 400-mesh copper grids with a nitrocellulose film. The rHA proteins were diluted 5-fold in water, applied to the grid, and immediately stained with uranyl formate solution (1%). Electron microscopy was performed at room temperature. Ten images were obtained for each rHA at a magnification of 135,000 × .
Differential scanning fluorimetry (DSF) {#Sec24}
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DSF was performed using a fluorescent dye (ProteoStat, Enzo Life Sciences) and a real time PCR machine (Applied Biosystems 7500 Fast Real-Time PCR System). Samples were scanned from 25°C to 99°C, and the fluorescence intensity was monitored as a function of temperature. The temperature where rHA unfolded (characterized by a transition in the fluorescence signal) was determined from the second derivative plot, and expressed as midpoint transition temperature (T~m~). The T~m~ is the temp where 50% of the molecules are in the unfolded state. The data were analyzed using the Applied Biosystems Protein Thermal Shift Software (Version 1.1).
Reverse phase (RP) HPLC analysis {#Sec25}
--------------------------------
RP-HPLC was performed using a polystyrene POROS R1/10 (2.1 mm × 100 mm) column (Applied Biosystems, 1-1012-16) on a Waters Alliance 2695 HPLC system with a PDA detector. Mobile phase A consisted of 0.1% trifluoroacetic acid, 5% acetonitrile in water (Solvent A), and mobile phase B consisted of 0.1% trifluoroacetic acid in acetonitrile (Solvent B). The column was pre-equilibrated in 20% B. The following mobile phase gradient was applied to each sample: 2 min 20-40% B, 1 min 40% B, 7.5 min 40-100% B, and 3.5 min 100% B. A flow-rate of 0.8 mL/min was used and the absorbance was monitored at 214 nm. To prevent carry-over between samples, the column was washed after each sample by injecting 1% Zwittergent (100 μL) on to the column and applying the following wash gradient: 100-20% B, 8 minutes. The rHA samples were pre-treated for 30 minutes with 25 mM DTT using a 500 mM DTT stock, and were filtered using 0.45 μm syringe filter units (Millipore, SLVR04NL) prior to RP-HPLC analysis using Empower 2 Chromatography Data Software (Waters Corporation, Milford, MA). Each sample was analyzed in duplicate using approximately 20 μg of rHA per injection.
In vitro potency measurements {#Sec26}
-----------------------------
The rHA potency was determined by the SRID assay as described previously \[[@CR19],[@CR20]\]. Briefly, rabbit polyclonal antiserum for the wild-type H3 A/Perth rHA antigen was added to melted 1% agarose (Cat\# 50010, SeaKemME, Lonza, Rockland, ME ) in 1 × PBS (pH 7.2) (Cat\# 20012--050, Life Technologies Corporation) at 54-56°C and allowed to solidify at ambient temperature on GelBond film (Cat\# 53734, Lonza, Rockland, ME). Wells of 4 mm in diameter were punched into the gels and serial dilutions of both the reference standard of known potency, and the purified rHA antigens were loaded. Reference and sample proteins were incubated with Zwittergent 3--14 (Cat\# 693017, Calbiochem, Darmstadt, Germany) at a final concentration of 1% for at least 30 minutes prior to preparing the serial dilutions in 1 × PBS containing 1% Zwittergent 3--14. The gels were placed in a sealed moist chamber at room temperature for \~18 hours. Following incubation, the gels were washed first with 1 × PBS (pH 7.2) and then with water. The gels were allowed to dry prior to staining with Coomassie Brilliant Blue R250 (Cat\#BO149, Sigma). The gels were then destained and dried again for analysis. The diameters of the precipitin rings were measured in two orthogonal directions using the GT Vision SRID Reading Program (GT Vision LLC, Hagerstown, MD). Recombinant HA potency was calculated in μg/mL by the parallel line bioassay method using reference and test rHA antigen response curves (log antigen dilution vs. log zone diameter). Statistical parameters for determining test validity were based on correlation coefficients (r ≥ 0.95) and the equality of slopes (t \< 4.604) between test and reference antigens.
Hemagglutination inhibition (HAI) {#Sec27}
---------------------------------
The HAI assay was performed in 96-well u-bottom microtiter plates. Each rHA antigen was standardized to have an HA titer of 4 HA units/25 μL (this titer provides four wells of hemagglutination activity). The standardized preparations of diluted rHA were then mixed with 2-fold serially diluted antibody. Mouse serum samples were pre-treated with receptor destroying enzyme (RDE (II) "SEIKEN", Denka Seiken Co., LTD., Japan) prior to testing to remove non-specific binding of the rHA antigen. The antigen and antibody were allowed to incubate for approximately 15 minutes prior to the addition of an equal volume of 0.5% guinea pig red blood cells. Plates were incubated at ambient temperature for approximately 45 minutes to 1 hour, the time required for the cells to completely settle in the absence of any hemagglutinating activity (negative control lane) in PBS buffer. The HAI titer, the reciprocal of the last dilution of antiserum that completely inhibits hemagglutination, was determined. The assay was performed using two polyclonal antisera: rabbit polyclonal anti-H3 antibody generated against BEVS derived wild-type H3 A/Perth rHA and sheep polyclonal anti-H3 antibody generated against bromelain cleaved HA derived from the H3/Victoria/361/2011 influenza virus propagated in eggs. A reference antigen from Center for Biologics Evaluation and Research (CBER) for H3 A/Perth/16/2009 HA (lot\# 70) was included in the assay for comparison to the rHA proteins.
Mouse study {#Sec28}
-----------
The antigen formulations were shipped to Josman LLC for immunization of acclimated Balb/c mice (10 mice per cohort). The mice received a 25 μL intramuscular injections on day 0 and day 21. The mice in the control antigen cohorts, A1, A2, and A3, received 1, 3, and 10 μg of the wild-type H3 A/Texas rHA. The mice in the test antigen cohorts, B1, B2, and B3, received 1, 3, and 10 μg of the H3 A/Texas 5Cys SDV rHA. The mice in the placebo cohort C were administered a 25 μL intramuscular injection of formulation buffer. Blood (\~250 μL) was collected from each mouse before the first injection on day 0 and at the end of the study on day 42. The blood was allowed to clot for approximately 2 hours at ambient temperature prior to centrifuging to isolate the sera in the supernatant. The sera samples were stored frozen at −20°C until testing in the HAI assay. This study was performed under protocol JLP-005.010 by Josman LLC, a licensed research facility (USDA license number 93-R-0260; OLAW-NIH/PHS Assurance license number A3404-01) that adheres to guidelines set forth through the Animal Welfare Act (7 U.S.C. 2131 et seq.), and through the Office of Laboratory Animal Welfare of the National Institutes of Health.
**Competing interests**
All authors work for Protein Sciences Corporation, which has a financial interest in influenza vaccines.
**Authors' contributions**
KMH designed the study, performed testing including potency measurements, RP-HPLC, and HAI, coordinated EM testing and the mouse immunogenicity study, and drafted the manuscript. PSR performed stability testing including total protein, potency measurements, SDS-PAGE, RP-HPLC, and DLS. EEM performed DSF testing and the modelling work using the TMHMM software, and helped to draft the manuscript, and participated in data interpretation. YH performed site directed mutagenesis and cloning, and helped draft the manuscript. NK and JM generated the recombinant baculovirus, prepared the fermentations, and helped draft the manuscript. MJR purified the rHA proteins and performed the trypsin resistance and hemagglutination assays. DGR performed the SEC testing, helped to draft the manuscript, and participated in the data interpretation. IKS supervised the project, participated in the experimental design, data interpretation, and manuscript preparation. MMC and CEM participated in the manuscript preparation. All authors read and approved the final manuscript.
We would like to thank Drs. Barry Buckland, Wayne Hachey and Elena Semenova from Protein Sciences Corporation for critically reading the manuscript and Armen Donabedian from Biomedical Advanced Research and Development Authority (BARDA) for his valued insights and support. We would like to thank Andrea Lassen, Peter DiMauro, and Guang Liu for their expert technical contributions. This project has been funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, Department of Health and Human Services, under Contract No. HHSO100200900106C.
| 2024-02-19T01:26:35.434368 | https://example.com/article/1147 |
Tuesday, October 03, 2006
What Happened to the Temple Menorah after the Hurban?
The Peace Temple [Templum Paci] in Rome was not the end of the Menorah's wanderings. This temple was one of the most grandiose in Rome [see Italian description below]. Built in the year 75 CE, the great nave in the middle had eight Corinthian columns. The building is believed to have been 300 feet by 200 feet.
The Vandals, a Germanic tribe who had migrated through Gaul [today France] and Spain to North Africa, were the next usurpers of the Menorah. They attacked Rome [452 CE], looted the Peace Temple, and brought the Menorah --with other loot-- to their capital of Carthage, now in ruins. Then, the army of the Eastern Roman Empire --usually called the Byzantine Empire-- conquered Carthage [534 CE] led by its outstanding general Belisarius. He took the Menorah and other Temple loot back to his capital, Constantinople [today Istanbul, called in Hebrew Kusta], then ruled by Justinian. There too the Menorah was carried in a victory procession, as in Rome some 460 years before. The Menorah was deposited in the palace compound of the emperors in Kusta.
Then, according to Procopius, a Jew connected to the court warned the officials that the presence of the Menorah and other Jewish holy objects in Rome had brought disaster to the Romans, and likewise its presence in Carthage had done the same for the Vandals. He said that it would be right that they be placed in the Land where King Solomon had set them up. Supposedly, Justinian then ordered that they be transferred to one of the Christian holy places in Jerusalem. If the Menorah and other Jewish holy objects were deposited in one of the Jerusalem churches, then it is likely --according to Yohanan Levi-- that they were looted by the Persians in their invasion of 614.
However, Levi seems not to take into account that the Persians at the time were allied with the Jews living in Israel --still a substantial population at that time. The Jews would have been extremely eager to have the Menorah and the other objects restored to them. Levi considers that the guardians of the church depository of the Jewish objects might have buried or otherwise hidden them from the Persians. The church where Levi thinks they were placed was destroyed by an earthquake at the end of the 8th century and not rebuilt [the Arab rulers did not allow rebuilding of destroyed religious buildings of dhimmis, non-Muslims; this prohibition was --and is-- part of the dhimma]. It is conjectured that this church was located facing the southwest corner of the Temple Mount. Hence, Levi conjectures, the holy objects might be located under the rubble of the church's ruins. Levi died an untimely death in 1945. Since the 1967 Six Day War, that area has been excavated without the holy objects of the Temple turning up.
Nevertheless, the 10th century Byzantine emperor, Constantinos Porphyrogennitos, reported that the Menorah was kept in the imperial palace and was lit on the occasion of holiday processions. A seventh century Jewish midrash reported that some of the holy Temple objects were kept in the House of Julian, a library built by the scholarly emperor Julian ["the Apostate"] in the palace compound [see Levi]. Maybe the Byzantine court kept the Menorah there too. Levi says that Titus looted two golden Menorahs from the Jerusalem Temple, according to Josephus. He considers the possibility that two menorahs were brought to Carthage and from there to Kusta, and that Justinian sent one to Jerusalem and kept the other in Kusta in the imperial palace compound [fn 11]. Levi goes on to speculate that the menorah that stayed in Kusta was looted by the Crusaders and Venetians in 1204, together with other valuable objects from the palace. If so, the objects looted in 1204 in Kusta may have been melted down for their simple worth as gold.
The depiction of the Menorah on the Arch of Titus in Rome is the model for the menorah on official Israeli documents. There are other models of what the Menorah looked like. These are found on ancient Jewish coins, for example, plus stone carvings, mosaic floors, and paintings in ancient synagogues in Israel and elsewhere, on ornamented glassware, amulets, seals, rings, etc. Representations of the Menorah are also found on Jewish sarcophagi and ossuaries, and in the Jewish catacombs of Rome [see "Menorah," Encyclopedia Judaica, vol 11]. Of course, all models have seven branches for seven lights and these branches are on a vertical plane.
Here is a description in Italian of the "Peace Temple" in Rome built by the Flavians. According to this description, the "Peace Temple" contained loot from Judea [IVDAEA] besides the objects looted from the Second Temple in Jerusalem.
About
The world swims in lies. Who doesn't know that? Even the dupes are told there are lies about. We aim to dispel the fog of lies, especially about Israel, like our prophets of old and our poets like Yehudah haLevi.
We feature historic sources, documents, excerpts from the classics, etc.
How shall I render my vows and my bonds, While yet
Zion lieth beneath the fetter of Edom, and I in Arab chains?
The false prophets cry Peace, and there is no peace.
A new post every 2 or 3 days.
About Me
צלום דבורה בת יהודה לייב ז''ל
Dvoyreh bas Yehudah Leyb, Eliyahu's mother. My own photo will have to await more peaceful times.
I have been an observer of
the human comedy, and the human tragedy for many years. | 2023-10-22T01:26:35.434368 | https://example.com/article/2154 |
/*
* Copyright (C) 2013 The Android Open Source Project
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package com.example.android.common.media;
import android.media.*;
import android.os.Handler;
import android.os.Looper;
import android.view.Surface;
import java.io.IOException;
import java.nio.ByteBuffer;
import java.util.ArrayDeque;
import java.util.Locale;
import java.util.Queue;
/**
* Simplifies the MediaCodec interface by wrapping around the buffer processing operations.
*/
public class MediaCodecWrapper {
// Handler to use for {@code OutputSampleListener} and {code OutputFormatChangedListener}
// callbacks
private Handler mHandler;
// Callback when media output format changes.
public interface OutputFormatChangedListener {
void outputFormatChanged(MediaCodecWrapper sender, MediaFormat newFormat);
}
private OutputFormatChangedListener mOutputFormatChangedListener = null;
/**
* Callback for decodes frames. Observers can register a listener for optional stream
* of decoded data
*/
public interface OutputSampleListener {
void outputSample(MediaCodecWrapper sender, MediaCodec.BufferInfo info, ByteBuffer buffer);
}
/**
* The {@link MediaCodec} that is managed by this class.
*/
private MediaCodec mDecoder;
// References to the internal buffers managed by the codec. The codec
// refers to these buffers by index, never by reference so it's up to us
// to keep track of which buffer is which.
private ByteBuffer[] mInputBuffers;
private ByteBuffer[] mOutputBuffers;
// Indices of the input buffers that are currently available for writing. We'll
// consume these in the order they were dequeued from the codec.
private Queue<Integer> mAvailableInputBuffers;
// Indices of the output buffers that currently hold valid data, in the order
// they were produced by the codec.
private Queue<Integer> mAvailableOutputBuffers;
// Information about each output buffer, by index. Each entry in this array
// is valid if and only if its index is currently contained in mAvailableOutputBuffers.
private MediaCodec.BufferInfo[] mOutputBufferInfo;
private MediaCodecWrapper(MediaCodec codec) {
mDecoder = codec;
codec.start();
mInputBuffers = codec.getInputBuffers();
mOutputBuffers = codec.getOutputBuffers();
mOutputBufferInfo = new MediaCodec.BufferInfo[mOutputBuffers.length];
mAvailableInputBuffers = new ArrayDeque<>(mOutputBuffers.length);
mAvailableOutputBuffers = new ArrayDeque<>(mInputBuffers.length);
}
/**
* Releases resources and ends the encoding/decoding session.
*/
public void stopAndRelease() {
mDecoder.stop();
mDecoder.release();
mDecoder = null;
mHandler = null;
}
/**
* Getter for the registered {@link OutputFormatChangedListener}
*/
public OutputFormatChangedListener getOutputFormatChangedListener() {
return mOutputFormatChangedListener;
}
/**
*
* @param outputFormatChangedListener the listener for callback.
* @param handler message handler for posting the callback.
*/
public void setOutputFormatChangedListener(final OutputFormatChangedListener
outputFormatChangedListener, Handler handler) {
mOutputFormatChangedListener = outputFormatChangedListener;
// Making sure we don't block ourselves due to a bad implementation of the callback by
// using a handler provided by client.
mHandler = handler;
if (outputFormatChangedListener != null && mHandler == null) {
if (Looper.myLooper() != null) {
mHandler = new Handler();
} else {
throw new IllegalArgumentException(
"Looper doesn't exist in the calling thread");
}
}
}
/**
* Constructs the {@link MediaCodecWrapper} wrapper object around the video codec.
* The codec is created using the encapsulated information in the
* {@link MediaFormat} object.
*
* @param trackFormat The format of the media object to be decoded.
* @param surface Surface to render the decoded frames.
* @return
*/
public static MediaCodecWrapper fromVideoFormat(final MediaFormat trackFormat,
Surface surface) throws IOException {
MediaCodecWrapper result = null;
MediaCodec videoCodec = null;
// BEGIN_INCLUDE(create_codec)
final String mimeType = trackFormat.getString(MediaFormat.KEY_MIME);
// Check to see if this is actually a video mime type. If it is, then create
// a codec that can decode this mime type.
if (mimeType.contains("video/")) {
videoCodec = MediaCodec.createDecoderByType(mimeType);
videoCodec.configure(trackFormat, surface, null, 0);
}
// If codec creation was successful, then create a wrapper object around the
// newly created codec.
if (videoCodec != null) {
result = new MediaCodecWrapper(videoCodec);
}
// END_INCLUDE(create_codec)
return result;
}
/**
* Write a media sample to the decoder.
*
* A "sample" here refers to a single atomic access unit in the media stream. The definition
* of "access unit" is dependent on the type of encoding used, but it typically refers to
* a single frame of video or a few seconds of audio. {@link android.media.MediaExtractor}
* extracts data from a stream one sample at a time.
*
* @param input A ByteBuffer containing the input data for one sample. The buffer must be set
* up for reading, with its position set to the beginning of the sample data and its limit
* set to the end of the sample data.
*
* @param presentationTimeUs The time, relative to the beginning of the media stream,
* at which this buffer should be rendered.
*
* @param flags Flags to pass to the decoder. See {@link MediaCodec#queueInputBuffer(int,
* int, int, long, int)}
*
* @throws MediaCodec.CryptoException
*/
public boolean writeSample(final ByteBuffer input,
final MediaCodec.CryptoInfo crypto,
final long presentationTimeUs,
final int flags) throws MediaCodec.CryptoException, WriteException {
boolean result = false;
int size = input.remaining();
// check if we have dequed input buffers available from the codec
if (size > 0 && !mAvailableInputBuffers.isEmpty()) {
int index = mAvailableInputBuffers.remove();
ByteBuffer buffer = mInputBuffers[index];
// we can't write our sample to a lesser capacity input buffer.
if (size > buffer.capacity()) {
throw new MediaCodecWrapper.WriteException(String.format(Locale.US,
"Insufficient capacity in MediaCodec buffer: "
+ "tried to write %d, buffer capacity is %d.",
input.remaining(),
buffer.capacity()));
}
buffer.clear();
buffer.put(input);
// Submit the buffer to the codec for decoding. The presentationTimeUs
// indicates the position (play time) for the current sample.
if (crypto == null) {
mDecoder.queueInputBuffer(index, 0, size, presentationTimeUs, flags);
} else {
mDecoder.queueSecureInputBuffer(index, 0, crypto, presentationTimeUs, flags);
}
result = true;
}
return result;
}
private static MediaCodec.CryptoInfo sCryptoInfo = new MediaCodec.CryptoInfo();
/**
* Write a media sample to the decoder.
*
* A "sample" here refers to a single atomic access unit in the media stream. The definition
* of "access unit" is dependent on the type of encoding used, but it typically refers to
* a single frame of video or a few seconds of audio. {@link android.media.MediaExtractor}
* extracts data from a stream one sample at a time.
*
* @param extractor Instance of {@link android.media.MediaExtractor} wrapping the media.
*
* @param presentationTimeUs The time, relative to the beginning of the media stream,
* at which this buffer should be rendered.
*
* @param flags Flags to pass to the decoder. See {@link MediaCodec#queueInputBuffer(int,
* int, int, long, int)}
*
* @throws MediaCodec.CryptoException
*/
public boolean writeSample(final MediaExtractor extractor,
final boolean isSecure,
final long presentationTimeUs,
int flags) {
boolean result = false;
if (!mAvailableInputBuffers.isEmpty()) {
int index = mAvailableInputBuffers.remove();
ByteBuffer buffer = mInputBuffers[index];
// reads the sample from the file using extractor into the buffer
int size = extractor.readSampleData(buffer, 0);
if (size <= 0) {
flags |= MediaCodec.BUFFER_FLAG_END_OF_STREAM;
}
// Submit the buffer to the codec for decoding. The presentationTimeUs
// indicates the position (play time) for the current sample.
if (!isSecure) {
mDecoder.queueInputBuffer(index, 0, size, presentationTimeUs, flags);
} else {
extractor.getSampleCryptoInfo(sCryptoInfo);
mDecoder.queueSecureInputBuffer(index, 0, sCryptoInfo, presentationTimeUs, flags);
}
result = true;
}
return result;
}
/**
* Performs a peek() operation in the queue to extract media info for the buffer ready to be
* released i.e. the head element of the queue.
*
* @param out_bufferInfo An output var to hold the buffer info.
*
* @return True, if the peek was successful.
*/
public boolean peekSample(MediaCodec.BufferInfo out_bufferInfo) {
// dequeue available buffers and synchronize our data structures with the codec.
update();
boolean result = false;
if (!mAvailableOutputBuffers.isEmpty()) {
int index = mAvailableOutputBuffers.peek();
MediaCodec.BufferInfo info = mOutputBufferInfo[index];
// metadata of the sample
out_bufferInfo.set(
info.offset,
info.size,
info.presentationTimeUs,
info.flags);
result = true;
}
return result;
}
/**
* Processes, releases and optionally renders the output buffer available at the head of the
* queue. All observers are notified with a callback. See {@link
* OutputSampleListener#outputSample(MediaCodecWrapper, android.media.MediaCodec.BufferInfo,
* java.nio.ByteBuffer)}
*
* @param render True, if the buffer is to be rendered on the {@link Surface} configured
*
*/
public void popSample(boolean render) {
// dequeue available buffers and synchronize our data structures with the codec.
update();
if (!mAvailableOutputBuffers.isEmpty()) {
int index = mAvailableOutputBuffers.remove();
// releases the buffer back to the codec
mDecoder.releaseOutputBuffer(index, render);
}
}
/**
* Synchronize this object's state with the internal state of the wrapped
* MediaCodec.
*/
private void update() {
// BEGIN_INCLUDE(update_codec_state)
int index;
// Get valid input buffers from the codec to fill later in the same order they were
// made available by the codec.
while ((index = mDecoder.dequeueInputBuffer(0)) != MediaCodec.INFO_TRY_AGAIN_LATER) {
mAvailableInputBuffers.add(index);
}
// Likewise with output buffers. If the output buffers have changed, start using the
// new set of output buffers. If the output format has changed, notify listeners.
MediaCodec.BufferInfo info = new MediaCodec.BufferInfo();
while ((index = mDecoder.dequeueOutputBuffer(info, 0)) != MediaCodec.INFO_TRY_AGAIN_LATER) {
switch (index) {
case MediaCodec.INFO_OUTPUT_BUFFERS_CHANGED:
mOutputBuffers = mDecoder.getOutputBuffers();
mOutputBufferInfo = new MediaCodec.BufferInfo[mOutputBuffers.length];
mAvailableOutputBuffers.clear();
break;
case MediaCodec.INFO_OUTPUT_FORMAT_CHANGED:
if (mOutputFormatChangedListener != null) {
mHandler.post(new Runnable() {
@Override
public void run() {
mOutputFormatChangedListener
.outputFormatChanged(MediaCodecWrapper.this,
mDecoder.getOutputFormat());
}
});
}
break;
default:
// Making sure the index is valid before adding to output buffers. We've already
// handled INFO_TRY_AGAIN_LATER, INFO_OUTPUT_FORMAT_CHANGED &
// INFO_OUTPUT_BUFFERS_CHANGED i.e all the other possible return codes but
// asserting index value anyways for future-proofing the code.
if (index >= 0) {
mOutputBufferInfo[index] = info;
mAvailableOutputBuffers.add(index);
} else {
throw new IllegalStateException("Unknown status from dequeueOutputBuffer");
}
break;
}
}
// END_INCLUDE(update_codec_state)
}
private class WriteException extends Throwable {
private WriteException(final String detailMessage) {
super(detailMessage);
}
}
}
| 2024-04-05T01:26:35.434368 | https://example.com/article/9738 |
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Toronto police say two men were injured in separate shootings overnight.
Police said officers received reports of the first incident around 11:50 p.m. Monday.
A 19-year-old man was shot in the leg on Thorncliffe Park Drive in East York and transported to hospital in non-life-threatening condition, police said.
Officers said they received reports of the second shooting around 2:20 a.m. Tuesday when a caller reported hearing gunshots and seeing people running and a vehicle driving away on Dollery Court in North York.
A 25-year-old man was later located with injuries to his buttocks and forearm, police said.
He was transported to hospital with non-life-threatening injuries.
Story continues below advertisement
Police have not released suspect descriptions in either of the shootings.
1:53 Man fatally stabbed near downtown Toronto Man fatally stabbed near downtown Toronto | 2024-06-24T01:26:35.434368 | https://example.com/article/2554 |
"I've never seen such a high prevalence of very sick animals," lead author Lori Schwacke of the Medical University of South Carolina noted. "There is disease in any wild population. We just haven't seen animals that were in such bad shape as what we saw in Barataria Bay."
Researchers captured 32 dolphins from the bay, a 24-km stretch near southeastern Louisiana, and deemed half of them to be seriously ill or dying.
Among the cases? Liver disease, crippling pneumonia and even a pregnant female carrying a dead fetus.
In a company statement, BP said: "Symptoms observed in the study have been seen in other dolphin mortality events that have been related to contaminants and conditions found in the northern Gulf, such as polychlorinated biphenyls (PCBs), DDT and pesticides.
"Any increase in reported mortality observations after the spill may simply reflect an increase in the number of observers in the Gulf and an increased awareness among Gulf residents rather than an actual increase in dolphin deaths."
The study results, according to BP, are "inconclusive as to any causation associated with the spill." | 2024-07-19T01:26:35.434368 | https://example.com/article/4986 |
Prevalence of diagnosed Tourette syndrome in persons aged 6-17 years - United States, 2007.
Tourette syndrome (TS) is an inheritable, childhood-onset neurologic disorder marked by persistent multiple motor tics and at least one vocal tic. Tics are involuntary, repetitive, stereotypic movements or vocalizations that are usually sudden and rapid and often can be suppressed for short periods. The prevalence of TS is uncertain; the broad range of worldwide estimates, from 1-30 per 1,000 population, likely is the result of differences in study methodology. This report presents the first estimate of national prevalence of diagnosed TS among a national sample of U.S. children and adolescents aged 6-17 years. Based on data from the 2007 National Survey of Children's Health (NSCH), the estimated prevalence of a lifetime diagnosis of TS by parent report was 3.0 per 1,000. A diagnosis of TS was almost three times as likely for boys as girls, twice as likely for persons aged 12-17 years than for those aged 6-11 years, and twice as likely for non-Hispanic white persons than for Hispanic and non-Hispanic black persons. Among persons ever diagnosed with TS, 79% also had been diagnosed with at least one co-occurring mental health or neurodevelopmental condition. CDC sponsors efforts by the Tourette Syndrome Association to educate health-care providers and school personnel about TS to ensure earlier identification and promote appropriate medical, educational, and comprehensive behavioral interventions for children with TS and co-occurring mental health or neurodevelopmental conditions. | 2024-01-03T01:26:35.434368 | https://example.com/article/5413 |
Q:
OpenCv with Android studio 1.3+ using new gradle - undefined reference
I'm having trouble using native OpenCv 2.4.11 (3.0.0 is also ok) with Android Studio 1.3+, with new ndk support. All tutorials about .mk files, but I want to use it with new experimental gradle.
Using Kiran answer OpenCV in Android Studio
I achived to work fine in java. Also I have changed gradle-wrapper.properties:
distributionUrl=https\://services.gradle.org/distributions/gradle-2.5-all.zip
build.gradle(application):
classpath 'com.android.tools.build:gradle-experimental:0.2.0'
build.gradle(module):
apply plugin: 'com.android.model.application'
model {
android {
compileSdkVersion = 23
buildToolsVersion = "23.0.0"
defaultConfig.with {
applicationId = "android.overloaded.nativetestv4"
minSdkVersion.apiLevel = 18
targetSdkVersion.apiLevel = 23
versionCode = 1
versionName = "1.0"
}
}
android.ndk{
moduleName = "mymodule"
ldLibs += ['log']
cppFlags += "-std=c++11"
cppFlags += "-fexceptions"
cppFlags += "-I${file("C:/DevAndroid/OpenCV-android-sdk/sdk/native/jni/include")}".toString()
cppFlags += "-I${file("C:/DevAndroid/OpenCV-android-sdk/sdk/native/jni/include/opencv")}".toString()
ldLibs += ["android", "EGL", "GLESv2", "dl", "log", "z"] //added z
stl = "stlport_static"//"gnustl_shared" changed to stlport static
}
android.buildTypes {
release {
minifyEnabled = false
proguardFiles += file('proguard-rules.pro')
}
}
android.productFlavors { //added all productFlavors code
create("arm") {
ndk.with {
abiFilters += "armeabi"
File curDir = file('./')
curDir = file(curDir.absolutePath)
String libsDir = curDir.absolutePath+"\\src\\main\\jniLibs\\armeabi\\" //"-L" +
ldLibs += libsDir + "libnative_camera_r4.3.0.so"
ldLibs += libsDir + "libopencv_contrib.a"
ldLibs += libsDir + "libopencv_core.a"
ldLibs += libsDir + "libopencv_highgui.a"
ldLibs += libsDir + "libopencv_imgproc.a"
ldLibs += libsDir + "libopencv_info.so"
ldLibs += libsDir + "libopencv_java.so"
ldLibs += libsDir + "libopencv_legacy.a"
ldLibs += libsDir + "libopencv_ml.a"
ldLibs += libsDir + "libopencv_ts.a"
}
}
create("armv7") {
ndk.with {
abiFilters += "armeabi-v7a"
File curDir = file('./')
curDir = file(curDir.absolutePath)
String libsDir = curDir.absolutePath+"\\src\\main\\jniLibs\\armeabi-v7a\\" //"-L" +
ldLibs += libsDir + "libnative_camera_r4.3.0.so"
ldLibs += libsDir + "libopencv_contrib.a"
ldLibs += libsDir + "libopencv_core.a"
ldLibs += libsDir + "libopencv_highgui.a"
ldLibs += libsDir + "libopencv_imgproc.a"
ldLibs += libsDir + "libopencv_info.so"
ldLibs += libsDir + "libopencv_java.so"
ldLibs += libsDir + "libopencv_legacy.a"
ldLibs += libsDir + "libopencv_ml.a"
ldLibs += libsDir + "libopencv_ts.a"
}
}
create("fat") {
}
}
dependencies {
compile fileTree(include: ['*.jar'], dir: 'libs')
compile 'com.android.support:appcompat-v7:23.0.0'
compile project(':openCVLibrary2411')
}
With this changes I can call my native dummy function in c++ file under jni folder. Also #include <opencv2/core/core.hpp> and others are supported by CLion... When I declare cv::Mat mat; gives me this error:
Linker failed while linking libmymodule.so failed.
C:\DevAndroid\OpenCV-android-sdk\sdk\native\jni\include/opencv2/core/mat.hpp:278: error: undefined reference to 'cv::fastFree(void*)'
C:\DevAndroid\OpenCV-android-sdk\sdk\native\jni\include/opencv2/core/mat.hpp:367: error: undefined reference to 'cv::Mat::deallocate()'
collect2.exe: error: ld returned 1 exit status
c++ code:
#include <jni.h>
#include <vector>
#include <string>
#include "helpers.h"
#include <opencv2/core/core.hpp> //This is supported by CLion
#include <opencv2/imgproc/imgproc.hpp>
#include <opencv2/highgui/highgui.hpp>
using namespace std;
extern "C" {
JNIEXPORT jstring JNICALL
Java_android_overloaded_nativetestv4_MainActivity_FuncV1(JNIEnv *env, jclass type) {
cv::Mat mat; //causing error
string s = "Cpp v1 - succ ";
return env->NewStringUTF(s.data());
}
}
Update
- added "z" to ldLibs
- added android.productFlavors block
Now compilation is successfull, application starts for second and then crashes with this messages
Event log:
IllegalArgumentException: Error while starting native debug session: Unable to find process for android.overloaded.nativetestv4 on device huawei-huawei_y530_u00-64a6513ccd8e
Debug info:
Restart ADB integration and try again
Waiting for process: android.overloaded.nativetestv4
DEVICE SHELL COMMAND: run-as android.overloaded.nativetestv4 mkdir -p /data/data/android.overloaded.nativetestv4/lldb/bin
DEVICE SHELL COMMAND: cat /data/local/tmp/lldb-server | run-as android.overloaded.nativetestv4 sh -c 'cat > /data/data/android.overloaded.nativetestv4/lldb/bin/lldb-server; chmod 700 /data/data/android.overloaded.nativetestv4/lldb/bin/lldb-server'
DEVICE SHELL COMMAND: rm /data/local/tmp/lldb-server
DEVICE SHELL COMMAND: cat /data/local/tmp/start_lldb_server.sh | run-as android.overloaded.nativetestv4 sh -c 'cat > /data/data/android.overloaded.nativetestv4/lldb/bin/start_lldb_server.sh; chmod 700 /data/data/android.overloaded.nativetestv4/lldb/bin/start_lldb_server.sh'
DEVICE SHELL COMMAND: rm /data/local/tmp/start_lldb_server.sh
Now Launching Native Debug Session
Error while starting native debug session: java.lang.IllegalArgumentException: Unable to find process for android.overloaded.nativetestv4 on device huawei-huawei_y530_u00-64a6513ccd8e
log:
A/libc﹕ Fatal signal 11 (SIGSEGV) at 0x00000000 (code=1), thread 3077 (ed.nativetestv4)
A:
After few weeks of pain, I succed. Here is my correct code for Android studio 1.3.1, OpenCv 2.4.11. First you should do this OpenCV in Android Studio
(don't use paths which contains white space, both for project and opencv extraction folder) then, for opencv to be native:
gradle-wrapper.properties:
distributionUrl=https\://services.gradle.org/distributions/gradle-2.5-all.zip
build.gradle(application):
classpath 'com.android.tools.build:gradle-experimental:0.2.0'
build.gradle(module):
apply plugin: 'com.android.model.application'
model {
android {
compileSdkVersion = 23
buildToolsVersion = "23.0.0"
defaultConfig.with {
applicationId = "android.overloaded.nativetestv4"
minSdkVersion.apiLevel = 18
targetSdkVersion.apiLevel = 23
versionCode = 1
versionName = "1.0"
}
}
android.ndk{
moduleName = "mymodule"
ldLibs += ['log']
cppFlags += "-std=c++11"
cppFlags += "-fexceptions"
cppFlags += "-I${file("C:/DevAndroid/OpenCV-android-sdk/sdk/native/jni/include")}".toString()
cppFlags += "-I${file("C:/DevAndroid/OpenCV-android-sdk/sdk/native/jni/include/opencv")}".toString()
// ldFlags += linkOpt
ldLibs += ["android", "EGL", "GLESv2", "dl", "log", "z"]// , "ibopencv_core"
stl = "gnustl_shared"//"gnustl_static"//"gnustl_shared"//"stlport_static"
}
android.buildTypes {
release {
minifyEnabled = false
proguardFiles += file('proguard-rules.pro')
}
}
android.productFlavors {
create("arm") {
ndk.with {
abiFilters += "armeabi"
File curDir = file('./')
curDir = file(curDir.absolutePath)
String libsDir = curDir.absolutePath+"\\src\\main\\jniLibs\\armeabi\\" //"-L" +
ldLibs += libsDir + "libnative_camera_r4.3.0.so"
ldLibs += libsDir + "libopencv_contrib.a"
ldLibs += libsDir + "libopencv_core.a"
ldLibs += libsDir + "libopencv_highgui.a"
ldLibs += libsDir + "libopencv_imgproc.a"
ldLibs += libsDir + "libopencv_info.so"
ldLibs += libsDir + "libopencv_java.so"
ldLibs += libsDir + "libopencv_legacy.a"
ldLibs += libsDir + "libopencv_ml.a"
ldLibs += libsDir + "libopencv_ts.a"
}
}
create("armv7") {
ndk.with {
abiFilters += "armeabi-v7a"
File curDir = file('./')
curDir = file(curDir.absolutePath)
String libsDir = curDir.absolutePath+"\\src\\main\\jniLibs\\armeabi-v7a\\" //"-L" +
ldLibs += libsDir + "libnative_camera_r4.3.0.so"
ldLibs += libsDir + "libopencv_contrib.a"
ldLibs += libsDir + "libopencv_core.a"
ldLibs += libsDir + "libopencv_highgui.a"
ldLibs += libsDir + "libopencv_imgproc.a"
ldLibs += libsDir + "libopencv_info.so"
ldLibs += libsDir + "libopencv_java.so"
ldLibs += libsDir + "libopencv_legacy.a"
ldLibs += libsDir + "libopencv_ml.a"
ldLibs += libsDir + "libopencv_ts.a"
}
}
create("x86") {
ndk.with {
abiFilters += "x86"
}
}
create("mips") {
ndk.with {
abiFilters += "mips"
}
}
create("fat") {
}
}
}
dependencies {
compile fileTree(include: ['*.jar'], dir: 'libs')
compile 'com.android.support:appcompat-v7:23.0.0'
compile project(':openCVLibrary2411')
}
.cpp
#include <jni.h>
#include <vector>
#include <string>
#include "helpers.h"
#include <opencv2/core/core.hpp>
using namespace std;
#ifdef __cplusplus
extern "C" {
#endif
JNIEXPORT jstring JNICALL
Java_android_overloaded_nativetestv4_MainActivity_FuncV1(JNIEnv *env, jclass type) {
cv::Mat mat(33,22, 1);
string s = "Cpp v1 - succ, rows#:" + Helpers::ToStringNum(mat.rows);
Helpers::Log(s);
return env->NewStringUTF(s.data());
}
}
.java
package android.overloaded.nativetestv4;
import android.support.v7.app.AppCompatActivity;
import android.os.Bundle;
import android.view.Menu;
import android.view.MenuItem;
import android.widget.TextView;
import android.widget.Toast;
public class MainActivity extends AppCompatActivity
{
static {
System.loadLibrary("mymodule");
}
public static native String FuncV1();
@Override
protected void onCreate(Bundle savedInstanceState)
{
super.onCreate(savedInstanceState);
setContentView(R.layout.activity_main);
Toast.makeText(this, FuncV1(), Toast.LENGTH_LONG).show();
((TextView)findViewById(R.id.txtInfo)).setText(FuncV1());
}
Update for Android Studio 1.5.1, OpenCV 3.1
1. First you should do this OpenCV in Android Studio (don't use paths which contains white space, both for project and opencv extraction folder), after that you should have normal working Java app
2. Change build.gradle in project root:
buildscript {
repositories {
jcenter()
}
dependencies {
classpath "com.android.tools.build:gradle-experimental:0.4.0"
// NOTE: Do not place your application dependencies here; they belong
// in the individual module build.gradle files
}
}
allprojects {
repositories {
jcenter()
}
}
task clean(type: Delete) {
delete rootProject.buildDir
}
Change gradle-wrapper.properties:
distributionBase=GRADLE_USER_HOME
distributionPath=wrapper/dists
zipStoreBase=GRADLE_USER_HOME
zipStorePath=wrapper/dists
distributionUrl=https\://services.gradle.org/distributions/gradle-2.8-all.zip
Change build.gradle in opencv module:
apply plugin: 'com.android.model.library'
model {
android {
compileSdkVersion = 23
buildToolsVersion = "23.0.2"
defaultConfig.with {
minSdkVersion.apiLevel = 11
targetSdkVersion.apiLevel = 23
}
}
android.buildTypes {
release {
minifyEnabled = false
proguardFiles.add(file("proguard-rules.txt"))
}
}
}
Change build.gradle in app module:
apply plugin: 'com.android.model.application'
model {
android {
compileSdkVersion = 23
buildToolsVersion = "23.0.2"
defaultConfig.with {
applicationId = "android.overloaded.opencv31v1" //Name of package
minSdkVersion.apiLevel = 11
targetSdkVersion.apiLevel = 23
versionCode = 1
versionName = "1.0"
}
}
android.ndk {
moduleName = "native" // Name of C++ module, for System.loadLibrary("native")
cppFlags.add("-std=c++11") // Add provisions to allow C++11 functionality
cppFlags.add("-fexceptions")
// YOUR OPENCV DIRECTORY!!!
cppFlags.add("-I${file("C:/DevAndroid/OpenCV-android-sdk/sdk/native/jni/include")}".toString())
ldLibs.addAll(["android", "EGL", "GLESv2", "dl", "log", "z"])
stl = "gnustl_shared"
}
android.buildTypes {
release {
minifyEnabled = false
proguardFiles.add(file("proguard-rules.txt"))
}
}
android.productFlavors {
create("arm") {
ndk.with{
abiFilters.add("armeabi")
File curDir = file('./')
curDir = file(curDir.absolutePath)
String libsDir = curDir.absolutePath + "\\src\\main\\jniLibs\\armeabi\\"
ldLibs.add(libsDir + "libopencv_core.a")
ldLibs.add(libsDir + "libopencv_highgui.a")
ldLibs.add(libsDir + "libopencv_imgproc.a")
ldLibs.add(libsDir + "libopencv_java3.so")
ldLibs.add(libsDir + "libopencv_ml.a")
}
}
create("armv7") {
ndk.with {
abiFilters.add("armeabi-v7a")
File curDir = file('./')
curDir = file(curDir.absolutePath)
String libsDir = curDir.absolutePath + "\\src\\main\\jniLibs\\armeabi-v7a\\"
ldLibs.add(libsDir + "libopencv_core.a")
ldLibs.add(libsDir + "libopencv_highgui.a")
ldLibs.add(libsDir + "libopencv_imgproc.a")
ldLibs.add(libsDir + "libopencv_java3.so")
ldLibs.add(libsDir + "libopencv_ml.a")
ldLibs.add(libsDir + "libopencv_ts.a")
}
}
}
android.sources{
main{
jni{
source{
srcDirs += ['src/main/jniMy']
}
}
}
}
}
dependencies {
compile fileTree(dir: "libs", include: [$/*.jar/$])
compile "com.android.support:appcompat-v7:23.1.1" //Do not use 23.2.0
compile project(":openCVLibrary310")
}
Create dir app/src/main/jniMy, this is place for yours .cpp files
Optionally create file chelper.c in jniMy, with this code:
#ifndef OPENCV31V1_CHELPER_H
#define OPENCV31V1_CHELPER_H
#include <jni.h>
#include <vector>
#include <string>
#include <sstream>
#include <android/log.h>
using namespace std;
class Helpers{
public:
template <typename T>
static string ToStringNum(T tNumber){
ostringstream ostrStream;
ostrStream << tNumber;
return ostrStream.str();
}
static void Log(string s){
__android_log_print(ANDROID_LOG_INFO, "My", s.data());
}
static void Log(std::exception ee){
string s = "Exception: " + string(ee.what()) ;
__android_log_print(ANDROID_LOG_INFO, "My", s.data());
}
static long Time(){
struct timespec now;
clock_gettime(CLOCK_MONOTONIC, &now);
return (long)((int64_t)now.tv_sec * 1000LL + now.tv_nsec /1000000LL);
}
static string Time(long iTime){
return ToStringNum(Time() - iTime) + "ms";
}
};
#endif //OPENCV31V1_CHELPER_H
Create file native_exporter.cpp in jniMy, with this code:
#include <jni.h>
#include <string>
#include <opencv2/core/core.hpp>
#include "chelper.h"
extern "C"{
JNIEXPORT jstring JNICALLJava_android_overloaded_opencv31v1_MainActivity_FuncV1(JNIEnv *env,
jclass type) {
cv::Mat mat(33,22, CV_32FC2);
string s = "Cpp v1 - succ, rows#:" +Helpers::ToStringNum(mat.rows);
Helpers::Log(s);
auto i = 5;
for (int i2 : {1,3,5}){
Helpers::Log(Helpers::ToStringNum(i2));
}
return env->NewStringUTF(s.data());
}
}
Code in MainActivity.java:
package android.overloaded.opencv31v1;
import android.os.Bundle;
import android.support.v7.app.AppCompatActivity;
import android.util.Log;
import android.view.SurfaceView;
import android.widget.TextView;
import android.widget.Toast;
import org.opencv.android.CameraBridgeViewBase;
import org.opencv.core.CvType;
import org.opencv.core.Mat;
public class MainActivity extends AppCompatActivity implements CameraBridgeViewBase.CvCameraViewListener2
{
private static void Log(String sMsg){Log.i("My", "MainActivity." + sMsg );}
static{
System.loadLibrary("opencv_java3");
System.loadLibrary("native");
}
public native String FuncV1();
JavaCameraViewCustom2 _javaCameraView; //Similar to JavaCameraView
@Override
protected void onCreate(Bundle savedInstanceState)
{
super.onCreate(savedInstanceState);
setContentView(R.layout.activity_main);
if(getSupportActionBar() != null)getSupportActionBar().hide();
String sRes = FuncV1();
Toast.makeText(this, sRes, Toast.LENGTH_LONG).show();
((TextView)findViewById(R.id.txtInfo)).setText(sRes);
_javaCameraView = (JavaCameraViewCustom2)findViewById(R.id.cameraView);
_javaCameraView.setVisibility(SurfaceView.VISIBLE);
_javaCameraView.setCvCameraViewListener(this);
}
@Override
protected void onResume()
{
super.onResume();
_javaCameraView.enableView();
}
@Override
protected void onPause()
{
super.onPause();
_javaCameraView.disableView();
}
Mat _imgBgrTemp;
@Override
public void onCameraViewStarted(int width, int height)
{
_imgBgrTemp = new Mat(height,width, CvType.CV_8UC4);
}
@Override
public void onCameraViewStopped()
{
_imgBgrTemp.release();
}
@Override
public Mat onCameraFrame(CameraBridgeViewBase.CvCameraViewFrame inputFrame)
{
_imgBgrTemp = inputFrame.rgba();
return _imgBgrTemp;
}
}
Android Studio will ask you to change jdk, also it will install new gradle, you should do everything it ask.
| 2023-10-28T01:26:35.434368 | https://example.com/article/1557 |
Disclosed herein is an air shower for dust collectors and, more particularly, in-line “air blade” showers for mobile dust collectors.
Inhalable and/or respirable silica dioxide (SiO2) is a major problem facing the oil and gas (O&G) industry. Silica dioxide is a commonly occurring element found in two forms—crystalline and amorphous. Quartz and sand are common examples of crystalline silica. Silica dioxide is particularly hazardous when it is broken down, creating inhalable or respirable silica dust (very small crystalline particles and/or amorphous particles). The Center for Construction Research and Training (CPWR) has stated that “inhaling crystalline silica dust can lead to silicosis, bronchitis, or cancer as the silica dust becomes lodged in the lungs and continuously irritates them.” According to the World Health Organization (WHO), whenever people inhale airborne silica dust at work, they are at risk of occupational disease. Year after year, both in developed and in developing countries, overexposure to silica dust causes disease, temporary and permanent disabilities and deaths. Silica dust in the workplace may also contaminate or reduce the quality of products, be the cause of fire and explosion, and damage the environment.
Field workers in the O&G industry are exposed to silica dust which can cause silicosis through over exposure. While personal protective equipment (PPE) is generally employed to prevent exposure, secondary exposure (for example, from residual silica dust on clothing) is sometimes forgotten.
Generally, air shower systems are used to remove contaminants from a person before or after they enter or leave a clean room. Clean rooms are used so that the person will be as free from contaminants as possible before they enter “sterile” facilities such as hospital operating rooms, research laboratories, semiconductor fabrication facilities, and pharmaceutical fabrication facilities. It is imperative that these facilities be free from contaminants such as dirt, dust, skin cells, bacteria, and mold.
In use, a person enters the air shower through a door that then closes behind him. Known air showers use a large air pumping system to power air flow. The air pumping system may include a fan and/or compressed air. (The use of compressed air necessitates an additional, substantially larger, air tank to supply the demands of the air shower. Compressed air also presents a health risk to people as the high pressure can cause injuries, such as a failure in the regulating system that could cause tissue damage.) Once inside the air shower, air nozzles (installed on the vertical walls and/or the ceiling of the air shower) blow air onto a person's surfaces to remove contaminants. Exhausted air and contaminants are removed from the air shower via air discharge holes. The contaminants may be filtered from the air, and may be stored if required by laws relating to the collection and disposal of contaminants. The filtered air is either recirculated through the air shower or is exhausted out into the environment. These known air showers are generally large and expensive. Known air showers require their own transport and possibly even a crane to move them. The expense and difficulties associated with known air showers limits their utility.
Patents describing known air shower systems include U.S. Pat. No. 4,267,769 to Davis et al. (the “Davis reference”), U.S. Pat. No. 4,624,690 to Byrnes (the “Byrnes reference), U.S. Pat. No. 4,765,352 to Strieter (the “'352 Strieter reference”), U.S. Pat. No. 4,967,645 to Mattson (the “Mattson reference”), U.S. Pat. No. 5,558,112 to Strieter (the “'112 Strieter reference”), U.S. Pat. No. 5,692,954 to Lee et al. (the “'954 Lee reference”), U.S. Pat. No. 5,746,652 to Lee et al. (the “'652 Lee reference”), U.S. Pat. No. 5,816,908 to Tsou (the “Tsou reference”), U.S. Pat. No. 7,465,225 to Ohmura et al. (the “Ohmura reference”), U.S. Pat. No. 7,887,614 to Yamazaki et al. (the “Yamazaki reference”), Patent Cooperation Treaty (PCT) Application No. PCT/CN2012/082839 to Tianjin Tianxing Electronics Co., Ltd. et al. (the “Tianjin reference”), Chinese Patent No. 103464420 to Weiping et al. (the “Weiping reference”), and Korean Patent No. 10-1449938 to Cho (the “Cho reference”).
What is relatively common in the O&G field are mobile vacuum systems (also referred to as “dust collectors”) designed to capture and remove silica dust during on-site O&G operations. Fracking, specifically, requires large volumes of sand (hundreds or even thousands of tons) to be pumped downhole. This sand is generally silica sand, and, therefore, any movement of the sand generates silica dust. The use of coated sand can lower the generation of silica dust, but it is not cost effective. Washing the sand is similarly costly and any further movement of the sand will simply create new silica dust particles through impaction. PPE can be worn to protect workers, but this is considered a last resort and does not help when site operations are near residential areas.
Known mobile dust collectors are large trailer mounted units capable of moving very large volumes of air at low pressure. Exemplary dust collectors include, but are not limited to, the mobile vacuum machine described in U.S. Pat. No. 4,578,840 to Pausch (the “Pausch reference”), the portable vacuum cleaning system described in U.S. Pat. No. 5,030,259 to Bryant et al. (the “Bryant reference”), the mobile pneumatic material transfer machine described in U.S. Pat. No. 5,840,102 to McCracken (the “McCracken reference”), the vacuum-cleaning apparatus for a stable described in U.S. Pat. No. 7,430,784 to Cowan (the “Cowan reference”), and the mobile work trailer described in U.S. Pat. No. 9,073,473 to Cramer (the “Cramer reference”). In addition, dust collectors may include Industrial Vacuum Equipment Corporation's Cyclone 20DC Portable Diesel Powered Dust Collector 20000CFM, ARS Recycling Systems, LLC's DC45 45000CFM, Robovent's BNM6818CT200 20000CFM, Entech Industries Ltd's Cyclone 45DC Mobile Dust Collector 45000CFM, and Entech Industries Ltd's Cyclone 20DC Mobile Dust Collector 20000CFM. | 2024-05-18T01:26:35.434368 | https://example.com/article/5706 |
1. Field of the Invention
The present disclosure generally relates to the fabrication of semiconductor devices, and, more particularly, to a method for reducing gate height variation due to overlapping masks.
2. Description of the Related Art
In modern integrated circuits, such as microprocessors, storage devices and the like, a very large number of circuit elements, especially transistors, are provided and operated on a restricted chip area. In integrated circuits fabricated using metal-oxide-semiconductor (MOS) technology, field effect transistors (FETs) (both NMOS and PMOS transistors) are provided that are typically operated in a switching mode. That is, these transistor devices exhibit a highly conductive state (on-state) and a high impedance state (off-state). FETs may take a variety of forms and configurations. For example, among other configurations, FETs may be either so-called planar FET devices or three-dimensional (3D) devices, such as finFET devices.
A field effect transistor (FET), irrespective of whether an NMOS transistor or a PMOS transistor is considered, and irrespective of whether it is a planar or 3D finFET device, typically comprises doped source/drain regions that are formed in a semiconductor substrate that are separated by a channel region. A gate insulation layer is positioned above the channel region and a conductive gate electrode is positioned above the gate insulation layer. The gate insulation layer and the gate electrode may sometimes be referred to as the gate structure for the device. By applying an appropriate voltage to the gate electrode, the channel region becomes conductive and current is allowed to flow from the source region to the drain region. To improve the operating speed of FETs, and to increase the density of FETs on an integrated circuit device, device designers have greatly reduced the physical size of FETs over the years. More specifically, the channel length of FETs has been significantly decreased, which has resulted in improving the switching speed of FETs. However, decreasing the channel length of a FET also decreases the distance between the source region and the drain region. In some cases, this decrease in the separation between the source and the drain makes it difficult to efficiently inhibit the electrical potential of the source region and the channel from being adversely affected by the electrical potential of the drain. This is sometimes referred to as a so-called short channel effect, wherein the characteristic of the FET as an active switch is degraded.
In contrast to a FET, which has a planar structure, a so-called finFET device has a three-dimensional (3D) structure. FIG. 1A is a perspective view of an illustrative prior art finFET semiconductor device 100 that is formed above a semiconductor substrate 105. In this example, the finFET device 100 includes two illustrative fins 110, 112, a placeholder gate structure 115 (e.g., polysilicon with an underlying gate insulation layer (not shown)), sidewall spacers 120 (e.g., silicon nitride), and a gate cap 125 (e.g., silicon nitride). When employing a gate replacement fabrication technique, the placeholder gate structure 115 is subsequently replaced with a high-k gate insulation layer and one or more metal materials to serve as a gate electrode for the device. The fins 110, 112 have a three-dimensional configuration. The portions of the fins 110, 112 covered by the gate structure 115 define channel regions for transistor devices. An isolation structure 130 is formed between the fins 110, 112.
As illustrated in FIG. 1B, in a conventional process flow, the portions of the fins 110, 112 that are positioned outside of the spacers 120, i.e., in the source/drain regions of the device 100, may be increased in size by performing one or more epitaxial growth processes to form epitaxial semiconductor material 135 on the fin 110 and epitaxial semiconductor material 140 on the fin 112. The process of increasing the size of the fins 110, 112 in the source/drain regions of the device 100 is performed to reduce the resistance of source/drain regions and/or make it easier to establish electrical contact to the source/drain regions.
In some devices, such as memory devices, the fin 110 is associated with an N-type transistor device, and the fin 112 is associated with a P-type transistor device, while the gate structure 115 is shared by the devices. The type of epitaxial semiconductor material 135, 140 employed is different for the different types of transistor devices. Typically, a first mask is used to cover the fin 112 while the epitaxial semiconductor material 135 is grown. The first mask is removed and a second mask is employed to cover the epitaxial semiconductor material 135 to allow the epitaxial semiconductor material 140 to be grown on the fin 112. Due to the etch processes for removing the masks and imperfect alignment, a bump feature 145 is typically formed in an overlap region at the boundaries of the first and second masks. This bump feature 145 may be formed from remnants of the masks and from material loss in the cap layer 125.
FIG. 1C illustrates a cross-sectional view of the finFET device 100 and a second finFET device 150 in a different region of the integrated circuit product. The cross-sectional view of FIG. 1C is taken through the fin in the gate length direction of the two transistor devices 100, 150. The device 100 includes transistor devices having different types with a shared gate structure 115. Due to the overlapping masks employed to grow the different epitaxial materials on the fins of differing conductivity types, a bump feature 145 is present above the gate structure 115 of the device 100. In contrast, the device 150 represents a device with fins associated with transistor devices having the same conductivity type, so overlapping masks are not used and no bump feature 145 is present.
In a gate replacement technique, a planarizing process is employed to expose the placeholder gate structures 115 of both devices 100, 150 so that they can be removed and replaced with a conductive material, such as metal. Due to the absence of a bump feature 145 on the device 150, the polishing process exposes the placeholder structure 115 more quickly, resulting in dishing of the device 150 and a lower gate height as compared to the device 100, as illustrated in FIG. 1D. A similar disparity can arise in regions with different device densities, and as a result different bump densities. The region with a lower bump density is planarized more aggressively and more quickly than the region with higher bump density, so more dishing occurs and the gate height is comparatively reduced. In some instances, due to the bump height differences, the placeholder structure 115 may be incompletely exposed, resulting in the formation of defects during the gate replacement process.
The present disclosure is directed to various methods and resulting devices that may avoid, or at least reduce, the effects of one or more of the problems identified above. | 2024-03-18T01:26:35.434368 | https://example.com/article/9275 |
(PhysOrg.com) -- A series of photographs of cannibalism in polar bears have been released, and the researchers who witnessed the act think the rate of cannibalism may be increasing. They observed three instances of adult male polar bears killing and eating young cubs during summer and autumn in the Svalbard archipelago in Norway and made a series of photographs of one episode.
At the American Geophysical Union (AGU) Fall Meeting, Jenny Ross, an environmental photojournalist, presented a series of photographs of an adult male polar bear (Ursus maritimus) carrying the carcass of a young cub. Ross said the bear's behavior suggested it considered the cub to be food, and it carried the corpse in its jaws to another floe to get away from the researchers. When it was some distance away it then devoured the cub.
Dr Ian Stirling of Environment Canada, who co-wrote the paper published in the journal Arctic, said cannibalism among polar bears has been witnessed before, but he said the rate of cannibalism may be increasing as the sea ice now melts earlier in the year. The primary food source for polar bears is seals, which they normally hunt from ice floes. The ice floes melt during summer and in some places the ice disappears altogether, making hunting for seals more difficult. Ross said the bears are forced to seek out other foods such as sea birds and their eggs, and human foods and waste, but these are not enough to sustain them.
Ross said cannibalism has always occurred to some extent and bear cubs were probably easy prey, particularly for a large male bear. She said the cannibalistic behavior may rise as hunting becomes more difficult with the climate continuing to warm in the Arctic. She also said there were increasing numbers of observations of cannibalism, especially on land among bears that had no food for extended periods.
The observation of cannibalism in polar bears is not new. A 1985 paper in Arctic listed incidents of cannibalism dating back to 1896, while a 1999 paper by Derocher and Wiig in Arctic concluded that cannibalism in polar bears may be more common in Svalbard because the population is close to carrying capacity or because geographic features reduce patial segregation of age and sex classes. Hunting of polar bears in the Svalbard-Barents sea area ceased in 1956 in Russia and 1973 in Norway, which Derocher and Wiig said allowed the population to increase and reach carrying capacity.
Cannibalism has also been observed among captive polar bear populations in zoos, such as an incident in 2008 in Nuremburg zoo, in which a mother bear killed and ate her two cubs, despite being well fed. According to the president of the Kivalliq Inuit Association, Jose Kusugak, the behavior is quite normal.
© 2011 PhysOrg.com | 2024-03-04T01:26:35.434368 | https://example.com/article/6684 |
// Copyright (c) .NET Foundation. All rights reserved.
// Licensed under the Apache License, Version 2.0. See License.txt in the project root for license information.
using System;
using System.Security.Cryptography;
using System.Text;
namespace NuGetGallery.Infrastructure.Authentication
{
public class ApiKeyV4
{
private const int IdPartLengthBytes = 10;
private static readonly byte[] IdPrefix = Encoding.ASCII.GetBytes("v4");
internal const int IdPartBase32Length = 20;
internal const int IdAndPasswordLength = 46;
internal const int IdAndPasswordHashedLength = 124;
/// <summary>
/// Plaintext format of the ApiKey
/// </summary>
public string PlaintextApiKey { get; private set; }
/// <summary>
/// Hashed format of the ApiKey. Will be set only if Create() method was used.
/// </summary>
public string HashedApiKey { get; private set; }
/// <summary>
/// Id part of the ApiKey
/// </summary>
public string IdPart { get; private set; }
/// <summary>
/// Password part of the ApiKey (plaintext)
/// </summary>
public string PasswordPart { get; private set; }
private ApiKeyV4()
{
}
/// <summary>
/// Creates a random ApiKey V4.
/// </summary>
public static ApiKeyV4 Create()
{
var apiKey = new ApiKeyV4();
apiKey.CreateInternal();
return apiKey;
}
/// <summary>
/// Parses the provided string and creates an ApiKeyV4 if it's successful.
/// </summary>
public static bool TryParse(string plaintextApiKey, out ApiKeyV4 apiKey)
{
apiKey = new ApiKeyV4();
return apiKey.TryParseInternal(plaintextApiKey);
}
/// <summary>
/// Verified this ApiKey with provided hashed ApiKey.
/// </summary>
public bool Verify(string hashedApiKey)
{
if (string.IsNullOrWhiteSpace(hashedApiKey) || hashedApiKey.Length != IdAndPasswordHashedLength)
{
return false;
}
string hashedApiKeyIdPart = hashedApiKey.Substring(0, IdPartBase32Length);
string hashedApiKeyPasswordPart = hashedApiKey.Substring(IdPartBase32Length);
if (!string.Equals(IdPart, Normalize(hashedApiKeyIdPart)))
{
return false;
}
// The verification is not case sensitive. This is to maintain the existing behavior that ApiKey authentication is not case-sensitive.
return V3Hasher.VerifyHash(hashedApiKeyPasswordPart.ToUpper().FromBase32String(), PasswordPart);
}
private void CreateInternal()
{
// Create Id
var randomBytes = new byte[IdPartLengthBytes];
using (var rng = new RNGCryptoServiceProvider())
{
rng.GetNonZeroBytes(randomBytes);
}
byte[] idBytes = new byte[IdPartLengthBytes + IdPrefix.Length];
Buffer.BlockCopy(src: IdPrefix, srcOffset: 0, dst: idBytes, dstOffset: 0, count: IdPrefix.Length);
Buffer.BlockCopy(src: randomBytes, srcOffset: 0, dst: idBytes, dstOffset: IdPrefix.Length, count: randomBytes.Length);
// Convert to Base32 string. The length of the string is APIKeyV4_IdPartBase64Length
string idString = idBytes.ToBase32String().RemoveBase32Padding();
// Create password
var passwordString = Guid.NewGuid().ToByteArray().ToBase32String().RemoveBase32Padding();
passwordString = Normalize(passwordString);
// No need to remove padding or normalize here.. it's stored in the DB and doesn't need to be pretty
var hashedPasswordString = V3Hasher.GenerateHashAsBytes(passwordString).ToBase32String();
IdPart = Normalize(idString);
PasswordPart = passwordString;
PlaintextApiKey = IdPart + passwordString;
HashedApiKey = IdPart + hashedPasswordString;
}
private bool TryParseInternal(string plaintextApiKey)
{
if (string.IsNullOrEmpty(plaintextApiKey) || plaintextApiKey.Length != IdAndPasswordLength)
{
return false;
}
try
{
var id = plaintextApiKey.Substring(0, IdPartBase32Length);
var idBytes = id.AppendBase32Padding().ToUpper().FromBase32String();
bool success = idBytes[0] == IdPrefix[0] && idBytes[1] == IdPrefix[1];
if (success)
{
string password = plaintextApiKey.Substring(IdPartBase32Length);
PlaintextApiKey = plaintextApiKey;
IdPart = Normalize(id);
PasswordPart = Normalize(password);
}
return success;
}
catch (InvalidOperationException)
{
return false;
}
}
private string Normalize(string input)
{
return input.ToLowerInvariant();
}
}
} | 2024-05-20T01:26:35.434368 | https://example.com/article/2130 |
Q:
LNK 2019 При вызове объекта шаблонного класса
Ошибка происходит при инициализации объекта класса Interface;
Interface <int> test;
Если убрать шаблон из класса, то ошибка пропадает.
Interface.h:
#pragma once
#include <iostream>
using namespace std;
template <class T>
class Interface
{
private:
T dummy;
public:
Interface();
~Interface();
// void menu(void);
};
Interface.cpp:
#include "Interface.h"
template <class T>
Interface<T>::Interface()
{
}
template <class T>
Interface<T>::~Interface()
{
}
Список ошибок:
Ошибка 1 error LNK2019: ссылка на неразрешенный внешний символ "public: __thiscall Interface<int>::Interface<int>(void)" (??0?$Interface@H@@QAE@XZ) в функции _main
Ошибка 2 error LNK2019: ссылка на неразрешенный внешний символ "public: __thiscall Interface<int>::~Interface<int>(void)" (??1?$Interface@H@@QAE@XZ) в функции _main
Ошибка 3 error LNK1120: неразрешенных внешних элементов:
A:
Проблема решена переносом кода из .cpp в .h файл. Тем не менее, есть ли способы описать шаблонный класс раздельно?
| 2024-02-18T01:26:35.434368 | https://example.com/article/9787 |
package com.anly.githubapp.di.module;
import com.anly.githubapp.data.api.TrendingApi;
import com.anly.githubapp.data.net.TrendingRepoDataSource;
import com.anly.githubapp.data.net.client.GithubTrendingRetrofit;
import com.anly.githubapp.data.net.service.TrendingService;
import dagger.Module;
import dagger.Provides;
import retrofit2.Retrofit;
/**
* Created by mingjun on 16/7/18.
*/
@Module
public class TrendingRepoModule {
@Provides
TrendingApi provideTrendingApi(TrendingRepoDataSource dataSource) {
return dataSource;
}
}
| 2024-04-13T01:26:35.434368 | https://example.com/article/7252 |
Gold-induced thrombocytopenia. A clinical and immunogenetic study of twenty-three patients.
Thrombocytopenia developed in 23 patients with rheumatoid arthritis treated with gold salts over 25 years. All patients recovered, and there were no episodes of life-threatening hemorrhage; four patients eventually needed splenectomy. The clinical presentation of gold-induced thrombocytopenia and its treatment and outcome are reviewed. Because gold-induced thrombocytopenia is believed to have an immunologic basis, we sought an association between this complication and antigens of the human leukocyte antigen (HLA) region. The most significant finding was the association of the HLA-DR3 alloantigen in 12 of 15 of these patients compared with 26 of 84 in a control population (x2 12.9, p less than 0.001). This study provides further evidence that gold-induced thrombocytopenia is immunologically mediated and that genes of the major histocompatibility complex are involved. | 2024-01-13T01:26:35.434368 | https://example.com/article/5738 |
OTTAWA -- Claude Giroux playfully punched Sidney Crosby on the shoulder between drills Tuesday, producing a smile from the Team Canada captain.
Was it just four years ago these two guys dropped the gloves in a playoff game?
Go around Team Canada's dressing room and you'll find a long list of personal rivalries that have been put on hold for the World Cup of Hockey.
Or you might say, the hatred has been temporarily shelved for a month.
"It's pretty easy," Crosby said Tuesday after Day 2 of camp. "That's just the nature of competing and playing against one another. As soon as you put on that jersey, you're on the same team and you're all trying to accomplish the same thing. It's pretty easy. We played world championships last year and had a great experience there. He's a great player so, yeah, it's fun to play with him."
Shea Weber and Corey Perry are now Team Canada teammates, and have put this hit behind them. Victor Decolongon/Getty Images
Some events are rather fresh. It was just over two months ago in the Stanley Cup finals between the San Jose Sharks and Pittsburgh Penguins that Logan Couture called Crosby a cheater on faceoffs.
They've buried that hatchet on that one already.
"He said, 'No hard feelings.' He understood what we were fighting for, we were down 2-0" in the series, Couture said, smiling, on Tuesday.
And what of Corey Perry and Shea Weber? There was a certain forearm shiver that pancaked Perry into the ice in Game 5 of the Anaheim Ducks-Nashville Predators playoff series.
"I haven't talked to him about the hit yet that's all over TV," Perry said with a smile Tuesday. "But he'll hear about it."
And definitely no hard feelings, either, despite a massively physical series between those two star players, Weber trying his best to make sure Perry didn't get to make his normal living in the crease.
"We've played together for a long time in different situations and different competitions. He's a great guy off the ice," Perry said. "We're always friends. But on the ice we're two competitors and we both don't want to lose."
Added Weber: "There's a lot of guys here that play against each other and play against each other a lot. You got to put those things aside. At the same time, a lot of us are friends. We've played on teams together for a long time. But especially in the playoffs, teams want to win. He's going to do everything he can to beat me and I'm going to do the same against him. At the end of the day, we're still going to be friends."
Claude Giroux and Logan Couture are two guys shelving the hate for Team Canada. Sean Kilpatrick/The Canadian Press via AP
Perhaps there is no greater example of putting your country first than the intense rivalry between the Sharks and Los Angeles Kings. There are four Sharks and two Kings on Team Canada and their last two playoff series left wounds, to be sure.
"When you play each other in the playoffs, and one of us is crushing the other team's dream of winning a Stanley Cup, you're going to create a rivalry pretty quick," Kings defenseman Drew Doughty said. "Obviously, we played each other so many times in the season trying to battle for first place. We're both very good teams. We play a physical brand of style. That's going to create battles and hatred for each other. But I respect all four of those guys on this team, they're all awesome players and I'm so happy to get to play with all of them."
Add in the Ducks equation in that California triangle of hate and you also have Perry and Ryan Getzlaf on Team Canada. Getzlaf and Joe Thornton famously dropped the gloves during a 2009 playoff series.
"It's very intense," Thornton said Tuesday of the California hockey rivalries. "But they're all super guys. I see Drew in the summer with golfing and things like that. I've played with Pears and Getz before. So nothing really changes."
So intense again was the Kings-Sharks series, San Jose getting revenge this spring on L.A., that Doughty after the season told Los Angeles media not to overstate his friendship with Couture. a fellow native of London, Ontario.
Heat of the moment, Doughty now admits.
"When we come here, we put that stuff aside," Doughty said when asked about Couture. "We never even had to talk about it. It's just gone. We're back to being on the same team like when we were kids, trying to win hockey games together."
And yes, they've seen each other this summer in London.
"We've been skating together for a while," Couture said.
So, just to be clear, they're friends, right?
"Yeah, we're friends. Ask him, I think we are," said Couture, chuckling.
Crosby and Giroux, despite having the same agent, Pat Brisson of CAA Sports, never really crossed paths off the ice before finally playing together at the 2015 world championships, winning gold in Prague. They got to know each other there and there's a clear sense of respect and admiration there.
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"We enjoy the challenge of playing against each other but we also enjoying paying together, too," Giroux said in French on Tuesday.
"[Before playing at the worlds], we only knew each other on the ice, and didn't like each other too much," Giroux added with a chuckle. "But it made those games fun when you have a rivalry like that with a player. Obviously, off the ice he's a great guy."
As Crosby noted, he loves the fact that rugby players will share a beer after an intense match. Team Canada's players have had a few bonding nights here together in Ottawa, putting aside those NHL battles for love of country.
"Once you're here, you're all buddies, and then once the month's done, you're enemies again," Thornton said, laughing. "It's kind of funny." | 2023-12-29T01:26:35.434368 | https://example.com/article/1256 |
It took over a century to build, starting in 1386 and ending circa 1517, spanning the reign of seven kings. It took the efforts of fifteen architects (Mestre das Obras da Batalha), but for seven of them the title was no more than an honorary title bestowed on them. The construction required an enormous effort, using extraordinary resources of men and material. New techniques and artistic styles, hitherto unknown in Portugal, were deployed.
Work began in 1386 by the Portuguese architect Afonso Domingues who continued till 1402. He drew up the plan and many of the structures in the church and the cloister are his doing. His style was essentially Rayonnant Gothic, however there are influences from the English Perpendicular Period. There are similarities with the façade of York Minster and with the nave and transept of Canterbury Cathedral.
He was succeeded by Huguet from 1402 to 1438. This architect, who was probably of Catalonian descent, introduced the Flamboyant Gothic style. This is manifest in the main façade, the dome of the square chapter house, the Founder's Chapel, the basic structure of the Imperfect Chapels and the north and east naves of the main cloister. He raised the height of the nave to 32.46 m. By altering the proportions he made the interior of the church even seem narrower. he also completed the transept but he died before he could finish the Imperfect Chapels.
During the reign of Afonso V of Portugal, the Portuguese architect Fernão de Évora continued the construction between 1448 and 1477. He added the Cloister of Afonso V. He was succeeded by the architect Mateus Fernandes the Elder in the period 1480–1515. This master of the Manueline style worked on the portal of the Capelas Imperfeitas. Together with the famous Diogo Boitac he realized the tracery of the arcades in the Claustro Real. Work on the convent continued into the reign of John III of Portugal with the addition of the fine Renaissance tribune (1532) by João de Castilho. The construction came to a halt, when the king decided to put all his efforts in the construction of the Jerónimos Monastery in Lisbon.
The earthquake of 1755 did some damage, but much greater damage was inflicted by the Napoleonic troops of MarshalMasséna, who sacked and burned the complex in 1810 and 1811. When the Dominicans were expelled from the complex in 1834, the church and convent were abandoned and left to fall in ruins.
In 1840, king Ferdinand II of Portugal started a restoration program of the abandoned and ruined convent, saving this jewel of Gothic architecture. The restoration would last till the early years of the 20th century. It was declared a national monument in 1907. In 1980 the monastery was turned into a museum.
The Batalha convent was added in 1983 by UNESCO to its list of World Heritage sites.
The convent stands apart from the whole town, and although some dislike the implantation of new hotels by its side, they can always enjoy the interesting homes of the 18th century, the "guillotine" windows and the magnificent Manueline portal of the main church. It is one of the most fascinating pieces of Gothic and Manueline architecture within the country.
The ornate convent has been put up in limestone from Porto de Mós, that has turned yellow ochre in the course of time. It has an original Portuguese style, a mixture of rayonnant and flamboyant Gothic architecture combined with strong elements of English Perpendicular, that finds few parallels in Europe. As with all Dominican churches, this church has no bell tower.
The western façade, facing the large square with the equestrian statue of general Nuno Álvares Pereira, is divided in three by buttresses and huge pilasters : the Founder's Chapel (Capelo do Fundador), the side wall of an aisle and the projecting portal. On the right side of this façade are the Imperfect Chapels (Capelas Imperfeitas), a separate octagonal structure added to the complex.
Off the east side, next to the church choir is the chapterhouse (Sala do Capitulo). The closier of King João I borders on the church and this chapterhouse. The structure continues into the cloister of King Afonso V (Claustro de D. Afonso V). On the northern side of the complex lies the Tomb of the Unknown Warriors.
The portal shows in the archivolt a profusion of 78 statues, divided over six rows, of Old Testament Kings, angels, prophets and saints, each under a baldachin. The splays on both sides display (inferior copies of) statues of the apostles, with one standing on a chained devil. The tympanum shows us Christ enthroned, sitting under a baldachin and flanked by the Four Evangelists, each with his own attribute.
The church is vast and narrow (22m) in proportion to its height (32.4 m). The nave was raised to its present height by the second architect Huguet, altering the proportions of the church and giving it its present aspect. Its interior gives a sober and bare impression by its complete lack of ornaments and statues in the nave. The ribbed vaults, supported by compound piers, are closed by ornamented keystones. Light enters the church through ten stained-glass windows of the clerestory and the tall, traceried windows in the side walls and the transept and through the two rows of lanciform windows in the choir. The choir extends into two-bay transepts and consists of five apsidal chapels, with the central one projecting.
Batalha probably had the first workshop for stained-glass windows in Portugal. The art was introduced in Portugal by German artists from the regions of Franconia and Nuremberg. The oldest windows date back to the end of the 1430s. But the Manueline, ogival stained-glass windows in the choir date from the 1520s and 1530s and were produced by Portuguese masters, among them Francisco Henriques. They represent scenes from the lives of Christ and Mary: the Visitation, the Epiphany, the Flight to Egypt and the Resurrection of Christ.
The architect Mateus Fernandes and his wife are buried under a marble tomb-slab close to the portal. The tomb of the knight Martim Gonçalves de Maçada, who saved the king's life during the battle at Aljubarrota, can be found close to the Capela do Fundador.
Tombs of the four princes (from left to right): Ferdinand, John, Henry, Peter
The square Founders' Chapel (Portuguese: Capela do Fundador) was built between 1426 and 1434 by the architect Huguet on orders of King John I to become the first royal pantheon in Portugal. It gives a perfect synthesis between Flamboyant Gothic and the English Perpendicular style, as Philippa of Lancaster had brought along a few English architects. The chapel consists of three notional bays and a central octagon buttressed by eight piers, adorned with crockets, supporting deeply stilted arches.
The joint tomb of King John I of Portugal (d.1433) and his wife Philippa of Lancaster (d.1415) stands under the star vault of the octagon. Their statues lie in full regalia, with clasped hands (expressing the good relations between Portugal and England) and heads resting on a pillow, under elaborately ornamented baldachins. The coats of arms of the Houses of Aviz and Lancaster are put on top of these baldachins, together with the insignia of the order of the Garter. On the cover plate of the tomb are inscribed in repetition the mottos of the king Por bem (For the better) and of the queen Yl me plet (I am pleased).
The three tombs on the west wall are copies of the original tombs of King Afonso V (r.1438–1481), John II (r.1481–1495) (empty because the soldiers of Masséna threw away the bones) and his son and heir, Prince Afonso (who died in an accident at the age of seventeen, predeceasing his father).
As Capelas Imperfeitas (The Unfinished Chapels) remain as a testimony of the fact that the monastery was never actually finished. They form a separate octagonal structure tacked on the choir of the church (via a retrochoir) and only accessible from the outside. It was commissioned in 1437 by King Edward of Portugal ("Dom Duarte", d.1438) as a second royal mausoleum for himself and his descendants. But he and his queen Eleanor of Aragon are the only ones buried here (Eleanor died in exile in Toledo in 1445, her remains were only translated here in 1456).
The original design, begun by Huguet, was altered by successive architects, especially Mateus Fernandes (who is buried inside the church). The octagonal rotunda has seven radiating hexagonal chapels. In the corners of the chapels stand the massive unfinished buttresses, that were intended to support the vault. These pillars, designed by Diogo Boitac, are decorated with Manueline motives carved in stone.
The portal rises to a monumental fifteen metres. It was originally built in Gothic style, but was transformed beyond recognition by Mateus Fernandes into a masterpiece of Manueline style (completed in 1509). It is completely decorated into a lacework of sumptuous and stylized Manueline motives : armillary, spheres, winged angels, ropes, circles, tree stumps, clover-shaped arches and florid projections. This homage of King Manuel I to his predecessor King Edward mentions his motto Leauté faray tam yaserei (I will always be loyal). This motto is then repeated more than two hundred times in the arches, vaults and pillars of the chapels.
The Renaissance loggia, added at about 1533, was probably meant for musicians. It is ascribed to the architect João de Castilho.
This square room is especially notable for its star vault lacking a central support and spanning a space of 19 square meters. This was such a daring concept at the time that condemned prisoners were used to perform the task. It was completed after two failed attempts. When the last scaffolds were removed, it is said that Huguet spent the night under the vault in order to silence his critics.
The stained-glass Renaissance window in the east wall dates from 1508. It depicts scenes of the Passion and is attributed to the Portuguese painters Master João and Francisco Henriques.
The Royal Cloister (Portuguese: Claustro Real) is cloister was not part of the original project. It was built under the architect Fernão de Évora between 1448 and 1477. Its sober outward appearance is in stark contrast with the Flamboyant Gothic style of the church. The carved tracery decoration in Gothic style (including quatrefoils, fleurs-de-lis and rosettes) by Huguet in the ambulatory forms a successful combination with the Manueline style in the arcade screens, added later by Mateus Fernandes. Two different patterns alternate, one with the cross of the Order of Christ, the other with armillaries.
Situated in the northwestern corner of the Claustro Real, this work of Mateus Fernandes is of a beauty and harmony difficult to describe. It consists of a fountain and two smaller basins above. The whole is bathed in a golden glow seeping through the intricate tracery of the arches around it.
This sober cloister next to the Claustro Real was built in conventional Gothic style with double pointed arches. It was constructed in the second half of the 15th century by the architect Fernão de Évora. It stands in contrast with the Manueline flamboyance of the somewhat larger Claustro Real. The keystones in the vault carry the coat-of-arms of D. Duarte I and Afonso V. | 2024-06-19T01:26:35.434368 | https://example.com/article/1292 |
1. Field of the Invention
The present invention relates to a washing machine and, more particularly, to a fully automatic washing machine adapted to automatically perform the steps of washing, rinsing and drying. 2. Description of the Prior Art
In general, fully automatic washing machines proposed and used hitherto can be sorted into two types: namely, pulsator type machine in which a rotary blade unit is rotated in the washing and rinsing steps at a comparatively high speed in one and the other directions with a comparatively long interval of switching of rotation direction, and agitator type machine in which the rotary blade unit is rotated in the washing and rinsing steps at a comparatively low speed in one and the other direction at a comparatively low speed in one and the other directions with a comparatively short interval of switching of rotation direction.
More specifically, in the pulsator type washing machine, the direction of rotation of the rotary blade unit is switched at a long interval such that the rotation of the rotary blade unit is stopped for 3 seconds after a continuous forward rotation for 27 seconds and followed by a continuous backward rotation for 27 seconds. The rotation speed of each of forward and backward rotation is as high as 400 rpm. For these reasons, the pulsation type washing machines usually suffer the following problems.
(1) The wash is liable to be damaged because it is held for long time in contact with the rotary blade unit which rotates at a high speed.
(2) The wash, such as clothes or the like, are made to entangle with one another heavily so that it is often necessary to unfasten or loosen the clothes or the like before turning to the rinsing step or washing step.
(3) As the drying step is started following the rinsing step, an eccessively large unbalance of force is produced due to the entanglement of clothes which often results in an inconvenient stopping of the operation of the washing/drying machine.
(4) The entanglement of clothes results in an imperfect washing of the entangled portions by causing to cause uneven washing and rinsing.
The entanglement and the damage of clothes are not so great heavy in the agitator type washing machines because in this case the rotary blade unit is rotated in the forward and backward directions within an angle less than 360.degree. at a low speed. The agitator type washing machines, however, have the following drawbacks.
(1) The washing power is so limited that the contaminants of the clothes cannot be removed perfectly when the washing is made with cold water, i.e. unless warm water is used.
(2) A complicated mechanism is necessary for reciprocatingly rotating the rotary blade unit within the angle less than 360.degree. . This complicated mechanism seriously lowers the productivity of the washing machine
The present inventors have conducted a test with a washing machine in which the rotary blade unit has a greater diameter than the rotary blade unit of conventionally used pulsator type washing machine and a cylindrical member is attached to the rotary blade unit. The rotary blade unit was rotated in forward and backward directions at a speed lower than that in the conventionally used pulsator type washing machine. This washing machine proved to be able to overcome the problems such as entanglement and damaging of the clothes, but still suffered a problem that the wash such as clothes is inconveniently caught around the cylindrical member. | 2023-11-27T01:26:35.434368 | https://example.com/article/7990 |
A Beginner’s Guide To Hot Tub Chemistry
You definitely don’t need a science degree to keep the water in your hot tub balanced, but hot tub chemistry is the most important thing you can learn in order to keep your water clean and safe for its soakers.
I mean, who wants to sit around in a tepid pool of filth and bacteria, right?
Aside from making sure your water is clean, keeping the water chemistry balanced also helps prolong the life of your spa and equipment.
And let’s face it: all that stuff didn’t come cheap, so you would probably like to do everything you can to make it last.
So, let’s just dig right in to the what, how and why of it all.
You with me?
Chemical Factors
There are several factors that have to stay in balance in order to keep your water healthy.
The reason for this is that they all work together to keep your sanitizer working effectively.
But assuming you have a standard hot tub, let’s just cover the basics.
Proper Chlorine Levels: 1.0 - 3.0 ppm. Chlorine is the most popular and effective sanitizer you can use for hot tubs or pools, so it is the main one I’ll be talking about most of the time. But if you are opposed to the chemical, there are other options.
Proper Bromine Levels: 3.0 - 5.0 ppm. Bromine is another popular choice for hot tubs, especially if they are indoors. It’s not a good choice for outdoor spas or pools, however, because it's unstabilized and will be quickly eaten up by the sun’s UV rays. The main benefit of bromine is that it's practically odorless. So, if you really hate the chemical smell of chlorine or if it’s a little harsh for your skin, bromine might be your answer.
It’s important to know what your sanitizer levels are at all times.
If there's not enough sanitizer, bacteria and algae will start to creep in like uninvited house guests, but if it’s too high, it can actually be pretty harmful to the people in contact with it.
The good news is that it’s not all that hard to fix.
For sanitizer levels that are too low, the fix is as simple as adding more sanitizer.
If the levels are too high, that’s a little trickier, but still not crazy difficult. There are a few things you can do to lower them.
Step 1. The first thing you can do is just wait it out.
Since sanitizer does break down on its own, it will eventually return to normal.
Step 2. If you're ready to use your hot tub, though, and would rather not wait that long, you can simply dilute the water a bit.
Just grab a big bucket, dip out some water, and replace it with fresh water from the hose.
Step 3. Once you’ve done this, turn on the jets and allow the water to circulate for about 20 minutes and then retest it.
Step 4. If the levels are extremely high, you may need to dip out quite a bit of water, or drain it completely and start over.
pH
Proper pH Levels: 7.2 - 7.8
Your hot tub’s pH levels will affect how well the sanitizer is working.
What it measures is how acidic or basic the water is: if it’s too low, it’s considered acidic; too high will be considered more basic.
When pH levels are not properly balanced, your chlorine will not work as efficiently at killing off unwanted bacteria and algae.
But that’s not all.
Water with pH levels that are too low can start to damage your hot tub lining and plumbing, but too high can cause buildup and scaling that clogs things up and is hard to remove. Either extreme can cause skin and eye irritation.
The problem with pH is how unstable a factor it is.
It’s affected by debris, rain or practically anything else that slips into the water.
So, in order to keep it where it needs to be, you will need to keep some stuff on hand to balance it.
To raise your hot tub’s pH levels, you can use a product containing either sodium carbonate or you just use straight sodium bicarbonate (baking soda).
There are pH increasers you can buy that help take the guesswork out of it by giving you exact amounts and instructions.
Lowering pH levels can be done with muriatic acid or sodium bisulfate.
I recommend getting a product made specifically for this purpose and specifically for hot tubs.
Read the directions and add the amounts appropriate for your spa’s size.
Allow the jets to run and circulate the water for a little while (15-20 minutes should do the trick), then test it again.
If your calcium hardness level is too high, it can cause calcium buildup and scaling that can clog your filter and become difficult to remove. It will also cause your water to look cloudy and dry out your skin when you soak in it.
If it is too low, on the other hand, your water will start looking for places to get more.
In pools, this usually means it starts stealing calcium from the surrounding plaster or cement.
Since hot tubs typically don’t have any of that, it will start to corrode the internal parts of your equipment, like spa heaters and pipes.
Prevention is the easiest way to keep your calcium hardness levels in check.
I always recommend using a pre-filter when filling your hot tub to filter out most of the junk from your water supply that causes problems.
You can also use a chemical that helps prevent scaling if you already know you have hard water in your area.
Shocking Your Hot Tub
Shocking your water just means giving it a super dose of sanitizer to kill everything bad off and kind of give all your chemicals a reboot.
Shocking your hot tub will keep you from having to drain your water too often, and it’s a good way to make sure you’re not harboring any nasty bacteria that can build up in hot water.
For chlorine hot tubs, you can use either more chlorine than usual or some non-chlorine shock.
Either way, you'll need to add the chemicals to the water and let the jets run for a bit to circulate it. Then let it work overnight and test the levels in the morning.
Never let anyone get in the hot tub until the sanitizer levels are back in normal range!
Bromine hot tubs can be shocked with an extra dose of bromine or also with non-chlorine shock.
Bottom Line
Most issues with things like scaling and unbalanced chemicals are usually due to the minerals in the water supply.
That’s why I always recommend starting off right by using your pre-filter to fill your hot tub.
But the great thing about hot tubs is that they're easier to drain and refill than a pool. So if you have problems keeping something level, you can always start fresh and try again.
Now you know just about everything there is to know about hot tub chemistry and you are well on your way to being a pro.
But if you run across a problem and need a little advice, we're always here to help. | 2023-08-29T01:26:35.434368 | https://example.com/article/3992 |
UK space scientists and engineers have designed a mission to investigate a potentially hazardous asteroid.
The 300m-wide (980ft) rock, known as Apophis, will fly past Earth in April 2029 at a distance that is closer than many communications satellites.
Astrium, based in Stevenage, Herts, wants a probe to track the asteroid so its orbit can be better understood.
The concept will compete for a $50,000 (£25,000) Planetary Society prize, but a full mission would cost millions.
The British design calls for a small, remote-sensing spacecraft, dubbed Apex (Apophis Explorer), which could rendezvous with Apophis in January 2014.
It would then spend the next three years tracking the rock, sending data back to Earth about the object's size, shape, spin, composition and temperature.
From this information, orbit modelling would enable a more accurate prediction of the risk of any future collision.
Astrium says that if its concept won the prize, it would donate the money to charity.
"The real prize for us would be if the European or US space agencies thought there was merit in our proposal and asked us to carry the feasibility study forward," said Dr Mike Healy, the company's space science director.
A full mission would be expected to cost about $500m (£250m) dollars to develop, launch and operate.
Early warning
Apophis caused some consternation in 2004 when initial observations suggested there was an outside chance it might hit Earth in 2029.
Further study by ground-based telescopes indicated there was virtually no possibility of this happening, and the expectation is that the object will whiz past the Earth at a close but comfortable distance of just under 36,000km (22,400 miles).
APOPHIS - SPACE ROCK
Orbits the Sun every 324 days, crossing Earth's orbit twice
Not spherical, diameter of 300m; a mass of 27m tonnes
Name: Ancient Egyptian god Apep ('The Destroyer')
Discovery: In 2004 by a University of Hawaii team
Talk of a possible strike on another visit in 2036 has also been dampened by astronomers who have kept a careful watch on the rock's progress through space.
However, there is always some uncertainty associated with an asteroid's orbit.
One reason is the Yarkovsky effect. This describes what happens when an asteroid radiates energy absorbed from the Sun back into space.
Releasing heat in one direction nudges the object in the opposite direction. The resulting acceleration is tiny, but over the centuries acts like a weak rocket and could make the difference between a hit or a miss in some circumstances.
The close encounter with Earth in 2029 will also perturb Apophis' orbit gravitationally.
A mission like Apex to track and study the rock would help reduce uncertainties and give solid predictions about the rock's course long into the future.
Political support
At the moment, scientists stress Apophis is not thought to be a serious danger to Earth.
But were such a rock to hit the planet, it could cause devastation on a country-wide scale, leading possibly to the deaths of many millions of people.
An Apophis-like object striking at about 20km/s (45,000mph) would gouge a crater 5km (three miles) wide. Even standing 30km (18 miles) away from the impact site, a thermal blast would ignite your clothes and the ground would shudder with an earthquake measuring more than six on the Richter Scale.
The dinosaurs are thought to have suffered in a space impact
Rocks thrown up into the air by the impact would rain down - many of them huge lumps a metre wide.
Given sufficient warning, though, a potential impactor could be deflected out of Earth's path, scientists believe.
Some have suggested such a rock might be nudged on to a safe trajectory by hitting it with a small mass. Others have proposed flying a spacecraft next to the object, to use gravity to tug the asteroid clear of the planet.
The issue of asteroid or comet strikes is a topical one as researchers continue to gather more information about their frequency during Earth history.
At least one of the planet's mass extinction events - which included the demise of the dinosaurs 65 million years ago - has been attributed to the impact of a large space object.
Liberal Democrat MP Lembit Opik has campaigned for the research area to be given more funding. His grandfather, renowned Estonian astronomer Ernst Opik, did much to raise science's understanding of Earth-crossing comets and asteroids.
The politician told the BBC News website: "The question isn't whether Earth is hit by an asteroid - it is when.
"Good luck to Astrium; they are showing that if we have the political will, we certainly have the technical know-how to do something about threatening objects."
The US-based Planetary Society has organised its competition in co-operation with the European Space Agency (Esa), the US space agency (Nasa), the Association of Space Explorers (ASE), the American Institute of Aeronautics and Astronautics (AIAA), and the Universities Space Research Association (USRA).
The winning entry will be submitted to space agencies to see if they want to carry the ideas through. | 2024-04-21T01:26:35.434368 | https://example.com/article/1319 |
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| 2024-01-29T01:26:35.434368 | https://example.com/article/9511 |
1. Field of the Invention
The present invention relates to a light emission control technique and, more particularly, to a light emission control circuit controlling light emission of a plurality of light-emitting elements.
2. Description of the Related Art
Battery-driven portable equipment such as a portable telephone and a personal data assistant (PDA) use light-emitting diodes (LED) for a variety of purposes. For example, LEDs are used to provide backlight for a liquid crystal display (LCD) or an electronic flash light for a charge-coupled device (CCD) camera. LEDs emitting different colors are operated to blink for illumination. Patent Document No. 1 describes the use of blue, green and red LEDs and mixing of colors emitted by these diodes to produce colors other than blue, green and red for illumination. Light emission of an LED is controlled according to the pulse width modulation (PWM) method. Three LEDs are connected to three PWM circuits via three output transistors, respectively.
The drain of the output transistor is connected to the cathode of the LED, the source of the output transistor to a reference voltage, the gate of the transistor to the PWM circuit. When a pulse signal output from the PWM circuit is at a high (H) level so that the output transistor is turned on, the LED emits light. When the duration of H level of the pulse signal is extended so that the duty ratio of the pulse signal is accordingly large, the duration of on period of the output transistor is accordingly extended. As a result of this, the quantity of light emitted by the LED is increased. In order for the three LEDs to provide illumination with a color other than blue, green or red, it is ensured that the quantity of light emitted by the LED differs from color to color by controlling the duty ratio of the pulse signal output from the three PWM circuits accordingly. | 2024-07-02T01:26:35.434368 | https://example.com/article/9825 |
Kolkata: Firhad Hakim, state Urban Development and Municipal Affairs minister, inaugurated the country's first hanging restaurant in New Town on Saturday.
The restaurant is a part of the Biswa Bangla Gate which was opened by Chief Minister Mamata Banerjee from the dais of the 43rd Kolkata International Book Fair on January 31. There are rooftop restaurants in several metropolitan cities but this hanging restaurant is a one-of-its-kind in India. Though there are 72 seats, the restaurant will be opened with 50 only. Fine dine restaurant will be kept open from 7 pm to 10 pm after entry to the Biswa Bangla Gate is closed for the public. The viewing gallery will remain open from 12 noon to 5 pm and visitors will have to buy entry tickets online. They will be allowed to stay there for an hour.
The waiters will come to the tables and take the order on Ipads. A copy of the order will go to the kitchen which is housed on the ground floor while the other will go to for billing. There is a service lift to carry the food to the restaurant. Special lightings have been made to give a different feel. Battery-powered candles are there to give a candlelight dinner ambience. Wi-fi connection is free. A garden will be set up to increase the green cover in areas surrounding the Biswa Bangla Gate.
Bob Wickesskey, a US delegate who had come to attend the two-day Bengal Global Business Summit) visited the Gate and said it was fascinating to see one enjoying coffee and the scenic beauty while cars passed-by below. The restaurant is situated above one of the busiest intersections in the city.
The visitors' gallery is around 25 metres above the ground. Visitors can use the lifts on one side of the gate to reach the gallery and the cafeteria. The visitors' gallery along with the cafeteria is surrounded by glass, which will be part of the wall. The construction of the Gate has involved around 70 tonne of steel. The idea of the gallery has been conceived from the Eiffel Tower in Paris, while the cafeteria has been inspired by the hanging cafeteria of Malaysia. | 2024-01-03T01:26:35.434368 | https://example.com/article/4884 |
Junichi S, Daqing M. Can dexmedetomidine protect against surgical stress response?. Clin Transl Med. 2020;10:e96 10.1002/ctm2.96
Surgical stress, pain, and complications are associated with postoperative morbidity and mortality.[^1^](#ctm296-bib-0001){ref-type="ref"} Various strategies have been implemented to reduce the stress response,[^2^](#ctm296-bib-0002){ref-type="ref"} for which anesthetics/techniques in attenuating perioperative stress and improving outcomes have been reported in several clinical settings.[^2^](#ctm296-bib-0002){ref-type="ref"} Recently, the effectiveness of dexmedetomidine on perioperative stress response as well as on short‐ and long‐term outcomes have been well documented.[^3^](#ctm296-bib-0003){ref-type="ref"}, [^4^](#ctm296-bib-0004){ref-type="ref"} In the current issue, Zhang and his co‐workers[^5^](#ctm296-bib-0005){ref-type="ref"} reported a randomized controlled trial (RCT) investigating the effects of dexmedetomidine against perioperative stress response during and after thoracic surgery. Total 135 patients underwent lung surgery were randomly divided into three groups, general anesthesia alone, general anesthesia combined with thoracic paravertebral block (TPVB) mixed with dexmedetomidine, and placebo. They found that, when compared to TPVB with 0.5% ropivacaine alone, TPVB in combination with dexmedetomidine significantly decreased the inflammatory mediators of IL‐6 and TNF‐α, decreased apoptosis index and lung injury score of lung tissue, and promoted favorable changes of various proteins (HIF‐1a, Tom20, Bcl‐2, and others) in an additive or synergistic manner. Additionally, they also found that, when compared to general anesthesia alone, TPVB or thoracic epidural anesthesia maintained better immune function.
Several strengths of this study were noticed: (1) multimeasurements and time points and (2) direct evidence of biomarkers and very subjective assessments. The magnitude of surgical stress depends on surgery type. Unlike minor surgery, major surgery in general triggers high levels of stress. However, this "old" concept may not be right because this study was demonstrated that the thoracoscopic surgery caused very measurable traumatic stress response. This study clearly demonstrated that dexmedetomidine, even single injection but not continuous infusion, had various preferable effects against perioperative stress response, which was failed in the previous studies.[^6^](#ctm296-bib-0006){ref-type="ref"} An additional strength of this study is that the samples obtained from patients were analyzed and those data further supported other clinical end points.
However, this study is not without limitations. First, the impact of dexmedetomidine on the prognosis of patients, for example morbidity and mortality, was not assessed in the study. Second, even though anti‐inflammatory effect of dexmedetomidine was clearly showed, the present study failed to show the benefits of the short‐term clinical outcomes including acute pain core and incidence of chronic pain, though there were several benefits compared with general anesthesia alone. This might be due to inadequate sample size (only 41 patients received dexmedetomidine) because the sample size was based on the laboratory data not clinical outcomes. Third, the adverse event of dexmedetomidine, especially hypotension, bradycardia, and other cardiovascular events were not reported, although, compared with intravenous injection, its paravertebral injection might be less notified. The evaluation of those adverse events are crucial because previous large RCTs revealed that perioperative hypotension was an independent predictor of myocardial infarction[^7^](#ctm296-bib-0007){ref-type="ref"} and stroke and death,[^8^](#ctm296-bib-0008){ref-type="ref"} which was closely associated with the beta‐blocker and a~2~‐adrenoreceptor agonist (clonidine).
A recent meta‐analysis[^6^](#ctm296-bib-0006){ref-type="ref"} reported that perioperative use of dexmedetomidine effectively attenuated stress response; blood epinephrine, norepinephrine, cortisol, and blood glucose were significantly decreased by dexmedetomidine in surgical patients. Dexmedetomidine use also decreased the pro‐inflammatory cytokines such as IL‐6, TNF‐α, and C‐reactive protein and increased NK cells, B cells, and CD4+ cells, and the ratio of CD4+:CD8+ and Th1:Th2. These preferable effects of dexmedetomidine in surgical patients were likely due to its attenuation the hypothalamic‐pituitary‐adrenal axis and sympathoadrenal "tone." Excess stress response is associated with poor postoperative outcomes including the high incidence of postoperative delirium, postoperative cognitive dysfunction,[^9^](#ctm296-bib-0009){ref-type="ref"} myocardial infarction, and death.[^10^](#ctm296-bib-0010){ref-type="ref"} Indeed, Su and colleagues[^3^](#ctm296-bib-0003){ref-type="ref"} conducted an RCT to evaluate the incidence of postoperative delirium. They included 700 elder patients after noncardiac surgery and divided the patients into two groups: either placebo (n = 350) or dexmedetomidine (n = 350), and revealed that the incidence of postoperative delirium was significantly lower in the dexmedetomidine group (9%) compared with the placebo group (23%; odds ratio 0.35, 95% confidence interval (CI) 0.22‐0.54). Kawagoe et al[^4^](#ctm296-bib-0004){ref-type="ref"} also conducted multicenter RCT to evaluate the impact of dexmedetomidine on clinical outcome of sepsis patients with mechanical ventilation. They included 201 sepsis patients and divided the patients into two groups: receiving either sedation with dexmedetomidine (n = 100) or sedation without dexmedetomidine (n = 101). They showed that 28 days mortality was tend to be low in the dexmedetomidine group (22.8%) compared with the control group (30.8%; hazard ratio, 0.69; 95% CI, 0.38‐1.22; *P* = .20) even though due to underpower of this study the difference was not significant. These results suggest that anti‐inflammatory effect of dexmedetomidine has a potential to improve surgical patients' outcomes, but to date, there is not enough evidence regarding the association between dexmedetomidine and long‐term outcomes. Further RCTs with large sample size are needed to determine the association of dexmedetomidine and long‐term outcomes of surgical patients.
AUTHOR CONTRIBUTIONS {#ctm296-sec-0020}
====================
Junichi Saito drafted the manuscript. Daqing Ma conceived the study idea and is the archival author. All authors participated to write the manuscript.
{#ctm296-sec-0030}
Reprints will not be available from the authors.
CONFLICT OF INTEREST {#ctm296-sec-0040}
====================
All authors declare no conflict of interest.
| 2024-01-25T01:26:35.434368 | https://example.com/article/6068 |
The Forums, which have functioned in one way or another since 1996, have now been closed to new posting. However there is a wealth of accumulated wisdom that can be searched for and utilized, so we've archived the messages.
Join our new forum on Facebook, the Eat Right 4 Your Type Group.
I was in physical rehab for the last 4 weeks. While there, one of the therapists told me about the ER4YBT diet and I found the website online. I was morbidly obese at the end of April (390 pounds) and decided to stop drinking..... Permanently and I went on Atkins. While I did lose a lot of weight (about 60 pounds), I felt poorly. No energy and always tired. My meals consisted of eggs and sausage for breakfast. Cucumber, tomato and either tuna salad or chicken. Dinners consisted of either grilled chicken salads, grilled shrimp salads, supplemented by roasted chicken. I ate a LOT of chicken.I developed an excruciating pain in my right groin area which was not arthritis which I do have but this pain was much too severe. I wound up in the hospital where after a five days of not eating Atkins, the pain subsided somewhat. I was admitted to a physical rehab where I found about the ER4YBT diet. I ordered the book but could not get it until I got discharged last Tuesday. While there, I read all I could on the website where I discovered that I should NOT be eating chicken. shrimp or red meat.
I tried to stick to the ER diet while at rehab, but was limited by the choices of food available. Oatmeal and eggs for breakfast. I usually wound up with a Chef salad where I eventually requested turkey, no ham or cheese and a side of tuna salad, no bread. No desserts except for some grapes I asked one of the aides to buy for me. NO bread or pasta either.
At home, it is still eggs and oatmeal for breakfast. For lunch / dinner I have allowed veggies with either tuna, sardines, or turkey with EVVOO at each meal. I broiled salmon for the first time last nite.
While I look forward to finishing the book, I have to say that I notice my sinuses are not constantly clogged and that my energy level is up somewhat. I have arthritic hips and am able to walk for longer distances now.
I ordered and received some of the supplements sold here but am waiting to finish the book prior to taking them.
I also ordered the secretor kit but have been unable to feel as if I can produce 3 ml of saliva yet. Is there any trick to this? I have been on cyclobenzaprine, meloxicam, atenolol and furosemide (for years for high BP). I wonder if they can be causing my dryout?
I look forward to finishing the book. This plan makes a lot of sense to me.
BTW, I am down from 390 to 306.8 as of this morning. I am looking to get to about 220.
Welcome whitescorpion! You are one the path to recovery. Results are noticeable is a short amount of time and just keep getting better. Eventually you will no longer recognize the person you once were. Many blessings to you!
You may want to read the book : "Change you genetic destiny" by Dr. D'Adamo". It is about how we are various 'genotypes'. You can get the SWAMI X-PRESS program to help determine exactly what geno type you are. It's more in depth but can fast forward your health recovery, but it is good that you are reading ERFYBT.
whitescorpion, good for you for diving right in! Sometimes we have to get in a difficult situation before we are really propelled into the solution. At least I've found it to be that way. A serious illness motivated me to follow Dr. D'Adamo's recommendations with great dedication and it has paid off.
A number of members of the Forum here have lost large amounts of weight. Many people have decreased their meds or even been able to eliminate them. The more you post your experiences and progress, the more people you will meet who will be able to share experiences, encouragement and ideas with you.
I wish you steadily improving health and hope.
One thing that helped me work up enough saliva to do the saliva test was to drink a lot of water before trying to spit. Give the water some time to work its' way through your system. Even mild dehydration will lessen body fluids.
Normal day, let me be aware of the treasure you are.Let me not pass you by in quest of some rare and perfect tomorrow.~Mary Jean Irion
Another vote here for going the Swami route. I believe that as you continue to see results and begin to feel healthier, you'll be inclined to hop aboard anyway. Might as well do it now. As Dr. D observed, type AB's can have the most dramatic results of all. My own results were indeed dramatic, and I am enjoying the renewal that he spoke of.
Welcome good work so far.. keep it up and you will feel better so soon it's near impossible to grab..
some sups might be needed but food is more important always..
get a 'bullet' to make smoothies to make fresh vegetables and drink them to replenish what we lost...
eat fruit whole always..
you will do great in no time.. I see Super Beneficials as meds..
going off meds?.. carefully.. discuss but don't get discouraged- it will happen mostly- in time..
Being here is invaluable, but not enough. We need ALL the Doctors. I needed them for a very small cancer spot-I could never feel!!! Please do your mammograms! Doing so saved me from cancer later on. I am grateful! Thanks for learning from my experience! I was lucky! I wish the same for YOU!
I have always been one to go slowly so I want to finish the book before doing anything else. I am sure I will have questions (I usually drive my Supervisors and others crazy because of my attention to detail).
I would like to read more about SWAMI before diving in. Thanks for the tips regarding saliva collection.
I have stopped taking the Ultracets prescribed for me as I read that Tramadol is addictive and changes brain chemistry similar to antidepressants, I never received a warning from the Doctor who prescribed it.
mainly your own, Dr D has made his science available to all, and it is up to us to do the work......the more you find out about your individuality the more you will discover Dr D has already done the work for you
''Just follow the book, don't look for magic fixes to get you off the hook. Do the work.'' Dr.D.'98DNA mt/Haplo H; Y-chrom/J2(M172);ESTJThe harder you are on yourself, the easier life will be on you! | 2024-01-20T01:26:35.434368 | https://example.com/article/9864 |
Q:
server side framework for ios apps
I am new to the IOS app development. I go through the apple developer portal they use Objective -C as their server side framework.
The main problem is I need to develop the app in one month and I know C# web service or java server side framework.
Does these frameworks are supported by the iOS apps API. Please suggest me.
And if possible give me some reference for these existing frameworks.
Thanks in advance
A:
Usually an App communicates via an HTTP service (usually a REST service) with a server. The server can be written in any language which can be used to provide a REST service. For example ASP.NET Web API if you are familiar with .NET and C#
| 2024-05-07T01:26:35.434368 | https://example.com/article/9416 |
BEND, Ore. — Firefighters in Bend, Ore., are trained for rescues — even for saving a 300-pound black bear passed out 60 feet up a tree.
Police say the bear was knocking over trash cans and making other mischief Monday night in a city neighborhood before it scrambled up the tree. KTVZ-TV says Fish and Wildlife workers went to remove it and shot it with multiple tranquilizers because of its size.
After the bear nodded off, two firefighters climbed up and put harnesses on it, then took their time carefully lowering the bear to safety. | 2024-05-22T01:26:35.434368 | https://example.com/article/4380 |
AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells.
Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells. | 2024-07-07T01:26:35.434368 | https://example.com/article/7238 |
/*
* See the NOTICE file distributed with this work for additional
* information regarding copyright ownership.
*
* This is free software; you can redistribute it and/or modify it
* under the terms of the GNU Lesser General Public License as
* published by the Free Software Foundation; either version 2.1 of
* the License, or (at your option) any later version.
*
* This software is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU
* Lesser General Public License for more details.
*
* You should have received a copy of the GNU Lesser General Public
* License along with this software; if not, write to the Free
* Software Foundation, Inc., 51 Franklin St, Fifth Floor, Boston, MA
* 02110-1301 USA, or see the FSF site: http://www.fsf.org.
*/
package org.xwiki.bridge.event;
/**
* An event triggered after a wiki has been copied.
* <p>
* The event also send the following parameters:
* </p>
* <ul>
* <li>source: the source wiki identifier as {@link String}</li>
* <li>data: the current {com.xpn.xwiki.XWikiContext} instance</li>
* </ul>
*
* @version $Id: 55de3f2699f6abce9b0acd8c348bcf82aa4429e9 $
* @since 4.3M1
*/
public class WikiCopiedEvent extends AbstractWikiEvent
{
/**
* The version identifier for this Serializable class. Increment only if the <i>serialized</i> form of the class
* changes.
*/
private static final long serialVersionUID = 1L;
/**
* The wiki where the documents have been copied.
*/
private String targetWikiId;
/**
* Matches all {@link WikiCopiedEvent} events.
*/
public WikiCopiedEvent()
{
}
/**
* Matches events affecting the same wikis.
*
* @param sourceWikiId the source wiki identifier
* @param targetWikiId the target wiki identifier
*/
public WikiCopiedEvent(String sourceWikiId, String targetWikiId)
{
super(sourceWikiId);
this.targetWikiId = targetWikiId;
}
@Override
public boolean matches(Object otherEvent)
{
boolean matches = super.matches(otherEvent);
if (matches) {
WikiCopiedEvent wikiCopiedEvent = (WikiCopiedEvent) otherEvent;
matches = getTargetWikiId() == null || getTargetWikiId().equals(wikiCopiedEvent.getTargetWikiId());
}
return matches;
}
/**
* @return the source wiki identifier
*/
public String getSourceWikiId()
{
return getWikiId();
}
/**
* @return the target wiki identifier
*/
public String getTargetWikiId()
{
return this.targetWikiId;
}
}
| 2024-04-04T01:26:35.434368 | https://example.com/article/3211 |
Display all by
Display with the brief description
Defence Line of Amsterdam
Defence Line of Amsterdam
Extending 135 km around the city of Amsterdam, this defence line (built between 1883 and 1920) is the only example of a fortification based on the principle of controlling the waters. Since the 16th century, the people of the Netherlands have used their expert knowledge of hydraulic engineering for defence purposes. The centre of the country was protected by a network of 45 armed forts, acting in concert with temporary flooding from polders and an intricate system of canals and locks.
Outstanding Universal Value
Brief synthesis
The Stelling van Amsterdam (Defence Line of Amsterdam) is a complete ring of fortifications extending more than 135 km around the city of Amsterdam. Built between 1883 and 1920, the ring consists of an ingenious network of 45 forts, acting in concert with an intricate system of dikes, sluices, canals and inundation polders, and is a major example of a fortification based on the principle of temporary flooding of the land.
Since the 16th century, the people in the Netherlands have used their special knowledge of hydraulic engineering for defence purposes. The area around the fortifications is divided into polders, each at a different level and surrounded by dikes. Each polder has its own flooding facilities. The depth of flooding was a critical factor in the Stelling’s success; the water had to be too deep to wade and too shallow for boats to sail over. Water levels were maintained by means of inlet sluices and barrage sluices. Forts were built at strategic locations where roads or railroads cut through the defence line (accesses). They were carefully situated at intervals of no more than 3500 m, the spacing being determined by the range of the artillery in the forts. The earlier ones were built of brick, the later of massed concrete.
The land forts have an important place in the development of military engineering worldwide. They mark the shift from the conspicuous brick/stone casemated forts of the Montalembert tradition, in favour of the steel and concrete structures that were to be brought to their highest level of sophistication in the Maginot and Atlantic Wall fortifications. The combination of fixed positions with the deployment of mobile artillery to the intervals between the forts was also advanced in its application.
Criterion (ii): The Stelling van Amsterdam is an exceptional example of an extensive integrated European defence system of the modern period which has survived intact and well conserved since it was created in the late 19th century. It is part of a continuum of defensive measures that both anticipated its construction and were later to influence some portions of it immediately before and after World War II.
Criterion (iv): The forts of the Stelling are outstanding examples of an extensive integrated defence system of the modern period which has survived intact and well conserved since it was created in the later 19th century. It illustrates the transition from brick construction in the 19th century to the use of reinforced concrete in the 20th century. This transition, with its experiments in the use of concrete and emphasis on the use of unreinforced concrete, is an episode in the history of European architecture of which material remains are only rarely preserved.
Criterion (v): It is also notable for the unique way in which the Dutch genius for hydraulic engineering has been incorporated into the defences of the nation's capital city.
Integrity
The Stelling van Amsterdam and its individual attributes are a complete, integrated defence system. The defence works have not been used for military purposes for the past four decades. As the surrounding area was a restricted military zone for many decades, its setting has been preserved through planning development control, although it could in the future be vulnerable to development pressures.
The ring of forts make up a group of connected buildings and other structures whose homogeneity and position in the landscape have remained unchanged and distinguishable in all its parts. They form the main defence line together with the dikes, line ramparts, hydraulic properties, forts, batteries and other military buildings, and the structure of the landscape.
Authenticity
The fortifications have been preserved as they were designed and specified. The materials and building constructions used have also remained unchanged. Repair in arrears applies in some cases. No parts of the Stelling have been reconstructed. The Outstanding Universal Value is expressed in the authenticity of the design (the typology of forts, sluices, batteries, line ramparts), of the specific use of building materials (brick, unreinforced concrete, reinforced concrete), of the workmanship (meticulous construction apparent in its constructional condition and flawlessness), and of the structure in its setting (as an interconnected military functional system in the human-made landscape of the polders and the urbanised landscape).
The Stelling van Amsterdam is a coherent human-made landscape, one in which natural elements such as water and soil have been incorporated by humans into a built system of engineering works, creating a clearly defined landscape.
Protection and management requirements
The Province of Noord-Holland is the site-holder. Responsibility for the conservation is also in the hands of the national government, the Province of Utrecht, 23 municipal authorities and three water boards. In addition, the many management bodies and owners of sections of the Stelling van Amsterdam (e.g. nature conservation organisations and private parties) play a role. The north side of the Stelling van Amsterdam overlaps with the Beemster Polder, another World Heritage property. The Stelling van Amsterdam has no buffer zone.
Protection of the properties is multi-level and comprehensive. The Stelling is protected by the Provincial By-law governing Monuments and Historic Buildings [Provinciale Monumenten-verordening] (more than 125 elements of the Stelling are provincial heritage sites) and the national 1988 Monuments and Historic Buildings Act [Monumentenwet 1988] (more than 25 elements are state monuments).
In 2011, the Dutch government adopted the National Policy Strategy for Infrastructure and Spatial Planning (SVIR). This agenda came into force in 2012 and ensures the maintenance of World Heritage properties when it comes to the spatial development of the Netherlands. In line with this national policy, a specific preservation regime on the basis of the Dutch Spatial Planning Act (Wro) has been adopted for the Defence Line of Amsterdam in the General Spatial Planning Rules Decree (Barro). This regime involves legally binding rules that instruct provinces to ensure that the maintenance of the attributes of the World Heritage properties is guaranteed in local zoning plans.
In 2005, the Province of Noord-Holland set up a programme office for the Stelling van Amsterdam in order to manage the property (preservation and development). The programme office is in charge of carrying out the Stelling van Amsterdam Implementation Plan [Uitvoeringsprogramma] 2009-2013, adopted by the Provincial Council of Noord-Holland in 2009. The planning framework for the Stelling has been set out in the Policy Framework for Spatial Planning [Ruimtelijk Beleidskader] (2008); quality assurance is regulated in the Visual Quality Plan [Beeldkwaliteitsplan] for the Stelling van Amsterdam (2009).
The Stelling van Amsterdam is subject to the provincial Strategic Structure Agenda for 2040 [Structuurvisie 2040] since 2010. The relevant provincial By-law lists the key attributes and Outstanding Universal Value of the Stelling van Amsterdam and sets out rules for dealing with spatial aspects of the Stelling van Amsterdam as a World Heritage property and National Landscape. The relevant municipal authorities will incorporate these policy rules into their zoning plans. The section of the Stelling van Amsterdam located in the Province of Utrecht is covered by the 2005-2015 Regional Plan for Utrecht [Streekplan Utrecht], superseded by the Strategic Structure Agenda for Utrecht [Structuurvisie Utrecht] in 2013.
The Stelling van Amsterdam programme office intends to develop three visitor centres: one on the southeast side of the Stelling (Fort Pampus, opened in 2011), one on the west side (Fort Benoorden Spaarndam) and one in the northwest (Fort bij Krommeniedijk). Because the Stelling van Amsterdam is located in a spatially and economically dynamic area, planning tools and management mechanisms will be crucial to ensure that spatial developments do not have a detrimental impact on the Outstanding Universal Value of the property and the original open nature of its landscape setting. | 2023-08-05T01:26:35.434368 | https://example.com/article/8204 |
/*
* Copyright © 2016-2020 Canonical Ltd.
*
* This program is free software: you can redistribute it and/or modify it
* under the terms of the GNU General Public License version 2 or 3 as
* published by the Free Software Foundation.
*
* This program is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
* GNU General Public License for more details.
*
* You should have received a copy of the GNU General Public License
* along with this program. If not, see <http://www.gnu.org/licenses/>.
*
* Authored by: Alan Griffiths <alan@octopull.co.uk>
*/
#include "application_info_internal.h"
#include "miral/window.h"
#include <mir/scene/session.h>
void miral::ApplicationInfo::add_window(Window const& window)
{
self->windows.push_back(window);
}
void miral::ApplicationInfo::remove_window(Window const& window)
{
auto& siblings = self->windows;
for (auto i = begin(siblings); i != end(siblings); ++i)
{
if (window == *i)
{
siblings.erase(i);
break;
}
}
}
| 2024-07-08T01:26:35.434368 | https://example.com/article/3516 |
A multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptor.
Voltage-gated Na(+) (Na(v)) channels are responsible for initiating action potentials in excitable cells and are the targets of local anesthetics (LA). The LA receptor is localized to the cytoplasmic pore mouth formed by the S6 segments from all four domains (DI-DIV) but several outer pore-lining residues have also been shown to influence LA block (albeit somewhat modestly). Many of the reported amino acid substitutions, however, also disrupt the inactivated conformations that favor LA binding, complicating the interpretation of their specific effects on drug block. In this article, we report that an externally accessible aromatic residue in the Na(v) channel pore, DIV-Trp1531, when substituted with cysteine, completely abolished LA block (e.g., 300 microM mexiletine induced a use-dependent block with 65.0 +/- 2.9% remaining current and -11.0 +/- 0.6 mV of steady-state inactivation shift of wild-type (WT) channels versus 97.4 +/- 0.7% and -2.4 +/- 2.1 mV of W1531C, respectively; p < 0.05) without destabilizing fast inactivation (complete inactivation at 20 ms at -20 mV; V(1/2) = -70.0 +/- 1.6 mV versus -48.6 +/- 0.5 mV of WT). W1531C also abolished internal QX-222 block (200 microM; 98.4 +/- 3.4% versus 54.0 +/- 3.2% of WT) without altering drug access. It is interesting that W1531Y restored WT blocking behavior, whereas W1531A channels exhibited an intermediate phenotype. Together, our results provide novel insights into the mechanism of drug action, and the structural relationship between the LA receptor and the outer pore vestibule. | 2023-10-30T01:26:35.434368 | https://example.com/article/5945 |
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The Quebec City Shooting: Calling A Spade A Spade
On Sunday, January 29th Alexandre Bissonnette went into a Quebec City mosque and took the lives of six people. The 27-year old University of Laval student injured another nineteen, five of whom are still in critical condition. The Canadian government was quick to call the attack an act of terrorism, and the Canadian public was left reeling at the worst act of violence in recent memory.
Accounts of Bissonnette’s recent activity online and in person revealed that he had become ‘radicalized’ in the brand of xenophobia and nationalism espoused by Marine LePen, who had recently visited Quebec. His classmates also gave accounts of Bissonette as a Trump supporter, and that his loud and frequent clashes at school had made him something of a pariah.
He has subsequently been charged with six counts of first-degree murder and awaits trial later this year. There is little doubt that he will be convicted.
However, whether he will be convicted of terrorism, or even charged with it, is still a matter of some debate. The prevailing sentiment in the Canadian legal community is that charging him with terror will diminish chances of his conviction under that charge and draw out the legal process unnecessarily. Criminal lawyer Eric Stutton told the CBC, “He's facing multiple charges of murder, and the potential sentence goes beyond whatever could be imposed on him even if he was charged with terrorist activities. There’s no real purpose.”
But there is a purpose. To name this act what it is, terror and nothing else, is important. Terror which, incidentally, is defined in Canada as an act committed "for a political, religious or ideological purpose, objective or cause" that has "the intention of intimidating the public, or a segment of the public with regard to its security." If an attack on a religious institution can have any other intention or objective, I welcome the insight. Calling this attack terrorism, and not a murder or the act of a ‘lone wolf’ or lunatic, is essential to dismantling the apparatus of hate that produced it.
But, of course, there’s an underlying reason that the Canadian government and the courts of Quebec will not charge Bissonnette with terrorism; if they do, they will be tacitly linking the ideologies of the Trumps and LePens around the world with terrorism. There is a danger in admitting that Canada’s closest allies are a breeding ground for terrorist ideology.
The reluctance to prosecute Bissonnette as a terrorist, to place him firmly in the category we all so roundly condemn, is symptomatic of why the climate of hate is allowed to thrive in North America. We do not want to see ourselves as its enablers, or indeed its source.
But we are. It is no coincidence that 29 hate crimes were reported in the 48 hours following the attack. Many people felt affirmed in their beliefs and encouraged to act within a community. According to the American Psychological Association, this is a typical phenomenon with terrorist causes.
These people acted as part of a community of hate.
We allow that hate to spread by calling it by other names. I cannot count the number of times my liberal friends have dismissed Donald Trump or Marine LePen as ‘crazy’ or a ‘nutcase,' a ‘lunatic’ or a ‘psychopath.' They called Alexandre Bissonnette the same thing in the wake of the shooting. And therein lies the problem, because neither man is a lunatic or a psychopath.
Now, you may say that the conflation of a murderer and the president is unfair, and I grant you there may be some truth to that, but I submit for your consideration the American Psychological Association’s conditions for recruitment into terrorist organizations:
Feeling angry, alienated or disenfranchised.
Believing that their current political involvement does not give them the power to effect real change.
Identifying with perceived victims of the social injustice they are fighting.
Feeling the need to take action rather than just talking about the problem.
Believing that engaging in violence against the state is not immoral.
Having friends or family sympathetic to the cause.
Believing that joining a movement offers social and psychological rewards such as adventure, camaraderie and a heightened sense of identity.
The nationalistic, America-first ideologues, seem – on paper – to exhibit a lot of the characteristics one would expect to find in a young radical ready to be indoctrinated in a terrorist organization. That’s because these qualities are not unique to foreign terrorists, a group that we still tend to think of overwhelmingly as Muslim and trying to get into America.
The reality is that the seeds of radicalization and terror are being sown well within the confines of increasingly closed borders. People feel disenfranchised; they are angry at their poverty and station, they have lost faith in a broken political system, they are told that a specific group (immigrants, Muslims, the elite, etc.) are responsible. When Sean Spicer took the podium in the wake of the Montreal attack and said, “It’s a terrible reminder of why we must remain vigilant and why the president is taking steps to be proactive rather than reactive when it comes to our nation’s safety and security.” Was that a terrible, self-aware moment of realization?
In an article on terrorism for Psychology Today, Dr. Steven Taylor said, “psychologists who have studied terrorist groups have found that terrorists tend to be stable individuals, not paranoid or delusional.” These people are not crazy, they are rational and have come to embrace an ideology of hate that is hiding behind nationalism, patriotism or the ire of their peers.
It’s about time we started taking them seriously and calling the hate and terror what it really is. | 2024-05-31T01:26:35.434368 | https://example.com/article/9154 |
Finally Dragon Quest series is back on the big screen once more.
Dragon Quest series is a long running JRPG series from Square Enix. Famous for it’s traditional / classic style of RPG & also the character designer, Akira Toriyama, the mangaka of Dragon Ball series. Dragon Quest VIII: Journey of the Cursed King was the last Dragon Quest to get a console release back in 2004. Since then, Dragon Quest IX, and then the remake of VII & VIII was released on Nintendo 3DS, while IV-VI got a NDS version. And with the success of Dragon Quest XI, Dragon Quest I to III are slated for PS4 release. (Dragon Quest I & II have already been released on Japanese PSN for PS4). Dragon Quest X is not considered as the main series because it’s an MMORPG, but it’s coming as well to PS4 soon in Japan.
For those who never played Dragon Quest series before, DON’T WORRY. Just like Final Fantasy, even though the game has numbering, the games don’t actually related to each other. So if this game is gonna be your first Dragon Quest, then let me say, “Welcome to the club”.
Dragon Quest XI is released on 28 July 2017 in Japan. 2 Versions of the game came out on the same day. The PS4 Version & 3DS Version. So, my review here is going to be based on the PS4 Version.
Before we go into an in-depth review of the game, please take a look of the trailer below to get the “feel” of the game.
Now that you have watched it, let’s get into the in-depth review!
Story
The game starts with a 4 minutes prologue which shows the peaceful Yugnoa Kingdom which was destroyed by monsters over night. Our hero is still a baby, and in the attempt of running away from the monsters, our Hero fell into the river and got separated from his family. The next day an Old Guy from Ishi Village found him and took care of him as a family.
16 Years after that tragedy, our hero is about to finish his coming of age ritual. Together with his childhood friend, Ema, they are supposed to climb to the top of God’s Rock behind the village. Together with Ema, both of them reach the top of the mountain together. And at that moment, the “Mark of Hero” starts flashing and call upon the lightning to save Ema who almost fell from the mountain due to monster attack. And that’s where your journey begins. The Hero is an incarnation of Legendary Hero who beats the Devil King a long time ago. To find out the meaning of the “Mark of Hero”, he embarks on a journey not knowing what’s waiting in front of him. Play the game and find out about it!
At first, Dragon Quest XI’s plot might feel a lil bit too simple. Going on a journey to defeat the evil king, just like any normal JRPG. But the back story to the plot & each characters are very well written. Like why Kamui became a thief, or the story behind Veronica & Senya, etc. Not to mentioned the character development which are super interesting. Every character in the game has a reason to join with our hero, and has a very good background story to back it up as well. Unlike Final *cough* Fantasy *cough* XV, you can see that the story connect from one to another and doesn’t feel rushed. And on top of that, the plot twist & story development is awesome. The story definitely caught me by surprise. You will never gonna be able to guess how the story is gonna end. I finished the game in 120 Hours, so the game itself packs a pretty great deal of volume in it.
I know this is going to feel a little bit overrated, but i guarantee you that Dragon Quest XI’s story is one of the best & exciting adventure you can get in this generation. (Yes, I personally think it’s better than Persona 5).
10/10 for the story. It gave me a complete satisfaction by the time i finished the game, without anything to complain.
Gameplay
If you ever played any of the Dragon Quest Series before, you won’t have any trouble playing this one as well. The battle system hasn’t changed since Dragon Quest I. In fact, i like how they keep everything simple. It’s still the same old Turn Based JRPG, where you can use magic and skill. Other JRPGs are getting complicated each time they release a new game, but not Dragon Quest. It’s easy, it’s simple, and it’s still the same throughout the whole series. But of course there are new stuffs as well, such as Skill Panel & Combination Attack. Skill Panel
Not too complicated, the skill panel is similar to Final Fantasy X Sphere Grid. When you level up, you will get Skill Point that can be used to unlock the Skill Panel. The skill panel is usually based on the type of weapon you are using & type of character you want to create. For example, our hero starts with 3 Skill Panel, which are One Handed Sword, Two Handed Sword, & Hero. While Martina has Claws, Spear, Fighter, Sex Appeal skill panel. So it’s better if you stick to one choice of weapon per character due to the skill panel development. You will get an increase stats / new skill / new magic from the Skill Panel. Combination Attack
I don’t think i have ever seen any combination attack on the previous Dragon Quest series. This is the first time they are using the combination attack system and it turns out to be awesome. So, you character will go into “Zone” mode every once in a while. (Kinda like limit break or something). During that “Zone” mode, your stats will increase greatly and you can do combination attack with other characters in your main party. There are 2 persons combination attack, 3 persons combination attack, and also 4 persons combination attack. Each one has a unique cutscene for the combination attack. By unlocking the skill panel, you’ll get the skill that you needed to do a combination attack. It’s automatically registered to the combination attack list once you have unlock all the skills needed for the attack. For example, Hero’s Fire Slash & Kamui’s Steal, by unlocking those two skills, you’ll get a combination attack called “Treasure Hunter”. Transportation
In the field you can ride horse, a small robot, bone monster, and even a small dragon to help you go through & explore the big maps. Talking about transportation, there are Sea & Sky Transportation in this game as well. Mini Game
And there are also some mini-game that you can do in this game. Such as Casino & Horse Race. Costume
How generous of Square Enix, this time Costumes are part of the item in game. By equipping a set of items, you can change the appearance of your characters. As far as i know there are no DLC for Dragon Quest XI at the moment. This slideshow requires JavaScript. Sub-Quest
This game has total of 60 Quests that you can take. You can check the progress and where you can get the quest from the Progress menu. Other than those 60 Quests, there are also secret quests that don’t appear on the list. Just like the old Dragon Quests series, there are secret quest for getting the strongest weapon and such things. It will be fun to find those secret missions on your playthrough.
If you ever played any of the Dragon Quest Series before, you won’t have any trouble playing this one as well. The battle system hasn’t changed since Dragon Quest I. In fact, i like how they keep everything simple. It’s still the same old Turn Based JRPG, where you can use magic and skill. Other JRPGs are getting complicated each time they release a new game, but not Dragon Quest. It’s easy, it’s simple, and it’s still the same throughout the whole series. But of course there are new stuffs as well, such as Skill Panel & Combination Attack.
Another 10/10 for the gameplay. The gameplay is simple and easy to understand for the new comer and for the fans of the series. It’s a good thing that they are keeping things that are good and not changing the whole system. But instead, they are adding new things to the system that people are familiar with.
Graphics
My experience of the game is based on my gameplay on PlayStation 4 Pro. Personally i think that the graphics are awesome, although everything might be too colorful. Check out some of the screenshots i took during my gameplay.
As you can see, the fields are really beautiful. Not to mention the town and village are big and can be explored. Even when you start playing the game, in one of the tutorial, they write something about “enjoying the scenery as you play”. And character model, faces, & expressions are also awesome. Most of the cut scenes in the game runs in real time (Not using a cutscene movie). By real time, i mean that it’s the same quality as when you are moving your characters. And also the detail of the clothing. If you zoom in into the Hero’s cloth, you can actually guess the material, because it looks so real. Villagers face also looks very good.
The graphics is easily 10/10. One of the best looking JRPG to date.
Sound & Music
For those who used the play the old Dragon Quest series, the sound effect is still the same. Like when you go to church to pray, when you sleep, attack sound, or conversation sound. And the music are Orchestra, the Main Theme is still the same as ever with a new arrangement.As you all has already heard, this game has no voice over at all. I don’t know if they will include voice over for the Western version. The first time i heard about it, i was quite disappointed. The reason that it doesn’t have any voice over is so that the developer team can change the script however they want & no re-recording just because one sentence changed. That way, they can keep the originality of Dragon Quest & deliver it to us faster. Although it some events, i really wish that they have voice, because it will have much more impact to it. But what they lack in voice, they make it up on the background music. The BGMs of the game are AWESOME. Everything is in orchestra, and all of the musics are right for the moments of the game.
9/10 for the Sound & Music. I personally want a voice over for this game. Doesn’t mean that the game is bad without voice over. It’s already great. But with such great musics, if they also have voice over then it will be perfect.
The Verdict
I can say with confidence, that this is the best JRPG for PlayStation 4 to date. I won’t compare it to Persona 5, because fundamentally it’s a different kind of JRPG. Dragon Quest is an adventure JRPG, you feel like you travel the whole world together with the team. If you like classic RPG and this generation graphics, then you shouldn’t think twice about getting this game. It’s a must have. Oh and Square Enix is also giving us a surprise with an unannounced secret party member 😉
The score : 9.75/10
This might seems like an overrated score, but trust me, it’s that good. With an unexpected story, well developed back story, beautiful world, I enjoyed 120 hours I spent in Lotozetasia. Perhaps the Golden Era of JRPG might be coming back after all.
Erhanz wrote this review based on his experience in the game. He spent 120 Hours in it, finishing all the sub-quests, and getting a platinum trophy for it. This review is made based on the japanese version of the game. | 2024-05-28T01:26:35.434368 | https://example.com/article/8749 |
Q:
Android, How to make a transparent status bar correctly
I'm trying to make transparent status bar on Android 4.4+
I know how to make it transparent by defining my own style:
<style name="Theme.MyTheme" parent="Theme.MyTheme.Base">
<item name="android:windowTranslucentStatus">true</item>
<item name="android:windowTranslucentNavigation">true</item> </style>
I found here:
https://stackoverflow.com/a/20573595/2633630
The problem is that when status bar is transparent, it doesn't match the color of the action bar and the activity in the background is seen:
So I found that I can use android:fitsSystemWindows="true" and android:clipToPadding="false" in my layout that I found here http://mindofaandroiddev.wordpress.com/2013/12/28/making-the-status-bar-and-navigation-bar-transparent-with-a-listview-on-android-4-4-kitkat/
<LinearLayout xmlns:android="http://schemas.android.com/apk/res/android"
xmlns:tools="http://schemas.android.com/tools"
android:layout_width="match_parent"
android:layout_height="match_parent"
android:background="@color/background_darkRed"
android:fitsSystemWindows="true"
android:clipToPadding="false"
tools:context="com.sandak.......">
<ScrollView
android:layout_width="match_parent"
android:layout_height="match_parent">
....
That solves the top problem with transparent status bar and looks ok.. Unfortunately there is problem at the bottom on the "nav bar" with the system buttons, which is red and not transparent as I wish:
I was trying all possible variants to achieve working result, but I cannot figure out how to solve it. My only working solution is set top padding about 60dp to the root element. But this solution is ugly and on different devices can look different and may be not working.
I found a few applications on Google Play which working Ok with transparent background, so I'm curious how they make it work.
For example:
https://play.google.com/store/apps/details?id=com.trello and few others
A:
//UPDATE:
Ok, this is quite old answer. Now you can use Material theme to handle this and it is pretty easy. Just set target api to 21+, use support library if you need to and create theme with material theme where you can specify status bar color directly
<style name="AppTheme"
parent="Theme.AppCompat.Light.DarkActionBar">
<!-- colorPrimary is used for the default action bar background -->
<item name="colorPrimary">@color/color_primary</item>
<!-- colorPrimaryDark is used for the status bar -->
<item name="colorPrimaryDark">@color/color_primary_dark</item>
<!-- colorAccent is used as the default value for colorControlActivated
which is used to tint widgets -->
<item name="colorAccent">@color/accent_orange</item>
</style>
=======================================================================
OLD ANSWER:
Ok, It seems that I solve my problem. It is not the best and clearest solution, but it is working solution.
If anybody in the future will find out better and more clear solution, please let me know and I will update my answer / or mark your answer as correct one. But for now, I have no better solution than this little hack:
The root element of the layout has to be RelativeLayout. Than should follow your main layout like ScrollView or any kind of others layouts, it doesn't matter. At the end before closing Relative Layout tag follows empty LinearLayout which has set the same background as your Action Bar and fixed height (height of Status Bar).
<RelativeLayout xmlns:android="http://schemas.android.com/apk/res/android"
xmlns:tools="http://schemas.android.com/tools"
android:layout_width="match_parent"
android:layout_height="match_parent"
tools:context="com.sandak....">
<ScrollView
android:fitsSystemWindows="true"
android:clipToPadding="false"
android:layout_width="match_parent"
android:layout_height="match_parent">
.... all your main views etc..
</ScrollView>
<LinearLayout
android:id="@+id/statusBarBackgroundLinearLayout"
android:layout_width="match_parent"
android:orientation="horizontal"
android:layout_height="30dp"
android:background="@color/background_darkRed"
android:clickable="false"
android:focusable="false">
</LinearLayout>
</RelativeLayout>
Ok then you have to set in code the same Linear Layout height as the Status bar has:
private void setStatusBarBackground(View rootView) {
setStatusBarLayout(rootView);
statusBarHeight = getStatusBarHeight();
setStatusBarLayoutHeight(statusBarHeight);
}
private void setStatusBarLayout(View rootView){
statusBarBackgroundLinearLayout = (LinearLayout) rootView.findViewById(R.id.statusBarBackgroundLinearLayout);
if (isPreKitkatDevice()) {
hideStatusBarLayout();
}
}
private int getStatusBarHeight() {
int statusBarHeight = 0;
int resourceId = getResources().getIdentifier("status_bar_height", "dimen", "android");
if (resourceId > 0) {
statusBarHeight = getResources().getDimensionPixelSize(resourceId);
}
return statusBarHeight;
}
private boolean isPreKitkatDevice(){
return Build.VERSION.SDK_INT < Build.VERSION_CODES.KITKAT;
}
private void hideStatusBarLayout(){
statusBarBackgroundLinearLayout.setVisibility(View.INVISIBLE);
}
private void setStatusBarLayoutHeight(int height){
RelativeLayout.LayoutParams layoutParams = (RelativeLayout.LayoutParams) statusBarBackgroundLinearLayout.getLayoutParams();
layoutParams.height = height;
}
And then just call setStatusBarBackground in your onCreate() method. This is working solution for all different kind of deviceas. For pre KitKat devices where transparent background is not allowed you have to hide the Linear Layout.
| 2023-08-10T01:26:35.434368 | https://example.com/article/4787 |
894 F.2d 1000
UNITED STATES of America, Appellee,v.Antonio Nonato EVIDENTE, Appellant.
No. 88-5208.
United States Court of Appeals,Eighth Circuit.
Submitted April 25, 1989.Decided Jan. 29, 1990.Rehearing and Rehearing En Banc Denied March 9, 1990.
Scott F. Tilsen, Minneapolis, Minn., for appellant.
James E. Lackner, Asst. U.S. Atty., Minneapolis, Minn., for appellee.
Before ARNOLD, JOHN R. GIBSON and BOWMAN, Circuit Judges.
BOWMAN, Circuit Judge.
1
Antonio Nonato Evidente fled from Guam to the Philippines, apparently to avoid criminal prosecution in Guam. Several years later he was returned to Guam (in disputed circumstances that are irrelevant to the issues in this appeal) and was found guilty in the United States District Court for the District of Guam on several federal charges, including conspiracy and mail fraud. He was sentenced in May 1987 to a twelve-year term of imprisonment. On December 7, 1987, while serving his sentence at the federal prison at Sandstone, Minnesota, Evidente escaped from a work detail. He fled to Mexico, where he was arrested on or about December 30, 1987. Found in his possession at the time of his arrest were documents indicating that he was trying to obtain a Philippines passport under an assumed name. He did not voluntarily surrender and was apprehended only after considerable investigation and the cooperation of an informant. He was brought back to the United States and charged with escape from federal custody in violation of 18 U.S.C. Sec. 751(a) (1982). He pleaded guilty to this charge. The District Court1 imposed a sentence under the Sentencing Guidelines of eighteen months.
2
In this direct appeal, Evidente challenges only his sentence. He argues: (1) the sentence imposed was in violation of law because the Sentencing Commission violated its directive from Congress in establishing the guideline for the offense of escape; (2) the court incorrectly applied the Guidelines by failing to give a reduction for acceptance of responsibility; and (3) the court erred in failing to depart downward. We affirm.
I.
3
Evidente contends that the offense level for escape established by the Sentencing Commission violates the governing statute2 because the Commission irrationally failed to consider and adjust for several circumstances that mitigate or aggravate the seriousness of the offense. Evidente specifically contends that Section 2P1.1 does not vary the offense level according to the method of escape (e.g., walking away as opposed to bribing a guard or digging a tunnel) or the kind of facility from which the defendant has escaped (e.g., escape from a work camp as opposed to a maximum security prison). Evidente contends that the failure to include such distinctions renders the offense level unresponsive to the congressional directive and, therefore, that his sentence was imposed in violation of law. 18 U.S.C. Sec. 3742(a)(1), (e)(1) (1988).
4
In reviewing this sort of challenge to one of the guidelines, our task is not to determine what would be the best guideline for the offense in question, but rather to determine whether the guideline promulgated by the Commission is "sufficiently reasonable" in light of the congressional directive. Cf. Federal Election Commission v. Democratic Senatorial Campaign Committee, 454 U.S. 27, 39, 102 S.Ct. 38, 46, 70 L.Ed.2d 23 (1981) (quoting Train v. Natural Resources Defense Council, 421 U.S. 60, 65, 95 S.Ct. 1470, 1475, 43 L.Ed.2d 731 (1975)). Section 2P1.1 of the Guidelines gears the offense level to several circumstances that determine the appropriate guideline range. The primary distinction drawn by the guideline is based on the kind of custody from which the defendant escapes. Section 2P1.1(a)(1) assigns a base offense level of thirteen to escape from lawful custody arising from a conviction or lawful felony arrest, while Section 2P1.1(a)(2) assigns a base offense level of eight to escape by a person designated as a recalcitrant witness, a person awaiting extradition, or a person lawfully arrested for a misdemeanor.
5
In addition, the guideline increases or decreases the offense level depending on (1) whether the use or threat of force is involved (increase), (2) whether the escape is from a nonsecure facility and voluntary return occurs within ninety-six hours (decrease), and (3) whether the defendant who instigated or assisted the escape is a correctional officer or employee of the Department of Justice (increase).
6
We cannot say that Section 2P1.1 is not a sufficiently reasonable response to the congressional directive. Although the Commission might have written a guideline on escape that would have included some of the finer distinctions that Evidente urges and that the guideline as promulgated does not contain, we believe it is clear that the Commission was not obligated to do so. We therefore hold that the guideline complies with the congressional directive and that Evidente's sentence was not imposed in violation of law.
II.
7
Evidente argues that the District Court erred in declining to give him credit for acceptance of responsibility. Section 3E1.1(a) of the Guidelines instructs the sentencing court to reduce the offense level by two levels "[i]f the defendant clearly demonstrates a recognition and affirmative acceptance of personal responsibility for his criminal conduct." However, "[a] defendant who enters a guilty plea is not entitled to a sentencing reduction under this section as a matter of right." U.S.S.G. Sec. 3E1.1(c). Instead, the sentencing court may look to several factors suggested by the Guidelines, including whether the defendant voluntarily terminated or withdrew from the criminal conduct and the timeliness of the defendant's conduct in manifesting his acceptance of responsibility. U.S.S.G. Sec. 3E1.1, comment. (n. 1(a), (g)).
8
The question of whether a defendant has accepted responsibility is a factual one, depending largely on credibility assessments by the sentencing judge, who can far better evaluate the defendant's acceptance of responsibility than can a reviewing court. Consequently, "the determination of the sentencing judge is entitled to great deference on review and should not be disturbed unless it is without foundation." U.S.S.G. Sec. 3E1.1, comment. (n. 5); See also United States v. Nunley, 873 F.2d 182, 187 (8th Cir.1989).
9
Evidente argues that the reasons given by the District Court in refusing to give credit for acceptance of responsibility were without foundation. First, Evidente contends that his flight from Guam seven years ago (after perpetrating the crime for which he was later convicted) is irrelevant to the court's assessment of his present acceptance of responsibility.3 We disagree. We believe that Evidente's past failure to accept responsibility for his criminal conduct, and his demonstrated propensity for flight, properly could be considered by the sentencing court in evaluating Evidente's present claim of contrition.
10
Next, Evidente argues that his conduct during the commission of his escape from federal custody (he fled to Mexico and was attempting to reach the Philippines) is irrelevant because it is part of the offense. We again disagree. The fact that Evidente was captured in Mexico while seeking passage to the Philippines shows that he did not voluntarily withdraw from his criminal conduct. See U.S.S.G. Sec. 3E1.1, comment. (n. 1(a)).
11
Finally, Evidente contends that the District Court erred as a matter of law in giving insufficient weight to his guilty plea. This contention lacks merit. At sentencing, the court stated: "I agree with the government that merely the plea of guilty by itself is meaningless." Sentencing Transcript at 19. The Guidelines provide that "[a] guilty plea may provide some evidence of the defendant's acceptance of responsibility. However, it does not, by itself, entitle a defendant to a reduced sentence." U.S.S.G. Sec. 3E1.1, comment. (n. 3). We are satisfied that the court's statement, read in the context of the entire sentencing proceeding, is properly understood as the court's way of saying, consistent with the Guidelines, that Evidente's plea is, by itself, not enough to warrant a reduction. Indeed, we have difficulty in seeing any critical difference between the court's statement and the Guidelines. In substance, both say that a plea of guilty, by itself, does not entitle the defendant to a reduction. We therefore hold that the court's statement does not provide a basis for overturning the court's decision to withhold credit for acceptance of responsibility.
12
Evidente has no factual basis for claiming credit for acceptance of responsibility other than his plea and a remorseful letter written four days prior to sentencing. We conclude that this showing is plainly insufficient to overcome the great deference to which the determination of the District Court is entitled. Accordingly, we conclude that the District Court did not err in refusing to give Evidente credit for acceptance of responsibility.
III.
13
Evidente argues that the District Court abused its discretion in failing to depart downward for certain circumstances not adequately taken into consideration by the Sentencing Guidelines.4 We conclude that this issue is nonreviewable.
14
The District Court has the authority, which it may exercise in its discretion, to depart from the applicable guideline if the court finds that there exists an aggravating or mitigating circumstance not adequately taken into consideration by the Sentencing Commission in formulating the Guidelines. See 18 U.S.C. Sec. 3553(b) (1988); U.S.S.G. Sec. 5K2.0. Our review of sentences has been carefully spelled out and limited by statute. A reviewing court must uphold a sentence unless it was "imposed in violation of law," was "imposed as a result of an incorrect application of the sentencing guidelines," was "outside the range of the applicable sentencing guideline and is unreasonable," or was "imposed for an offense for which there is no applicable sentencing guideline and is plainly unreasonable." 18 U.S.C. Sec. 3742(e) (1988). The following subparagraph, section 3742(f) (1988), makes it crystal clear that we are to affirm the sentence unless we determine that the district court has erred in one of the four ways specified in section 3742(e) and cited above. Section 3742(f) thereby reiterates the plainly stated limits to our review of sentences under section 3742(e). The statutory bounds of our power to review sentences precisely track the limited statutory grounds for appeal by a defendant (Section 3742(a)) and for appeal by the government (Section 3742(b)).
15
Here, the sentence imposed by the District Court covers an offense for which there is an applicable sentencing guideline, and is not outside the range of that guideline. Further, Evidente does not argue that the court incorrectly applied the Guidelines, nor does he argue that the District Court's imposition of a sentence within the applicable guideline range was in violation of law. Rather, Evidente argues that the District Court abused its discretion in refusing to depart. We hold, however, that we lack authority to review this aspect of the sentencing determination. This Court simply is not empowered under 18 U.S.C. Sec. 3742, or any other statute, to review a sentencing court's exercise of its discretion to refrain from departing either upward or downward from the range established by the applicable guideline.5
16
Our conclusion is supported by decisions from the First, Second, Third, Fifth, Sixth, Seventh, and Eleventh Circuits. See United States v. Tucker, 892 F.2d 8 (1st Cir.1989) ("Congress made a conscious choice: whereas a decision to depart is appealable, a decision not to depart is not."); United States v. Colon, 884 F.2d 1550, 1551 (2d Cir.1989) ("[T]he discretionary failure to depart downward is not appealable...."); United States v. Whyte, 892 F.2d 1170 (3rd Cir.1989) (LEXIS, Genfed library, 3 Cir. file, * 2) ("[A] district court's discretionary refusal to depart is not appealable.") (citing United States v. Denardi, 892 F.2d 269 (3rd Cir.1989); United States v. Buenrostro, 868 F.2d 135, 139 (5th Cir.1989) ("A claim that the district court refused to depart from the guidelines and imposed a lawful sentence provides no ground for relief."); United States v. Draper, 888 F.2d 1100, 1105 (6th Cir.1989) ("A sentence which is within the Guidelines,
17
and otherwise valid, ... is not appealable on the grounds that the sentencing judge failed to depart from the Guidelines on account of certain factors which the defendant feels were not considered by the Guidelines and should reduce his sentence."); United States v. Franz, 886 F.2d 973, 978 (7th Cir.1989) ("Congress did not intend a district court's decision refusing to depart from the guidelines to be appealable."); United States v. Fossett, 881 F.2d 976, 979 (11th Cir.1989) ("The Sentencing Reform Act prohibits a defendant from appealing a sentencing judge's refusal to make a downward departure from the guideline sentencing range.").
18
Had the District Court somehow believed it lacked power to exercise discretion to grant Evidente a downward departure from the applicable guideline range, a different case would be presented. See Fossett, 881 F.2d at 979 (a claim that the district court did not believe it had the statutory authority to depart from the guideline range "presents a cognizable claim on appeal" under Section 3742(a)(1) or (2)). In an appeal raising such a claim, we would have jurisdiction either to confirm or reject the sentencing court's conclusion that it lacked authority to depart. If we determined that the sentencing court had such authority, we would remand the case to that court and direct it to consider whether on the facts of the case the court wishes to exercise its discretion in favor of a departure. Evidente, however, does not claim that the District Court thought it lacked discretion to depart. The District Court clearly was aware that it had the authority to depart downward. The court exercised its discretion and concluded that on the facts of Evidente's case a departure would be denied. We therefore reject this ground of the appeal as presenting a nonreviewable matter.
IV.
19
The sentence imposed by the District Court is affirmed.
1
The Honorable Robert G. Renner, United States District Judge for the District of Minnesota
2
28 U.S.C. Sec. 994(c) (Supp. V 1987) provides, in part:
The Commission, in establishing categories of offenses for use in guidelines and policy statements governing the imposition of ... imprisonment ... shall consider whether the following matters ... have any relevance ... and shall take them into account only to the extent that they do have relevance--
....
(2) the circumstances under which the offense was committed which mitigate or aggravate the seriousness of the offense;
....
3
In addition to arguing that his flight from Guam is irrelevant, Evidente claims that this factor should not have been used by the District Court because when he left Guam he did not know he was under criminal investigation. Obviously, the District Court did not believe this contention. Evidente left Guam in 1982, leaving behind his family and his job of thirteen years as Deputy Director of Public Health and Social Services, after using his position to steal nearly $350,000 in food stamps. We hold that the District Court's determination of Evidente's credibility was not clearly erroneous
4
Specifically, Evidente contends that the court should have departed from the guideline range because: (1) his original sentence will be increased by the loss of good time and the extension of his parole date; (2) he has a good institutional record; (3) he is a Vietnam veteran; and (4) he lives some 12,000 miles away from his family
5
Our decision in United States v. Justice, 877 F.2d 664 (8th Cir.1989), does not require a different conclusion. Justice concerned claims that the defendant was entitled to a downward departure (1) under U.S.S.G. Sec. 5K1.1 because of his substantial cooperation with the government, even in the absence of a motion by the government as is required for a departure under Sec. 5K1.1, and (2) under U.S.S.G. Sec. 4A1.3 because his criminal history category overstated the seriousness of his criminal background. In these contexts, the Court reviewed the district court's refusal to depart from the guideline range under an abuse of discretion standard. In contrast, Evidente claims that he is entitled to a departure under 18 U.S.C. Sec. 3553(b), which authorizes departures if the district court finds "an aggravating or mitigating circumstance of a kind, or to a degree, not adequately taken into consideration by the Sentencing Commission in formulating the guidelines." 18 U.S.C. Sec. 3553(b). Justice correctly holds that as a matter of statutory interpretation Sec. 3553(b) has no application to claims of the kind asserted by the defendant in that case, since that section specifically rules out departures based on factors adequately addressed by the Commission in its guidelines, policy statements, and official commentary. 877 F.2d at 666. Because the Commission provided policy statements authorizing departures for substantial assistance (Sec. 5K1.1) and for overstatement of the seriousness of the defendant's criminal history (Sec. 4A1.3), a departure under Sec. 3553(b) on these grounds would be legally improper. 877 F.2d at 666. Justice therefore does not establish any standard of review for a district court's exercise of its discretion to grant or deny departures under Sec. 3553(b) and thus does not govern the issue now before us. Moreover, Justice does not discuss in any manner the issue of whether appellate jurisdiction exists to review the discretionary refusal to exercise departure authority, nor does the opinion even refer to the statute that creates limited appellate jurisdiction over Sentencing Guidelines appeals, 18 U.S.C. Sec. 3742. The jurisdictional issue simply was not raised either by the parties or the panel. Thus Justice cannot be read as having decided that issue, and it remains open for consideration in the present case
| 2023-11-19T01:26:35.434368 | https://example.com/article/8217 |
Among the more insidious aspects of cancer is its capacity for escaping the anti-cancer defenses of the host. New research suggests that some estrogens may further reinforce this evasion of host immunity, even as those same hormones stimulate the growth and spread of hormone-responsive cancers. According to David Shapiro, a medical and biochemistry professor at the University of Illinois at Urbana--Champaign, the new findings highlight the role that estrogen-related interference with immune cell function may play in the development and progression of breast cancer.
Shapiro and his colleagues, reporting in a paper posted 22 January 2007 ahead of publication in *Oncogene*, observed that estrogen induces the expression of a newly discovered gene in humans for proteinase inhibitor 9 (PI-9). When estrogen binds to receptors in the cancer cell, the resulting complex promotes production of the PI-9 protein, which in turn binds granzyme B, the primary protease used by natural killer (NK) cells to kill off transformed or infected cells.
NK cells normally play a central role in immune surveillance against the metastatic spread of cancer. Previous research out of Leiden University Medical Center in the Netherlands, published in the 25 September 2001 issue of *Proceedings of the National Academy of Sciences*, had shown that increased levels of PI-9 in some tumors and tumor-derived cell lines may enhance these tumors' ability to evade apoptosis mediated by NK cells and cytotoxic T cells.
In the current paper, the researchers linked increasing concentrations of estrogen with increasing levels of PI-9 and progressively blocked cell death by NK cells. "The levels of estrogen required to induce \[PI-9\] in breast cancer cells are extremely low," says Shapiro. Moreover, at elevated levels of epidermal growth factor and estrogen receptor--α, the induction of PI-9 by either estradiol or the breast cancer drug tamoxifen effectively blocked the killing of cancer cells by NK cells. Levels of epidermal growth factor are elevated in many women with breast cancer, and this adversely affects the prognosis. The presence of estrogen receptor--α at the time of diagnosis is an indication for using tamoxifen or other forms of endocrine therapy.
Tamoxifen is known to have mixed agonist/antagonist effects on estrogen, stimulating uterine cancer at low doses while inhibiting this and other estrogen-responsive cancers at higher doses. In contrast, the drug raloxifene, which is commonly used to prevent osteoporosis and has also been shown to reduce the risk of some breast cancers, had no immune-disrupting effects.
Shapiro's findings come with the following caveat: most estrogen-responsive breast tumors contain low to moderate levels of estrogen receptors, and in these tumors tamoxifen will not induce a level of PI-9 that enables the breast cancer cells to evade killing by immune cells. Only in the relatively small subset of breast tumors that contain very high levels of estrogen receptors will tamoxifen have an effect that could effectively shield the cancer from attacking immune cells.
Indeed, a 21 June 2006 *JAMA* study---a prospective, double-blind, randomized clinical trial conducted in nearly 200 cancer treatment centers throughout North America---directly compared tamoxifen and raloxifene, and found both drugs to be chemopreventive. "In that large trial, tamoxifen even \[seemed to perform\] better in the control of noninvasive breast cancers," says V. Craig Jordan, scientific director for the Fox Chase Cancer Center Medical Science Division. "So while these \[University of Illinois\] data are important and insightful, we should not lose sight of what the clinical data are telling us."
Estrogenic compounds such as DDT and dioxins may also impede immune protection against breast cancer cells. "The mechanism that this study provides for estrogen-mediated decreases in NK cell function may also be operative in the decreases in NK function that have been observed with certain environmental estrogens, such as DDT," says Margaret Whalen, an associate professor of chemistry at Tennessee State University who has studied the immune-suppressive effects of various organochlorine pesticides. Most human exposures to xenoestrogens involve mixtures at relatively low levels, Whalen adds, and concurrent exposure to multiple chemicals may alter the immunotoxicity of a particular chemical.
Shapiro and his colleagues are now looking into the factors that contribute to regulation of PI-9 in postmenopausal women. "Blocking the production of this protein represents a potential new target for breast cancer therapies," he says.
| 2024-03-11T01:26:35.434368 | https://example.com/article/2080 |
Article content
Baie-d’Urfé is planning to honour hometown star Rhian Wilkinson by renaming a park after the Canadian soccer player.
Mayor Maria Tutino said the town decided to rename Dorset Park in her honour, describing her as a Canadian soccer superstar and a role model for Canadian youth.
We apologize, but this video has failed to load.
tap here to see other videos from our team. Try refreshing your browser, or Baie-d'Urfé park to be renamed after Canadian soccer star Back to video
“That was her backyard for many years,” the mayor said of Wilkinson’s ties to Dorset Park.
While a council resolution approved the move last week, a formal dedication ceremony will be held next spring. Dorset Park, a sprawling green space between Victoria, Dorset and Cornwall streets, has a couple of youth soccer pitches, Tutino said.
Wilkinson, 33, who grew up in Baie-d’Urfé and attended Dorset elementary school, has represented Team Canada in 165 matches on the international soccer stage, earning a bronze medal at the London Olympics in 2012. Previously, she won a gold medal at the 2011 Pan American Games and a bronze at the 2007 Pan American Games. In 2008, she was a finalist for the Canadian Soccer Association’s Female Athlete of the Year award. Though she has played as a forward and midfielder, her primary position has been right fullback. | 2024-02-21T01:26:35.434368 | https://example.com/article/3219 |
Description
Traditionally scent, temperature and taste are the key elements for the enjoyment of scotch or whiskey. Now with the RockRoller you can add motion & chilling into the mix.
A simple wrist motion rolls each of the chilling balls around the bottom and the outward curve prevents them from rolling out while sipping. The dual stainless steel chilling balls chill faster and longer with ZERO dilution. A pair of tongs are included for safe handling of chilling balls.
The RockRoller’s chilling & motion will take your experience to the next level!
Shape of glass is specifically designed to conform to the shape of the chilling ball
Outward curve prevents the chilling balls from rolling out while sipping | 2023-12-30T01:26:35.434368 | https://example.com/article/7693 |
HOODIES & SWEATSHIRTS(2 products found)
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There's nothing basic about Casual Canine® Basic Hoodies! These brightly colored pet sweatshirts are comfortable, made of poly/cotton, and accessorized with the same attributes as hoodies made for humans.
Casual Canine® Basic Fleece Dog Hoodies are a simple yet stylish design that will keep pets warm in cold weather. These dog sweatshirts feature a high cut belly, a leash hole on back, and velcro closures from neck to belly. | 2023-08-17T01:26:35.434368 | https://example.com/article/8815 |
Q:
Vertically center a link within a div
I have an unordered list...
<ul class="hide">
<li class="home">
<div class="link">
<a href="/">Home</a>
</div>
</li>
<li class="about">
<div class="link">
<a href="/about">About Our Community</a>
</div>
</li>
<li class="contact">
<div class="link">
<a href="/contact">Contact Us</a>
</div>
</li>
</ul>
My CSS looks like this....
#sitenav ul li .link a {
color: #555;
text-decoration: none;
float: left;
padding-right: 3px;
margin-top: auto;
margin-bottom: auto;
}
But the margins do not center the link vertically
Any ideas?
A:
This solution could work for you: http://jsfiddle.net/WLQAS/8/
margin-top: auto; and margin-bottom: auto; don't work to align vertically the objects.
Updated CSS
li {
color: #555;
text-decoration: none;
float: left;
padding-right: 3px;
}
.link {
vertical-align: middle;
display: table-cell;
height: 50px;
}
A:
Here's a cross browser compatible solution for vertical aligning an a-element with an unknown height within a div:
Works with link texts with and without line-breaks.
CSS
* { margin: 0; padding: 0 }
ul {}
ul li {
display: table;
height: 75px;
#position: relative; /* ie hack */
overflow: hidden;
border: 1px solid red;
}
ul li div {
#position: absolute; /* ie hack */
#top: 50%; /* ie hack */
display: table-cell;
vertical-align: middle;
}
ul li div a {
#position: relative; /* ie hack */
#top: -50%; /* ie hack */
border: 1px solid green
}
It's not recommended to use CSS hacks here, use conditional comments instead.
Live demo: http://jsfiddle.net/ahdzg/1/
More infos about this trick: http://www.jakpsatweb.cz/css/css-vertical-center-solution.html
Hope this helps. Otherwise feel free to ask.
| 2024-05-14T01:26:35.434368 | https://example.com/article/6839 |
1. Field of the Invention
The present invention relates to an abnormal Internet Protocol Security (IPSec) packet control system using IPSec configuration and session data, and a method thereof, and more particularly to an abnormal IPSec packet control system using IPSec configuration and session data which detects whether or not the packets encrypted by an Encapsulating Security Payload (ESP) extended header are abnormal using IPSec configuration and session data tables without decrypting them, thereby blocking harmful packets, and a method thereof.
2. Background Art
As generally known in the art, an IPSec is a standard protocol for security in a network layer during network communication, and has been developed by an Internet Engineering Task Force (IETF) for use in realizing a Virtual Private Network (VPN) in the Internet. IPSec secures integrity and confidentiality of transmission data, and supports authentication for data and communication subject. However, since harmful packets are often sent, as is the case where a large quantity of abnormal session configuration request messages are sent, making poor use of IPSec, or where the packets, to which IPSec is applied, are sent while adding abnormal data thereto, there is a need for security technology to solve this problem. For instance, such technology includes a firewall, an Intrusion Detection System (IDS), an Intrusion Prevention System (IPS), a harmful packet control system, etc., which control packets using a packet filtering rule.
FIG. 1 is a block diagram for explaining conventional technology of blocking harmful packets. As illustrated in the conventional technology using the packet filtering rule, the packet filtering rule 2 is configured for the purpose of blocking harmful packets created in the Internet, and a packet 1 is blocked 3 or passed 4 depending upon its consistency or inconsistency with a corresponding rule. For reference, a reference numeral 5 denotes a network manager, and a reference numeral 6 denotes a creation module of a packet filtering rule, a detailed explanation of which, however, is omitted.
In particular, the conventional technology of blocking an abnormal IPSec traffic in an IPv6 network can be in general classified into the following two types. The first type is an IP header information-based security system, which had been used in a conventional IPv6 so as to detect and cope with misuse or abnormal operation using IP header information and high layer information. The second type is a key distribution based security system, which copes with corresponding attacks by sharing a key for use in IPSec communication between the security system and a host or a security gateway in charge of IPSec session configuration and communication.
The IP header information-based security system cannot process encrypted IPSec traffic itself, or if it does, it detects abnormal IPSec traffic with only IP header information and high layer information. In addition, the key distribution-based security system detects and copes with it by decrypting encrypted data, to which an ESP extended header is adapted, with a shared key.
An example of packet control technology is disclosed in Korean Unexamined Patent Publication No. 2002-00515996 (published on Jun. 28, 2002, and entitled ‘Security Policy System in Distributed Computing Environment, and a Method thereof’).
The technology disclosed in Korean Unexamined Patent Publication No. 2002-00515996 relates to a security policy system and method, which improve system efficiency by allocating a Security Policy Database (SPDB) storing policy information to a kernel memory and an application memory. In the security policy system in a distributed computing environment divided into an application region and a kernel region, the application region includes: a policy listener that stands by in a block state, while writing a policy request of a kernel in a reading area of a communication channel between the application region and the kernel region, and in response to this, requests negotiations about a new policy and security association (SA), or returns an Existence Assurance Message (EAM) to the kernel; an SPDB that, if the policy request is made by the policy listener, stores packet control-concerned security policy information for a firewall or a packet filtering module, including policy resources for a policy administration system, such as IPSec engine, etc., or a key-concerned system, such as an Internet Key Exchange (IKE), etc.; and a policy adapter that, when the new policy or the SA is negotiated by the policy listener, collects corresponding policy values, and transmits, to the kernel, information on a security policy of the new SA. The kernel region includes: a selDB that stores fields which are used in the kernel except the fields used in the application SPDB, and data on the security policy of the new SA, which are transmitted by the policy adapter; and a Policy Enforcement Point (PEP) that reads, from the selDB, a security policy corresponding to a request, and adapts and enforces the same. That is, in the technology disclosed in Publication No. 2002-00515996, in all the security systems using a security policy, a security policy database is mapped to the kernel as well as to the application to thus minimizes delay of the policy adaptation process, thereby improving system efficiency and performance.
Further, another example of packet control technology is disclosed in Korean Registered Patent No. 0470915 (registered on Jan. 31, 2005, entitled ‘Control Method of Internet Information Protection System for Packet Security in IP Layer’).
The technology disclosed in Korean Registered Patent No. 0470915 relates to a control method of an Internet information protection system for packet security in an IP layer, which provides a packet protection function in the IP layer for providing, controlling, managing, and evaluating an information protection service in the Internet. The method comprises a first step of, after creating an IP header of a packet intended to be transmitted, determining whether or not a security service for each packet is selected with reference to a security based rule database and a security-associated database, a second step of, if the security based rule database and the security-associated database do not exist, configuring a security based rule through conducting negotiations with a recipient's-side security based rule control server, a third step of negotiating security association with a recipient's-side key exchange server based on the configured security based rule, a fourth step of storing the negotiated security association in a key management server, a fifth step of linking the security based rule concerned to the security association, and a sixth step of transmitting the packet using the security based rule and the security association linked together, while adapting IPSec. In the technology disclosed in Korean Registered Patent No. 0470915, an information protection service can be selectively provided in the process that a message created from a high application layer in converted into a type of IP packet that can be transmitted via the Internet, a multiple-security service can be provided, and an information protection service can be provided to all Internet services without changing the high layer service program.
The technology using the conventional packet filtering rule, however, has a problem in that, since the contents of a packet in the process of IPSec communication are encrypted so that it cannot be known whether or not the packet is harmful, it is difficult to configure a packet filtering rule for a harmful packet.
Moreover, the header information based security system of the prior art also has a problem in that, since it detects an attack with only IP header information and high layer information, when an attack is so launched from many hosts to a single target host as to generate heavy traffic, such as a distributed service denial attack, even traffic of a normal host is detected and blocked.
Furthermore, the key distribution based security system also has a problem in that, although it is possible to configure the packet filtering rule by sharing a key with hosts in IPSec communication, it needs decryption and encryption processes for all packets, so that the system performance deteriorates. In addition, in order to distribute keys, it needs to gain access to additional IPSec communication, or to directly copy the key values, and IPSec end-to-end security is to be broken. Besides, in the case of gaining access to additional IPSec communication, the security system should carry out decryption and encryption processes with other keys, so that the process time is increased. | 2024-06-17T01:26:35.434368 | https://example.com/article/9045 |
Sexual Health and Overall Wellness (SHOW) survey in men and women in selected European and Middle Eastern countries.
To investigate whether better sexual health is associated with improvements in overall health and wellness, a more loving and intimate relationship, and a more positive outlook on life. The Sexual Health and Overall Wellness survey used self-administered questionnaires to collect data from men and women aged 25-74 years who had had sexual intercourse at least once within the previous 12 months. Across nine countries, 3780 self-administered questionnaires were completed: 1893 from men (mean age, 44.6 years); 1887 from women (mean age, 44.2 years). The majority of men and women were satisfied with the frequency of sexual intercourse over the previous 4 weeks (59% and 66%, respectively); the majority (67% and 55%, respectively) reported that having sex was 'very important' or 'absolutely essential'. For men and women, there was a strong association between satisfaction with sex and overall health, and between satisfaction with sex and an overall positive outlook on life. For men and women, satisfaction with different aspects of sex was important, and was strongly associated with satisfaction with general health, relationships and other aspects of wellbeing. | 2024-03-12T01:26:35.434368 | https://example.com/article/4925 |
Q:
Python - Tweepy - What do I need to add to make this code reply to an account rather than a keyword?
This is my current code that I use, which responds immediately to any tweet containing any keyword. Instead, I want to change this code to automatically respond to a specific account (whenever it tweets). What do I need to add or remove to make this happen? This current code works, I just would like to know how to change what it replies to.
import tweepy
from tweepy import Stream
from tweepy.streaming import StreamListener
import json
class StdOutListener(StreamListener):
def on_data(self, data):
clean_data = json.loads(data)
tweetId = clean_data["id"]
tweet = "YOUR REPLY HERE"
respondToTweet(tweet, tweetId)
def setUpAuth():
auth = tweepy.OAuthHandler("consumer_key", "consumer_secret")
auth.set_access_token("access_token", "access_token_secret")
api = tweepy.API(auth)
return api, auth
def followStream():
api, auth = setUpAuth()
listener = StdOutListener()
stream = Stream(auth, listener)
stream.filter(track=["KEYWORDS"])
def respondToTweet(tweet, tweetId):
api, auth = setUpAuth()
api.update_status(tweet, in_reply_to_status_id=tweetId, auto_populate_reply_metadata=True)
if __name__ == "__main__":
followStream()
A:
Solved!
For anyone else wondering how this was done, here's what I did:
I changed this line in my code:
stream.filter(track=["KEYWORDS"])
to:
stream.filter(follow=["TWITTER_ID"])
TWITTER_ID = the twitter id of the user you want to automatically reply to, which can be found by plugging their handle into tweeterid.com.
For example realdonaldtrump's twitter id is 25073877, therefore you would replace TWITTER_ID with 25073877.
| 2024-01-06T01:26:35.434368 | https://example.com/article/7949 |
Police suspect five deaths all related to bad heroin
AKRON — At least five people have died in Akron after taking what police believe is a “bad batch” of heroin, Akron Police Department (APD) officials announced last week.
Capt. Michael Shearer, commander of the APD’s Narcotics Unit, said several additional people have been recently treated in local hospitals after taking heroin but survived.
On June 17, two suspected victims, a 31-year-old Schiller Avenue man and a 58-year-old Florida man, were found dead. Three other heroin-related deaths also were reported in Akron over the previous two weeks, according to APD officials.
The APD is working closely with the Summit County Alcohol, Drug Addiction and Mental Health Services Board (ADM) on dealing with the increase of heroin overdoses and deaths.
It has not yet been determined why the current rash of heroin deaths has taken place, APD officials stated in the release. There may have been a deadly item added to the heroin, or the quality of the heroin may be the cause, according to APD officials.
Police are warning illicit drug users not to take heroin procured over the past few weeks.
They also advise if you or someone you know is addicted to opiates or heroin, help is available 24 hours a day, seven days a week by calling the ADM Crisis Center at 330-996-7730. | 2023-12-06T01:26:35.434368 | https://example.com/article/4233 |
Humans can only see a small patch of the electromagnetic spectrum – a mere 310nm range. Other animals can see into the ultraviolet and infrared, but none can see the wavelengths used for wireless networks. Imagine if we could. Luis Hernan has given us a vision of what that might be like.
Hernan, a PhD student at the Newcastle University, UK, maps wireless signals in a room using what he calls the Kirlian Device. Then he translates the signals into color. In a reversal of the actual energy of colors, the strongest signals are converted to red, the weakest to blue.
“I call the images ‘spectres’ because wireless networks remind me of ghosts,” Hernan said. “They are there but you can’t see them with the human eye.”
“The fact we are becoming increasingly reliant on something that we can’t see intrigues me,” Hernan added. “I wanted to find a way to show the wireless which is around us and also to show how it changes. It is an impossibly fragile and volatile infrastructure that holds our digital technologies together, and shapes the way in which we interact with the digital world. Something as seemingly inconsequential as walking around the house will interfere with and reshape their propagation and strength field. Close the wrong door, and the bedroom becomes a dead spot for wireless.”
Hernan was inspired by Seymon Davidovich Kirlian, who discovered a way to photograph electrical discharges. Kirlian, and many followers, became convinced that they had found evidence of paranormal phenomenon, equating the images produced with aura and seeing evidence of an energy field unique to living things.
A Kirlian Device App is available for Android phones (sorry iPhone users). “I would love other people to get involved and to create their own images using the app,” Hernan said. “I used it as part of an exhibition of my work, where we hung mobile phones from the ceiling and it showed how signal strength was varying as people moved around the room.” | 2023-11-17T01:26:35.434368 | https://example.com/article/7887 |
Introduction
============
Despite advances in the detection and treatment of breast cancer, one in eight women in the United States will develop breast cancer in her lifetime, and this disease is the sixth leading cause of cancer death in females in the People's Republic of China.[@b1-ott-7-1033],[@b2-ott-7-1033] Although there has been development of new targeted drugs, more effective and safe therapeutics for breast cancer are still needed.
Gemcitabine (2′,2′-difluorodeoxycytidine) is a difluorinated analog of deoxycytidine. It is an S-phase--specific drug that requires intracellular transport and activation to exert its cytotoxic effects.[@b3-ott-7-1033] It is used in combination with other drugs for the treatment of locally advanced or metastatic non-small-cell lung cancer, bladder cancer, and ovarian cancer, and as a single agent for the treatment of adenocarcinoma of the pancreas.[@b4-ott-7-1033] Clinical studies have also demonstrated its extensive activity against breast carcinomas, including male breast cancer,[@b5-ott-7-1033] metastatic breast cancer, and triple-negative breast cancer.[@b6-ott-7-1033],[@b7-ott-7-1033] In recent years, gemcitabine resistance has emerged and has become a serious concern in clinical practice; however, the exact mechanism of gemcitabine resistance in breast cancer is still unknown.
The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is often constitutively activated in drug-resistant breast cancer, and this activation is correlated with increased cell survival and poor prognosis for breast cancer patients. mTOR is a serine/threonine kinase of the PI3K-related kinase family.[@b8-ott-7-1033] Accumulating data from genetic and cancer biology studies have indicated that the mTOR pathway has a prominent role in both normal physiological development and carcinogenic processes, including cell growth (cell size or mass),[@b9-ott-7-1033] proliferation (cell number), apoptosis,[@b10-ott-7-1033] autophagy,[@b11-ott-7-1033] response to stress such as nutrient starvation (glucose or amino acids), and survival.[@b8-ott-7-1033],[@b12-ott-7-1033],[@b13-ott-7-1033] The downstream effects of mTOR activation include phosphorylation of p70S6 kinase and 4E-binding protein, both of which are critical for protein-synthesis regulation.[@b8-ott-7-1033],[@b14-ott-7-1033] Given recent findings that mTOR activation can be controlled by the interplay between AKT kinase and AMPK, there is now extensive evidence validating various components of this pathway as potential molecular targets for cancer treatment. Autophagy can induce both cell survival and cell death under nutrient starvation, tumorigenesis including breast cancer,[@b15-ott-7-1033] neurodegeneration, and other physiological and pathological processes.[@b16-ott-7-1033],[@b17-ott-7-1033] The conversion of LC3-I to LC3-II reflects the occurrence of autophagy.[@b18-ott-7-1033] Two relatively well-established pathways that regulate autophagy contain the mTOR and IP3 cascades. Inhibition of mTOR activity or a decrease of IP3 level can each induce autophagy.[@b19-ott-7-1033]
The mitogen-activated protein kinase (MAPK) pathway is highly conserved across eukaryotes and transmits signals from the cell surface receptors to nuclear transcription. Three major MAPK pathways are known to function in humans. Activation of Raf--mitogen-activated protein kinase kinase (MEK)--extracellular signal-regulated kinase (ERK) is critical for both normal and cancer cellular development.[@b20-ott-7-1033] Antiproliferative and proapoptotic effects in breast cancer are mediated through p38 phosphorylation[@b21-ott-7-1033] and it is also involved in apoptosis of prostate cancer.[@b22-ott-7-1033] MAPK pathways also take part in many drug resistance patterns in cancer cells.[@b23-ott-7-1033],[@b24-ott-7-1033] There is a large level of cross-talk and a number of feedback loops between kinases of these two pathways, and inhibition of one cascade often activates the other. The lack of efficacy of some chemotherapy drugs in cancer may be due to loss of feedback inhibition. In this study, we generated gemcitabine-resistant breast cancer cells to explore the roles of PI3K/AKT/mTOR and MAPK in drug resistance and to search for more-potent molecular targets to overcome breast cancer cell resistance to gemcitabine.
Materials and methods
=====================
Cell lines and culture
----------------------
The human breast cancer cell line MDA-MB-231 (hereafter, "231") was obtained from the American Type Culture Collection (Manassas, VA, USA). The cells were cultured in the recommended medium (Dulbecco's Modified Eagle's Medium \[DMEM\]) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. The cultures were incubated at 37°C in a humidified 5% CO~2~ atmosphere. Cell culture medium and fetal bovine serum were purchased from Thermo Fisher Scientific (Waltham, MA, USA).
Establishment of gemcitabine-resistant breast cancer cell line
--------------------------------------------------------------
Gemcitabine-resistant cells were generated by exposure to gradually increasing concentrations of gemcitabine for 12 months, as described previously.[@b25-ott-7-1033] Parental 231 cells were exposed to gemcitabine at an initial concentration of 12 nM, and then exposed repetitively to stepwise increased gemcitabine concentration. The final concentrations were 60 μM. Through this process, we successfully established the gemcitabine-resistant breast cancer cell line MDA-MB-231/gemcitabine (hereafter, "231/Gem").
Drugs and reagents
------------------
Gemcitabine was purchased from Lilly France (St-Cloud, France) (Lot No A875303A). Antibodies against β-catenin (51067-2-AP, 1:800), LC3A/B (66139-1-1g, 1:1,000), Cyclin D1 (60186-1-1g, 1:1,000) and GAPDH (60004-1-Ig, 1:1,000) were from Proteintech Group, Inc., (Chicago, IL, USA). Antibodies against MEK1/2 (9126, 1:1,000), Phospho-MEK1/2 (2338, 1:1,000), Phospho-ERK1/2 (4376, 1:1,000), AKT (4691, 1:1,000), Phospho-AKT (4060P, 1:1,000), Phospho-P38 (4511, 1:1,000), Phospho-JNK (4668, 1:1,000), E-Cadherin (3195, 1:1,000), Phospho-p53 (9284, 1:1,000), and mTOR Substrates Sampler kit (CST 9862), which includes Phospho-mTOR, mTOR, Phospho-p70s6389 (Thr389), Phospho-P70389 (Thr371), Phospho-4EBP1 (Thr37/46), and anti-rabbit IgG, were purchased from Cell Signaling Technology, Inc., (Danvers, MA, USA). Antibodies against p38 (sc-7149, 1:1,000), P53 (sc-126, 1:1,000) and JNK (sc-571, 1:1,000) were from Santa Cruz Biotechnology Inc. (Dallas, TX, USA). PD98059 (MEK inhibitor, 9900, 20 UM), rapamycin (mTOR inhibitor, 9904, 10 nM), and LY294002 (PI3K Inhibitor, 9901, 50 μM) were purchased from Cell Signaling Technology.
Growth inhibition assay
-----------------------
The growth inhibition assay was performed using the Cell Counting Kit-8 (CCK-8; Dojindo Laboratories, Kumanoto, Japan). In brief, cells were incubated for 5 days under several concentrations of gemcitabine in 96-well plates at a density of 2,000 per well (200 μL) and cultured in growth medium. The number of cells was counted according to CCK-8 protocol.
Cell apoptosis analysis
-----------------------
The effect of gemcitabine on cell viability was assessed using flow cytometry by staining with Annexin V/propidium iodide (PI) (V13241; Thermo Fisher Scientific). Briefly, cells were cultured for 3 days after receiving gemcitabine treatment and washed twice in ice-cold phosphate-buffered saline. A total of 1×10^5^ cells were resuspended in 100 μL binding buffer to which 5 μL of 2 mg/mL Annexin V and 5 μL of 50 μg/mL PI was added. Following 15 minutes of incubation in the dark, flow cytometry was performed. All tests were performed three times.
Cell cycle analysis
-------------------
We plated 231 and 231/Gem cells in 60 mm diameter dishes with medium containing 10% fetal bovine serum. The next day, cells were treated with 35 μM gemcitabine for 3 days. Floating and adherent cells were collected and fixed overnight in cold 70% ethanol at 4°C. After washing, the cells were subsequently treated with 100 μg/mL PI and 100 μg/mL RNase A for 30 minutes in the dark and then subjected to flow cytometric analysis to determine the percentage of cells in specific phases of the cell cycle. All the experiments were performed three times.
Proliferation assay
-------------------
Cell proliferation was detected by using CCK-8. Cells were plated in 96-well plates at a density of 2,500 per well (100 μL) and cultured in growth medium. The number of the cells was counted according to the protocol of the kit from the company.
Western blot
------------
Western blot analysis was performed according to the standard protocols. Briefly, aliquots of total protein (30 μg) were electrophoresed on sodium dodecyl sulfate polyacrylamide Tris-HCl gels. The separated proteins were transferred to polyvinylidene difluoride membranes (EMD Millipore, Billerica, MA, USA) and incubated with primary antibodies for 2 hours. Chemiluminescent detection was performed, and images were captured by LAS-3000 system (Fuji Photo Film Co, Ltd, Tokyo, Japan).
Migration assay
---------------
Chemotaxis assays were performed using Transwell insert polycarbonate membranes (8 μm pore size, BD, Franklin Lakes, NJ, USA). First, 1×10^5^ cells were seeded in the top compartment and 600 μL DMEM with 10% fetal bovine serum was added to the bottom at 37°C for 13 hours. Nonmigratory cells on the upper membrane surface were removed, and migratory cells attached to the bottom surface of the membrane were fixed with 10% formalin and stained with 0.1% crystal violet for 30 minutes at room temperature. Migrated cells in five random fields were counted using a light microscope at 200× magnification. All assays were performed in triplicate.
Invasion assay
--------------
Invasion experiments were carried out with a Matrigel invasion chamber (BD). Each well insert was layered with 75 μL of 1:4 mixture of Matrigel/DMEM. Serum-starved cells (1×10^5^) were added to the upper compartment and 600 μL DMEM with 10% fetal bovine serum was added to the bottom at 37°C for 24 hours. Invasion was assessed by counting the cells that had traveled across the filter and were attached to the bottom side of the filter. Briefly, the filters were fixed in 10% formalin and stained with 1% crystal violet. Cells that had invaded through the Matrigel and reached the lower surface of the filter were counted under a light microscope at 200× magnification. Five fields were counted for each sample.
Statistical analysis
--------------------
Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software Version 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Analysis of variance and Student's *t*-test were used to determine the statistical significance of differences between experimental groups in vitro. Values of *P*\<0.05 were considered statistically significant. Graphs were created with GraphPad Prism 5 (GraphPad Software, Inc., La Jolla, CA, USA).
Results
=======
Establishment of gemcitabine-resistant breast cancer cell line
--------------------------------------------------------------
To investigate the chemosensitivity of 231/Gem cells as compared to parental cells, flow cytometry assay was performed. 231 and 231/Gem were cultured and harvested after 3 days following treatment of 35 μM gemcitabine. As shown in [Figure 1A](#f1-ott-7-1033){ref-type="fig"}, the number of apoptotic cells induced by gemcitabine was greatly increased in 231 cells compared to 231/Gem cells, as indicated by the quantitative analysis in [Figure 1B](#f1-ott-7-1033){ref-type="fig"}. Additionally, the half-maximal inhibitory concentration (IC~50~) of gemcitabine was higher for 231/Gem than for control cells ([Figure 1C](#f1-ott-7-1033){ref-type="fig"}).
Gemcitabine resistance increases breast cancer cell proliferation and invasion
------------------------------------------------------------------------------
To investigate whether 231/Gem cells displayed increased proliferation and invasion, we used the proliferation and invasion assays and compared to control cells. As shown in [Figure 2A](#f2-ott-7-1033){ref-type="fig"}, the CCK-8 result showed that 231/Gem cells displayed greater proliferation than 231 cells. Further studies indicated that in comparison to parental cells, the percentage of S-phase cells in 231/Gem was increased and G-phase cells were reduced after gemcitabine treatment for 3 days ([Figure 2B](#f2-ott-7-1033){ref-type="fig"}), as indicated by the quantitative analysis in [Figure 2C](#f2-ott-7-1033){ref-type="fig"}. Next, we tested the migration and invasiveness of 231 and 231/Gem cells. We first observed morphology alteration by inverted microscopy. As shown in [Figure 2D](#f2-ott-7-1033){ref-type="fig"}, 231/Gem displayed a greater number of projections than parental cells. Transwell chambers were used to evaluate the invasiveness of 231 and 231/Gem cells, and the results showed that more 231/Gem cells than parental cells intruded into the bottom chamber ([Figure 2E and F](#f2-ott-7-1033){ref-type="fig"}). We then tested the expression of cell adhesion-associated proteins by Western blot, showing a significant decrease of E-cadherin in 231/Gem cells ([Figure 2G](#f2-ott-7-1033){ref-type="fig"}). These data suggest that 231/Gem cells gained enhanced proliferative and invasive abilities after developing resistance to gemcitabine.
Involvement of the PI3K/AKT, MAPK, and mTOR pathways in gemcitabine resistance
------------------------------------------------------------------------------
Because previous studies have shown that the signaling pathways of PI3K/AKT, MAPK, and mTOR may promote cancer chemoresistance and radioresistance, we evaluated the expression of the major proteins of these three pathways by Western blot. As shown in [Figure 3](#f3-ott-7-1033){ref-type="fig"}, there is no difference in basal level of total AKT expression in both cell lines, whereas phosphorylated (p)-AKT was increased in gemcitabine-resistant 231/Gem cells. These data show that activation of the PI3K/AKT signaling pathway is associated with gemcitabine-resistance in breast cancer cells.
We then tested the major protein expression of MAPK and mTOR pathways. Though the total ERK level was similar in both cell lines, the level of p-ERK was markedly increased in 231/Gem cells. However, the level of p-P38 was significantly decreased in 231/Gem cells, and no change of total p38 protein expression was found. As for the mTOR pathway, we found that either mTOR or p-mTOR were significantly increased in 231/Gem cells compared with 231 cells, although the downstream proteins of mTOR pathway, p-P70S6K and p-4EBP, were upregulated in 231/Gem cells. Many studies have shown that inhibition of mTOR activity could trigger autophagy. In our study, 231/Gem cells exhibited decreased expression of LC3 protein, a marker of autophagy, suggesting that autophagy may contribute to gemcitabine-resistance of breast cancer cells. Additionally, AMPK as a negative regulator of mTOR and Cyclin D1 were tested by Western blot, which revealed that their expressions were no different.
The PI3K/AKT pathway and mTOR, but not MAPK, regulates gemcitabine resistance-augmented cell proliferation
----------------------------------------------------------------------------------------------------------
To further elucidate the mechanisms underlying the growth-promoting effects of acquired gemcitabine resistance, we used the CCK-8 assay to detect whether inhibitors of the above three pathways would reverse increased proliferative ability of 231/Gem. As shown in [Figure 4](#f4-ott-7-1033){ref-type="fig"}, treatment with PD98059 (a MAPK inhibitor) did not affect cell proliferation. Cell proliferation was significantly inhibited in 231/Gem cells treated with LY294002 (a PI3K inhibitor), while rapamycin (an mTOR inhibitor) had a slight inhibitory effect on cell proliferation in 231/Gem.
Phosphorylation of AKT controls acquired proliferation of gemcitabine- resistant breast cancer cells
----------------------------------------------------------------------------------------------------
The above results demonstrated that suppression of MAPK and mTOR pathways did not significantly influence 231/Gem cell proliferation, which is not consistent with previous studies.[@b20-ott-7-1033] To examine the exact mechanism, we performed Western blot analysis. Our data show that with treatment of LY294002, PD98059, and rapamycin, expression levels of p-AKT, p-MEK, p-p70S6K, and p-mTOR were decreased, respectively, indicating that the three inhibitors were effective ([Figure 5](#f5-ott-7-1033){ref-type="fig"}).
Treatment with LY294002 downregulated expression of p-MEK, p-mTOR and p-p70S6K. We found that after treatment with either PD98059 or rapamycin, p-AKT protein expression markedly increased while p-mTOR and p-p70S6K expression levels were reduced. Our results demonstrate that p-AKT is the upstream regulatory protein in the pathway, which could activate downstream pathway components including MAPK and mTOR. In addition, the downstream pathway demonstrated negative feedback for upstream regulation of PI3K/AKT.
Discussion
==========
Chemotherapy resistance is commonly associated with multiple genetic and epigenetic abnormalities; however, changes in one or a few main genes remain crucial for maintaining cell survival and malignant phenotype. In recent years, increasing evidence has demonstrated that the PI3K/AKT/mTOR and ERK/MAPK signaling pathways are involved in many drug-resistance patterns among different types of cancer.[@b26-ott-7-1033]--[@b29-ott-7-1033]
In this study, we generated a gemcitabine-resistant human breast cancer cell model (231/Gem) to investigate whether PI3K/AKT/mTOR and ERK/MAPK pathways were involved in the chemoresistance. The long-term culture of MDA-MB-231 to establish MDA-MB-231/Gem cell line did not activate AKT, mTOR and ERK pathways ([Figure S1](#SD1-ott-7-1033){ref-type="supplementary-material"}). Flow cytometry, apoptosis assay, and CCK-8 demonstrated that gemcitabine-resistant breast cancer cells (231/Gem) were successfully established. The results showed that 231/Gem displays increased proliferation, a larger number cells in S phase of the cell cycle, and more cellular projections and invasion than parental cells. Western blot E-cadherin protein was reduced, which can lead to enhanced cellular invasion as compared to parental cells.
These data suggested that 231/Gem cells gained increased proliferative and invasive abilities after obtaining resistance to gemcitabine. Further mechanistic studies confirmed that PI3K/AKT/mTOR and MEK/MAPK signaling pathways were activated through elevated expression of p-ERK, p-AKT, mTOR, p-mTOR, and p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem as compared to control cells. However, no significant change of cyclin D1 and p-AMPK can be found between MDA-MB-231 and MDA-MB-231/Gem cell lines ([Figure S2](#SD2-ott-7-1033){ref-type="supplementary-material"}). In culture, inhibitors of PI3K/AKT and mTOR but not MEK/MAPK could reverse the enhanced proliferative ability of 231/Gem. Further Western blot analysis showed that with treatment of PI3K/AKT inhibitor, the expression of p-AKT, p-MEK, p-mTOR, and p-P70S6K was decreased; however, treatment with either a MEK/MAPK or an mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mediated by activation of the PI3K/AKT signaling pathway through elevation of expression of p-AKT protein to promote cell proliferation and is negatively regulated by MEK/MAPK and mTOR pathways.
In recent years, many mechanisms have been reported with respect to gemcitabine resistance in various cancers. Zheng et al[@b30-ott-7-1033] reported that ERK1/2 activity contributed to gemcitabine resistance in pancreatic cancer cells. Mei et al[@b31-ott-7-1033] indicated that the gene therapy of antiangiogenesis by intramuscular delivery of plasmid DNA encoding chemokine CXCL10 combined with gemcitabine has synergistic effects on tumor by inhibiting the proliferation of endothelial cells, inducing the apoptosis of tumor cells, and recruiting lymphocytes to tumor in murine models. CXCL12--CXCR4 signaling axis can play a role in conferring gemcitabine resistance to pancreatic cancer cells and suggest that it could serve as a novel therapeutic target for pancreatic cancer therapy, alone and in combination with the cytotoxic drug.[@b32-ott-7-1033]
In breast cancer studies, Liang et al[@b33-ott-7-1033] showed that 3-phosphoinositide-dependent protein kinase-1 (PDK1) may be a superior alternative to AKT1 as a target for sensitizing breast cancer cells to chemotherapeutic agents, particularly gemcitabine. Moreover, Hernandez-Vargas et al[@b34-ott-7-1033] performed gene expression analysis to shed light on nuclear factor-kappa B pathway activation as a potential mechanism of resistance. Although the AKT/mTOR pathway has been reported to be involved in gemcitabine resistance induced by Annexin II in pancreatic cancer cells,[@b35-ott-7-1033] the role of PI3K/AKT/mTOR and MAPK signaling pathways and their cross-talk and feedback loops in gemcitabine resistance in breast cancer cells is still unknown. To receive highly effective clinical benefit, dual inhibition of the target plus the subsequent feedback loop is necessary. In this study, we have not detected the inhibition of the combination of AKT, mTOR, or MEK and this hypothesis also needs to be tested in future clinical trials. Our study suggests that targeting PI3K/AKT/mTOR and MAPK signaling pathways may help to develop more effective therapies in patients with gemcitabine-resistant breast cancer.
Supplementary materials
=======================
######
Change of signaling pathway after long time culture.
**Note:** To confirm whether the activated AKT, mTOR and ERK pathways are due to the long-term culture or gemcitabine induced resistance, we examined the activation of these pathways between the parental cells (231) and another type of cells that our lab cultured for a long time \[231(2)\]. As a result, these proteins are almost not changed by the long-term culture.
**Abbreviations:** 231, human breast cancer cell line MDA-MB-231; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; mTOR, mammalian target of rapamycin; p, phosphorylated.
######
Change of cyclin D1 and p-AMPK after treatment by gemcitabine.
**Note:** No significant change of cyclin D1 and p-AMPK can be found between MDA-MB-231 and MDA-MB-231/gemcitabine cell lines.
**Abbreviations:** 231, human breast cancer cell line MDA-MB-231; 231/Gem, chemoresistant human breast cancer cell line MDA-MB-231/gemcitabine; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; p-AMPK, phosphorylated adenosine monophosphate-activated protein kinase.
The authors wish to acknowledge funding from the National Natural Science Foundation of China (Grant No 81172506), and the Shanghai Committee of Science and Technology, China (Grant No 12DZ2260100).
**Disclosure**
The authors report no conflicts of interest in this work.
{#f1-ott-7-1033}
{#f2-ott-7-1033}
{#f3-ott-7-1033}
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| 2024-03-15T01:26:35.434368 | https://example.com/article/3870 |
In the global conflict that was World War II, the 1941 battle for Crete was a significant scuffle . . . but one that deservedly lingers large in New Zealand's history.
"The battle should not fade away; it is one that was very important for New Zealand at the time," Dunedin writer Ron Palenski - whose new account of the Crete campaign, Men Of Valour, is out now - said.
"So many New Zealanders died there, so it should not fade away. If that means the battle is going to be debated, so be it: there are things in it that need to be debated."
The New Zealand Division had already had a taste of action, serving during the ill-fated attempt to stem Germany's invasion of Greece. It, along with other British and Empire forces, were evacuated to the island of Crete, with orders to hold it at all costs.
Germany launched the largest airborne assault thus seen to attempt to wrest Crete from Allied hands. The battle was over in a few short days, with most of the surviving Allied troops evacuated, exhausted, to Egypt.
Argument has raged ever since, with veterans and historians mounting argument and counter-argument over whether the island could have been held or not.
Palenski is very much in the "could not" camp.
"When the official histories first came out, a conscious decision had been made to hang a couple of officers out to dry as they needed a scapegoat for the loss. That sort of thing needs to be discussed," Palenski said.
"Freyberg (Bernard Freyberg, NZ Division commander) said it very succinctly, that they had to fight in order to get out. That means he knew that they could never hold it . . . they were told to hold it, Freyberg said they couldn't. They did the best they could against odds that were insurmountable, and inevitably they lost and left, as they were always going to do.
"The question of who to blame, I don't think should even arise. The blame should lie, if anywhere, perhaps with the British Government or perhaps Wavell (British commander of theatre) for not ensuring Crete was defended, but you could excuse him by saying Crete was just one tiny little bit of a huge theatre he had to control."
"One tiny little bit", but one in which the first flush of New Zealand's volunteer army was based. Of about 7700 New Zealanders on the island, 671 were killed, 967 wounded and 2180 taken prisoner.
Men Of Valour is full of simple but effective touches, such as identifying where each veteran came from before quoting them; obvious, but it makes Crete feel like a whole of New Zealand battle rather than some far-off field. New Zealand had been in real danger of having its division captured or wiped out and Palenski's vivid account is a constant reminder of the peril that a citizen army - and the country - faced.
"War is often called a men's thing, but to me that's rubbish," Palenski said.
"All these men had mothers, quite a lot of them had wives, they all probably had girlfriends at one stage or another, a lot of them had sisters . . . doing the fighting is probably the easy bit. These women are back in New Zealand wondering what the hell is going on and some of them didn't know until 1945 what had happened to their blokes. That is as much involvement in war as it is actually fighting."' | 2024-02-21T01:26:35.434368 | https://example.com/article/5761 |
Harmony Archtone H1213
LEFT: In 1963, the Harmony Archtone H1213 sold for under $40.
RIGHT: Made of solid wood, as opposed to laminates, the Archtone sports a birch body.
Hey Zach,
I have a Harmony archtop acoustic with the following numbers
inside: F-63-HB and 3714H1213. I know Harmony
guitars aren’t worth much, but this guitar plays quite well.
Can you identify it for me and tell me how much it’s worth?
Thanks!
—Chad in St. Paul, MN
Hey Chad,
Cool guitar! And you’re right—
most Harmony guitars aren’t
worth much, or in other words,
they aren’t very collectible.
That said, I wonder how many
guitarists reading this column
started out learning to play on
a Harmony. There are hundreds
of thousands of Harmony guitars
out there, and though these
are mostly entry-level instruments,
they’re very much a part
of guitar history.
Harmony was the largest US
guitar manufacturer between the
1930s and late 1960s. At the
height of the guitar boom in the
mid-1960s, Harmony was building
more than 1000 instruments
per day. Not only were they
producing Harmony-branded
guitars, there was a time when
the Chicago-based factory was
making guitars for 57 different
brand names and trademarks. At
one point, Harmony was selling
40 percent of their guitars
through Sears & Roebuck under
the Silvertone brand.
Your guitar is a model
H1213 Archtone made in 1963.
Harmony did a great job of
stamping model numbers and
dates of manufacture on their
guitars, but they often require
some decoding. The F-63-HB
is the date code and the two
numbers, not surprisingly, indicate
1963. The “F” preceding
the year was often thought to
be a fall production indicator
while the other letter stamp they
would use was an “S,” which
researchers thought stood for a
spring production instrument.
However, a former Harmony
employee notified a Harmony
database website that it is more
likely an “F” stands for “first”
and “S” stands for “second.”
He explained that Harmony
would shut the factory down
for two weeks in July and that
guitars produced before this
break were stamped “F,” while
guitars produced after were
stamped “S.” The H1213 is
the model number as indicated
in Harmony’s catalogs and literature.
The “3714” is the serial
number of your guitar, but little
information has been uncovered
as to what this series of numbers
represents. More than likely, it
was a consecutive production
number of that particular model
for either the first or second half
of the year.
The Archtone acoustics were
some of the most popular guitars
ever produced by Harmony.
While production totals are
unavailable, we can safely say
that tens of thousands of these
instruments were manufactured.
The Archtone had a non-cutaway
body and was advertised
as being constructed from
hardwoods. These “hardwoods”
were actually birch (grained to
resemble mahogany and spruce)
and maple (grained to look like
rosewood) for the fretboard. The
binding was actually painted on!
Other Archtone owners may
notice a slightly different model
number, but with the exception
of a tenor version, the only difference
is the finish. The H1213
(your model) was finished with
a shaded-brown sunburst, the
H1214 was ivory-colored with
a flame effect, and the H1215
was a sunburst with a grained
effect. In excellent condition,
this model is worth between
$200 and $250 today. But in the
average condition yours appears
to be, it’s worth between $100
and $150.
According to Harmony’s 1963
price list, the H1213 Archtone
sold for $37.75. If we take inflation
into account, this same guitar
would actually sell for around
$270 today. This is roughly the
same price for most entry-level
acoustic guitars these days, but
the two main differences are that
the H1213 is an archtop and
it was made in the US (most
modern entry-level acoustics are
flattops produced in Asia).
While most collectors aren’t
necessarily going to boast that
they own a number of Harmony
guitars, we shouldn’t forget
the important “first axe” role
Harmony played for many guitarists.
This company took mass
production of guitars to the next
level. And though you may have
to sort through a few to find
one that is completely intact
and doesn’t allow a car to drive
under the strings, they were
quality-made instruments for
the most part. For those of you
who first learned on a Harmony
Archtone, this is certainly a
childhood treasure!
Zachary R. Fjestad
is author of Blue Book of
Acoustic Guitars, Blue Book
of Electric Guitars, and Blue
Book of Guitar Amplifiers.
For more information, visit
bluebookinc.com or email
Zach at guitars@bluebookinc.com.
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On PremierGuitar.com, "Sponsored Content" refers to articles, videos, or audio recordings that are produced or curated by an advertiser but that Premier Guitar is happy to share alongside our own editorial content due to the Sponsored Content’s educational, musical, or entertainment value. Sponsored Content is clearly labeled everywhere it appears, and Premier Guitar's editorial department has no involvement in its creation. | 2024-06-03T01:26:35.434368 | https://example.com/article/7681 |
Case: 16-14710 Date Filed: 06/21/2017 Page: 1 of 11
[DO NOT PUBLISH]
IN THE UNITED STATES COURT OF APPEALS
FOR THE ELEVENTH CIRCUIT
________________________
No. 16-14710
Non-Argument Calendar
________________________
D.C. Docket No. 4:14-cv-01424-AKK-HGD
BILLY W. REID,
Plaintiff-Appellee,
versus
BRIAN STREIT,
Sgt., Deputy with, Jefferson County Sheriff's Office,
WEBBER,
Deputy with Jefferson County Sheriff's Office,
Defendants-Appellants.
________________________
Appeal from the United States District Court
for the Northern District of Alabama
________________________
(June 21, 2017)
Before ED CARNES, Chief Judge, MARTIN and ANDERSON, Circuit Judges.
PER CURIAM:
Case: 16-14710 Date Filed: 06/21/2017 Page: 2 of 11
Billy Reid, proceeding pro se, sued Sergeant Brian Streit and Deputy
Jonathan Webber under 42 U.S.C. § 1983 for deliberate indifference to his serious
medical needs in violation of his Fourteenth Amendment rights. He asserted those
claims against the officers in their official and individual capacities, seeking
declaratory, injunctive, and monetary relief. The officers filed a motion for
summary judgment, raising the doctrines of sovereign and qualified immunity.
The district court denied that motion and the officers now appeal. 1
I.
On July 30, 2012, at around 8:00 P.M., Streit and Webber arrived at Reid’s
home intending to question him about some allegations his girlfriend had made,
including that Reid had punched a wall with his right hand during an argument,
had held her against her will, had beaten her, and had raped her. 2 Reid was in his
backyard when the officers arrived, and when he heard someone yell at him, he
began running away. Webber chased him, and after Reid ignored his commands to
stop, Webber shot him with a taser gun, causing Reid to fall to the ground. Reid
used his already-injured right hand to help break his fall, which exacerbated the
injury he had sustained by punching the wall a few days earlier. Although Reid
1
We have interlocutory appellate jurisdiction over the denial of immunity. See Mitchell
v. Forsyth, 472 U.S. 511, 530, 105 S. Ct. 2806, 2817 (1985).
2
At the summary judgment stage, we must view the evidence in the light most favorable
to the non-moving party, keeping in mind that “what we state as ‘facts’ in this opinion for
purposes of reviewing the ruling on the summary judgment motion[ ] may not be the actual
facts.” Swint v. City of Wadley, 51 F.3d 988, 992 (11th Cir. 1995).
2
Case: 16-14710 Date Filed: 06/21/2017 Page: 3 of 11
began complaining about the pain in that hand, the deputies placed him in
handcuffs and transported him to a police substation for questioning.
Upon their arrival at that substation, Reid continued complaining and
requested medical attention for his hand because it was red, swollen, and causing
intense pain. Webber contacted Streit, who had left the substation to obtain a
search warrant for Reid’s home, and Streit instructed Webber to call the
paramedics. Webber did so and after the paramedics arrived and examined Reid’s
hand, they informed Webber and Reid that the injury was too severe for them to
treat and that Reid should be taken to the hospital immediately. Webber again
called Streit and told him what the paramedics had said, and Streit instructed
Webber not to take Reid to the hospital and to stay at the substation so that Streit
could interview him. Sometime later, Streit arrived back at the substation, ate
dinner, and then interviewed Reid.
That interview began at 12:31 A.M., about four and a half hours after Reid
was apprehended. Before the interview began Streit told Reid that he would not
receive medical care until he gave a “satisfactory statement.” After completing the
hour-long interview, and after reviewing the evidence found at Reid’s home, Streit
told Reid that he was under arrest. Streit then notified Webber that after the
necessary arrest paperwork was completed, Webber could take Reid to the
hospital. Reid was placed in a holding cell while Streit began that paperwork.
3
Case: 16-14710 Date Filed: 06/21/2017 Page: 4 of 11
While the accounts differ as to how Reid escaped from that holding cell, he did and
left the substation without permission at around 2:30 A.M, went home, and took
some pain medicine. When he woke up later that day, he went to the emergency
room but was turned away because he could not provide proof of insurance and did
not have the money to pay for treatment.
Reid was arrested about two weeks later. Following his arrest, he received
medical treatment, was diagnosed with a “[b]oxer’s type fracture” on his right
hand, and eventually received orthopedic surgery to reset the bone and stabilize the
hand with a titanium plate and screws. According to Reid, his hand is now
“permanently impaired.”
II.
“We review de novo a district court’s denial of summary judgment based on
[the doctrine of] immunity, applying the same legal standards that governed the
district court.” Feliciano v. City of Miami Beach, 707 F.3d 1244, 1247 (11th Cir.
2013); see also Pellitteri v. Prine, 776 F.3d 777, 779 (11th Cir. 2015). “Summary
judgment is appropriate when the record evidence, including depositions, sworn
declarations, and other materials, shows ‘that there is no genuine dispute as to any
material fact and the movant is entitled to judgment as a matter of law.’”
Feliciano, 707 F.3d at 1247 (quoting Fed. R. Civ. P. 56(a)).
4
Case: 16-14710 Date Filed: 06/21/2017 Page: 5 of 11
A.
The officers first contend that Reid lacks standing to pursue his equitable
claims against them in their official capacities.3 Standing “is a threshold
jurisdictional question which must be addressed prior to and independent of the
merits of a party’s claims.” AT&T Mobility, LLC v. NASCAR, 494 F.3d 1356,
1359 (11th Cir. 2007) (quotation marks omitted). And although the officers did
not clearly raise this standing argument in the district court, the question of a
party’s standing “is not subject to waiver” and we have “an independent obligation
to examine [our] own jurisdiction.” Bischoff v. Osceola Cty., 222 F.3d 874, 877–
78 (11th Cir. 2000) (quotation marks omitted). As is the case here, “when standing
is questioned for the first time by an appellate court, standing must affirmatively
appear in the record.” Region 8 Forest Service Timber Purchasers Council v.
Alcock, 993 F.2d 800, 806 (11th Cir. 1993) (quotation marks omitted).
The injunctive and declaratory relief Reid seeks is forward-looking, and as a
prospective remedy it “will provide no relief for an injury that is, and likely will
remain, entirely in the past.” Church v. City of Huntsville, 30 F.3d 1332, 1337
(11th Cir. 1994) (quotation marks omitted). As a result, to establish standing to
seek injunctive and declaratory relief, Reid must demonstrate “a sufficient
3
They also contend that they are entitled to sovereign immunity from Reid’s official
capacity claims for monetary damages. Reid does not dispute that contention. The district court
did err in denying the officers summary judgment on Reid’s official capacity claims seeking
monetary relief. See Carr v. City of Florence, 916 F.2d 1521, 1525–27 (11th Cir. 1990).
5
Case: 16-14710 Date Filed: 06/21/2017 Page: 6 of 11
likelihood that he will be affected by the allegedly unlawful conduct in the future.”
Wooden v. Bd. of Regents of Univ. Sys. of Ga., 247 F.3d 1262, 1283 (11th Cir.
2001); see Malowney v. Fed. Collection Deposit Grp., 193 F.3d 1342, 1346 (11th
Cir. 1999).
The record evidence does not show any likelihood that Reid will again
encounter and be injured by Streit or Webber’s deliberate indifference to his
serious medical needs. And there is no indication that, were we to remand for the
district court to develop the record further as to standing, Reid would be able
submit additional evidence to demonstrate otherwise. As a result, Reid lacks
standing to pursue his equitable claims for injunctive and declaratory relief against
the officers in their official capacities.
B.
As to Reid’s claims for monetary relief against Streit and Webber in their
individual capacities, the officers contend that they are entitled to qualified
immunity. The doctrine of qualified immunity “allow[s] government officials to
carry out their discretionary duties without the fear of personal liability or
harassing litigation, protecting from suit all but the plainly incompetent or one who
is knowingly violating the federal law.” Lee v. Ferraro, 284 F.3d 1188, 1194 (11th
Cir. 2002) (quotation marks and citation omitted).
6
Case: 16-14710 Date Filed: 06/21/2017 Page: 7 of 11
To obtain qualified immunity, Streit and Webber first must show that they
were acting within their discretionary duty. Mobley v. Palm Beach Cty. Sheriff
Dep’t, 783 F.3d 1347, 1352 (11th Cir. 2015). The parties agree that they were. To
overcome qualified immunity, Reid must show (1) that the officers violated his
constitutional rights and (2) that “the law clearly established those rights at the
time of the alleged misconduct.” Id. at 1352–53 (quotation marks omitted).
We first address whether a reasonable jury could find that the officers acted
with deliberate indifference to Reid’s serious medical needs in violation of his
Fourteenth Amendment due process rights. A plaintiff bringing a deliberate
indifference to a serious medical need claim must show: “(1) a serious medical
need; (2) the defendants’ deliberate indifference to that need; and (3) causation
between that indifference and the plaintiff’s injury.” Mann v. Taser Intern., Inc.,
588 F.3d 1291, 1306–07 (11th Cir. 2009). Further, “[w]hen [officers] ignore
without explanation a . . . serious medical condition that is known or obvious to
them, the trier or fact may infer deliberate indifference.” Brown v. Hughes, 894
F.2d 1533, 1538 (11th Cir. 1990).
The officers do not dispute that Reid’s broken hand was a serious medical
need. They instead dispute whether they had any duty to provide medical
treatment for an injury sustained before they took Reid into custody and, if they
7
Case: 16-14710 Date Filed: 06/21/2017 Page: 8 of 11
did, whether they were deliberately indifferent to that need and whether that
indifference caused Reid’s injury.
As to the officers’ first contention — that they had no duty to provide
medical care for an injury sustained before they took Reid into custody — they
base that argument on their version of the facts, which is that Reid’s fall during his
capture did not worsen his pre-existing injury. Taking the facts, as we must, in the
light most favorable to Reid, a jury could infer that his fall after being shot with the
taser further injured his hand. The Fourteenth Amendment “require[s] the
responsible government or governmental agency to provide medical care to [those]
who have been injured while being apprehended by the police.” Revere v. Mass.
Gen. Hosp., 463 U.S. 239, 244, 103 S. Ct. 2949, 2983 (1983). As a result, Streit
and Webber had a duty not to act with deliberate indifference to Reid’s hand
injury.
As to the officers’ second contention — that even if they had a duty to treat
Reid’s hand injury they did not act with deliberate indifference — the deliberate
indifference element of Reid’s claims requires: “(1) subjective knowledge of a risk
of serious harm; (2) disregard of that risk; (3) by conduct that is more than mere
negligence.” McElligott v. Foley, 182 F.3d 1248, 1255 (11th Cir. 1999).
The officers had subjective knowledge of a risk of serious harm. Reid
consistently complained about the pain he was experiencing, and paramedics told
8
Case: 16-14710 Date Filed: 06/21/2017 Page: 9 of 11
Webber (who in turn told Streit) that Reid’s hand was broken and that he should be
taken immediately to a hospital. And the evidence shows that the officers
disregarded that risk by keeping Reid at the substation. Indeed, they waited four
and a half hours after he arrived to interview him and told him that he would not be
taken to the hospital until he provided a “satisfactory statement.”
By delaying taking Reid to the hospital, Streit and Webber acted
intentionally, not negligently. They knew that Reid’s hand was seriously injured,
and DVD footage of Streit’s interview of Reid shows Reid bent over at his waist
cradling his right hand with his left hand. Not only that but during the interview
Reid more than once told Streit that he was in immense pain.
While “[t]he tolerable length of delay in providing medical attention
depends on the nature of the medical need and the reason for the delay,” Harris v.
Coweta Cty., 21 F.3d 388, 393–94 (11th Cir. 1994), the evidence does not show
that the officers had a good reason to delay taking Reid to the hospital. Streit’s
affidavit explains that, during the four and a half hour period between taking Reid
to the substation and interviewing him, Streit was procuring and executing a search
warrant of Reid’s home. But there is no evidence explaining what Webber was
doing while waiting for Streit to interview Reid. And the officers have provided
no reason why Webber could not have taken Reid to the hospital while Streit
9
Case: 16-14710 Date Filed: 06/21/2017 Page: 10 of 11
searched Reid’s home. 4 As a result, the delay in treating Reid was at best
unexplained, and “an unexplained delay of hours in treating a serious injury states
a prima facie case of deliberate indifference.” Brown, 894 F.2d at 1538; see
also Harris, 21 F.3d 394 (“A few hours’ delay in receiving medical care for
emergency needs such as broken bones . . . may constitute deliberate
indifference.”).
Streit and Webber also contend that Reid cannot show that their deliberate
indifference caused his injury. While there is no evidence showing that the
officers’ delay caused the need for Reid’s surgery, a jury could find from the
evidence that Reid suffered from extreme pain that night in the substation and the
officers did nothing to alleviate it. “Our cases . . . have recognized that [officers]
may violate the [Constitution]’s commands by failing to treat an inmate’s pain”
and letting him needlessly suffer. McElligott, 182 F.3d at 1257. Even if the
officers’ delay in treating Reid’s hand did not cause the need for Reid’s hand
surgery, a reasonable jury could find that the delay caused him unnecessary pain.
As a result, a genuine issue exists as to whether the officers acted with deliberate
indifference to Reid’s serious medical needs in violation of his Fourteenth
Amendment rights.
4
Although Streit may have had an explanation for why he personally could not have
taken Reid to the hospital — he was busy searching Reid’s home — he was aware that Reid
needed to go to the hospital. And he specifically instructed Webber not to take Reid to the
hospital and instead to wait for Streit to return so that he could interview Reid.
10
Case: 16-14710 Date Filed: 06/21/2017 Page: 11 of 11
Streit and Webber concede the law is clear that the Constitution requires
“the responsible government or governmental agency to provide medical care to
persons . . . who have been injured while being apprehended by the police.” City
of Revere, 463 U.S. at 244, 103 S. Ct. at 2983. And at the time of the violation the
law was clearly established that an “unexplained delay of hours in treating a
serious injury states a prima facie case of deliberate indifference.” Brown, 894
F.2d at 1538. And, again, there is nothing in the record to explain why Webber
could not have taken Reid to the hospital. Based on the facts as we must take them
at this summary judgment stage of the proceedings, Streit and Webber are not
entitled to qualified immunity, and the district court properly denied them
summary judgment on Reid’s claims against them in their individual capacities.
AFFIRMED IN PART; REVERSED AND REMANDED IN PART.
11
| 2024-06-25T01:26:35.434368 | https://example.com/article/5603 |
Kanojia claims Starry's network, which runs in the 38Ghz unlicensed wireless band, will be able to deliver gigabit speeds to homes wirelessly for far less than traditional broadband. There also won't be any data caps. It will start beta testing its network around Boston this summer.
The company's equivalent to cellular towers are active phase array devices it's calling Starry Beam. They can be installed on rooftops and other high vantage points, and they offer a range of between 0.6 and 1.2 miles (or one to two kilometers). Actual internet access will come from leased fiber connections from companies like Level 3. Accessing the network at your home requires a small device that sits right outside your window, dubbed Starry Point, which is like an over-the-air TV antenna.
The company's biggest challenge will be installing enough Beam devices to cover cities -- their range is affected by weather conditions, and their signals can't pass through walls or big obstacles (which is why the Starry Point sits outside your window). Update: When you sign up for Starry's service, you'll receive both a Starry Point and the company's router (more on that below). There's still no word on overall cost, and the company will likely let you continue using your current router if you wish.
"People have historically assumed fiber is the answer at all times," said Kanojia, who agreed fiber would be a great solution for future broadband rollouts if it was government sponsored. But without that, he believes Starry's technology is the best way to deploy scalable broadband to consumers.
Starry is targeting both traditional ISPs and cellular carriers when it comes to home broadband. During the launch event, Kanojia listed some familiar stats: 70 percent of Americans have no choice when it comes to their home ISP, while 20 percent don't have any access to broadband at all. Meanwhile in cellular land, there's plenty of competition, but pricing and data caps aren't feasible for dedicated home internet. By relying on high-frequency millimeter radio waves, Starry is able to deploy its network to far more easily than wired broadband providers and offer access at a much lower cost than wireless carriers.
The company plans to roll out a suite of products to connect to its future wireless network, all of which you'll be able to install on your own. The first is a stylish new touchscreen WiFi router, dubbed the Starry Station. Its pyramid-like design is a huge departure from typical router design (which Kanojia described as being like upside-down dead spiders), and it'll also give you details about your internet's health.
Starry Station offers 802.11ac WiFI as well as 802.15 support for Internet of Things products. You can order it for $350 on Starry's site and Amazon, and the company plans to start shipping it in March. There's also a WiFi extender, Starry Wing, planned for this summer.
Sure, Starry sounds amazing on paper, but there's still plenty we don't know about its service. We don't have any pricing details yet, and the company still needs to test large-scale deployments. The underlying technology behind Starry isn't new -- the military has been using it for decades -- but it's never been used for a widespread consumer product before. Starry has the potential to be as groundbreaking as Aereo, I'm just hoping it sticks around longer. | 2024-07-27T01:26:35.434368 | https://example.com/article/1597 |
Introduction and related work {#s1}
=============================
Neuronal models and neural mass models, usually based on coupled systems of differential equations, contain many degrees of freedom which determine the dynamics of the system. In a neural network, these models are interconnected and the strength of the interactions between elements can also change through time.
Since biological evidence to specify a complete set of parameters for a neural network model is often incomplete, conflicting, or measured to an insufficient level of certainty, parameter fitting is typically required to obtain outputs comparable to experimental results (see for example, López-Cuevas et al., [@B23]; Schuecker et al., [@B38]; Zaytsev et al., [@B47]; Schirner et al., [@B37]). And even *if* we had infinite experimental data available, Cubitt et al. ([@B10]) have shown that, regardless of how much experimental data is acquired for a general system, the inverse problem of extracting dynamical equations from experimental data is intractable: "extracting dynamical equations from experimental data is NP hard." This implies that in neural networks, the problem of finding the exact free parameters for a simulation leading to results matching experimental measurements cannot be solved in polynomial time, at least under the current understanding of computational complexity.
However, we can explore the parameter space with forward simulations in order to discover the system\'s characteristic behaviors and thus limit the search space to a computationally tractable sub-problem in an educated manner. The definition of these subspaces can then be the basis for robust---and non-arbitrary---parameter determination (in other words, mathematically valid performance function minimization). In fact, given the known mathematical characteristics of the dynamics of neuronal and neural mass networks, investigators should characterize the solution spaces of sufficiently complex networks and models before selecting what they propose are statistically diagnostic simulation trajectories. In practice, this rarely happens, even though parameter fitting without sufficient constraints and a rigorous exploration of the possible solution space can lead to conclusions valid only around local minima or around non-minima. Researchers frequently stay within arbitrary regions in the parameter space which show interesting behaviors, leaving other regions unexplored.
Visual parameter space exploration has been successfully applied in several key scientific areas, as detailed by Sedlmair et al. ([@B39]). Combined with interactive simulation steering, the time for obtaining optimal parameter space solutions can be significantly reduced (Matković et al., [@B24], [@B25]). Whitlock et al. ([@B44]) present an integration of VisIt (Childs et al., [@B8]), a flexible end-user visualization system, into existing simulation codes. This approach enables *in situ* processing of large datasets while adding visual analysis capabilities at simulation runtime. A similar approach has been suggested by Fabian et al. ([@B16]) for ParaView (Henderson, [@B17]).
Coordinated multiple views (CMVs) as proposed by North and Shneiderman ([@B28]) and Wang Baldonado et al. ([@B42]) can assist in visual parameter space exploration. CMVs are a category of visualization systems that use two or more distinct views to support the investigation of a single conceptual entity. For example, a CMV system can display a 3D rendering of a building (the conceptual entity) alongside a top-down view of its schematics---whenever a room is selected within the schematic overview, the 3D rendering will highlight the room\'s location. Roberts ([@B34]) shows that CMVs support exploratory data analysis by offering interaction with representations of the same data while emphasizing different details. Ryu et al. ([@B36]) present CMV systems that have been successfully utilized to uncover complex relationships by enabling users to relate different data modalities and scales, and assisting researchers in context switches, comparative tasks, and supplementary analysis techniques. Additional examples of such systems are presented by North and Shneiderman ([@B29]), Boukhelifa and Rodgers ([@B6]), and Weaver ([@B43]).
Visual exploration of neural network connectivity, e.g., by displaying spatial connectivity data in 3D renderings, has previously been employed by scientists to better understand and validate models as well as to support theories regarding the networks\' topological organization (Migliore et al., [@B27]; Roy et al., [@B35]). The infinite solution space of suitable connectivity paths and end configurations for neural networks makes fully automatic parameter fitting "hard," since it involves satisfying multiple contradictory objectives and qualitative assessment of complex data, as explained by Sedlmair et al. ([@B39]). Kammara et al. ([@B20]) conclude that for multi-objective optimization problems, visualization of the optimization space and trajectories permits more efficient and transparent human supervision of optimization process properties, e.g., diversity and neighborhood relations of solution qualities. They also point their work toward interactive exploration of complex spaces which allows expert knowledge and intuition to quickly explore suitable locations in the parameter space.
To address efficient but rigorous parameter space exploration, we have developed an interactive tool for visualizing and steering parameters in neural network simulation models. In this work, we focus particularly on the generation of connectivity, since finding suitable connectivity configurations for neural network models constitutes a complex parameter search scenario. The generation of local connectivity is achieved using structural plasticity in NEST (Bos et al., [@B5]) following simple homeostatic rules described in Butz and van Ooyen ([@B7]). We specify the problem from the control theory perspective, as variations in the structure system control the transition in its dynamics from an initial to a final state following a defined trajectory. The tool allows researchers to steer the parameters of the structural plasticity during the simulation, thus quickly growing networks composed of multiple populations with individually targeted mean activities. The flexibility of the software allows the exploration of other connectivity and neuron variables apart from those presented as use cases. We use CMVs to interactively plot firing rates and connectivity properties of populations while the simulation is performed. Moreover, simulation steering is realized by providing interactive capabilities to influence simulation parameters on the fly.
We have developed this tool based on two use cases where visual exploration is key for obtaining insights into non-unique dynamics and solutions. The first use case focuses on the generation of connectivity in a simple two population network. Here we show how the generation of connectivity to a desired level of average activity in the network can be achieved by taking multiple trajectories with different biological significance. The second use case is inspired by a whole brain simulation described in Deco et al. ([@B12]), where the exploration of non-unique connectivity solutions is desired to understand the behavior of the model.
Applying this approach, an intractable inverse problem can be reduced to a tractable subspace, and the requirements for statistically valid analyses can be determined. Visualization can simplify a complex parameter search scenario, helping in the development of mathematically robust descriptions amenable to further automated investigation of characteristic solution ensembles. Observing the evolution of connectivity, especially in cases where several biologically meaningful paths may lead to the same solutions, can be useful for a better understanding of development, learning and brain repair. This work is a first step toward developing new analytic and computational solutions to specific inverse problems in neuronal and neural mass networks. Our software platform promotes rigorous analysis of complex network models and supports well-informed selection of parameters for simulation.
This paper is structured as follows: first, we present an introduction to generic dynamic neural network models from a control theory perspective. Next, we describe connectivity construction and its effects on the dynamics of the system. Then, the development process and design of the steering and visualization tool is detailed. The fifth section describes the results of using the steering tool in two different use cases. Finally, we discuss our results and present open questions and future work.
General form of network dynamics {#s2}
================================
Let a neural network be defined by a set of ordinary differential equations in which *x*~1~(*t*), *x*~2~(*t*)...*x*~*n*~(*t*) are state variables of the system at time *t*. We assume that neurons in this model can be either in an active or quiescent state. The master equation of a neural network has been derived and explained in Cowan ([@B9]) and Ohira and Cowan ([@B31]). This equation provides a mathematical description of the evolution of stochastic neural networks in the form of a Liouvillian:
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where α is the decay function after a neuron has spiked, Δ~+*i*~ and Δ~−*i*~ are the raising and lowering operators which take a neuron *i* to and from an activation state, *n*~*i*~ is the number of connections to neuron *i*, *N* is the total number of neurons in the network, ϕ is the activation rate function which depends on the neuron model and ω~*ij*~ is the strength of the connection between neuron *i* and *j*. Synaptic growth and connectivity variations in neural networks further increase the complexity of the system. In the case of variable connectivity, the network master equation is transformed into:
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where both ω~*ij*~ and *n*~*i*~ depend on the control signal *u* coming from the synaptic and structural plasticity algorithms at time *t*. We introduce this formulation to expose variables *u*(*t*) in the system, which can be controlled. We are interested in modifying these signals in order to induce changes in the network and thus achieve a target dynamic profile. However, it is worth noting that our approach is also applicable to non-stochastic neural networks.
Control theory for network state trajectories
---------------------------------------------
Both synaptic and structural plasticity can be seen as biological controllers in a multi-objective optimization problem. Under this view, the system gradually creates and destroys connections between neurons, or modifies the strength of existing synapses (control), to achieve a transition from one initial state to a final steady (or even homeostatic) state. This final state can be a previously known activity state which has been altered, as in repair after a lesion, or a new activity state to be achieved, as is the case in learning. Thus, the evolving connectivity problem can be mathematically expressed in terms of control theory as defined in Kirk ([@B21]).
In our case, the control signals refer to the variations in the connectivity of the network while the states refer to the dynamics of the network. The state equations take the form of:
x
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where **u** is the history of control signals during the interval \[*t*~0~, *t*~*f*~\], and the state trajectory denoted by **x** is the history of state values during the same time interval. A control history which satisfies the constraints of the system (in this case, experimental parameters of neurons and synapses) during the time interval of interest is called an "admissible control." On the other hand, an "admissible trajectory" is a state trajectory which satisfies the constraints of the state variables through the whole period of interest. The final state of the system is then required to lie in a specific region, defined as the target set, of the *n*+1-dimensional state-time space.
By applying the control signal **u**(*t*) from *t*~0~ to *t*~*f*~, the system will evolve from its initial state *x*~0~ following some trajectory to a final state *x*~*f*~. The "performance" of this trajectory is the difference between a desired and the obtained measure for a heuristic involving the dynamics of the system. In our case, the performance function is given by the homeostatic rules the system must follow. To reach a defined target activity regime, we cannot know *a priori* whether an optimal admissible control exists, which leads the system through an admissible trajectory for a given performance function. It may be impossible to find such a control history, and even if it exists, it may not be unique or numerically stable.
The optimization problem posed seeks a global minimum for one or more admissible trajectories of the system. For the class of neural networks described by the dynamical equations above, the problem of finding the exact control signals or free parameters for a simulation leading to experimental results cannot be solved in polynomial time. However, it may still be possible to confirm solutions in polynomial time.
Connectivity generation in neural networks {#s3}
==========================================
Previous research by Sporns et al. ([@B41]) has found that the assembly of anatomical connections among neurons, also known as the connectome, plays a fundamental role in explaining the high-level activities of the brain. However, the exact relationship between anatomical links and the functions performed by the brain has aspects that remains unclear. An attempt to model biologically realistic circuits immediately runs into the problem that the structure of the brain has yet to be comprehensively characterized. Existing connectomic datasets are incomplete or contain large uncertainties (Bakker et al., [@B3]). Conversely, information about the average electrical activity in specific brain regions is easier to acquire either directly, e.g., electroencephalogram, extracellular electrode recordings of spiking activity and local field potential, or indirectly, e.g., functional magnetic resonance imaging and optogenetics/calcium imaging.
Variations in the physical elements, which constitute a neural network, can be modeled using synaptic and structural plasticity. Structural plasticity, a model of the dynamic creation and deletion of synapses in a neural network, is desirable from two main perspectives. The primary purpose is to study the neurobiological phenomenon of morphological transformations that a neuron or set of neurons undergoes through time, leading to the creation or deletion of synapses. This phenomenon is part of brain development, learning and repair. However, a promising secondary role suggested by Diaz-Pier et al. ([@B13]) is the automatic generation of neuron-to-neuron synapses to compensate for gaps in experimental connectivity data. Using structural plasticity, a network can autonomously generate synapses to achieve a stable desired profile of electrical activity, a measure that is experimentally more accessible than detailed connectivity data. By progressively and slowly changing the connections between neurons in the network and the weight of these connections for all regions, the structural plasticity algorithm is able to find stable configurations within the desired firing rate profile.
The structural plasticity implementation in NEST is based on the model proposed by Butz and van Ooyen ([@B7]) and described in detail by Diaz-Pier et al. ([@B13]). In this plasticity framework, neurons have contact points called synaptic elements which increase or decrease in number according to simple homeostatic rules. When new synaptic elements become available, they can be used to create new synapses. If the contact points are eliminated, the synapses formed earlier are destroyed. Homeostatic rules applied to the synaptic elements are intended to take the mean electrical activity to a desired state.
A Gaussian curve (Figure [1](#F1){ref-type="fig"}) is an example of a homeostatic rule describing the growth rate of connection points for neurons. The original model by Butz and van Ooyen ([@B7]) uses intracellular calcium concentration as a proxy for the mean firing rate. In this paper\'s examples, we will use a variation directly referencing the mean firing rate as our homeostatic rule.
{ref-type="fig"} for an equivalent Gaussian growth curve for the two-population example in this paper, and the resulting free (not driven) dynamics in Figures [5C--E](#F5){ref-type="fig"}.](fninf-12-00032-g0001){#F1}
The parameters defining the growth and decay of synapses are the minimum firing rate η required to generate synaptic elements (or destroy them, depending on sign of ν), the value ν of the growth rate curve when the firing rate is (ε−η)/2, and the target firing rate ε. Modifying these values alters the way connectivity is created and destroyed in the network.
Thus, to calculate the number of synaptic elements per second (d*n*/d*t*) to create (or remove, if negative), we use:
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where pow~2~*x* is the power function 2^*x*^ and H\[*x*\] is the Heaviside step function equal to 0 when *x* \< 0, otherwise 1. Equation (4) is equivalent to the Gaussian used in Diaz-Pier et al. ([@B13]) after directly replacing the calcium concentration with the firing rate λ. In this paper\'s simulations, this form is not biologically motivated, but is a homeostatic meta-rule being used to numerically solve for networks consistent with fixed firing rates.
The firing rate λ at time *t* used in Equation (4) is calculated by low-pass filtering spike train data by convolving that data with an exponential decay kernel (Park et al., [@B32]): the current firing rate λ is increased by 1/τspikes/s for each spike and decays exponentially with a time constant τ = 10s between firing times. Thus,
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where *t*^*f*^ are the firing times of the neuron and δ is the Dirac delta function. This calculation is internal to NEST and independent of our tool. When the convolution technique isn\'t suitable, an alternate mean firing rate can be computed using a user-defined window size applied to binned spike trains.
As discussed in the previous section, synaptic and structural connectivity can be seen as multi-objective optimization algorithms which take the network from an initial state to a final state where *something has been learned* or *a new activity pattern has been enabled*. Partial information about the connectivity can be combined with information about average activity in the system to initialize models of structural plasticity filling the gaps in the constraints of the system. However, finding suitable connectivity configurations and generation trajectories for neural network models is non-trivial, which is exacerbated by the nature of experimental data. The known experimental data often fails to sufficiently constrain the model to parameter subspaces that can be completely explored with reasonable resources within reasonable time frames.
Enabling structural plasticity for a single population to reach a targeted activity level is usually unproblematic, fast, and relatively insensitive to the choice of parameters such as ν and η. However, a big challenge arises when structural plasticity is involved simultaneously on several interconnected populations with differing levels of activity. Even small changes in the connectivity of each population will impact the activity of all others to which it is connected, leading to a propagated destabilization. Another parameter which has a great impact on stability is the update interval at which synapses can be deleted or created. As in any control system, the delay between a control change and the response of the system strongly determines the capability of the controller to keep the system in a stable region.
In Diaz-Pier et al. ([@B13]), the simulations were performed statically, meaning no steering was possible during runtime. Due to the large combination of parameters to be controlled and variables to be observed during the search process, brute-force parameter search based on static simulation proved to be insufficient to obtain stable states. The selection of adequate parameters to define and constrain the growth of network connectivity, especially for multi-population or coupled networks, is not trivial since some values might lead to unstable setups. Therefore, modifying the characteristics of the growth behavior (ν and η see Figure [1](#F1){ref-type="fig"}) for each population and the update interval *during simulation* becomes crucial for finding a suitable stable state for multi-population networks. We use the terms "population" and "region" interchangeably to refer to groups of neurons. The term chosen depends on the use case. In general, a region contains one or more populations while populations specify groups of neurons of the same type. Connectivity exists both within and between populations and regions. All types of connectivity can be subject to plasticity or remain fixed after setup. The software can be modified to take into account any number of populations per region, arbitrary types of neurons, and any number of regions. The user can also specify different types of connections between the same populations and apply various structural plasticity rules to each of them. The user can choose between a variety of connectivity modalities in NEST, ranging from one-to-one, all-to-all, fixed in-degree, fixed out-degree, fixed total number of connections, and pairwise Bernoulli. However, structural plasticity support is only currently implemented for one-to-one and all-to-all connectivity. Other modalities can be used, but structural plasticity will not affect these connections.
In the context of a simulation with evolving connectivity, the dynamic nature of the parameter search workflow derived from the two use cases presented later requires: W1: The simultaneous analysis of several changing variables by an expert.W2: Comparing the level of activity of several populations simultaneously.W3: Changing simulation parameters at any moment in each population of the network.W4: Snapshotting a time point in the simulation and storing the connectivity state.W5: Loading a previously stored connectivity state.
This workflow can potentially be assisted with an interactive tool enabling scientists to explore and steer such simulations within the space of possible trajectories. To achieve this goal, a scientist needs interactive feedback on the number of connections and the level of electrical activity in all populations.
*In situ* visualization and steering of connectivity generation {#s4}
===============================================================
To enable navigation through the connectivity generation parameter space, we developed a tool enabling interactive steering and visualization. The development was driven by the need to rapidly reach stable configurations of connectivity in multiple tightly connected populations. We then extended the tool to support further use cases which are presented later. The tool allows for the visualization of trajectories that the system undergoes during simulation by showing the changes in the observable states of the network (specifically the activity and connection properties of the network). In addition, this tool allows for the modification of the control signals for the generation of connectivity, i.e., the plasticity algorithm\'s parameters.
The developed tool realizes a CMV system by applying principles of event-driven architectures as presented in Abram and Treinish ([@B1]), Michelson ([@B26]), and Nowke et al. ([@B30]). The development of the tool was organized into four stages: first, the simulation script was modified to retrieve electrical activity and connectivity values; second, the visualization components and user interfaces were developed; third, processing of parameter changes from the user interface was added; and finally, the simulation script was optimized to run on supercomputers.
In the first step, we started by reproducing the plots from the non-interactive analysis workflow used in the second use case. This initial design phase revealed the following visualization requirements (**R1--R5**), followed by the requirements for simulation steering (**R6--R10**). These requirements hold for all presented use cases: R1: Deal with at least 2 × *N* representations of time series data (electrical activity and connectivity), where N is the number of populations in the simulation.R2: Interactively plot the firing rate for selected populations. The firing rate from the last simulation step should be displayed as soon as its computation concludes.R3: Interactively plot connections for each population. As for the firing rate, the latest total connections per population should be displayed.R4: Enable the selection and filtering of populations for plotting and further investigation. The means to select and filter populations of interest must be provided.R5: Have a well defined way to distinguish populations in the plot. Since multiple populations can be selected for comparison, visual clutter needs to be avoided.R6: The user interface must allow for the modification of each population\'s growth rate ν and apply each value in the simulation.R7: The user interface must allow for the modification of a population\'s minimum electrical activity η and transfer the new value to the simulation engine.R8: The user interface must allow for the modification of the update interval and transfer its change to the simulator.R9: Control the NEST simulation from within a graphical user interface. Provide the means to start or stop the simulation, trigger the saving and loading of a network state, and allow convenient access to the visualizations.R10: Enable loading and saving of the current network state (connections and user controlled parameters).
Requirements **R1--R5** cover the parameter search workflow **W1** and **W2**. **R6--R10** target **W3--W5**. Based on these requirements, we developed the software architecture as depicted in Figure [2](#F2){ref-type="fig"}. Each box in this figure we term a service. Services and the simulation engine NEST exclusively communicate via events. Communication via events allows us to treat each visualization as an independent loosely-coupled service. One benefit of this approach is that all services are independent of each other, facilitating the production of small reusable software components that are easy to maintain and can be reused in different contexts.
{ref-type="fig"}.](fninf-12-00032-g0002){#F2}
Event-communication is realized with the "*nett* " messaging framework (see Supplementary Material), which is an open source C++ network library facilitating data transfer between application boundaries based on the publish and subscribe pattern. To enable communication between applications, *nett* provides *slots*. A slot is an unidirectional communication channel strictly typed to an event. Slots exist in two flavors: out-slots for publishing events and in-slots for subscribing to these. Consequently, subscribing slots can be connected to several publishers emitting the same event. An event is defined via a customizable schema, describing the fundamental data types the event is composed of. Moreover, *nett* provides Python bindings, making it possible to communicate between Python, i.e., the visualization implementations, and C++ applications, i.e., NEST.
Streaming simulation results from NEST is already possible with the MUSIC interface (Djurfeldt et al., [@B14]). However, MUSIC is specifically built for transferring large arrays of structured data in parallel with a certain step size and with a focus on latency. It is tailored to multi-scale coupling and large data transfer. In comparison, *nett* focuses on arbitrary serialization of data through tiny pipes and is based on a publish-and-subscribe communication mechanism. In addition, it is intended for point-to-point continuous streaming and is event-driven in comparison to the pull-driven communication regime by MUSIC. Furthermore, *nett* offers routing discovery while MUSIC relies an a static configuration on startup. In summary, *nett* is tailored to concise and light data transport and easy to integrate data streaming from C++ or Python codes.
The rest of this section will outline the required simulation instrumentation and the visualization services in more detail.
Simulation instrumentation
--------------------------
Interactive steering relies on a bidirectional communication between the visualization and steering interfaces to a simulator. In our setup, activity levels and connectivity from populations computed by NEST are transferred via event communication over a network connection to the visualizations, where users can modify parameters of the simulation model, which in turn are fed back to the simulator. The values of interest are the firing rate of each population which serves as a proxy for electrical activity and a population\'s total connections formed due to connectivity generation. These are the observable states of the network. Steering parameters are the minimum firing rate η and the growth rate ν of each population, the update interval for the connectivity generation, and finally, basic commands to NEST such as ending or resetting the simulation, and storing or loading the current network state.
To retrieve firing rates and total connections, instrumentation of the simulation script is required. To this end, the simulation acquires the latest firing rates and total connections of each population in each iteration and publishes these as events. Then, parameter changes from the graphical steering interfaces, asynchronously retrieved during the model\'s computation, are applied and the next iteration is continued.
To adapt a NEST simulation to a different use case, the first step consists of determining what data needs to be transferred from or to the simulation. The next step consists of creating an event definition schema for the data to be transferred if one is not yet present. Then, slots for communicating this data definition can be created: out-slots for publishing data and in-slots to retrieve it. Once slots are created, in-slots need to be connected to their corresponding out-slots. Any in-slot should be used in a thread to asynchronously retrieve data without blocking the computation of the simulation. Once an event is received by a slot, its data needs to be applied in the next iteration of the simulation. In a complementary fashion, out-slots send the simulation results for each iteration by retrieving values of interest from the simulation and filling the slot\'s event and sending it. The same methodology is used for visualizations or graphical user interfaces which are use case specific.
Visualization system overview
-----------------------------
The visualization system consists of six services fulfilling the above listed requirements. A demonstration video of the tool can be found in Supplementary Material (see video Movie [1](#SM1){ref-type="supplementary-material"}). In the following, we outline each service and its responsibility in the workflow.
### Control panel
The *Control Panel* is the central place to provide convenience functionality, i.e., to start the simulation, all visualization services, steering interfaces, the *Color Editor*, and *Region Selector* (see Figure [3](#F3){ref-type="fig"}). It serves as an entry point for users to start the investigation of structural plasticity. The user interface facilitates changing the update interval (**R8**) and allows the simulation to be paused or restarted (**R9**). In addition, it provides a graphical interface for loading and saving the network state (**R10**).
{ref-type="supplementary-material"} in Supplementary Material, for a detailed explanation of the tool\'s interface.](fninf-12-00032-g0003){#F3}
### Region selector
The *Region Selector* is a graphical interface displaying a list of all populations in the simulation (see Figure [3](#F3){ref-type="fig"}, rightmost element). These populations are defined by the network modeler in the simulation script as part of the instrumentation process. This is detailed in the instrumentation manual in Supplementary Material. The list provides the means to select populations of interest whose connectivity and firing rates should be plotted (**R4**). To this end, the *Region Selector* retrieves the number of populations from the simulation (see Figure [2](#F2){ref-type="fig"}). The user can then select multiple populations by clicking on them. All connected visualizations are linked with the current selections; thus it can be used to synchronize all tools for filtering data and in this way populations of interest can be focused (**R4**). The *Region Selector* can also be used to inspect individual populations of interest. By double clicking on a population in the list, an additional *Activity Plot* and *Connectivity Plot* is created plotting only the selected population of interest. This functionality can be used on multiple populations, independently of selections performed later on and facilitates the pairwise comparison of populations.
### Activity plot
The assessment of the simulation results is based on the inspection of a population\'s firing rate. The *Activity Plot* is an interactive service that plots the firing rates of populations selected in the region selector (**R1**). It is used to visualize the trajectories that the network traverses in terms of its functional states. To this end, it connects to the region selector and listens for incoming selection events (**R4**). To display the firing rate (**R2**), the service directly connects to the simulation to retrieve the last iteration result. Interactive zooming and panning capabilities allow the scientist to focus on details on demand, following the "information seeking" mantra postulated by Shneiderman ([@B40]). Interactive zooming can be used to zoom into a specific time interval and assess the depicted curve in more detail. Panning allows the user to move the selected time interval of interest, effectively moving the curve to the left or right. The information seeking mantra states that users should be able to get an overview first, then zoom and filter the data, and finally query details on demand. Furthermore, axes can be independently scaled or their data range confined. In the *Activity Plot\'s* initial configuration, which can be modified by the user, both axes will be scaled in such a way that all retrieved firing rate values are visible. The tool also allows the user to export the plot as a figure. To distinguish multiple curves, a color table can be defined via the *Color Editor* (**R5**), as discussed below. A legend in the upper left corner relates the selected populations to the depicted curves shown in Figure [3](#F3){ref-type="fig"} in the upper left window. In addition, it shows the latest firing rate next to each population\'s legend label. The legends can be changed by the user of the tool. In this work we use the label *e* and *i* to identify excitatory and inhibitory populations and a number to identify the region they belong to. Individual *Activity Plots* can be used in conjunction with the region selector by specifying a population of interest. Therefore, multiple plots can be used for comparison tasks (**R1**). In this setup, the visualization ignores user input and is fixed to the initial selection.
### Connectivity plot
The *Connectivity Plot* (see Figure [3](#F3){ref-type="fig"}, upper right window) displays the total number of connections for a population in accordance with **R3**. Since structural plasticity is responsible for a change in the total connections depending on the population\'s firing rate, the plot is the primary means to verify the structural plasticity model. It shows the trajectories of the network in terms of its structure. This visualization is connected to the region selector and thus enables filtering of the populations to be displayed (**R4**). Analogously to the *Activity Plot*, it is linked to the *Color Editor*. Whenever attributes like color, line-style-drawing, or thickness are changed, these values are applied. The legends can be changed by the user of the tool. In this work we use the label *r* and a number to identify the total connectivity values for an specific region. Like the *Activity Plot* service, it offers interactive zooming and panning functionality. Likewise, axes are automatically scaled such that all retrieved connectivity values are depicted. In addition, plots can be exported as figures for publication purposes or the tracking of results.
### Color editor
The *Color Editor* provides a graphical user interface that mediates the customization of color, line drawing style, and line thickness for each population\'s firing rate and connectivity plots. Whenever the user changes an entry, a "color changed" event is emitted and processed by the *Activity Plots* and *Connectivity Plots*. In addition, the color table is saved to disk for later reuse. Its primary use is to help in distinguishing curves within the plotting visualizations (**R5**). The *Color Editor* enables the customization of the depicted firing rate and connectivity curves in the plot. Here, users can select a color for a population\'s inhibitory (I) and excitatory (E) population by clicking on the corresponding list entry. In addition, line drawing style and thickness can be controlled. The population\'s name is equal to its specified counterpart in the simulation.
### Manipulation of structural plasticity parameters
The user interfaces for η and ν are the primary means of steering the simulation for the parameter space exploration (**R6** and **R7**). This interface allows for the modification of the control signals, enabling the structural plasticity algorithm to take the system from its current state to a desired final state (see Figure [3](#F3){ref-type="fig"}, bottom center). Both steering interfaces are designed as separate standalone services that can be started within the *Control Panel*. The η and ν services provide graphical user interfaces, each presenting one slider for each population. Their influence on the creation or deletion of synapses is indicated in Figure [1](#F1){ref-type="fig"}. Each slider is named according to the population\'s label and shows the current value used in the simulation. Whenever the user changes a value by adjusting the slider, an event is emitted which is subsequently processed and applied by the simulation in its next iteration step. The upper and lower limits for the control parameters can be defined inside the scripts for each controller interface. Please refer to the instrumentation manual in [Supplementary Material](#SM3){ref-type="supplementary-material"}, for more details.
### Loading and saving network states
To re-use previously found connectivity patterns in neighboring points of the parameter space, we implemented a save and load functionality (**R10**). The current values for η and ν are saved for each population as well as the connectivity update interval. All current connections between all neurons are also saved. These connections are defined by a source neuron, a target neuron and the synapse model which links them. Finally, the total number of connections for each population are exported to a file which can be used in the next phase of the simulation loop.
To re-use a previously created snapshot, we first load the types of all synaptic elements for each population. When using the structural plasticity framework in NEST, the first step consists of defining the plastic synapses. This requires the specification of a synapse model as well as the definition of pre- and post-synaptic elements between which a synapse can be created. The growth curves for these synaptic elements are reconstructed using the stored values for η and ν. Then the synaptic elements are registered in the structural plasticity framework and the update interval is set for the simulation. This is performed by using the set status functions of NEST through PyNEST/CyNEST (Eppler et al., [@B15]; Zaytsev and Morrison, [@B46]). Finally, all connections are recreated, marking them as non-static links which can be modified by the structural plasticity algorithm. In this way, a new network with differing global parameters such as global coupling or inhibitory strength can start from a partial solution and arrive at the target activity values more quickly. For more details about the implementation of the structural plasticity framework please refer to Diaz-Pier et al. ([@B13]). This functionality can be triggered from the *Control Panel*.
Results {#s5}
=======
In this section, we present the results obtained from two use cases in connectivity generation. For the first use case, the results of running structural plasticity simulations before the interactive visualization tool was developed were previously reported in Diaz-Pier et al.([@B13], Figure [5](#F5){ref-type="fig"}, section 3.3.1). Figure [4](#F4){ref-type="fig"} (from this current paper) shows the equivalent output for the second use case, reflecting the previous visualization approach. Due to the large number of unlabeled curves, the inability to focus on data for particular populations and the lack of interactivity with the visualization, using this static approach makes it very difficult for the user to identify the evolution of connectivity in relation to parameter changes. Moreover, a new simulation run is required whenever any parameter needs to be changed. Even when some regions have easily reached the target activity of 3spikes/s, for some set-ups it is extremely challenging to identify suitable trajectories that lead to stable solutions for all populations.
{ref-type="fig"}).](fninf-12-00032-g0004){#F4}
{ref-type="fig"}); **(C)** growth rate dynamics; **(D)** evolution of the firing rate; and **(E)** evolution of the total number of connections during the simulation. Colors in **(B--E)** are as in **(A)**.](fninf-12-00032-g0005){#F5}
In this type of simulation, the system is constrained by connectivity data and desired activity levels obtained from experimental measurements. However, these constraints still allow the system to reach non-physiological states such as saturating at high firing rates (see Figure [4](#F4){ref-type="fig"}). Moreover, the system may follow several trajectories to reach these implausible states, indicating that the system is under-constrained. On the other hand, there are many admissible trajectories which take the system to biologically plausible states. Biologically meaningful trajectories should be identified by heuristics, expert knowledge, and further experimental measurements gained through a deeper understanding of the parameter space to which the neural circuit is subject. At first glance, it is not clear how to explore the parameter space in these complex systems, as the large number of variables and long simulation times make it unfeasible to find stable populations through a brute force approach, and no heuristic is available to reduce the dimensionality. Without expert knowledge in a closed loop setup, admissible trajectories are fundamentally hard to find.
In the following sections, we demonstrate the challenges of parameterizing network models and the potential for an interactive visualization and steering tool, such as the one we propose, to address them. All experiments have been implemented with NEST 2.10.0 (Bos et al., [@B5]) and its Python language bindings which are described in Eppler et al. ([@B15]); Zaytsev and Morrison ([@B46]). The complete NEST scripts used in this work can be found in a GitHub repository. For more details, please see Supplementary Material.
Two population model
--------------------
In this use case, we create a model with two populations of point neurons, one excitatory and one inhibitory as shown in Figure [5A](#F5){ref-type="fig"}. The whole network contains 1,000 leaky integrate-and-fire neurons with exponential-shaped post-synaptic currents, of which 80% belong to the excitatory population and the rest to the inhibitory population. Parameters for the point neurons are listed in Table [1](#T1){ref-type="table"}. All neurons receive independent background excitatory Poisson noise at a rate of 10kHz. At the beginning of the simulation, no connections between neurons are present. The system is allowed to create both excitatory and inhibitory connections (red and blue dashed arrows, respectively, in Figure [5A](#F5){ref-type="fig"}), using the structural plasticity framework in NEST. The weights for the created synapses are 1 and −1 respectively. The evolution of the firing rate (Figure [5C](#F5){ref-type="fig"}) and the growth of connections (Figure [5C](#F5){ref-type="fig"}) is regulated by two homeostatic rules defined by Gaussian curves, as shown in Figure [5D](#F5){ref-type="fig"}. The target average activity of the inhibitory population is set to 20Hz while the target average activity in the excitatory population is set to 5Hz. Figure [5C](#F5){ref-type="fig"} shows the evolution of the growth rate for excitatory synaptic elements in both populations during a simulation. These dynamics originate from the fixed firing rate curves shown in Figure [5B](#F5){ref-type="fig"}. The structural plasticity algorithm uses that relation at every simulation step to decide how many connections to create or delete.
######
Network parameters for the first and second use cases.
**Parameter** **Value**
------------------------------------------ --------------------
Capacitance of the membrane *C*~m~ 0.25 nF
Resting potential *V*~L~ −65 mV
Threshold membrane potential *V*~thr~ −50 mV
Reset membrane potential *V*~res~ −65 mV
Refractory time τ~ref~ 2 ms
Growth rate excitatory synaptic elements 0.0001 elements/ms
Growth rate inhibitory synaptic elements 0.0004 elements/ms
The evolution of the connectivity generation can be guided by modifying the growth rate and shape of the Gaussian curve linked to each type of connection. Figures [5D,E](#F5){ref-type="fig"} show an example of this process. In this use case, an interesting feature to observe using the visualization and steering tool is the path to the solution. With the configurations used here, one can see how allowing faster growth of inhibition triggers an overshoot in the generation of excitatory connection to compensate. As a result, a rewiring of the system is obtained. These paths to the solution can be linked to onsets of critical periods in learning and healing or by external stimulation (Hensch, [@B18]). By regulating the speed of the creation of connections in the system, scientists can explore different paths to solution where the relationship between excitation and inhibition changes through time.
Figure [6](#F6){ref-type="fig"} shows the evolution of growth rate (synaptic elements/s), firing rate (Hz) and connectivity (total number of connections) for six examples of the multiple trajectories and connectivity configurations that the network can show. All examples start with an initial growth rate of 0.0001 synaptic elements/ms. Figure [6A](#F6){ref-type="fig"} shows a smooth growth similar to Figure [5](#F5){ref-type="fig"}, but where the control signals have been modified to reduce the overshoot in the inhibitory population. That is done by reducing the initial growth rate to 0.00005 at iteration 8 (mark a.1). Figure [6B](#F6){ref-type="fig"} shows an example of a simulation where the control signals for growth start with aggressive growth values, producing a constant oscillatory behavior. That is achieved by changing the growth rate from 0.0001 to 0.0010 at iteration 38 (mark b.1) and then to 0.0030 at iteration 80 (mark b.2). Following these signals, the connectivity update interval is increased to 500 ms (from the standard length of 100 ms), which produces a big oscillation, triggering a rewiring of the network (mark b.3). Finally, growth is reduced to a slower pace, which helps the system settle at a stable state. This reduction is achieved by setting the growth rate to 0.00005 at update 161 (mark b.4). The final connectivity is very similar to the one reached in Figure [5](#F5){ref-type="fig"}. This example shows a different trajectory which reaches the same final state.
{#F6}
Figure [6C](#F6){ref-type="fig"} illustrates very fast initial growth by changing the growth to 0.004 at iteration 46 (mark c.1). Then, a sharp reduction in growth when the system oscillates near the target firing rate. The growth rate is changed to 0.0018 at iteration 98 and further down to 0.0007 at iteration 103 (marks c.2 and c.3 accordingly). Figure [6D](#F6){ref-type="fig"} shows a case which seems stable in terms of activity, but is unstable in terms of connectivity, as it exhibits a constant race between excitation and inhibition in the connectivity to maintain the target activity. The growth rate is set to 0.001 at iteration 24 (mark d.1), to 0.0056 at iteration 52 (mark d.2) and to 0.0020 at iteration 78 (mark d.3). Figure [6E](#F6){ref-type="fig"} shows a trajectory which is not biologically meaningful. This network has been built only from excitatory connections by modulating the growth of connections very carefully around the target activity. Here, we have defined a growth curve that does not allow the creation of inhibitory connections unless the activity is above the desired firing rate. Finally, in Figure [6F](#F6){ref-type="fig"}, we see a trajectory which is not admissible (not biologically meaningful) because the network is taken to an artificially high firing rates before it settles back to its target. At iteration 17, the growth rate is set to 0.002 (mark f.1) and then slowly reduced to 0.00056 at iteration 60, to 0.0002 at iteration 80 and finally to 0.00005 at iteration 90 (marks f.2, f.3, and f.4 accordingly). This graph shows how a network can traverse biologically inadmissible trajectories and still reach the target activity.
These results show that several instantiations of the same system using different dynamics lead to the same target activity but different connectivity patterns. Visualization and steering is fundamental for producing, observing, studying and cataloging these behaviors in the network. See Bahuguna et al. ([@B2]) for an example of the same phenomenon exhibited in a more complex network. Thus using target activity as a tuning parameter without this kind of exploration leads to selecting one of these network connectivity states arbitrarily. The resulting model may not be representative of the kinds of networks that produce this activity, or of the target system to be modeled.
In other words, the target activity does not uniquely identify a network, or even a contiguous volume of parameter space, but is the property of a distribution of distinct networks distinguished by parameters that are not the direct targets of research---this class of inverse problem is degenerate. The network structure may be critically path-dependent, dependent upon parameters which are stochastic sequences (external control variables) or even dependent upon numerically unstable parameter functions. Simple networks such as the one shown in this example are frequently used in computational neuroscience but rarely with consideration to the careful characterization of the parameter spaces. Thus, in the absence of analytical methods to identify alternative solutions in the parameter space, steered visualization is a highly effective method for producing, observing, comparing and cataloging network configurations.
Whole brain simulation
----------------------
This use case is inspired by a previous study by Deco et al. ([@B11]). The experiment consists of a whole brain simulation using 68 interconnected brain regions, each of which represented by a spiking network containing 200 conductance-based leaky integrate-and-fire neurons, as illustrated in Figure [7A](#F7){ref-type="fig"}. The original work by Deco et al. ([@B11]) uses a Dynamic Mean Field Model (DMFM) originally developed in Wong and Wang ([@B45]).
![Use case 1 inspired by Deco et al. ([@B11]) whole brain model. **(A)** Abstract representation of the whole brain model including 68 regions. A subset of the regions is selected (pink area). The zoom-in view of one of the regions shows the abstract model of each region, consisting of two populations, one excitatory (red) and one inhibitory (blue). Inhibitory connections to excitatory neurons in the same region (blue dashed arrow labeled *J*) are subject to structural plasticity. **(B)** *Activity Plot* (see section 4.2.3) of selected regions (0--10) as a function of biological time. Regions are numbered from 0 to 67. Tags *eX* and *iX* identify curves for excitatory and inhibitory populations in the *Xth* region. A legend (upper left) indicates the current selection. The number following the colon after the tag is the region\'s firing rate during the last simulation step. Vertical dashed lines separate sections of the simulation with differing values of the global connectivity coupling (see section 5), *G* = (A) 0.5; (B) 1.0; (C) 1.5; (D) 2.0. The vertical dashed lines are superimposed on this plot and are not part of the *Activity Plot* service. Increases to the global coupling parameter lead to an increase in the strength of the connections between regions. The firing rate spikes initially as a response to this change; in response, structural plasticity modifies connectivity according to the homeostatic rules until the firing rate stabilizes again closer to the target firing rate.](fninf-12-00032-g0007){#F7}
The coupled non-linear stochastic equations of the DMFM describe the behavior of mean-field neuronal regions and their influence on each other:
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τ
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where *H* represents the population firing rate function; **s** is the vector representing the average gating variable for each region; *a*, *b*, *d*, and σ are scaling parameters; γ and τ~*s*~ are kinetic parameters; ν is the stochastic input vector; *w* is the local excitatory recurrence; *J*~*N*~ is the synaptic coupling; *G* is the general coupling factor; **C** is the connectivity matrix; *I*~*o*~ is the effective external current; and **x** is the state variable vector for the regions. This model is applied in Deco et al. ([@B12]) to describe a system dominated at the measured time frame by NMDA gating, while AMPA and GABA gating are neglected as "fast" variables. For a complete description and analysis of the model, see Wong and Wang ([@B45]) and Deco et al. ([@B11]).
Here, we apply a mapping from the DMFM to a network of point neurons. In our simulation, each region contains two populations, one excitatory (80% of the total neurons in the region) and one inhibitory (20%). In this case, neurons in NEST do not represent biological neurons but processing units whose mathematical description at population level is equivalent to the elements which comprise the DMFM. The initial parameters used to set up the network are taken from Deco et al. ([@B12]) and detailed in Table [2](#T2){ref-type="table"}. For a complete explanation of the model and its motivation, see Deco et al. ([@B12]) and Wong and Wang ([@B45]).
######
Network parameters taken from Deco et al. ([@B12]) for each region.
**Parameter** **Excitatory neurons** **Inhibitory neurons**
--------------------------------------- ------------------------ ------------------------
Number of neurons *N*~r~ 160 40
Capacitance of the membrane *C*~m~ 0.5 nF 0.2 nF
Membrane leak conductance *g*~m~ 25 ns 20 ns
Resting potential *V*~L~ −70 mV −70 mV
Threshold membrane potential *V*~thr~ −50 mV −50 mV
Reset membrane potential *V*~res~ −55 mV −55 mV
Refractory time τ~ref~ 2 ms 1 ms
Recurrent excitatory connections have a strength of 1.4pA, while recurrent inhibitory connections have a weight of −1.0pA. Each neuron per region initially receives 160 excitatory connections from the local excitatory population. Only inhibitory connections are created during the simulation (blue dashed arrow tagged *J* in the region zoom in of Figure [7A](#F7){ref-type="fig"}) since we are only interested in substituting the feedback inhibition control algorithm described by Deco et al. ([@B11]). The inter-regional connectivity (black lines between regions in Figure [7A](#F7){ref-type="fig"}) is specified from structural data obtained by DTI, which results in a connectivity matrix *C*, but further regulated by the general coupling parameter *G*, a multiplicative factor. This enables the linear modification of the strength of the connections without altering the ratio of connectivity among regions. Thus, the total weight of the connections between regions is equal to *G*·*C*pA. Each connection between regions is made between a single representative neuron in each excitatory population. Connections between regions are only excitatory. Additionally, all neurons receive independent background input from a Poisson generator producing spike trains with a rate of 11.9kHz.
We followed the procedure described by Deco et al. ([@B11]) through the generation of synaptic activity, substituting the feedback inhibition control used in that paper with our interactive exploration method. The strength of the background input was tuned to achieve a firing rate of 3spikes/s for the excitatory population and 8spikes/s for the inhibitory population when regions were isolated (without inter-region connections). In Deco et al. ([@B11]), an iterative tuning strategy was used to determine the intra-region inhibition for the DMFMs required to produce an activity profile consistent with experimental observations. The key insight inspiring our approach is that finding the intra-region inhibition can be mapped on to determining the number of inhibitory connections required to produce the same activity pattern in a multi-area spiking neuronal network. Finding the right amount of inhibition per region which satisfies all the dependencies is still a hard multi-objective optimization problem, especially if the space cannot be interactively explored. This is demonstrated in Figure [4](#F4){ref-type="fig"}, which shows the result of simulating one static parameter setup for the connectivity generation programmatically.
In this setup, the tool was used with different values for the inter-region global coupling factor *G*. A complete view of the visualization and steering tool for this use case is shown in Figure [3](#F3){ref-type="fig"}. By using the tool, we detected that as *G* grows, it becomes more difficult to bring all regions to the desired activity state, and the standard deviation of the average firing rate increases as well. *G* has this impact because any change in one region due to *G* has a strong impact on all other regions dynamically reacting to the change in *G*. This effect is visible in Figures [7](#F7){ref-type="fig"}, [8](#F8){ref-type="fig"}, where the time it takes for all regions to stabilize increases as the value of *G* grows.
{#F8}
We are also able to detect which regions are more crucial for stability, since they have a higher inter-connectivity to other regions. Figure [9](#F9){ref-type="fig"} shows a comparison of the evolution of the firing rate and outgoing connections of four regions. Each peak shows an increment in the global coupling value *G* by 0.5, starting from a base value of 0.5. Regions 25 and 63 show large oscillations due to their high connectivity with multiple other regions. Conversely, regions 0 and 10 rapidly reach a stable state even for high values of *G*. This capacity for detailed inspection allows the researcher to verify that all regions reach the desired average activity while the simulation is running, and thus drastically decreases turn-around times to research this behavior.
{#F9}
The search algorithms proposed in Deco et al. ([@B11]) and Schirner et al. ([@B37]) are based on an update pattern which (in the same terms as the algorithms used in this work) can be described by a fixed step update around the target activity, as shown in Figure [10](#F10){ref-type="fig"}. The effectiveness of a fixed search approach in the connectivity parameter space depends mainly on two factors. First, the effectiveness is dependent on the size of the correlation step. If the step is too small, it will take too long to reach the target activity if the initial conditions are not close to the solution. If the step is too large, the system will oscillate because the corrections are too coarse. Second, the effectiveness is dependent on the accuracy. The speed to find a solution is inversely proportional to the desired accuracy. The correction step should also be smaller than the accuracy, otherwise the system may oscillate indefinitely around the final target state without ever reaching a state with the desired accuracy. In summary, the ability of the search algorithm to find a solution depends on the initial conditions, the size of the update step and the desired accuracy. Our proposed approach allows the size of the update step and the speed with which changes take place to be adapted during simulation. This solves the problem of the dependency between step and accuracy and also allows the system to potentially find a solution from a broader range of initial conditions due to the capacity to increase the resolution of the search as the target state is approached.
![Connectivity update rule employed in the algorithms proposed in Deco et al. ([@B11]) and Schirner et al. ([@B37]), where a fixed value is added or subtracted iteratively to the inner inhibitory connectivity until convergence to the desired firing rate is achieved in each simulated region.](fninf-12-00032-g0010){#F10}
In addition to the advantages in speed and use of computational resources which our expert-steered approach confers over brute force parameter search (and which may, in fact, be computationally intractable), the process of steering allows the researcher more insight into the system. Whereas in the first use case, the primary finding was that multiple connectivity configurations can result in the same activity profile, in the second use case we are able to identify which regions are most critical for the overall network stability, as illustrated in Figure [9](#F9){ref-type="fig"}. Thus, interactive visualization can support the researcher in sensitivity analysis, which is essential for understanding the main driving parameters of the model and for making better inferences about the relations between parameters and function. As with the multiple configurations observed in the first use case, it is rare to encounter a network modeling study in computational neuroscience where a sensitivity analysis has been carried out (but see Bos et al., [@B4] for a counter example).
Usage of the tool
-----------------
In this section, we summarize the main steps required to use the tool to take the system from its initial state to a final connectivity setup where the target mean activity values are achieved. A step-by-step tutorial video of carrying out parameter exploration on a network using our tool is provided in Supplementary Material (Movies [1](#SM1){ref-type="supplementary-material"}, [2](#SM2){ref-type="supplementary-material"}). In the following, we make reference to the requirements listed in section 4. The first step during the simulation steering is to determine which regions have one or more of the following characteristics (**R2--R5**): the electrical activity is far from the target activity, and there is no tendency of the system to correct for this error (or the correction is too slow);the electrical activity oscillates around the target activity and the oscillations are of equal or higher amplitude in each cycle;or the number of connections does not converge even though electrical activity is around the target activity.
This is achieved using the visualization tool by observing the firing rate and connectivity plots. Figure [7](#F7){ref-type="fig"} shows the evolution of the firing rate for the first ten regions of the brain model. Figure [8](#F8){ref-type="fig"} shows the changes in connectivity which are guided by the homeostatic growth rules defined for the structural plasticity algorithm. Each curve in the plot is uniquely identified by color and linked to a population or region, thus enabling the assessment of the three above listed characteristics. Reaching the targeted stable state is indicated when all firing rate curves converge to the target activities while the connection curves flatten to horizontal lines. This allows the user to simply and effectively identify which regions deviate from the target state and to correct the structural parameters according to the following criteria: If the actual electrical activity is far away from the target activity, the growth rate ν for that region should be increased (**R6**).If the actual electrical activity oscillates around the target activity, the growth rate ν for that region should be decreased in small increments and the value of η should be reduced to decrease the rate of change in the number of created and deleted synaptic elements around the target point ε (**R6--R7**).If the number of connections does not converge, highly interconnected regions should be identified and the growth rate ν should be modified down in all of them (**R7**). In this case, the update interval can also be modified to a smaller value to have a faster response of the control changes in the connectivity (**R8**). A shorter update interval allows better and smoother control, but impacts the performance of the simulation.
The resulting network state can be saved and used later as a starting point for other parameter combinations, thereby minimizing the need for further computations using similar values of the global coupling term (**R9--R10**).
Implementing further use cases
------------------------------
Using an event-driven architecture, our framework provides a convenient way for domain scientists to extend the tool to their needs. This tool can be used with any neuron and any synapse model in NEST, except for gap junctions. By using the scripts provided in the Supplementary Material (versions for all use cases discussed in this manuscript) as templates, the user can easily change the neuron and synapse model to explore the impact of these variations. An instrumentation manual which specifies the steps required to integrate the tool with other network models implemented in NEST can be found as part of the Supplementary Material. The instrumentation manual provides instructions based on examples for NEST, but the tool can be adapted to other simulators providing a Python interface by replacing the corresponding functionality. However, if the simulator does not provide an interface to Python, instrumentation will require substantial development effort by the user. Table [3](#T3){ref-type="table"} provides estimates for the complexity of adapting the *nett* messaging library to different use cases. The complete tool and the underlying messaging framework is open source (for further details, see Supplementary Material).
######
Estimation on the complexity to adapt the *nett* messaging framework to different steering and visualization use cases.
**Challenge** **Solution** **Complexity**
---------------------------------------------------- ---------------------------------------------------------------- ----------------
Change network topology Change number of populations Simple
Increase the size of the network Increase the number of neurons in the simulation script Simple
Retrieve additional parameter Create new event definition Medium
Add a new model parameter Create new event definition Medium
Connect different simulators with Python interface Create new event definition for the specific simulation values Medium-hard
No Python / C++ environment None Hard
Simulating on a supercomputer
-----------------------------
To leverage the power of supercomputers to reduce turn-around times for parameter space exploration, the simulation scripts can be adapted to use MPI. In this section, we show an example of adapting the whole brain simulation use case described in section 5.2 to supercomputers. To ensure that each process is in sync with all steering commands, one process (rank 0) serves as master. Only this master process establishes a connection to the visualization front-ends and processes their steering events. Then parameter synchronization is conducted via synchronization barriers with the remaining compute nodes. The master process is responsible for gathering the electrical activities and total connections from all other compute nodes to finally send these to the visualization front-ends.
After all the simulations had been parallelized, we adapted the tool to cope with the supercomputing environment. A challenge of the current usage conditions of most supercomputing environments is their batch-mode operation where users submit jobs which are granted compute time after a possibly long delay; interactive supercomputing is still a work in progress as outlined in Lippert and Orth ([@B22]). Since our tool relies on a network connection to NEST, the IP-address of the compute-node running the simulator is unknown *a priori*. To circumvent this issue, we rely on the supercomputer\'s global file system: when the simulation is granted compute time, the node\'s IP-address is obtained and written to disk. Subsequently, all visualization services use this configuration file and connect to the given address. However, one limitation of this approach is the need to start the simulation first.
Since the visualization tools are independent of the network topology and size, the scaling impact of the network\'s performance can be measured while neglecting the communication overhead. To simulate a larger number of populations with a larger number of neurons, it is crucial to use supercomputers. To this end, we deployed the tool to the JURECA supercomputer at the Jülich Super Computing Centre. JURECA has 260 compute nodes with Intel Xeon E5−2680 v3 Haswell CPUs with 2 × 12 cores per CPU, 128 GB of RAM per node and runs CentOS 7. To assess the speed-up obtained using this machine, we used the third use case\'s setup and measured the execution times for 50 updates of connectivity in the network, with an update interval of 100 ms. Using a full node on JURECA, we were able to obtain a 2.94-fold speed-up compared to the workstation setup, which uses 8 Intel Core i7−4710MQ CPUs @ 2.50 GHz and 16 GB of RAM running on Ubuntu 16.10.
Figure [11](#F11){ref-type="fig"} shows a strong scaling test for different numbers of neurons per population. Simulation scalability increases with the number of neurons per population---particularly for 8, 000 neurons per population (a total of 544, 000 neurons in the network). This is due to the network size and spike distribution overhead; larger networks benefit more from the larger number of compute-nodes and overcomes the inter-process communication and intra-process spike distribution overhead up to the point that the global number of spikes dominates performance (for a current discussion, see Jordan et al., [@B19]). In addition, the number of synapses increases quadratically with the number of neurons per population, which highly impacts the scalability of the simulation.
{#F11}
On the other hand, visualization scalability is dominated by the data gathering step at every update interval. For the case of large networks like the 8, 000 neuron network, the impact of the data gathering step can be reduced by gathering information from only a portion of the network. A well selected statistical sample would provide enough information about the ensemble behavior of the populations while benefiting performance. The current paradigm for the tool funnels data from a large number of compute backends to a single frontend visualizer. In order to scale with increasing numbers of backend nodes for massive supercomputing, a more complex data flow and analysis framework will be needed, such as a multi-node reduction stage to reduce the impedance between the backends and frontend, as well as reducing the load on the fronted. A generalized software framework for such infrastructure to couple visualization with supercomputing at scale is, to our knowledge, currently not available, and is a work in progress.
Discussion and conclusion {#s6}
=========================
In this paper, we have introduced a visualization and steering tool for the interactive analysis of connectivity generation in NEST. To show its applicability, we have presented two use cases where the tool was used to visualize and steer populations of point spiking neurons to reach a desired target activity level. Our results indicate that by interactively exploring the parameter space and possible trajectories, scientists can gain a better understanding of the system and concentrate on regions of biological interest, as compared to a blind brute force exploration. The improvements over brute force exploration are due to the effects of changes in specific parameters in the network which can be visualized and states outside the admissible regions which can be identified and excluded from further simulation. These improvements lead to a reduction in computational resources and an educated definition of interesting parameters, states and trajectories.
In this work, we have presented results using the interactive steering and visualization tool for two use cases where a desired firing rate was set by the modeler at the beginning of the simulation. We have used firing rate calculations produced internally in NEST to guide the generation of connectivity. This method for computing the mean firing rate can impact the performance of the control system since controllability depends on the delay between measuring an observable and producing a response. However, the tool is independent of this calculation and other techniques, such as spike train binning, can be used instead to increase the controllability. Calculation of firing rates on streams of spike trains might become computationally intensive with increasing network size. Future implementation of other techniques to increase the data gathering speed will lower delays and allow other spike processing techniques to be efficiently implemented as alternatives to the convolution approach.
The use cases presented were selected for their differing degrees of complexity in terms of connectivity and network definition. In the simple use case, different connectivity configurations lead to the same activity profiles even when some of the trajectories are biologically inadmissible. With our approach, the user can concentrate on exploring only those configurations which are of interest in answering the scientific question posed. In Figure [6](#F6){ref-type="fig"}, we show different trajectories produced using structural plasticity following homeostatic rules to fit the system to a firing rate profile. Even the non-biological parameters of the optimizing algorithm itself have an impact on the final configuration of the network. For example, if one performs a gradient descent to optimize the activity profile of a network, the results will be sensitive to any arbitrary choice of initial states of the populations and connectivity. With our tool we can characterize the distribution of representative models and results.
In the second use case, our tool also enables a sensitivity analysis of the system by visualizing the effect that changes in the connectivity have on the dynamics of the full system. Thus, the user can draw better conclusions about the relationships between the controllable parameters, in this case connectivity, and the observables of the system, in this case the firing rate of each population. We can see the relative sensitivity of the system to the biologically relevant parameters (connectivity) and the non biological parameters of the optimization algorithm. Our tool can provide more insight into how different types of synapses are created or modified in the neural circuit to give rise to different features in the dynamics of the system.
As we have discussed in this paper, a brute force exploration of the parameters of a network can easily become a computationally intractable problem. Choosing a single random configuration or even only a small sample of configurations from the whole space without a proper characterization of their distribution is unlikely to lead to a statistically valid distribution of the results. Interactive visualization is a way to move toward statistically validated conclusions as it allows an assessment of the essential features of the system, ultimately leading to automated sampling.
While the resulting connectivity patterns are not necessarily unique, our approach enables exploration and assessment of these solutions and their paths. The main contribution of this approach is the use of interactive visualization and parameter control techniques. These techniques allow the system to be controlled and stabilized within a physiological configuration space by an expert. When increasing the number of neurons and populations, the number of parameters to tune increases, resulting in an ever harder-to-reach stable state. Thus, interactive visualization becomes even more important. The knowledge gained through interactive exploration can lead to the development of automated tools assisting in the parameter space exploration.
Using this approach, we can reduce the turn-around times of exploring different connectivity configurations in comparison to simulating all possible parameter configurations and assess reasonable configurations in a later phase. The speed-up achieved by this exploration is mainly due to four factors. First, it is not necessary to simulate the system for long times iteratively; instead, the modifications are performed on demand. Second, partial solutions can be reused for different global parameter combinations, resulting in the reduction of total computational costs. Third, the user can visualize the behavior of the system\'s observables with respect to individual parameters, allowing the user to isolate regions of interest and form a better understanding. Finally, we can study the transition points in the activity of the networks, which are produced by the underlying connectivity variations, and interact with the tuning algorithms by visualizing their impact.
As stated before, the connectivity solutions and paths to solutions for the presented use cases are not unique, rendering a knowledgeable exploration process crucial. Thus, the interactive analysis process can help the user accomplish the following: Form an understanding of the implication of different parameter setups for each network model.Validate the models.Define biologically meaningful populations of interest for the simulation.Derive measures for the automatic or semi-automatic assessment of the models\' behavior leading to automated tools guiding the exploration process.
While the generation of connectivity based on empirical constraints for the dynamic system or experimental data inherently leads to non-unique solutions and especially solutions which are physiologically implausible, the ability to identify and explore subsets of the solution space is valuable to form an understanding of the dynamic nature of these systems.
In this work, we have formalized the effects of dynamic connectivity of a network in terms of control theory. We take into account that the network starts at an initial state and is taken to a final state through the introduction of control signals which alter the connectivity of the network. In this case, control of the synapse creation and deletion is induced by the structural plasticity algorithm. The eigenvalues of the Liouvillian of the network are thus modified with these signals through the evolution of the simulation and the state of the neurons in the network is changed. Visualization shows the immediate effects of the control signals in the system. The results shown in section 5.1 exemplify how even a simple network can traverse different admissible trajectories (Figures [6A--E](#F6){ref-type="fig"}) using different elements from the set of all possible controls. We show how the unconstrained system can traverse an inadmissible trajectory (Figure [6F](#F6){ref-type="fig"}) or end in states outside of the admissible set (Figure [6D](#F6){ref-type="fig"}). We have also seen how inadmissible control signals are still able to give rise to admissible trajectories and final states (Figure [6E](#F6){ref-type="fig"}).
We adapted the tool to scale with supercomputers allowing larger networks to be simulated and finer simulation stepping to be used, thus achieving more accurate results. This way, researchers can explore the manifold solutions and paths of connectivity satisfying average activity targets in a variety of neural network models. Our tool gathers data from the simulation at specific intervals, which impacts the performance as the networks become larger. Continuously streaming data from of the simulation by using, for example, MUSIC (Djurfeldt et al., [@B14]) or the NEST I/O backends can reduce this bottleneck and allow greater flexibility in the network size.
In summary, our interactive tool provides the means to visualize and steer connectivity generation of a running NEST simulation to stabilize complex non-linear systems. The applied concepts of the tool are generalizable and extensible to other types of systems with similarly large degrees of freedom. Adapting and exploring further model parameters, e.g., synaptic weights and delays, background input frequency, and variation in weights of spike-timing-dependent plasticity synapses is possible. Our implementation is open to the public (see Supplementary Material).
In the future, we would like to explore further techniques to track already explored parameter spaces, to develop semi-automatic systems to guide researchers in tracking manifold solution spaces and to extend the tool to support further use cases. Currently, the saved state refers only to the connectivity and last values of all variables at the time of saving. We are working to provide a visualization that shows parameter changes for reproducing all trajectories. For the moment, the loading features are limited and the subject of future work. In addition, we are adding support for machine learning algorithms coupled with the interactive exploration for various network variables beyond connectivity. Our goal is to to detect oscillations and other troubling behavior in the network using machine learning and then to correct this behavior by use of the controllers. Other target control measures such as power-spectrum shape and inter-population correlations may be interesting as complex control variables in the context of machine learning. The modularity of the software, primarily derived from applying an event driven design, allows for such additions in a non-intrusive manner.
Linking the time axes of the activity and connection plots to allow for coordinated zooming is currently not supported but would be a useful extension to the analysis workflow. A visualization of changes in the network\'s eigenvalues as connectivity evolves is also subject to future work. The creation of additional plots for further variables is simple and can be achieved by adapting the scripts used in the presented use cases (see Supplementary Material). Connecting another visualization application to the NEST simulator is in principle feasible but requires adapting the visualizer to our communication protocol.
We argue that it is crucial to explore the distribution of paths to solutions instead of focusing on just *a* possible solution satisfying a set of constraints. To develop this understanding, interactive exploration of dynamic systems is a key tool for developing mathematical intuition, and thus for deriving mathematically robust descriptions. These descriptions are then amenable to further automated investigation of characteristic solution ensembles.
Author contributions {#s7}
====================
CN and SD-P have contributed equally to this paper. CN developed the interactive steering tool and the framework. In addition, he designed the data flow for steering the main structural plasticity parameters. SD-P, AP, and AM defined the use cases. SD-P evaluated the results and compared the process of parameter navigation with and without the steering tool. AP provided the high performance computing knowledge to port and optimize the code for supercomputing usage. BW, BH, and TK provided scientific guidance on the visualization tool. AM provided neuroscientific guidance and assessed the usability of the tool for generalized use cases. CN, SD-P, AM, and AP wrote the paper.
Conflict of interest statement
------------------------------
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.
**Funding.** The authors would like to acknowledge the support by the Excellence Initiative of the German federal and state governments, the Jülich Aachen Research Alliance---High-Performance Computing, the Helmholtz Association through the portfolio theme Supercomputing and Modeling for the Human Brain (SMHB) and the Initiative and Networking Fund. In addition, this project has received funding from the European Union\'s Horizon 2020 Research and Innovation Programme under grant agreement No 720270 (HBP SGA1) and No 785907 (HBP SGA2). Finally, this project has received funding from the German Federal Ministry of Education and Research ("D-USA Verbund: Mechanistische Zusammenhänge zwischen Struktur und funktioneller Dynamik im menschlichen Gehirn," project no. 01GQ1504B). Responsibility for the content of this publication belongs to the authors.
Supplementary material {#s9}
======================
The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fninf.2018.00032/full#supplementary-material>
######
Introduction to the interactive steering and visualization tool.
######
Click here for additional data file.
######
Using the interactive steering and visualization tool in a specific use case for structural plasticity in NEST.
######
Click here for additional data file.
######
Instrumentation manual.
######
Click here for additional data file.
We have included two videos as Supplemental Material that demonstrate our visualization tool. The first video presents its basic structuring and functionality. The second one discusses one use case for structural plasticity and explains how the tool can help in the assessment of the simulation. Moreover, we have included an instrumentation manual describing the general process for modifying simulation scripts in order to use the tool.
The *nett* messaging framework can be downloaded at <https://devhub.vr.rwth-aachen.de/VR-Group/nett.git>, and <https://devhub.vr.rwth-aachen.de/VR-Group/nett-python.git>. The NEST structural plasticity framework can be found at <https://github.com/sdiazpier/nest-simulator.git>, branch `sp_rate` and tag `sp_viz_rate`.
The visualization tool, simulation scripts for both use cases, and a user manual to build the code can be found at <https://github.com/sdiazpier/isv_neuroscience>. In addition to the use cases discussed in this work, a script showing the instrumentation of the cortical microcircuit model (Potjans and Diesmann, [@B33]) is also provided in the aforementioned git repository.
[^1]: Edited by: Robert Andrew McDougal, Yale University, United States
[^2]: Reviewed by: Salvador Dura-Bernal, SUNY Downstate Medical Center, United States; Jeffrey L. Krichmar, University of California, Irvine, United States; Marianne J. Bezaire, Boston University, United States
[^3]: †These authors have contributed equally to this work.
| 2024-07-26T01:26:35.434368 | https://example.com/article/6002 |
Nikki Haley is making a graceful exit from the Trump administration — a rarity these days — but it hints at something bigger.
TOP STORIES
Why Haley Is Leaving Trump’s Orbit
What to make of Nikki Haley’s plans to step down as ambassador to the United Nations at year’s end? Taken at face value, her resignation reflects a desire to take a break — and make more money. To those reading the tea leaves, it’s yet another sign that President Trump is feeling more empowered to press his nationalist “America first” agenda. Though Trump and Haley were all smiles Tuesday, she has not always toed the Trump line and her clout had diminished with the arrival of Secretary of State Michael R. Pompeo and national security advisor John Bolton. Now the guessing game over her successor is in full swing. But in case you wondered, Ivanka Trump already tweeted it won’t be her.
The MAGA Never Stopped
On Tuesday night in Council Bluffs, Iowa, Trump whipped up a crowd of about 9,000 people, calling Democrats an “angry mob” intent on “policies of anger, division and destruction.” It was his 32nd rally since taking the oath of office, and with the midterm election next month, he has a slew more scheduled. To longtime observers, they can be like a Grateful Dead concert (hardcore fans chanting “Lock her up!” and Trump’s greatest-hits list of grievances) or a morality play. Here’s a closer look at the makings of the Trump road show.
President Trump speaks during a rally at the Mid-America Center in Council Bluffs, Iowa. (Nati Harnik / Associated Press)
More Politics
-- A new poll says a slim majority of Americans believe Trump is just venting when he calls the press “enemies of the people.” But they also think his words can be dangerous.
-- New Justice Brett Kavanaugh quickly joined the questioning as the Supreme Court tried to make sense of a federal law that imposes longer prison terms on criminals who have three violent felonies on their records.
-- FBI Director Christopher A. Wray will testify before a Senate committee this morning amid fallout over the bureau’s background investigation of Kavanaugh.
A ‘Monstrous Storm’ Threatens Florida
Hurricane Michael is expected to move inland over the Florida Panhandle or the state’s Big Bend area today and bring powerful winds, life-threatening storm surge and torrential rain. At its current strength, it would be the most powerful storm to hit the U.S. mainland this year. Meanwhile, the hurricane created a political storm, as the Florida Democratic Party filed a suit in federal court to extend the state’s voter registration deadline by at least a week.
As California Grows, So Grows …
When California voters in 2016 chose to legalize recreational marijuana, they also made it easier for people with pot convictions to expunge their records. New Jersey, North Dakota and Michigan may soon follow suit. Proponents say the idea is to help many black and Latino neighborhoods that have been disproportionally targeted by drug law enforcement. Opponents say it just doesn’t work that way.
Between a Rock and a Frog Place
Williamson Rock was once a proving ground for Southern California rock climbers. But 13 years ago, the area around the sheer granite wall in the San Gabriel Mountains was closed to protect a colony of endangered frogs. Now a group of climbers is hoping the Trump administration will lend a hand, as the federal government looks to weaken protections on public lands.
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CALIFORNIA
-- The L.A. City Council voted unanimously to crack down on people for “disruptive acts” during its meetings at City Hall.
-- L.A. County supervisors voted to stop collecting fees once charged to families of juvenile delinquents for their incarceration, ending a practice decried by criminal justice advocates.
-- Mexican officials have discovered a sophisticated but unfinished cross-border tunnel that began in a home less than a football field away from the U.S.
-- After being convicted of criminal charges related to the death of a pit bull named Hershey, the mayor of Maywood says he didn’t own the dog and is being targeted because of his ethnicity.
HOLLYWOOD AND THE ARTS
-- Film critic Justin Chang did a second viewing of “First Man,” starring Ryan Gosling as Neil Armstrong, and found that it thrills, moves and perplexes.
-- Director Paul Greengrass’ “22 July” explores what it takes to overcome an act of pure evil. Critic Kenneth Turan says the film is riveting.
-- In the new CW teen football drama “All American,” a former NFL player’s life gets the Hollywood treatment.
-- Taylor Swift opened the American Music Awards but didn’t follow up on her newfound political outspokenness, although she did urge people to vote.
NATION-WORLD
-- Turkish media published images Wednesday of what it described as a 15-member “assassination squad” allegedly sent to target Saudi journalist Jamal Khashoggi.
-- South Korean officials say North Korean dictator Kim Jong Un wants Pope Francis to visit the officially atheist country.
-- Syrian President Bashar Assad announced an amnesty for army deserters and those who avoided military service, a gesture that could draw back thousands of refugees and displaced Syrians.
-- Mukalla is an oasis of stability in war-torn Yemen. So why do some residents miss Al Qaeda?
BUSINESS
-- Santa Monica-based Snap Inc. is getting into the scripted programming business, but an analyst says the company is “quickly running out of money.”
-- Jack in the Box franchisees want to get rid of the company’s chief executive. (And no, it’s not the guy with the ball head and pointy hat in the commercials.)
SPORTS
-- The Dodgers will face a tough Milwaukee Brewers squad when they begin their series Friday. Both teams have been playing their best baseball.
-- An L.A. judge has ruled that the “show-cause” penalty, one of the NCAA’s go-to sanctions, is no longer legal in California.
OPINION
-- The world is warming faster than we believed. All of us need to find the will to act now.
-- If you thought the Kavanaugh confirmation was ugly, brace yourself for what’s coming next.
WHAT OUR EDITORS ARE READING
-- The connection between that Russian bank computer and the Trump Organization server. (The New Yorker)
-- Now hockey’s Washington Capitals must decide what to do about the traditional White House visit after winning the Stanley Cup. (The Undefeated)
-- A new study finds that kids who grow up in homes with plenty of books reap the benefits into adulthood. (Pacific Standard)
ONLY IN L.A.
The makers of Juxtapoz magazine never expected to hit the heights with a publication devoted to “lowbrow” artists who had been excluded from the mainstream. Think hot-rodders, graffiti writers, and artists from the tattoo scene, skate and surf culture, psychedelia, underground comics and pop-surrealism. Yet, at nearly 25 years old, the outsider magazine is looking back at some of the success it’s had inside the art world.
If you like this newsletter, please share it with friends. Comments or ideas? Email us at headlines@latimes.com. | 2024-06-17T01:26:35.434368 | https://example.com/article/7225 |
Charley Reese
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Wednesday, December 01, 2010
Angry, Hyper-partisan Democrat Laments Partisanship in Washington
Let's all say thanks to Chris Dodd. For retiring. One of the most odious, loathsome scumbags in the history of the United States Senate gave his farewell speech and to no surprise, whined about partisanship in Washington. This is the new mantra from the left. They run roughshod of the GOP and Americans while they've got solid majorities. Now that people are running them out of office, it's time for us all to come together.
Sorry, Chris, that dog don't hunt.
Sen. Christpher J. Dodd decried an era of corrosive hyper-partisanship in his farewell address Tuesday, saying the political system is "completely dysfunctional" and telling his fellow senators that they could be effective only by working together.
If Dodd had any guts he's have been a man and run for re-election. But he knew his days were numbered and took the cowardly way out.
In an emotional goodbye after 30 years in office, the Connecticut Democrat bemoaned the gridlock that he says has overtaken the Senate, where his late father, Thomas Dodd, had served for 12 years before him.
"Intense partisan polarization has raised the stakes in every debate and on every vote, making it difficult to lose with grace and nearly impossible to compromise without cost,'' Dodd said. "Americans' distrust of politicians provides compelling incentives for senators to distrust each other, to disparage this very institution and disengage from the policy making process.''
Whose fault is this? Republicans have spent decades bending over backwards trying to accommodate the Democrats, even when they were in the majority. As soon as Democrats run they show the GOP has zero rights, zero privileges, they're told "I won," and treated like shit. Oh, but now we're all supposed to work together?
Piss off, Dodd. And quite frankly, I'm tired of jello-spined Republicans making nice-nice with this lowlife.
In a departure from typical partisanship, Dodd received praise and a standing ovation from colleagues who sat listening on both sides of the aisle. Senate Minority Leader Mitch McConnell (R-Ky.), after embracing Dodd, called his remarks "one of the most important speeches in the history of the Senate." | 2023-10-16T01:26:35.434368 | https://example.com/article/4353 |
A press release announcing the release of the Italian edition of "From the Depths of Our Hearts" for January 30th puts an end (or almost) to days and days of fierce controversy. The signatures will be "Robert Sarah with Joseph Ratzinger / Benedict XVI" to avoid further speculation. So the truth has been restored, but the wound of a media lynching against Cardinal Sarah and the pope emeritus remains, to which no one - for sure - will apologise. And there is also the "unsolved mystery" of a statement signed by Benedict XVI and Sarah last Friday: it should have been published by the Secretariat of State but all trace has been lost.
“Today and only today, when the clouds seem to clear (...) we announce the release of the book From the Depths of Our Hearts by Robert Sarah with Joseph Ratzinger / Benedict XVI for Thursday 30 January 2020, thanking the authors and all the friends who have been close to us during this delicate enterprise.” With these words David Cantagalli, the Italian publisher for Benedict XVI and Cardinal Robert Sarah, in an official press release puts an end (or almost) to the squalid story that enveloped the announcement of the publication of the book in defence of celibacy, co-authored by Cardinal Sarah and the Pope emeritus. So, no signature will be withdrawn after all, as Benedict's secretary, Monsignor Georg Ganswein, had informed news agencies after rumours revealed that Benedict XVI was unaware of the book's design. This led to the start of a real media lynching of Cardinal Sarah, but also the same old campaign against the Pope emeritus.
The book will be released in Italian as scheduled on January 30, with a minor formal change to the cover, as agreed with the French publisher Fayard, who manages all the contracts for translation: the signature of the authors will no longer be Robert Sarah-Benedict XVI, but "Robert Sarah with Joseph Ratzinger / Benedict XVI". The inclusion of his own name - Joseph Ratzinger - somehow intends to avoid the declared enemies of Benedict XVI using the pretentious topic of a text written by an "anti-pope"; but whoever reads this book must honestly admit that the spirit with which it is written is one of a contribution to the Truth, not of an ideological or power skirmish. And the addition of the preposition "with" in the signature clarifies what is explained in the publisher's note accompanying the edition. That is, the book is composed of an essay by Benedict XVI, another by Cardinal Sarah (both have already been explained by the Daily Compass, here and here), then an introduction and a conclusion physically written by Sarah but "read and shared" by Benedict XVI. Exactly what had already been explained from the start, but which was ignored to give rise to "incessant, nauseating and lying controversy", as Cardinal Sarah defined it a few days ago.
The controversies were particularly virulent by the usual sectors of the Catholic world, by “the revolutionary guardians" and by the Catto-progressive "intellectuals", who certainly did not spare Cardinal Sarah from their harsh insults including a request to muzzle the Pope emeritus. We have reached a level of lies perhaps never reached before, particularly serious when we consider that even the Italian bishops’s newspaper, Avvenire, put words in Benedict XVI mouth (January 15) that he never said and that could not be deduced even from the however unfortunate statements made by Ganswein: "Benedict: I do not sign Sarah's book on celibacy -" Never authorised the apposition, nor shared the premise and the conclusion”.
As evidence of the shared feeling between Cardinal Sarah and the pope emeritus, in the communiqué Cantagalli stresses that: «It is a book with a high theological, biblical, spiritual and human value, guaranteed by the expertise of the authors and by their willingness to make available the outcomes of their respective reflections, manifesting their love for the Church, for His Holiness Pope Francis and for all humanity.”
So: the book comes out, the truth is restored. One could say that everything ends well. But it is not quite like that. First of all because these weeks of poison, have not been canceled and the slime thrown above all on Cardinal Sarah will leave a stain. And you can be sure, no one will apologise - indeed, they will also avoid giving any importance to the news - on what has happened.
Secondly, events - as we have already said - that seemed to be controlled by a director who had every interest in creating a fuss over nothing in order to obscure the content of the book, certainly unwelcome to those trying to overturn the doctrine of the Church by attacking priestly celibacy. A goal, unfortunately, that has partially succeeded.
The third part, remains a mystery. After days of fierce controversy, Cardinal Sarah went to Mater Ecclesiae, the residence of Pope Benedict XVI, at 6 pm on Friday 17. It was a clarifying meeting that Sarah himself reported with some tweets: «Due to the incessant, nauseating and false controversies that have never stopped since the beginning of the week, concerning the book From the Depths of Our Hearts, I met Pope Emeritus Benedict XVI tonight ", wrote the Guinean cardinal, who then continues:" With Pope Emeritus Benedict XVI we have been able to ascertain that there are no misunderstandings between us. I came out of this lovely meeting very happy, full of peace and courage.” This is followed by recognition for the work done by the French publisher.
The meeting and the concordant atmosphere that characterised it was not denied by anyone, but the announcement via tweet by Cardinal Sarah seemed to herald something that would attest once and for all to this unity of purpose. In fact, we know that a joint communiqué, signed by Benedict XVI and Cardinal Sarah, was written at that meeting, aimed at confirming the double authorship of the book and putting an end to the media lynching of the two. In order to avoid further friction, it had been decided to deliver this press release to the Secretariat of State for publication, which should have happened no later than Monday 20. However, its traces have been lost: censored by the Secretariat of State? Left in Msgr. Ganswein’s bag or some other official’s? It is not known.
However, the unpleasant impression remains that everything is being done to prevent the total harmony between Benedict XVI and Cardinal Sarah in matters of priesthood, celibacy and not only, from emerging clearly. | 2023-09-16T01:26:35.434368 | https://example.com/article/6718 |
Illegal Procedure: How a 1974 Stadium Bill Put Reproductive Rights in the Sidelines
Fans of the University of Arizona football team will arrive by the thousands at Arizona Stadium on September 3, the start of the fall football season, as the UA Wildcats face off against the UTSA Roadrunners, a team they defeated 26 to 23 in San Antonio last September. For fans, the stadium is a place where legends and losses are remembered. For reproductive rights advocates, it represents a devil’s bargain that took place more than 40 years ago and continues to compromise health care to this day.
In 1974, abortion rights were sacrificed to expand Arizona Stadium.
Arizona has long had a unique role in the abortion battle. In 1962, Sherri Finkbine, a Phoenix-area woman, entered the national spotlight after she found out the thalidomide she was taking as a sleep aid could cause severe fetal abnormalities. The early mortality rate among infants who were exposed to the drug was about 40 percent, in large part due to internal defects that commonly affected the kidneys, heart, digestive tract, and reproductive system.
Fearing how thalidomide would affect the development of her own fetus, Finkbine wanted to terminate her pregnancy in a state — and nation — that put legal barriers in the way of abortion. Already known to many as the star of a locally produced children’s show, she became a topic of national debate when she shared her story with a reporter from the Arizona Republic. She spoke to the reporter in the hopes of warning other mothers about thalidomide. An unintended consequence was that the publicity made it harder to quietly seek an abortion; providers who might have otherwise taken a legal risk for her couldn’t escape the attention that followed her.
Finkbine went to the Arizona Supreme Court with a request to be pardoned from prosecution if she terminated her pregnancy. When her request was rejected, she had to travel to Sweden for the procedure, where providers confirmed that her child, had it been carried to term, would have been severely deformed. The effects of the drug exposure were severe enough that after the procedure they were unable to answer whether the fetus would have been a boy or a girl.
Finkbine’s story signaled a change in public feelings about abortion, a change that set the stage for the Supreme Court’s decision several years later in Roe v. Wade. But Arizona itself didn’t do an about-face on the issue — at least not its legislature. Just months after Roe v. Wade was decided in 1973, then-Rep. Jim Skelly (R-Phoenix) and a group of 14 House Republicans pressured the UA’s president at the time, John P. Schaefer, to order a moratorium on abortions at the university hospital. Skelly and the other House members threatened to withdraw a $543 million appropriations bill if the procedures continued.
It was the following year, however, that Skelly and fellow Republicans took a bigger step toward shutting down abortion at the university hospital. In 1974, Arizona Stadium was pushing its seating capacity at games. The opening game of that year’s football season filled more than 97 percent of its seats. The university had its mind set on expanding the stadium well before the season started, though. The Arizona Daily Star ran several articles in February, March, and April of that year, covering what began as an ordinary bond issue to finance a $5.5 million project to add 22,100 seats to the north and east sections of the stadium. The stadium bill became more newsworthy, as well as controversial, when Rep. Skelly added a rider that would prohibit the university’s College of Medicine from providing clinical training for abortion — and prohibit the hospital from providing the service. “The taxpayers are financing an abortion mill at the UA,” Skelly complained in an interview that spring.
Skelly’s rider was met with criticism by a fellow Republican House member Diane McCarthy (R-Phoenix), who argued that it was unconstitutional because the abortion issue was unrelated to bonding. Nevertheless, as the Star reported later, the House Education Committee approved the rider, and the bill made its way to the House Appropriations Committee. UA President Schaefer vowed to scrap the expansion project if the bill went through with the anti-abortion rider, promising that he would not “sacrifice any academic program” for the sake of stadium seating. “It would set a dangerous precedent to let a group of legislators dictate academic programs,” he stated. He called the rider “simply another version of book-burning.”
By mid-May, however, the Star was reporting that the Arizona Board of Regents and UA administrators had agreed to accept the bill — rider and all — but planned to challenge the anti-abortion provision in court. The UA officials kept their promise, but the Arizona Supreme Court upheld the provision two years later.
In addition to the bad precedent it established, the stadium bill meant that the responsibility for providing abortions has fallen entirely on private clinics, since no other hospital in the city provides elective abortions. Clinics have carried the burden of care for Arizona’s second-largest city — and many surrounding communities.
Eliminating abortion training also contributes to a larger, national problem: a critical shortage of abortion providers. Today, 87 percent of U.S. counties lack an abortion provider. There are 37 percent fewer providers today than there were in 1982, and 57 percent of current abortion providers are over the age of 50 — threatening to make the shortage even worse without more abortion providers entering health care.
Today, most medical schools — 55 percent — do not offer students any clinical experience with abortion. Medical students at those schools have to pursue abortion training outside of their standard curriculum, often at off-campus facilities, when they already face considerable time restraints. The American Congress of Obstetricians and Gynecologists also points out a more abstract effect: the reinforcement of the stigma of abortion among those in medical training.
What medical schools undermine by omission is further threatened by the intimidation medical students can expect to face if they pursue careers as abortion providers. A recent survey of clinics by the Feminist Majority Foundation found that almost 70 percent of abortion providers say they experience frequent harassment by opponents of reproductive rights. Their safety — and that of their patients — is even more uncertain after last year’s by Supreme Court’s decision to overturn buffer zone laws that were used to keep anti-abortion protesters at a safe distance from reproductive health clinics.
For more than 40 years, the stadium bill has stood in direct conflict with patients and their providers — and their ability to make their own decisions about reproductive health care. It has also stood in direct conflict with public opinion. Although abortion has long been a contentious issue, in almost every year since Roe v. Wade, polling has shown majority support for its legality under at least some circumstances. Its eradication from medical training clashes with popular will.
Today, 53 percent of Americans want Roe v. Wade upheld. In addition, recent research suggests that simply sharing personal stories about abortion can sway more voters to support abortion rights — much like Sherri Finkbine’s story did in the 1960s.
Abortion was never meant to be a bargaining chip. It was sacrificed in 1974 to give more football fans a seat at the game. It’s time undo the damage and give more abortion supporters a seat in the legislature.
About Matt
Matt has a background in human services, health disparities research, and administrative support at an academic health sciences center. In addition to Planned Parenthood Advocates of Arizona, he volunteers with Read Between the Bars, a program that sends books to people in Arizona’s prisons. In his free time, he enjoys reading, studying Spanish, and playing Scrabble.
Thanks so much for this, Matt. I was asking about the U of A and abortion training and Anna sent me the link. And Jessica, it looks like students have to pursue abortion training on their own time at the local PP. And medical students never have any time – you have to be committed to the practice beforehand to pursue it. | 2024-07-14T01:26:35.434368 | https://example.com/article/6435 |
What’s This Little Plastic Device We Call a Miniscope?
Blog
EyeQue
October 5, 2016
Share
EyeQue is all about creating new exciting directions in vision technology for consumers and eye care professionals all around the world. We are proud to announce our first product, the EyeQue Personal Vision Tracker.
The Personal Vision Tracker (PVT) is based on the simplest possible concept and implementation we could think of. Could we build a precise, yet easy to use device, that works as well as expensive auto-refractors yet at a tiny fraction of the cost? With today’s high resolution smartphone screens using displays that contain 400 or more pixels per inch, it should be possible to make very precise measurements of the refractive error of the human eye, to fractions of a millimeter, corresponding to an accuracy of 0.25 Diopters or better.
The team of EyeQue engineers came up with the EyeQue miniscopeTM, a small plastic device that weighs less than an ounce and attaches to your smart phone screen simply using micro-suction tape. We built a powerful smart phone app, myEyeQueTM, that when used with the miniscope lets you measure the refraction correction needed for your eyes. That is we provide the numbers that are used for making custom eyeglasses. Just imagine the possibilities for helping people, especially on a global scale for those who don’t have good access to professional eye care!
The PVT is fun, accurate, and easy to use and allows people to monitor their vision, learn about how their eyes work, and opens interesting possibilities related to vision tracking.
Give it a try if you like by becoming a beta tester. We are eager to get feedback to make the Personal Vision Tracker even better, as we are working to continually improve the technical performance and usability of this small but powerful system.
EyeQue®, the EyeQue logo, EyeQue Cloud®, EyeQue Personal Vision Tracker®, and
EyeGlass Numbers® are registered trademarks, and EyeQue Insight™, EyeQue Kids™,
and EyeQue VisionCheck™ are trademarks of EyeQue Corporation. All rights reserved.
EyeQue's products and services do not include any form of eye health exam.
EyeQue provides users with a refractive tool which, when operated correctly,
measures the user's refractive correction. Results can be used to determine
if corrective eyewear would be beneficial. | 2024-04-14T01:26:35.434368 | https://example.com/article/2314 |
Ionic 2, AngularJS 2 and the future of hybrid apps - Mike Hartington
Mike Hartington
Ionic Developer Advocate
Today we're joined by Mike Hartington, Ionic Developer advocate. We're discussing what's new in Ionic 2, Angular 2.0 along. Also, how to build you apps to ensure a smooth upgrade and even whether or not you should wait for the 2.0 release for your next web app.
No Fluff Just Stuff Podcast
Magician, CTO Mago:Tech
Since 2001, the No Fluff Just Stuff Software Symposium Tour has delivered over 525 events with over 85,000 attendees. NFJS is known for its attendee centric approach, excellent speakers and technically rich presentations which cover the latest trends within the modern software development and architecture space. Bring your team to a local No Fluff Just Stuff Tour Stop and join us for a one-of-a-kind experience! | 2023-11-14T01:26:35.434368 | https://example.com/article/4624 |
/*
*
* @APPLE_LICENSE_HEADER_START@
*
* Copyright (c) 1999-2008 Apple Inc. All Rights Reserved.
*
* This file contains Original Code and/or Modifications of Original Code
* as defined in and that are subject to the Apple Public Source License
* Version 2.0 (the 'License'). You may not use this file except in
* compliance with the License. Please obtain a copy of the License at
* http://www.opensource.apple.com/apsl/ and read it before using this
* file.
*
* The Original Code and all software distributed under the License are
* distributed on an 'AS IS' basis, WITHOUT WARRANTY OF ANY KIND, EITHER
* EXPRESS OR IMPLIED, AND APPLE HEREBY DISCLAIMS ALL SUCH WARRANTIES,
* INCLUDING WITHOUT LIMITATION, ANY WARRANTIES OF MERCHANTABILITY,
* FITNESS FOR A PARTICULAR PURPOSE, QUIET ENJOYMENT OR NON-INFRINGEMENT.
* Please see the License for the specific language governing rights and
* limitations under the License.
*
* @APPLE_LICENSE_HEADER_END@
*
*/
#include "PickerFromFile.h"
#include <stdlib.h>
#include "GetWord.h"
#include "Trim.h"
#include "MyAssert.h"
#include <sys/stat.h>
#ifndef __Win32__
#include <dirent.h>
#endif
#ifdef __hpux__
#include <sys/types.h>
#endif
#define kMaxPickerPath 512
#include <stdio.h>
static bool CompareNameToElement( PLDoubleLinkedListNode<LoopDetectionListElement>* node, void* name );
static void DisplayPickerErr( int pickErr, const char *message, const char*fname, int lineCount, const char*lineBuff );
static bool CompareNameToElement( PLDoubleLinkedListNode<LoopDetectionListElement>* node, void* name )
{
if ( !::strcmp( node->fElement->mPathName, (const char*)name ) )
return true;
return false;
}
static bool IsDir(char* path);
static bool IsDir(char* path)
{
struct stat data;
int err = stat(path, &data);
if (err == -1)
return false;
return ((data.st_mode & S_IFDIR) == S_IFDIR );
}
static void DisplayPickerErr( int pickErr, const char *message, const char*fname, int lineCount, const char*lineBuff )
{
char *errMessage;
qtss_printf( "- %s:\n", message );
if ( lineCount )
qtss_printf( " Playlist: %s, line# %i\n", fname, lineCount );
else
qtss_printf( " Playlist: %s\n", fname );
if ( lineBuff )
qtss_printf( " Playlist text: %s", lineBuff ); // lineBuff already includes a \n
switch ( pickErr )
{
case kPickerPopulateLoopDetected:
errMessage = "Include would create a loop.\n";
break;
case kPickerPopulateBadFormat:
errMessage = "Playlist file is missing *PLAY-LIST* identifier.\n";
break;
case kPickerPopulateFileError:
errMessage = "Playlist file could not be opened.\n";
break;
case kPickerPopulateNoMem:
default:
errMessage = "Internal error occurred.\n";
break;
}
qtss_printf( " Reason: %s\n", errMessage);
}
bool PathIsAbsolute(char *pathPtr)
{
bool result = false;
#ifdef __Win32__
if ( (pathPtr[1] == ':') && ( pathPtr[2] == kPathDelimiterChar ) )
result = true;
#else
if ( *pathPtr == kPathDelimiterChar )
result = true;
#endif
return result;
}
int PopulatePickerFromFile( PlaylistPicker* picker, char* fname, const char* basePath, LoopDetectionList *ldList )
{
Assert( picker );
Assert( fname );
FILE* weightings = NULL;
LoopDetectionListElement* ldElement = NULL;
LoopDetectionNode* ldNode = NULL;
int lineCount = 0;
int pickErr = kPickerPopulateNoErr;
char path[kMaxPickerPath];
#if kPartialPathBeginsWithDelimiter
if (PathIsAbsolute(fname))
{
if ( *basePath )
fname++;
#else
if ( !PathIsAbsolute(fname) )
{
#endif
// it's a partial path, expand it to include all
// previously traversed paths
::strncpy( path, basePath, kMaxPickerPath-1 );
::strncat( path, fname, kMaxPickerPath-1 );
}
else
{
// it's an absolute reference. use the path
// part of this for the new basePath
::strncpy( path, fname, kMaxPickerPath-1 );
}
// path is now either an absolute or working directory
// referenced partial path to the playlist file.
int len = strlen(path);
char lastChar = path[len-1];
if (lastChar == '\n' || lastChar == '\r' || lastChar == ' ')
path[len-1] = '\0';
// ldList is passed as NULL by the initial caller. recursive calls
// pass along the ldList we create hre
if ( ldList == NULL )
ldList = new LoopDetectionList;
Assert( ldList );
if ( !ldList )
pickErr = kPickerPopulateNoMem;
if ( !pickErr )
{
if ( ldList->ForEachUntil( CompareNameToElement, path ) )
{
// we're already in the include chain, this is a loop
// print a warning (error?) and continue past the loop.
//qtss_printf("- Playlists include loop at file: %s\n", path );
pickErr = kPickerPopulateLoopDetected;
}
}
if ( !pickErr )
{
ldElement = new LoopDetectionListElement( path );
Assert( ldElement );
if ( ldElement )
{ ldNode = new LoopDetectionNode( ldElement );
Assert( ldNode );
if ( !ldNode )
pickErr = kPickerPopulateNoMem;
}
else
pickErr = kPickerPopulateNoMem;
}
if (::IsDir(path))
return ::PopulatePickerFromDir(picker, path);
if ( !pickErr )
{
weightings = ::fopen( path, "r" );
if (!weightings)
{
qtss_printf("- Playlist picker failed opening list file %s\n", path);
pickErr = kPickerPopulateFileError;
}
}
if ( !pickErr )
{
SInt32 lineBuffSize = (kMaxPickerPath *2) - 1;
SInt32 wordBuffSize = kMaxPickerPath - 1;
char lineBuff[kMaxPickerPath * 2];
char wordBuff[kMaxPickerPath];
char* next;
char* pathEnd;
char* thisLine;
// add ourselves to the list
ldList->AddNode( ldNode );
// trim off the file name to get just the path part
pathEnd = ::strrchr( path, kPathDelimiterChar );
if ( pathEnd )
{
pathEnd++;
*pathEnd = 0;
}
else
*path = 0;
thisLine = lineBuff;
if ( ::fgets( lineBuff, lineBuffSize, weightings ) != NULL )
{
lineCount++;
thisLine = ::TrimLeft( lineBuff );
if ( 0 != ::strncmp(thisLine,"*PLAY-LIST*",11) )
{
//qtss_printf("- Playlist file missing *PLAY-LIST* identifier as first line:\n");
//qtss_printf(" %s%s\n", basePath, fname);
pickErr = kPickerPopulateBadFormat;
}
}
if ( !pickErr )
{
do
{
next = lineBuff;
if ( ::fgets( lineBuff, lineBuffSize, weightings ) == NULL )
break;
// qtss_printf("line = %s\n", lineBuff);
lineCount++;
next = ::TrimLeft( lineBuff );
if ( *next == '#' )
{
// it's a comment - just toss
//if ( *next )
// qtss_printf( "comment: %s" , &lineBuff[1] );
}
else if (*next == '+') // a list
{
next = ::TrimLeft( next+1 ); // skip past + include
if ( *next == '"' ) // get the name from the next part of the buff
next = ::GetQuotedWord( wordBuff, next, wordBuffSize );
else
next = ::GetWord( wordBuff, next, wordBuffSize );
// recusively populate from the include file.
pickErr = PopulatePickerFromFile( picker, wordBuff, path, ldList );
if ( pickErr )
{
DisplayPickerErr( pickErr, "Playlist Include failed", fname, lineCount, lineBuff );
pickErr = kPickerPopulateNoErr;
}
}
else if ( *next )
{
char numBuff[32];
char expandedFileName[kMaxPickerPath];
int weight = 10; // default weight is 10
// get the movie file name
if ( *next == '"' )
next = ::GetQuotedWord( wordBuff, next, wordBuffSize );
else
next = ::GetWord( wordBuff, next, wordBuffSize );
if (*wordBuff)
{
#if kPartialPathBeginsWithDelimiter
if ( PathIsAbsolute(wordBuff) )
{
char *wordStart = wordBuff;
if ( *path )
wordStart++;
// full or partial path to the movie
::strcpy( expandedFileName, path );
::strcat( expandedFileName, wordStart );
}
#else
if ( !PathIsAbsolute(wordBuff) )
{
// it's a partial path..
// cat the path and fname to form the
// full or partial path to the movie
::strcpy( expandedFileName, path );
::strcat( expandedFileName, wordBuff );
}
#endif
else
{ // it's an absolute path..
::strcpy( expandedFileName, wordBuff );
}
// then get the weighting ( if supplied )
next = ::GetWord( numBuff, next, 32 );
if ( *numBuff )
weight = ::atoi(numBuff);
// qtss_printf("expanded file name = %s\n", expandedFileName);
if (::IsDir(expandedFileName))
pickErr = ::PopulatePickerFromDir(picker, expandedFileName, weight);
else if ( !picker->AddToList( expandedFileName, weight ) )
pickErr = kPickerPopulateNoMem;
}
}
} while ( feof( weightings ) == 0 && pickErr == kPickerPopulateNoErr );
}
// remove ourselves from the list
ldList->RemoveNode( ldNode );
}
// only report unreported errors.
if ( ldList && ldList->GetNumNodes() == 0 && pickErr )
::DisplayPickerErr( pickErr, "Playlist error", fname, lineCount, NULL );
if ( ldNode )
delete ldNode; // node deletes element
else if ( ldElement )
delete ldElement;
if ( weightings )
(void)::fclose( weightings );
if ( ldList && ldList->GetNumNodes() == 0 )
{
// all done now!
delete ldList;
ldList = NULL;
}
return pickErr;
}
int PopulatePickerFromDir( PlaylistPicker* picker, char* dirPath, int weight )
{
static char expandedFileName[kMaxPickerPath]; // static so we don't build up the stack frame on recursion
int pickErr = 0;
if (dirPath != NULL)
strcpy(expandedFileName, dirPath);
#ifdef __Win32__
WIN32_FIND_DATA findData;
HANDLE findResultHandle;
Bool16 keepSearching = true;
int len = strlen(expandedFileName);
if (expandedFileName[len - 1] != kPathDelimiterChar)
{
expandedFileName[len] = kPathDelimiterChar;
expandedFileName[len+1] = 0;
len++;
}
strcat(expandedFileName, "*");
findResultHandle = ::FindFirstFile( expandedFileName, &findData);
if ( NULL == findResultHandle || INVALID_HANDLE_VALUE == findResultHandle )
{
//qtss_printf( "FindFirstFile( \"%s\" ): gle = %"_U32BITARG_"\n", searchPath, GetLastError() );
return 0;
}
while ( (pickErr == 0) && keepSearching )
{
expandedFileName[len] = 0; // retruncate name
if (findData.cFileName[0] != '.') // ignore anything beginning with a "."
{
strcat(expandedFileName, findData.cFileName);
if (findData.dwFileAttributes & FILE_ATTRIBUTE_DIRECTORY )
pickErr = PopulatePickerFromDir(picker, NULL, weight);
else if ( !picker->AddToList( expandedFileName, weight ) )
pickErr = kPickerPopulateNoMem;
}
keepSearching = FindNextFile( findResultHandle, &findData );
}
#else
DIR* dir;
struct dirent* entry;
int len = strlen(expandedFileName);
if (expandedFileName[len - 1] != kPathDelimiterChar)
{
expandedFileName[len] = kPathDelimiterChar;
expandedFileName[len+1] = 0;
len++;
}
dir = opendir(expandedFileName);
if (dir == NULL)
return kPickerPopulateFileError;
do {
entry = readdir(dir);
if (entry == NULL) break;
if (entry->d_name[0] == '.') // ignore anything beginning with a "."
continue;
if (len + strlen(entry->d_name) < kMaxPickerPath)
{
strcat(expandedFileName, entry->d_name);
#if __solaris__ || __sgi__ || __osf__ || __hpux__
if (::IsDir(expandedFileName))
#else
if ((entry->d_type & DT_DIR) != 0)
#endif
pickErr = PopulatePickerFromDir(picker, NULL, weight);
else if ( !picker->AddToList( expandedFileName, weight ) )
pickErr = kPickerPopulateNoMem;
}
expandedFileName[len] = 0; // retruncate name
} while (pickErr == 0);
//close the directory back up
(void)::closedir(dir);
#endif
return pickErr;
}
| 2023-12-09T01:26:35.434368 | https://example.com/article/9960 |
# ---
# jupyter:
# jupytext:
# text_representation:
# extension: .py
# format_name: light
# format_version: '1.5'
# jupytext_version: 1.5.2
# kernelspec:
# display_name: venv-siuba
# language: python
# name: venv-siuba
# ---
# +
import pandas as pd
import os
from airtable import Airtable
from siuba.spec import series
from siuba import _, select, inner_join, unnest, mutate, left_join, filter, pipe
def strip_dict_nans(d):
return {k: v for k, v in d.items() if not pd.isna(v)}
def get_backend_records(method_name, backends):
return [
{
"method_name": method_name,
"name": k,
**v,
}
for k, v in backends.items()
]
def record_needs_update(src, dst):
dst = dst.copy()
if 'is_property' in src:
dst.setdefault('is_property', False)
if set(src) - set(dst):
return True
return [dst[k] for k in src] != list(src.values())
# -
air_methods = Airtable("app11UN7CECnqwlGY", "tblWsICYtRPlLYJak", os.environ["AIRTABLE_API_KEY"])
air_backends = Airtable("app11UN7CECnqwlGY", "tblbmJgafdxiJLZz4", os.environ["AIRTABLE_API_KEY"])
# +
raw_methods = air_methods.get_all()
tbl_methods = (
pd.DataFrame(raw_methods)
>> mutate(fields = _.fields.apply(pd.DataFrame, index = [0]))
>> unnest("fields")
)
# +
raw_spec = pd.json_normalize([{"method": k, **v} for k,v in series.spec.items()])
spec_methods = (raw_spec
.siu_select(-_.startswith('backend'), -_.expr_frame, -_.expr_series)
.rename(columns = lambda s: s.replace('.', '_'))
)
joined_methods = (
spec_methods
>> left_join(_, select(tbl_methods, _.id, _.method), ['method'])
)
methods = joined_methods >> pipe(_.to_dict(orient = "records"))
# +
raw_map = {x['fields']['method']: x['fields'] for x in raw_methods}
inserts = []
updated = []
for entry in methods:
fields = strip_dict_nans({k:v for k,v in entry.items() if k != "id"})
dst_fields = raw_map.get(entry['method'], {})
if record_needs_update(fields, dst_fields):
updated.append(fields)
air_methods.update_by_field("method", entry["method"], fields = fields)
if pd.isna(entry["id"]):
inserts.append(fields)
if inserts:
air_methods.batch_insert(inserts)
print("Updated methods: ", ", ".join([d['method'] for d in updated]))
print("Inserted methods: ", ", ".join([d['method'] for d in inserts]))
#air_methods.batch_update(list(map(strip_dict_nans, method_inserts)))
#air_backends.batch_insert(backend_inserts)
# -
# ## Link method records to backends
raw_backend = {x['fields']['backend_method']: x['fields'] for x in air_backends.get_all()}
spec_backend_entries = sum(
[get_backend_records(k, entry.get('backends', [])) for k, entry in series.spec.items()],
[]
)
for fields in spec_backend_entries:
indx = fields["name"] + "-" + fields["method_name"]
dst_fields = raw_backend.get(indx, {})
if not dst_fields:
air_backends.insert(fields)
if record_needs_update(fields, dst_fields):
air_backends.update_by_field("backend_method", indx, fields)
all_method_entries = {entry['fields']['method']: entry['id'] for entry in air_methods.get_all()}
for entry in air_backends.get_all():
meth_name = entry['fields']['method_name']
meth_id = [all_method_entries[meth_name]]
air_backends.update(entry['id'], {'method': meth_id})
| 2023-10-31T01:26:35.434368 | https://example.com/article/2928 |
Q:
Amazon Alexa Intent Skill Console
Hey Is it just me or is Amazon having problems on their server?
I'm on the page where we set up our json intents and sample utterances
But when I try to save it. It's just loading and loading. I tested this out on another laptop and it's just loading as well
Am I the only one with this problem? Can someone try saving their intents on the developer console and get back to me?
You can see that the interaction Model just constantly loading
A:
This happens occasionally. Usually it sorts itself out after a few hours. Sometimes longer on a weekend. You can post a notice in their forums and they'll say "gosh I'm sorry" and usually get back to you when it's working again.
| 2024-01-10T01:26:35.434368 | https://example.com/article/1899 |
This application relates to lawn care equipment, and in particular, to a string trimmer attachment for a riding lawn mower, particularly to a zero turn mower.
String trimmers are commonly used to trim lawns where mowers cannot reach, for example, around trees and gardens, under shrubs, adjacent walls, etc. String trimmers, especially gas powered string trimmers, can be heavy. To facilitate moving the string trimmers, the trimmers have been provided with wheels. However, string trimmers can generate extensive vibrations which can make handling even wheeled trimmers more difficult. Additionally, the vibrations, which travel up the handle of the trimmer, can cause injuries—such as carpal tunnel syndrome and repetitive stress injuries to the user.
It would be desirable to have a string trimmer which is easy to control and which will reduce or even eliminate repetitive stress injuries to the user. | 2024-02-10T01:26:35.434368 | https://example.com/article/1967 |
INDIVIDUALS UNITED FOR FREEDOM-A branch of the RVC TEA PARTY Pages
Our mission is to raise awareness and educate the electorate of our Individual Rights and the Government trampling thereof. Ideas, such as those enumerated in the Constitution, are the ultimate cause for historical change. Empty slogans and political rhetoric are not the requirement of these times. This Age requires an understanding of why citizens are entitled to Life, Liberty, Private Property and the Pursuit of Happiness. Our purpose is to speak about and take ACTIONS to protect these precious Individual Rights. These are the ideas which have allowed our country to become great & exceptional, and have protected Americans for centuries and helped them prosper. People should join if they care about the type of country they will be living in and the reach of its government. People should join if they care about their Right to Free Speech, Freedom to Assemble, the rest of the Bill of Rights, the Constitution and by the natural extension of free markets.
The Rockville Centre Tea Party Patriots was founded on April 15th, 2009. On that day over 600 disgruntled residents joined together for Nassau County’s first official Tea Parties in Hicksville and Massapequa, NY. We are non-partisan and do not support any political party. We will support candidates from any party that shares our views. We welcome all new members regardless of the town you reside.
With few exceptions we hold our meetings the first Tuesday of the month at The American Legion Hall, 197 Maple Avenue Rockville Centre. Meetings run from 7:00 PM to 9:00 PM. We encourage you to attend and to bring a friend. All of our meetings are open to the public.
Mission Statement and Core Values The impetus for the Tea Party movement is excessive government spending and taxation. Our mission is to attract, educate, organize, and mobilize our fellow citizens to secure public policy consistent with our three core values of Fiscal Responsibility, Constitutionally Limited Government and Free Markets.
Our Philosophy: The Rockville Centre Tea Party Patriots as an organization believes in the Fiscal Responsibility, Constitutionally Limited Government, and Free Markets. We are a non-partisan grassroots organization of individuals united by our core values derived from the Declaration of Independence, the Constitution of the United States of America and the Bill Of Rights as explained in the Federalist Papers. We recognize and support the strength of grassroots organization powered by activism and civic responsibility at a local level. We hold that the United States is a republic conceived by its architects as a nation whose people were granted “unalienable rights” by our Creator. Chiefly among these are the rights to “life, liberty and the pursuit of happiness.” The Rockville Centre Tea Party Patriots stand with our founders, as heirs to the republic, to claim our rights and duties which preserve their legacy and our own. We hold, as did the founders, that there exists an inherent benefit to our country when private property and prosperity are secured by natural law and the rights of the individual | 2023-12-13T01:26:35.434368 | https://example.com/article/4884 |
HD Schrader
HD Schrader (born 1945), born Hans-Dieter Schrader, is a German sculptor. He is known in particular for his series of works titled Cubecracks, which may be attributed to Concrete Art.
Life
Schrader was born in 1945 in Bad Klosterlausnitz in Thuringia, in former East Germany. He studied (among other things) constructive design (under Max Herrmann Mahlmann) at the former Werkkunstschule Hamburg (School of Applied Arts) from 1965 to 1969. Schrader had his first solo exhibition in 1969 in the Galerie des Städtebauministeriums (gallery of the ministry for urban construction) in Bonn, showing his first series of works Quadratreihungen (Sequences of squares) consisting of drawings and relief pictures made of perspex. The following year he went on to produce his Kubusreihungen (Sequences of cubes) encompassing objects, acrylic paintings, drawings and silkscreen prints. In 1972, Schrader co-founded the artists’ group International Work Group for Constructive Art (AIFKG) in Antwerp, whose members included the artists Ewerdt Hilgemann, Richard Paul Lohse, Marcello Morandini and François Morellet. Up until 1986 he participated in six symposia held by the IAFKG work group in various European countries. Schrader sparked considerably more interest in 1973 with his work Kugel im Kubus (Sphere in Cube), which he was commissioned to create by the City of Hamburg after winning an open competition for Hamburg artists; the work was installed on the forecourt of the Hamburger Kunstverein. In 1974, Schrader took part in the 10th Biennale Internationale d’Art Menton in France.
Since 1986 Schrader has held a position as a professor for typography at the Dortmund University of Applied Sciences and Arts, in the department of design. He was awarded several prizes, such as, in 1990, the award Kultur aktuell in Schleswig-Holstein (Contemporary culture in Schleswig-Holstein) for the work of the citizens’ action group that campaigned to preserve the sculpture Kubus-Balance (Cube-Balance); or, in 1991, the regional art award Landesschaupreis Schleswig-Holstein. He was commissioned by the state government in Kiel to show his installation Kubuskoog (Cube polder) in the German pavilion at the EXPO 2000 in Hanover. In 2005, Schrader was invited to participate in a Chinese-German symposium on painting, held in Wuyishan in China. The following year he was appointed a member of the international jury for the Olympic Landscape Sculpture Contest in Beijing, China.
Schrader lives and works in Hamburg and Osterhever (in northern Germany).
Solo exhibitions
(Entries labelled “c” indicate exhibitions with an accompanying catalogue.)
1969 Galerie im Städtebauministerium, Bad Godesberg (D)
1974 Galerij Vecu, Antwerp (BE) [with Pierre de Poortere]
1975 Galerie Szepan, Gelsenkirchen (D) [with Pierre de Poortere]; Galerie Beckmann, Hamburg (D); Galleria Beniamino, San Remo (I) [with Pierre de Poortere]
1976 Galleria Dei Mille, Bergamo (I) [with Pierre de Poortere]
1979 Galleria de la Plaza, Varese (I) [with Pierre de Poortere]
1983 Standpunkte. Hamburger Kunsthalle (D)c
1992 Museum am Ostwall, Dortmund (D); Wilhelm-Hack-Museum, Ludwigshafen (D)c
1994 Museum Modern Art, Hünfeld (D)c
1995/1996 Cubecracks. Städtische Galerie des Emschertalmuseums, Herne (D), Flottmann-Hallen, Herne and the large steel sculptures Cubecracks in various public places in Herne / Museum für Konkrete Kunst, Ingolstadt (D) / Museum für Kunst und Kulturgeschichte (Katharinenkirche) der Hansestadt Lübeck (D) and in the Burgkloster, Lübeckc
1998/1999/2000 Kunstraum Kubus. Richard-Haizmann-Museum, Niebüll (D) / Stadtgalerie Brunsbüttel (D) / Stadtgalerie Kiel (D) / Städtisches Museum, Gelsenkirchen (D) / Museen im Kulturzentrum, Rendsburg (D)c
2000 Cubes and Trees. Schloss Agathenburg (D); German pavilion, EXPO 2000, Hanover (D) (courtyard)
2002 Kunstverein Schloss Plön (D)
2003 Mönchehaus Museum Goslar (D)c
2006 Contemporanea, Oberbillig/Trier (D)c (comprehensive retrospective)
2010 HD Schrader - Woodwatchers and others. Ludwig Museum, Coblence (D), in collaboration with the Today Art Museum, Beijing (CN)c,
2014 Cubes and Cracks. Kunstmuseum Bayreuth (D). Exhibition in the Neues Rathaus Bayreuth.
Work
With their unusual angular or pointed forms Schader’s Cubecracks are initially perceived as alien bodies – whether encountered in urban surroundings or in the countryside. Their impact is reinforced by his use of signal red. As Bernhard Holeczek wrote, “how the things are made is clear to see, but not the idea they are derived from”. While a Cubecrack can be read as an autonomous sculptural sign, it at the same time also addresses the viewer as if an emissary from a foreign world, as a sign whose meaning can only be elucidated with closer knowledge of Schrader’s work. Indeed, Schrader’s Cubecracks suggest a rational system, that of a cube or a cuboid. Since 1974, Schrader has been working in drawings, paintings, objects, installations, animated film and sculptures to explore the idea of “the cube as a space of art”. Whereas certain sculptures such as those executed in plaster grow in the course of being shaped by the artist’s hand, or others such as those made of marble diminish by being hewn with hammer and chisel until they achieve their final form, Schrader’s Cubecracks arise in an entirely different manner. He dissects a cuboid form – in this case a hollow steel body in the shape of a cube – into individual sections. The cuboid Schrader used for his first Cubecracks that were exhibited in 1995/96 in the towns of Herne, Ingolstadt and Lübeck, should be imagined as three 2.5 metre cubes, one stacked upon another. Schrader cut these cuboid forms into twelve sections: in each town he distributed six of the twelve sections, bright red, in various public places, while the other six were displayed in the museum of each town. Viewers encountered them as different entities, each with its own dynamism and immediate symbolic presence. But one soon sensed that these objects were necessarily separate parts of a whole which, while no longer physically extant, was nonetheless implicitly present in each of its individual components. As Schrader commented, “It is of course what has been omitted that determines each single piece.”
Adopting an approach rooted in constructive concrete art, when Schrader begins to conceive a work of art he subjects himself to a prescribed system of rules. In the case of his Cubecracks this would be equivalent to specifying that each individual element should derive from a systematic process of dissecting the surface of a cuboid. The Cubecracks series vividly illustrates that while the ensuing formal language can be explained rationally it cannot be developed from simple deduction. Indeed, the individual Cubecracks are certainly not products of accident: on the contrary, the artist consciously selects his cuts so as to create what strikes him as the most interesting forms. They are the product of subjective decisions or his artistic instinct. Thus the steel bodies are not simply fragmentary forms as parts of a whole; rather, each one develops its own aesthetic impact and signification.
It is scarcely possible to define Schrader’s art in terms of a single element or an individual work. Nonetheless, for the series of works titled Viereck und Viereck (quadrilateral and quadrilateral), for example, the point of departure was a series of drawings depicting variations on two falling cubes, represented by two quadrilaterals. “The dynamism is therefore not the expression of the form but a process of transformation.” (Andrzej Turowski) It should be mentioned that variations of this series were already installed in several locations (Hünfeld, Hofbieber and Hilders, in East Hesse) as early as 1986 as part of the exhibition Kunststrasse Rhön (Rhön regional art trail).
In 1999, Schrader began producing the series of works titled Elastic Cubes. Each one is assembled from eight square-section steel tubes, just enough to allow viewers to picture the framework of a cube. At each of the eight corners of the cube two square-section steel elements are held together by means of an axle or shaft – like joints on a skeleton. Since four of the twelve edges that would be required to fully construct a cube are missing, this framework of edges can be twisted or contorted. Accordingly, each Elastic Cube assumes its own individual physiognomy, if not also a personal style of movement. “As ‘figures’ they cause us almost to forget their constructional method, or at least relegate it to the background.” (Knut Nievers) Describing the effect of Elastic Cubes, Klaus Reeh wrote: “Atmosphere is ultimately Schrader’s style and, not unlike an architect, he creates sculptures that exude a powerful and lasting presence in the space surrounding them. With his Elastic Cubes he succeeded in forging a particularly aesthetic atmosphere by using means that could hardly be more minimal and as part of a process that surprises us with its simplicity.”
In 2000, Schrader presented a group of works titled Cubes and Trees in the park of Schloss Agathenburg. Here, the cubes and cuboids were simply conceived as bare skeleton models made of wood or aluminium. The objects can be seen through and reduce the objects’ materiality. At the same time, the bright red frames transform the previously unremarkable sites in nature where they are installed into arenas for challenging and even poetic encounters between organic forms and geometrically abstracted purity and clarity. The objects were fotographed in spring, summer, autumn and winter.
Works in public space
1973 Kugel im Kubus (Sphere in Cube), steel, forecourt of the Hamburger Kunstverein, Kunsthaus, Hamburg (until 1990); since 1994, installed in front of the Archäologisches Museum Hamburg in Hamburg-Harburg
1977 Cube in cube, stainless steel, Hamburg
1978-80 Gestaltung eines Schulwegs (design for a school path), white, red and black paving stones, a skeleton of cubes made of black-and-red varnished steel, at the school Kurt-Tucholsky-Gymnasium, Hamburg
1981 Steinspirale (Stone Spiral), granite, at the school Gymnasium Osdorf, Hamburg
1985 Viereck und Viereck (quadrilateral and quadrilateral), municipal park Hünfeld.
1986 Viereck und Viereck, Kunststation Kleinsassen; Viereck und Viereck, steel, sculpture park outside the Landesmuseum in Schloss Gottorf, Schleswig
1987 Viereck und Viereck, sculpture park Nortorf
1994 Viereck und Viereck, steel, Ingolstadt
1996 Kubuskoog (Cube Polder), wood, historic harbour in the area of the Vorderdeich, Brunsbüttel; Cubecrack No. 1–6, steel, Herne; Cubecrack No. 4 + 5, steel, Lübeck
2000 Elastic Cube, art museum Gelsenkirchen
2003 Kubushochzeit (Cube Wedding), steel, University of Applied Sciences Hof; Strömungen (Flows), stainless steel, Schifffahrtsamt (shipping office), Rostock; Cubecrack 2, steel, bestowal by the Schenning-Stiftung, Bergbaumuseum Rammelsberg, Goslar (“Goslar Sculpture of the year” 2003)
2005 Kubushochzeit, steel, Stormarn district administration, Bad Oldesloe
2006 Cubecrack Nr. 8, steel, Contemporanea, Oberbillig/Trier
2007 Kubushochzeit, steel, Völklingen
Publications
HD Schrader - Woodwatchers And Others. Catalogue for the exhibition in the Ludwig Museum Coblence, 12 December till 6 February 2011
HD Schrader: Cubecracks. Catalogue for the exhibition in the Lichtwark Forum in DG Hyp, Hamburg. Published by the Deutsche Genossenschaft-Hypothekenbank AG, 2003 (with essays by Lothar Romain and Doris von Drathen)
HD Schrader - Kunstraum Kubus. Catalogue for the exhibition in the Richard-Haizmann-Museum, Niebüll, 1998; in the Stadtgalerie Brunsbüttel, 1999; in the Stadtgalerie Kiel, 1999; in the Städtisches Museum, Gelsenkirchen, 1999; and in the Museen im Kulturzentrum, Rendsburg, 2000. Published by Richard-Haizmann-Museum, Niebüll, 1998
HD Schrader - Cubecracks. Catalogue for the exhibition in the Städtischen Galerie des Emschertalmuseums, Herne, 1995; in the Museum für Konkrete Kunst, Ingolstadt, 1996; and in the Museum für Kunst und Kulturgeschichte der Hansestadt Lübeck, 1996. Published by Emschertalmuseum, Herne, 1995
References
External links
10 Fragen an HD Schrader beim Deutsch-Chinesischen Kulturnetz - Goethe-Institut, China, 2011 [in German]
Category:1945 births
Category:German sculptors
Category:German male sculptors
Category:Abstract artists
Category:Living people
Category:German contemporary artists | 2024-01-08T01:26:35.434368 | https://example.com/article/7007 |
Introduction {#Sec1}
============
Acute kidney injury (AKI) is a critical complication that can follow cardiac surgery. Previous studies reported that the incidence of cardiac surgery-associated AKI varies widely from 7 to 40%, depending on the definition \[[@CR1]\]. Moreover, the high mortality of such patients has been recognized \[[@CR2]--[@CR4]\]. Cardiopulmonary bypass (CPB)-related injury to the kidneys involves numerous factors, such as hypoxia, vascular endothelial injury, inflammatory reactions, activation of reactive oxygen species (ROS) and the renin--angiotensin--aldosterone system (RAAS). It has also been reported that the incidence of AKI after CPB surgery correlates with a high activity of renin \[[@CR5]\]. Atrial natriuretic peptide (ANP), a hormone secreted primarily by atrial cardiomyocytes, is a potent natriuretic, diuretic and vasodilatory peptide that contributes to decreasing blood pressure \[[@CR6]\]. Previous studies have found that human ANP (hANP) preserves renal function in patients undergoing coronary artery bypass surgery \[[@CR7], [@CR8]\] and abdominal aortic aneurysm repair \[[@CR9]\]. One study showed that continuous infusion of hANP during cardiac surgery with CPB maintained postoperative renal function by preventing the activity of the RAAS \[[@CR7]\]. Recently, expressions of local RAAS in specific tissues have been recognized, and, in the kidney, intrarenal angiotensin II (Ang II) has been found to be formed by independent mechanisms \[[@CR10]\]. In addition, use of urinary angiotensinogen as an index of the activity of the intrarenal RAAS has been assessed \[[@CR11]\], and a previous study reported that elevated urinary angiotensinogen was associated with the development of AKI after cardiac surgery \[[@CR12]\].
Based on AKI diagnostic criteria, AKI is defined as an increase in serum creatinine (Cr) of ≥0.3 mg/dl or a relative increase of ≥1.5-fold from baseline \[[@CR13], [@CR14]\]. Further, even small serum Cr changes were reported to be significantly associated with mortality in a cohort study of cardiac surgery \[[@CR15]\]. However, because there is a time lag in the increase of serum Cr following the occurrence of AKI, serum Cr is not an efficient early biomarker for the detection of AKI \[[@CR16]\]. Therefore, in the present study, we examined two early urinary biomarkers as indices of AKI: neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid-binding protein (L-FABP). Both NGAL and L-FABP have been recognized as being effective in the detection of kidney injury, although the mechanisms of increasing urinary excretion of these two markers are quite different \[[@CR17]--[@CR20]\].
Previous research reported that the activity of the intrarenal RAAS directly affects the progression of renal disease \[[@CR10]\]. In addition, we previously showed in an animal experiment that ANP can prevent the activity of the intrarenal RAAS \[[@CR21]\]. Therefore, we hypothesized that ANP exerted renoprotective effects by inhibiting the activity of the intrarenal RAAS, not but the systemic RAAS. The primary endpoint of this study was to investigate whether hANP can prevent the occurrence of AKI during cardiac surgery, and the mechanisms of the renoprotective effects of hANP, with emphasis on the intrarenal RAAS, using NGAL and L-FABP as the biomarkers of AKI.
Materials and methods {#Sec2}
=====================
The protocol of this study was approved by the Ethics Committee of Kagoshima University Hospital and registered with the UMIN Clinical Trials Registry (UMIN 000012312) on November 18, 2013. This clinical trial was registered before patient enrollment, and was conducted in accordance with the principles of the Declaration of Helsinki. Prior written informed consent was obtained from each patient.
Study design and subjects {#Sec3}
-------------------------
Forty-eight patients undergoing cardiac surgery with CPB except aortic grafting surgery were enrolled. Exclusion criteria were emergency operation, over 80 years of age, obese patients (BMI \> 30 kg/m^2^), low left ventricular function (ejection fraction \<40%) and preoperative renal dysfunction (serum Cr level \>1.3 mg/dl). After exclusion, all patients were randomly divided into two groups using a computer-based stratified randomization method according to patient's age, sex and body mass index; one group received an infusion of hANP (carperitide; Daiichi-Sankyo Pharmaceutical Inc., Tokyo, Japan) and the other group was given an infusion of a nutrient-free saline solution in the same manner. We determined the sample size by analyzing the incidence of AKI in our institute based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria.
Anesthesia and study protocol {#Sec4}
-----------------------------
Patients were prepared according to standard preoperative procedures after overnight fasting. Morphine hydrochloride (0.2 mg/kg, intramuscularly) was given 30 min before the induction of anesthesia. An intravenous catheter was inserted into a forearm vein, and a cannula was inserted into the radial artery under local anesthesia. Anesthesia then was induced by injecting 0.08 mg/kg midazolam, 5 μg/kg fentanyl and 0.6 mg/kg rocuronium bromide intravenously. Propofol infusion was adjusted to the rate of 4--10 mg/kg/h to maintain bispectral index (BIS; Aspect Medical Systems, Norwood, MA, USA) values within the range of 40--60. The remifentanil infusion was adjusted to the range of 0.1--0.5 μg/kg/min depending on surgical invasiveness. After induction of anesthesia, the lungs were ventilated to normocapnia and red blood cells were transfused to maintain a hematocrit of 25% or more. Infusion of hANP at the rate of 0.025 μg/kg/min or an equivalent volume of a nutrient-free saline solution as placebo was performed via a central venous catheter inserted into the internal jugular vein, from the start of surgery till 12 h postoperatively. CPB was performed with non-pulsatile low-temperature perfusion (target rectal temperature: 34 °C). After surgery, all patients were transferred to the intensive care unit (ICU) and remained sedated for 3 h after surgery. Sedation was then discontinued and the trachea was extubated after confirming hemodynamic stability.
Measurements {#Sec5}
------------
Plasma renin activity, Ang II and aldosterone were measured at five points \[before surgery (base line), before and after CPB, at end of surgery, and 3 h after surgery\]. At the same time points, urinary angiotensinogen was measured using specific ELISA kits (IBL, Gunma, Japan). Urinary NGAL and L-FABP levels were also determined using specific ELISA kits (Bioporto Diagnostics, Hellerup, Denmark, and CMIC Co. Ltd, Tokyo, Japan, respectively). Urinary angiotensinogen, NGAL and L-FABP were adjusted for urinary creatinine concentrations. Moreover, serum Cr was measured preoperatively and on postoperative days 1, 2 and 3.
Statistical analysis {#Sec6}
--------------------
Data are expressed as mean ± standard deviation (SD). Patient background and outcome variables between the two groups were compared using *χ* ^2^ tests or unpaired Student's *t* tests. Other data were analyzed with repeated measures ANOVA using GraphPad Prism software (version 5). We considered *p* \< 0.05 to be statistically significant.
Results {#Sec7}
=======
Patient's background {#Sec8}
--------------------
Patient characteristics in the two groups are shown in Table [1](#Tab1){ref-type="table"}. There were no significant differences between the two groups. Since hypotension and hypovolemia often occur during cardiac surgery for many reasons, determination of whether hypotension, hypovolemia and electrolyte abnormalities are directly caused by hANP might be difficult. Therefore, we additionally analyzed the data on intraoperative urine output, red blood cell transfusion and fluid balance. We observed that there was no difference in the incidence of complications related to hANP, such as hypotension, hypovolemia and electrolyte abnormalities due to excessive urination, between the hANP and non-hANP groups. If patients developed hypotension, phenylephrine was mainly administered and volume loading was performed. The management of blood pressure was done according to the usual method at our institute, based on the decision of each anesthesiologist. However, no case of serious hypotension occurred because the dose of hANP was low. There was also no rebound phenomenon after discontinuation of hANP administration in the current study.Table 1Patient demographicshANP group (*n* = 24)Non-hANP group (*n* = 24)Age (years)64.7 ± 10.365.7 ± 10.9Sex (male/female)13/1115/9Body weight (kg)54.2 ± 12.857.6 ± 10.9Preoperative medication ARB1316 β-Blocker96Diagnosis Coronary artery disease97 Valvular disease1517Operating time (min)364.7 ± 60.3374.1 ± 65.1ACC time (min)102.2 ± 47.6110.8 ± 50.1CPB time (min)154.7 ± 52.6161.8 ± 49.1Intraoperative urine output (ml)935 ± 125.7847 ± 91.6Intraoperative RBC transfusion (ml)1220 ± 187.31176 ± 171.8Intraoperative fluid balance (ml)2225 ± 425.31805 ± 189.1There were no significant differences between the two groups*ARB* angiotensin receptor blocker, *ACC* aortic cross-clamp, *CPB* cardiopulmonary bypass, *RBC* red blood cell
Activities of systemic and intrarenal renin--angiotensin--aldosterone systems {#Sec9}
-----------------------------------------------------------------------------
Urinary angiotensinogen increased immediately after CPB compared to baseline in both groups, although urinary angiotensinogen levels were significantly lower in the hANP group than in the non-hANP group after CPB (hANP group 3.3 ± 1.4 mg/gCr versus non-hANP group 6.8 ± 3.6 mg/gCr; *p* = 0.04), at the end of surgery (hANP group 5.8 ± 3.1 mg/gCr versus non-hANP group 10.2 ± 5.1 mg/gCr; *p* = 0.03) and 3 h after surgery (hANP group 5.6 ± 3.9 mg/gCr versus non-hANP group 9.8 ± 6.6 mg/gCr; *p* = 0.04) (Fig. [1](#Fig1){ref-type="fig"}). Although renin activity, Ang II and aldosterone levels also started to increase after CPB compared to baseline in both groups, renin and Ang II levels did not differ significantly between the two groups (Fig. [2](#Fig2){ref-type="fig"}a, b). Aldosterone in the hANP group was significantly lower than in the non-hANP group only 3 h after surgery (Fig. [2](#Fig2){ref-type="fig"}c).Fig. 1Changes in urinary angiotensinogen from baseline (before surgery) to 3 h after surgery. Urinary angiotensinogen levels were significantly lower in the hANP group compared to the non-hANP group at the time points of after CPB, at end of surgery, and 3 h after surgery. *uAng* urinary angiotensinogen, *CPB* cardiopulmonary bypass Fig. 2Changes in renin activity (**a**), angiotensin II (**b**) and aldosterone (**c**) from baseline (before surgery) to 3 h after surgery. There were no significant differences in renin activities and angiotensin II levels between the hANP group and the non-hANP group. Aldosterone levels were lower in the hANP group than in the non-hANP group at 3 h after surgery. *CPB* cardiopulmonary bypass
AKI biomarkers {#Sec10}
--------------
Urinary NGAL and L-FABP levels in the non-hANP group reached a peak 3 h after surgery and at the end of surgery, respectively, with significant differences between the two groups in urinary NGAL and L-FABP levels at these time points. At 3 h after surgery, peak urinary NGAL levels in the hANP group and in the non-hANP group were 371.1 ± 413.6 and 761.4 ± 413.6 μg/gCr, respectively (*p* \< 0.01) (Fig. [3](#Fig3){ref-type="fig"}). On the other hand, peak urinary L-FABP levels at the end of surgery in the hANP and non-hANP groups were 238.8 ± 107.4 and 573.9 ± 370.1 μg/gCr, respectively (*p* \< 0.01) (Fig. [4](#Fig4){ref-type="fig"}).Fig. 3Changes in urinary NGAL from baseline (before surgery) to 3 h after surgery. Urinary NGAL levels were lower in the hANP group than in the non-hANP group at 3 h after surgery. *uNGAL* urinary neutrophil gelatinase-associated lipocalin, *CPB* cardiopulmonary bypass Fig. 4Changes in urinary L-FABP from baseline (before surgery) to 3 h after surgery. Urinary L-FABP levels were lower in the hANP group than in the non-hANP group at the end of surgery. *uL-FABP* urinary L-type fatty acid-binding protein, *CPB* cardiopulmonary bypass
Serum creatinine and the incidence of postoperative AKI {#Sec11}
-------------------------------------------------------
Serum Cr did not differ significantly between the two groups on postoperative days 1, 2 and 3 (Table [2](#Tab2){ref-type="table"}). However, there were 9 patients in the non-hANP group and 2 patients in the hANP group who developed postoperative AKI, which was diagnosed by an increase in serum Cr of 0.3 mg/dl or higher, based on KDIGO criteria \[[@CR14]\]. Hence, the incidence of postoperative AKI was significantly lower in the hANP group (*p* = 0.04).Table 2Pre- and postoperative serum Cr and incidence of AKIhANP group (*n* = 24)Non-hANP group (*n* = 24)*p* valuePreoperative sCr (mg/dl)0.84 ± 0.210.86 ± 0.220.770Postoperative day 1 sCr (mg/dl)0.95 ± 0.420.99 ± 0.350.719Postoperative day 2 sCr (mg/dl)0.98 ± 0.251.07 ± 0.340.336Postoperative day 3 sCr (mg/dl)0.94 ± 0.301.02 ± 0.380.483Incidence of AKI (based on KDIGO criteria)290.036*sCr* serum creatinine
Discussion {#Sec12}
==========
The present study demonstrated that low-dose hANP during CPB surgery could prevent an increase in NGAL and L-FABP, which are early biomarkers of AKI, and could reduce the incidence of postoperative AKI. Reportedly, low-dose hANP infusion protects renal function after cardiac surgery via inhibition of systemic RAA activity \[[@CR7]\]. However, in the present study, hANP could not completely prevent the increase in serum renin activity and Ang II and aldosterone levels as compared to the control group, all these hormones being activated after CPB in both groups. Recently, the role of the local RAAS in several tissues, such as the kidney, heart, vasculature, adrenal gland, liver, spleen and skeletal muscles, has been emphasized \[[@CR22]\]. In the kidney, all components of the renal RAAS are produced independently of the systemic RAAS, and contribute to the progression of both acute and chronic kidney diseases \[[@CR10]\]. Intrarenal Ang II can be produced independently from circulating Ang II, its concentrations reportedly being far higher than plasma Ang II levels in AKI, and directly related to the progression of AKI \[[@CR16]\]. Moreover, urinary angiotensinogen has been identified as an index of the activity of the renal RAAS \[[@CR11]\]. Previous animal experiments demonstrated that hANP attenuated renal injury that was induced by ischemia/reperfusion. The mechanism was attributed to inhibition of Ang II production and intrarenal RAAS activation, which, in turn, prevented the production of urinary angiotensinogen \[[@CR21]\]. The present study showed that hANP could significantly prevent the increase in urinary angiotensinogen levels after CPB, as compared to the control group, much earlier than prevention of the increase in both L-FABP and NGAL. On the other hand, hANP could not significantly prevent upregulation of the systemic RAAS, as indicated by plasma renin, Ang II and aldosterone levels, after CPB. Therefore, prevention of the activity of the renal RAAS, but not systemic RAAS, via hANP might inhibit the progress of renal damage after CPB. In a previous study, activation of the systemic RAAS occurred several hours or days later, by which time the biomarkers of AKI had already been upregulated \[[@CR1]\]. Increasing activation of the intrarenal RAAS might follow the pattern of systemic renin activity and Ang II and aldosterone concentrations.
The most frequent adverse event associated with hANP infusion is probably hypotension. The optimal dose of hANP for preventing postoperative AKI has not yet been established. We selected low infusion rates of 0.025 μg/kg/min as the dose of hANP in the present study, almost half that used in previous clinical research, which did not result in excessive reductions in blood pressure \[[@CR7], [@CR8], [@CR23]\]. Further, since no other noteworthy complications related to hANP infusion were observed, we believe that the dose of 0.025 μg/kg/min of hANP would be safe and efficacious in clinical settings.
Serum Cr has long been used in the diagnosis of kidney disease. However, an increase in serum Cr only indicates renal clearance failure. It has been pointed out that creatinine kinetics are insufficient as an index of acute kidney injury. In the present study, serum Cr did not differ between the two groups on postoperative days 1, 2 and 3, despite the reduced incidence of postoperative AKI with hANP. Hence, we could not demonstrate renoprotective effects of hANP based on an increase in serum Cr, which is contrary to what has been shown in previous randomized controlled studies \[[@CR7], [@CR8]\]. Besides, serum Cr does not increase until at least 24--48 h after the development of AKI. Recently, several research groups reported that small increments in serum Cr after cardiac surgery, which was not adopted as a diagnostic criterion for AKI, was significantly associated with the progression of postoperative AKI and mortality \[[@CR24], [@CR25]\]. It is possible that hemodilution and hydration may lead to falsely low serum Cr measurements, which in turn can confound the diagnosis of AKI after cardiac surgery. This low accuracy of serum Cr measurements, in addition to the delay in the increase in serum Cr after cardiac surgery, is another drawback of using serum Cr as a marker of AKI. Since serum Cr is not a completely accurate marker in the early diagnosis of AKI, several early and specific biomarkers of AKI are strongly needed.
In the present study, we assessed two typical urinary biomarkers, NGAL and L-FABP, for their utility in the diagnosis of AKI. NGAL is a 25-kDa protein belonging to the lipocalin superfamily, which is secreted by neutrophils \[[@CR26]\]. Urinary NGAL has been recognized as an early biomarker of AKI after cardiac surgery \[[@CR17], [@CR18]\]. On the other hand, L-FABP is a 14-kDa fatty acid-binding protein, and is a biomarker that is secreted in urine as a result of reactive oxygen stress. The usefulness of L-FABP as a biomarker in the early detection of AKI after cardiac surgery has also been reported \[[@CR19], [@CR20]\]. There is a difference between the mechanism of increase in urinary NGAL and L-FABP after CPB. Oxidative stress via renal tissue hypoxia upregulates L-FABP expression and increases the secretion of L-FABP into urine from damaged proximal tubules \[[@CR27]\]. In contrast, inflammation induced by various stresses increases serum NGAL, while impaired renal absorption increases urinary NGAL secretion \[[@CR28]\]. Therefore, the increase in urinary NGAL levels takes longer than urinary L-FABP levels \[[@CR27]\]. In the present study, although both urinary NGAL and L-FABP concentrations increased immediately after CPB in both the non-hANP and hANP groups, hANP prevented the increase in urinary L-FABP at the end of surgery and NGAL 3 h after surgery. Moreover, hANP could significantly prevent the increase in urinary angiotensinogen levels compared to that in the non-hANP group immediately after CPB, well before the increase in both urinary NGAL and L-FABP. Ischemia--reperfusion injury induced by CPB is accompanied by augmentation of the intrarenal RAAS, and the activated intrarenal Ang II promotes renal tissue inflammation, resulting in an increase in urinary NGAL \[[@CR28]\]. Ang II also inhibits oxygen delivery and increases oxygen consumption, which could induce the production of ROS \[[@CR29]\], which in turn increases the expression and secretion of L-FABP into urine. This suggests that hANP exerts renoprotective effects against inflammation and ROS, which are activated by CPB.
The present study shows that hANP prevents demonstrable activation of the intrarenal RAAS, but not systemic RAAS, which has protective effects against kidney injury. Previous studies measured serum Cr and Cr clearance, which increased 24 h postoperatively and beyond, to evaluate the renoprotective effects of hANP \[[@CR7], [@CR8], [@CR23]\]. On the other hand, we demonstrated the possible use of earlier biomarkers, NGAL and L-FABP, in the diagnosis of acute renal damage.
There are several limitations to the present study. One is that we could not directly clarify that hANP prevents an increase in postoperative serum Cr, although it did reduce the incidence of AKI, as determined by serum Cr levels based on the definition of AKI, probably because of the small sample size, although hANP could inhibit the secretion of urinary NGAL and L-FABP. Second, this study was not blinded because carperitide (hANP) has been used as a protective agent during cardiac failure only in Japan, and the utility of hANP in the prevention of AKI or the safety of patients with its administration during surgery has not been completely confirmed. Hence, our institutional ethics committee was not in favor of blinding in the study, although several studies have reported the protective effects of hANP on renal damage \[[@CR7], [@CR8], [@CR23]\]. Third, we could not directly prove that hANP prevents activation of the intrarenal RAAS through the secretion of urinary angiotensinogen, which is an indicator of intrarenal RAAS activity. Moreover, hANP inhibited the activity of the systemic RAAS to some extent, although the level of inhibition was not significant. Hence, there is still the possibility that inhibition of the activity of the systemic RAAS by hANP reduced the incidence of postoperative AKI. Further research, including in vivo and in vitro experiments, is needed to clarify the role of hANP in the intrarenal RAAS. In addition, we had intended to decide sample size based on the previous studies. However, the previous studies adopted the values of serum Cr concentrations as the index of AKI after cardiac surgery, while we defined the incidence of AKI based on KDIGO criteria, which adopted the increasing degrees of serum Cr, and there are few reports showing the efficacy of hANP in this manner. Therefore, we could not apply the previous power calculation to the present study for the determination of sample size. Also, we excluded aortic graft surgery from the study based on the advice of our expert statistician, because blood loss, CPB time and operative time were much larger than in other cardiac surgeries. A larger trial including aortic graft surgery with power calculation based on the present results is anticipated.
In conclusion, the efficacy of hANP for prevention of perioperative renal damage was investigated in the present study. hANP exerted renoprotective effects during cardiac surgery, and can possibly reduce the incidence of AKI after ischemia--reperfusion surgery. Moreover, this protective effect of hANP is mainly induced by inhibition of the intrarenal RAAS.
A comment to this article is available at <https://doi.org/10.1007/s00540-017-2434-z>.
Conflict of interest {#FPar1}
====================
None.
| 2024-07-31T01:26:35.434368 | https://example.com/article/3131 |
Development of a two-step screening ESI-TOF-MS method for rapid determination of significant stress-induced metabolome modifications in plant leaf extracts: the wound response in Arabidopsis thaliana as a case study.
To study the stress-induced effects caused by wounding under a new perspective, a metabolomic strategy based on HPLC-MS has been devised for the model plant Arabidopsis thaliana. To detect induced metabolites and precisely localise these compounds among the numerous constitutive metabolites, HPLC-MS analyses were performed in a two-step strategy. In a first step, rapid direct TOF-MS measurements of the crude leaf extract were performed with a ballistic gradient on a short LC-column. The HPLC-MS data were investigated by multivariate analysis as total mass spectra (TMS). Principal components analysis (PCA) and hierarchical cluster analysis (HCA) on principal coordinates were combined for data treatment. PCA and HCA demonstrated a clear clustering of plant specimens selecting the highest discriminating ions given by the complete data analysis, leading to the specific detection of discrete-induced ions (m/z values). Furthermore, pool constitution with plants of homogeneous behaviour was achieved for confirmatory analysis. In this second step, long high-resolution LC profilings on an UPLC-TOF-MS system were used on pooled samples. This allowed to precisely localise the putative biological marker induced by wounding and by specific extraction of accurate m/z values detected in the screening procedure with the TMS spectra. | 2024-05-15T01:26:35.434368 | https://example.com/article/5225 |
'''
Written for DigitalOcean's Hacktoberfest!
Requires cx_Freeze and must be built on Windows :(
Unfortunately, neither cx_Freeze nor py2exe support cross platform compilation
thus, this particular solution was set into motion
'''
import sys
from cx_Freeze import setup, Executable
setup(
name = "RSPET Test", #Change these values to your liking
version = "0.1",
description = "A Test Executable",
executables = [Executable("rspet_client.py", base = "Win32GUI")]) | 2023-10-21T01:26:35.434368 | https://example.com/article/1654 |
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