text stringlengths 12 4.76M | timestamp stringlengths 26 26 | url stringlengths 32 32 |
|---|---|---|
Minerals are important for your body to stay healthy. Your body uses minerals for many different jobs, including building bones, making hormones and regulating your heartbeat.
There are two kinds of minerals: macrominerals and trace minerals. Macrominerals are minerals your body needs in larger amounts. They include calcium, phosphorus, magnesium, sodium, potassium, chloride and sulfur. Your body needs just small amounts of trace minerals. These include iron, manganese, copper, iodine, zinc, cobalt, fluoride and selenium.
The best way to get the minerals your body needs is by eating a wide variety of foods. In many cases, your health care provider may recommend a mineral supplement. | 2024-07-28T01:26:59.872264 | https://example.com/article/8424 |
Never miss a local story.
Fresno has an MVP candidate in third baseman Matt Duffy, who has been with the club all season. Duffy was batting .311 with 17 home runs and a league-leading 99 RBIs.
As Fresno keeps winning, second-place Sacramento can only wonder what it has to do to catch up.
The River Cats have won a franchise record 12 games in a row, a streak that was still alive going into Saturday night. During its winning streak, Sacramento has gained exactly one game in the standings.
Other teams are streaking, too.
In the Pacific-South, El Paso went on an eight-game winning streak which ended Friday night. The Chihuahuas briefly knocked Las Vegas out of first place, but the 51s regained the top spot by a half-game with an 8-3 win over Omaha on Friday. The division title will likely come down to a head-to-head, four-game series which starts in Las Vegas on August 31.
Then there is New Orleans.
The Miami Marlins affiliate had lost 13 consecutive games — a franchise record — going into Saturday night. And it gets worse: the Zephyrs have lost 21 of their past 23 games, falling to 51-76 on the season. New Orleans was only six games under .500 when the slide began.
M’s Affiliate On Pace For Historic Low
The Clinton LumberKings have been a member of the Midwest League since 1954, but originated in 1937, when they joined the Three I League as a Brooklyn Dodgers affiliate.
Now a Seattle Mariners’ Single-A club, Clinton is on pace to break a dubious franchise record: most losses in a single season.
Clinton entered Saturday’s game against Cedar Rapids with a 39-83 record, and 17 games remaining on the schedule.
The LumberKings’ worst season ever came in 2006, when the then-Texas Rangers affiliate went 45-94.
To beat that mark, Clinton would have to go 7-10 over its final 17 games — a difficult task for a club that is 13-40 in the second half of the season, and hasn’t won more than two consecutive games since May 25.
The LumberKings have the worst record among all professional full-season teams in the major and minor leagues. | 2024-01-15T01:26:59.872264 | https://example.com/article/8322 |
Q:
Manually add an element to a selection in d3
I'm trying to programmatically create a table in d3 with quarters across the top and values along the left. Given a vector of quarters ["q1", "q2", "q3", "q4"], I would like the table:
| q1 | q2 | q3 | q4 |
v1 | | | | |
v2 | | | | |
What I am getting when running the code below is:
| q2 | q3 | q4 |
v1 | | | |
v2 | | | |
Note the first column is missing. I am using the following code:
var qtrs = ["q1", "q2", "q3", "q4"];
var info = d3.select("body"),
thead = info.append("thead"),
tbody = info.append("tbody");
thead.append("tr").append("th").text("")
thead.select("tr")
.selectAll("th")
.data(qtrs)
.enter()
.insert("th")
.text(function (d) { return (d); });
tbody.append("tr").insert("td").text("Value 1")
tbody.append("tr").insert("td").text("Value 2")
tbody.selectAll("tr").selectAll("td").data(qtrs).enter()
.append("td").text("0.0");
Which is also available here: http://jsfiddle.net/TpCJk/
The part I am struggling with is how to manually select/add a single element (ie the first column) to the table while using data(qtrs) to automatically generate the rest of the columns.
What seems to be happening is that the selectAll is also selecting the (manually created) empty cell and overwriting it. I've tried adding the first column later (putting thead.select("tr").insert("th").text("..."); after creating th however it always seems to land at the end of the table, not the start.
Note that the qtrs array here is an example, in my full application it will depend on the data passed to it (ie could be longer or shorter). The "Value 1" and "Value 2" lines are fixed.
Any help much appreciated!
A:
The problem is that you already have a table (header) cell that is not specified through the data. The way D3 matches data elements to DOM elements (in the data() function) is by index by default. That is, the first data element you pass in matches the first table (header) cell, which in your particular case is already there. Therefore, it is not in the .enter() selection.
The best way to fix this is to simply provide a function that tells D3 how to match data to DOM elements. The code
thead.select("tr")
.selectAll("th")
.data(qtrs, function(d) { return d; })
.enter()
.insert("th")
.text(function (d) { return (d); });
Inserts all the table headers correctly. If you specify the same matching function when adding the table cells, they will be added correctly (i.e. the correct number of columns) as well.
| 2023-08-25T01:26:59.872264 | https://example.com/article/3551 |
Q:
App force closes on playing audio android
i have code for playing two audios, one is a random audio from list and other one is set on button click. but whenever i press the button it keeps force closing randomly. please tell me resolution for this problem. Thanks!
package com.example.btn;
import java.net.SocketException;
import java.util.Random;
import android.app.Activity;
import android.app.AlertDialog;
import android.media.MediaPlayer;
import android.os.Bundle;
import android.os.Handler;
import android.view.View;
public class MainActivity extends Activity {
Handler mHandler; // global instance
Runnable your_runnable; // global instance
@Override
protected void onCreate(Bundle savedInstanceState) {
super.onCreate(savedInstanceState);
setContentView(R.layout.activity_main);
}
public void yolo(final View view) {
if (view == view) {
view.setBackgroundResource(R.drawable.btn1);// Change to this when
// clicked
final MediaPlayer mp11 = MediaPlayer.create(getBaseContext(),R.raw.animals009);// get mp3 dir
mp11.start(); // play mp3
mHandler = new Handler();
your_runnable = new Runnable() {
@Override
public void run() {
view.setBackgroundResource(R.drawable.btn2);// Revert back
// to this after
// timer
int[] sounds={R.raw.animals010, R.raw.animals012, R.raw.animals013,R.raw.animals019,R.raw.animals114};
Random r = new Random();
int Low = 0;
int High = 7;
int rndm = r.nextInt(High-Low) + Low;
MediaPlayer mp1 = MediaPlayer.create(getApplicationContext(),sounds[rndm]);
mp1.start();
}
};
mHandler.postDelayed(your_runnable, 3000L);// 3sec timer
}
}
}
log cat
09-01 07:38:41.673: V/MediaPlayer(16923): isPlaying: 1
09-01 07:38:41.673: V/MediaPlayer-JNI(16923): isPlaying: 1
09-01 07:38:42.658: D/AndroidRuntime(16923): Shutting down VM
09-01 07:38:42.658: W/dalvikvm(16923): threadid=1: thread exiting with uncaught exception (group=0x4170fc08)
09-01 07:38:42.663: E/AndroidRuntime(16923): FATAL EXCEPTION: main
09-01 07:38:42.663: E/AndroidRuntime(16923): Process: com.example.btn, PID: 16923
09-01 07:38:42.663: E/AndroidRuntime(16923): java.lang.IllegalStateException: Could not execute method of the activity
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.view.View$1.onClick(View.java:3969)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.view.View.performClick(View.java:4630)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.view.View$PerformClick.run(View.java:19339)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.os.Handler.handleCallback(Handler.java:733)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.os.Handler.dispatchMessage(Handler.java:95)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.os.Looper.loop(Looper.java:157)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.app.ActivityThread.main(ActivityThread.java:5335)
09-01 07:38:42.663: E/AndroidRuntime(16923): at java.lang.reflect.Method.invokeNative(Native Method)
09-01 07:38:42.663: E/AndroidRuntime(16923): at java.lang.reflect.Method.invoke(Method.java:515)
09-01 07:38:42.663: E/AndroidRuntime(16923): at com.android.internal.os.ZygoteInit$MethodAndArgsCaller.run(ZygoteInit.java:1265)
09-01 07:38:42.663: E/AndroidRuntime(16923): at com.android.internal.os.ZygoteInit.main(ZygoteInit.java:1081)
09-01 07:38:42.663: E/AndroidRuntime(16923): at dalvik.system.NativeStart.main(Native Method)
09-01 07:38:42.663: E/AndroidRuntime(16923): Caused by: java.lang.reflect.InvocationTargetException
09-01 07:38:42.663: E/AndroidRuntime(16923): at java.lang.reflect.Method.invokeNative(Native Method)
09-01 07:38:42.663: E/AndroidRuntime(16923): at java.lang.reflect.Method.invoke(Method.java:515)
09-01 07:38:42.663: E/AndroidRuntime(16923): at android.view.View$1.onClick(View.java:3964)
09-01 07:38:42.663: E/AndroidRuntime(16923): ... 11 more
09-01 07:38:42.663: E/AndroidRuntime(16923): Caused by: java.lang.ArrayIndexOutOfBoundsException: length=5; index=6
09-01 07:38:42.663: E/AndroidRuntime(16923): at com.example.btn.MainActivity.yolo(MainActivity.java:28)
09-01 07:38:42.663: E/AndroidRuntime(16923): ... 14 more
09-01 07:38:43.783: V/MediaPlayer(16923): message received msg=2, ext1=0, ext2=0
09-01 07:38:43.783: V/MediaPlayer(16923): playback complete
A:
You start mp11 immediately after you create it. So It will start playing immediately, which is pretty much the same instant mp1 is playing. If you want it to be delayed, trigger it in your runnable instead.
Additinal:
see the logcat line Caused by: java.lang.ArrayIndexOutOfBoundsException: length=5; index=6
You have set up your sounds[] with 5 items, but you are generating a random number between 0 and 7, so your ending up with numbers outside the bounds of the array. You should change your random number generation to between 0 and 4. A more flexible way would be to use the length of the array:
Random r = new Random();
int index = r.nextInt(sounds.length - 1);
| 2023-12-03T01:26:59.872264 | https://example.com/article/4433 |
Murray Todd
Murray Todd is an Australian Paralympic athletics competitor.
He was from South Australia. At the 1976 Toronto Games, he competed in three athletics throwing events and won a silver medal in the Men's Shot Put 2. At the 1980 Arnhem Games, he competed in two athletics throwing events and won the gold medal in the Men's Shot Put 2.
References
Category:Paralympic athletes of Australia
Category:Athletes (track and field) at the 1976 Summer Paralympics
Category:Athletes (track and field) at the 1980 Summer Paralympics
Category:Paralympic gold medalists for Australia
Category:Paralympic silver medalists for Australia
Category:Living people
Category:Year of birth missing (living people)
Category:Place of birth missing (living people)
Category:Medalists at the 1976 Summer Paralympics
Category:Medalists at the 1980 Summer Paralympics | 2023-11-28T01:26:59.872264 | https://example.com/article/9219 |
Parade participants react after a trailer carrying wounded veterans in a parade was struck by a train in Midland, Texas on Nov. 15. / James Durbin, AP
by USA TODAY
by USA TODAY
MIDLAND, Texas (AP) - Wounded U.S. military veterans leapt for their lives just before a freight train struck their parade in rural Texas, killing four veterans and injuring 16, and federal officials rushed to the scene Friday to piece together why it happened.
About two dozen veterans and their spouses had been sitting on the parade float, set up on a flatbed truck decorated with American flags. Many seemed to panic as the train's horn blared, said Patricia Howle, who was waiting in her car at a nearby traffic light.
"I was on the phone, and I just started screaming," she told The Associated Press after Thursday afternoon's crash. "The truck was on the other side of the train, but I did see the panic on the faces of the people and saw some of them jump off."
Police said the first truck with veterans safely crossed the tracks, but the second truck's trailer was still on the crossing as the Union Pacific locomotive approached.
The U.S. marked Veterans Day earlier this week, and the parade was part of an event to honor wounded veterans.
The scene just after the crash reminded Sudip Bose, a doctor and front-line physician in Iraq who had been volunteering at the parade, of war. He said veterans were already tending to the wounded with limited medical supplies when he arrived.
Police on Friday confirmed that all four of the dead were veterans. Midland city police spokesman Ryan Stout said 37-year-old Sgt. Maj. Gary Stouffer and 47-year-old Sgt. Maj. Lawrence Boivin were pronounced dead at the scene and 34-year-old Army Sgt. Joshua Michael and 43- year-old Army Sgt. Maj. William Lubbers were pronounced dead at a hospital.
A preliminary investigation indicated the crossing gate and lights were working, said Union Pacific spokesman Tom Lange, though he didn't know if the train crew saw the float approaching.
"There is going to be a very thorough investigation," Lange said. "It's obviously a very tragic incident." He said the train crew did not sustain any injuries but would be offered counseling.
Six people remained hospitalized Friday, including one in critical condition. Ten others were treated and released.
"The train honked its horn, but the 18-wheeler could not go anywhere because of the other one being right in front of it. It was a horrible accident to watch happen right in front of me," said Daniel Quinonez, who was in traffic that had been stopped to allow the parade to pass. "I just saw the people on the semi-truck's trailer panic, and many started to jump off the trailer. But it was too late for many of them because the train impacted the trailer so fast."
Pam Shoemaker said she and her husband, a special ops veteran, were on the float ahead of the one that was struck. She said they heard the train coming but had heard no warning before that. They jumped from the float just as crossing barriers had just started to come down.
Her husband, Tommy, resuscitated one person and applied a tourniquet to a bleeding woman.
"They are trained for tragedy," Shoemaker said.
The event was organized by Show Of Support, a local veterans group. Its president, Terry Johnson, did not immediately return an email for comment and his phone number was unlisted. The phone rang unanswered at the group's offices.
The chairwoman of the National Transportation Safety Board, Deborah Hersman, said Friday on NBC that the train was equipped with a forward-facing camera whose footage could help in the investigation.
"That will give us some video images if it survived the crash, and we can download it, as well as recorders on the train," Hersman said. "We're going to be looking at the signals â?¦ and making sure that the gates and lights were coming down."
Secretary of Defense Leon Panetta "was deeply saddened by news of the tragic accident involving veterans heroes and their spouses in Midland," Pentagon spokesman George Little said in a statement.
At a prayer vigil Friday morning, Mayor Wes Parry's voice cracked as he described how he had met Boivin, one of the victims, and his wife a day earlier.
"It's hard to believe today that he's not here anymore," Parry said.
Federal records show 10 previous collisions at the same railroad crossing.
Records reviewed by The Associated Press from the Federal Railroad Administration show that five cars and five trucks have been struck by trains or rail equipment there since 1979. Six drivers were injured, but there were no fatalities.
Copyright 2015 The Associated Press. All
rights reserved. This material may not be published, broadcast, rewritten or redistributed. | 2023-09-16T01:26:59.872264 | https://example.com/article/7527 |
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Good afternoon!
All our Christmas designs are on sale this month. Plus, free shipping
all the time on all US and Canada orders. (http://www.eurekastamps.com)
We are gradually adding the individual designs formerly from Biblical
Impressions. All the full sheets are up under the full sheets...
One of the past issues of Polymer Cafe had a fabulous article on using
the Pantone Color codes for mixing clay using the CMYK/RGB formulas.
Might anyone recall which issue that was...I've gone through my
magazine binder in a frenzy, going page by page thru each issue looking
for it, and just my...
I am having trouble finding 400-grit and up sandpaper. I don't have a
dremel or a sanding/buffing machine and the stuff they sell in craft
stores is not aptly suitable. I know some of the more popular clay
stores sell it, but honestly, it's too expensive. I used other grade
wet/dry grits going...
Hey all,
There's a bead show in town this weekend; just wondering if anyone from
the group would be coming in for this?
http://www.wholebead.com/shows_chicago.html
I'll be attending Sunday afternoon.
Cheers,
Hi All, I beenbusy busy, still packing up the Gallery Here to close
it down on thursday the 31 ! I will only be selling on line and vending
when i can the Brick and Mortar Shop Just got to hard to keep up with
and cost to much ! One chapter close another opens ! Got some bargins
on ebay ending...
hi there everybody! The Bead Bugle has a new issue up for August and there's
an article about my entry for AMACO's Itty Bitty Book Designer Challenge. It
features FIMO clay and designer gel, floral canes and transfers, and of
course, gilt edges!If you's like to see, here's the...
Hi,
I just started making clay beads. I made some 16mm pumpkins that are
just about ready to be baked. I think they look pretty good, but can't
help but wonder how the heck do you finish the small items with details
(leaves, stems, etc.) I see that alot of people are using different
grits of...
hi there! I've made some summertime updates to my pages! There's more to
come, so much to show and tell. So please do take a look and ssee how things
are coming along.
Sarajane
http://polyclay.com
--
Sarajane's Polyclay Gallery
Beads-Dolls-Wearable Art
Hi,
I just joined this group and thought I'd introduce my self. I make
beaded personalized rosaries, rosary bracelets, wrap around rosaries,
and medical ID bracelets.
I discovered polymer clay while I was searching for plane, train, and
truck beads for the bracelets I make. It was recommended...
Is anybody here planning to go to the Embellishments/International Quilt
Show in Houston Nov.2-5?
I just confirmed that Judith Skinner and I will be there with beads,
buttons, jewelry, and OUR NEW BOOK will make its debut--"Adapting Quilt
Patterns To Polymer Clay"
SJ
--
Sarajane's Polyclay...
hi there! I havent posted much lately because I've been so busy with the new
book with Judith , Adapting Quilt Patterns To Polymer Clay (due for release
in October), and webpages, but now at least a few things are up (its a
start) like my paper dolls. Now available at the new...
Do you have some beads you don't know what to do with!?
Why not wire wrap them! My new dvd "Whimsical Wire Wraps" will teach
you four of the hottest wire wrap techniques. Add value to your beads!
Check it out today! Save $5 by purchasing off...
Here are some I recommend:
http://snipurl.com/swel
Barbara
Beader and Polymer Clay Crusader
http://www.penguintrax.com and http://www.backseatgrammarian.com
There is a very fine line between a hobby and mental illness. (Dave Barry)
I was wanting some opinions on whether or not I should get a motor for
my new pasta machine. I used to have a Trattorina, which (as far as I know)
can't be fitted w/ a motor, so I have never worked w/ one. Is it worth the
extra money, or should I save the money and buy some other gadget? How...
Got another question--guns, extruders, etc.--yay or nay? I've seen
Sugarcraft's, Sculpey's and PCE's, along with caulking guns to help things
along. I've got one (don't know if it's a Kemper or a Sculpey--think some of
the disks snapped in half when I used it) and never found much use for it
since...
I've got project pictures and pictures of the show itself uploaded to
http://www.penguintrax.com/gallery/v/BnB2006/
There are polymer clay and metal clay class projects, plus some pics of
the show floor, the Swarovski booth and some other miscellaneous items.
Enjoy (I hope!)
--
Barbara | 2023-10-29T01:26:59.872264 | https://example.com/article/6623 |
/****************************************************************
* Licensed to the Apache Software Foundation (ASF) under one *
* or more contributor license agreements. See the NOTICE file *
* distributed with this work for additional information *
* regarding copyright ownership. The ASF licenses this file *
* to you 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 org.apache.james.imap.processor.fetch;
import java.io.Closeable;
import java.util.ArrayList;
import java.util.Iterator;
import java.util.List;
import org.apache.james.imap.api.ImapConstants;
import org.apache.james.imap.api.display.HumanReadableText;
import org.apache.james.imap.api.message.FetchData;
import org.apache.james.imap.api.message.FetchData.Item;
import org.apache.james.imap.api.message.IdRange;
import org.apache.james.imap.api.message.response.StatusResponseFactory;
import org.apache.james.imap.api.process.ImapProcessor;
import org.apache.james.imap.api.process.ImapSession;
import org.apache.james.imap.api.process.SelectedMailbox;
import org.apache.james.imap.message.request.FetchRequest;
import org.apache.james.imap.message.response.FetchResponse;
import org.apache.james.imap.processor.AbstractMailboxProcessor;
import org.apache.james.imap.processor.EnableProcessor;
import org.apache.james.mailbox.MailboxManager;
import org.apache.james.mailbox.MailboxSession;
import org.apache.james.mailbox.MessageManager;
import org.apache.james.mailbox.MessageManager.MailboxMetaData;
import org.apache.james.mailbox.exception.MailboxException;
import org.apache.james.mailbox.exception.MessageRangeException;
import org.apache.james.mailbox.model.ComposedMessageIdWithMetaData;
import org.apache.james.mailbox.model.FetchGroup;
import org.apache.james.mailbox.model.MessageRange;
import org.apache.james.mailbox.model.MessageResult;
import org.apache.james.mailbox.model.MessageResultIterator;
import org.apache.james.metrics.api.MetricFactory;
import org.apache.james.util.MDCBuilder;
import org.apache.james.util.MemoizedSupplier;
import org.slf4j.Logger;
import org.slf4j.LoggerFactory;
import com.github.fge.lambdas.Throwing;
import reactor.core.publisher.Flux;
public class FetchProcessor extends AbstractMailboxProcessor<FetchRequest> {
private static final Logger LOGGER = LoggerFactory.getLogger(FetchProcessor.class);
public FetchProcessor(ImapProcessor next, MailboxManager mailboxManager, StatusResponseFactory factory,
MetricFactory metricFactory) {
super(FetchRequest.class, next, mailboxManager, factory, metricFactory);
}
@Override
protected void processRequest(FetchRequest request, ImapSession session, Responder responder) {
boolean useUids = request.isUseUids();
IdRange[] idSet = request.getIdSet();
FetchData fetch = computeFetchData(request, session);
try {
final long changedSince = fetch.getChangedSince();
MessageManager mailbox = getSelectedMailbox(session)
.orElseThrow(() -> new MailboxException("Session not in SELECTED state"));
boolean vanished = fetch.getVanished();
if (vanished && !EnableProcessor.getEnabledCapabilities(session).contains(ImapConstants.SUPPORTS_QRESYNC)) {
taggedBad(request, responder, HumanReadableText.QRESYNC_NOT_ENABLED);
return;
}
if (vanished && changedSince == -1) {
taggedBad(request, responder, HumanReadableText.QRESYNC_VANISHED_WITHOUT_CHANGEDSINCE);
return;
}
final MailboxSession mailboxSession = session.getMailboxSession();
MemoizedSupplier<MailboxMetaData> metaData = MemoizedSupplier.of(Throwing.supplier(
() -> mailbox.getMetaData(false, mailboxSession, MailboxMetaData.FetchGroup.NO_COUNT))
.sneakyThrow());
if (fetch.getChangedSince() != -1 || fetch.contains(Item.MODSEQ)) {
// Enable CONDSTORE as this is a CONDSTORE enabling command
condstoreEnablingCommand(session, responder, metaData.get(), true);
}
List<MessageRange> ranges = new ArrayList<>();
for (IdRange range : idSet) {
MessageRange messageSet = messageRange(session.getSelected(), range, useUids);
if (messageSet != null) {
MessageRange normalizedMessageSet = normalizeMessageRange(session.getSelected(), messageSet);
MessageRange batchedMessageSet = MessageRange.range(normalizedMessageSet.getUidFrom(), normalizedMessageSet.getUidTo());
ranges.add(batchedMessageSet);
}
}
if (vanished) {
// TODO: From the QRESYNC RFC it seems ok to send the VANISHED responses after the FETCH Responses.
// If we do so we could prolly save one mailbox access which should give use some more speed up
respondVanished(mailboxSession, mailbox, ranges, changedSince, metaData.get(), responder);
}
processMessageRanges(session, mailbox, ranges, fetch, useUids, mailboxSession, responder);
// Don't send expunge responses if FETCH is used to trigger this
// processor. See IMAP-284
final boolean omitExpunged = (!useUids);
unsolicitedResponses(session, responder, omitExpunged, useUids);
okComplete(request, responder);
} catch (MessageRangeException e) {
LOGGER.debug("Fetch failed for mailbox {} because of invalid sequence-set {}", session.getSelected().getMailboxId(), idSet, e);
taggedBad(request, responder, HumanReadableText.INVALID_MESSAGESET);
} catch (MailboxException e) {
LOGGER.error("Fetch failed for mailbox {} and sequence-set {}", session.getSelected().getMailboxId(), idSet, e);
no(request, responder, HumanReadableText.SEARCH_FAILED);
}
}
private FetchData computeFetchData(FetchRequest request, ImapSession session) {
// if QRESYNC is enable its necessary to also return the UID in all cases
if (EnableProcessor.getEnabledCapabilities(session).contains(ImapConstants.SUPPORTS_QRESYNC)) {
return FetchData.Builder.from(request.getFetch())
.fetch(Item.UID)
.build();
}
return request.getFetch();
}
/**
* Process the given message ranges by fetch them and pass them to the
* {@link org.apache.james.imap.api.process.ImapProcessor.Responder}
*/
private void processMessageRanges(ImapSession session, MessageManager mailbox, List<MessageRange> ranges, FetchData fetch, boolean useUids, MailboxSession mailboxSession, Responder responder) throws MailboxException {
final FetchResponseBuilder builder = new FetchResponseBuilder(new EnvelopeBuilder());
FetchGroup resultToFetch = FetchDataConverter.getFetchGroup(fetch);
for (MessageRange range : ranges) {
if (fetch.isOnlyFlags()) {
processMessageRangeForFlags(session, mailbox, fetch, mailboxSession, responder, builder, range);
} else {
processMessageRange(session, mailbox, fetch, mailboxSession, responder, builder, resultToFetch, range);
}
}
}
private void processMessageRangeForFlags(ImapSession session, MessageManager mailbox, FetchData fetch, MailboxSession mailboxSession, Responder responder, FetchResponseBuilder builder, MessageRange range) {
SelectedMailbox selected = session.getSelected();
Iterator<ComposedMessageIdWithMetaData> results = Flux.from(mailbox.listMessagesMetadata(range, mailboxSession))
.filter(ids -> !fetch.contains(Item.MODSEQ) || ids.getModSeq().asLong() > fetch.getChangedSince())
.toStream()
.iterator();
while (results.hasNext()) {
ComposedMessageIdWithMetaData result = results.next();
try {
final FetchResponse response = builder.build(fetch, result, mailbox, selected, mailboxSession);
responder.respond(response);
} catch (MessageRangeException e) {
// we can't for whatever reason find the message so
// just skip it and log it to debug
LOGGER.debug("Unable to find message with uid {}", result.getComposedMessageId().getUid(), e);
} catch (MailboxException e) {
// we can't for whatever reason find parse all requested parts of the message. This may because it was deleted while try to access the parts.
// So we just skip it
//
// See IMAP-347
LOGGER.error("Unable to fetch message with uid {}, so skip it", result.getComposedMessageId().getUid(), e);
}
}
}
private void processMessageRange(ImapSession session, MessageManager mailbox, FetchData fetch, MailboxSession mailboxSession, Responder responder, FetchResponseBuilder builder, FetchGroup resultToFetch, MessageRange range) throws MailboxException {
MessageResultIterator messages = mailbox.getMessages(range, resultToFetch, mailboxSession);
SelectedMailbox selected = session.getSelected();
while (messages.hasNext()) {
final MessageResult result = messages.next();
//skip unchanged messages - this should be filtered at the mailbox level to take advantage of indexes
if (fetch.contains(Item.MODSEQ) && result.getModSeq().asLong() <= fetch.getChangedSince()) {
continue;
}
try {
final FetchResponse response = builder.build(fetch, result, mailbox, selected, mailboxSession);
responder.respond(response);
} catch (MessageRangeException e) {
// we can't for whatever reason find the message so
// just skip it and log it to debug
LOGGER.debug("Unable to find message with uid {}", result.getUid(), e);
} catch (MailboxException e) {
// we can't for whatever reason find parse all requested parts of the message. This may because it was deleted while try to access the parts.
// So we just skip it
//
// See IMAP-347
LOGGER.error("Unable to fetch message with uid {}, so skip it", result.getUid(), e);
}
}
// Throw the exception if we received one
if (messages.getException() != null) {
throw messages.getException();
}
}
@Override
protected Closeable addContextToMDC(FetchRequest request) {
return MDCBuilder.create()
.addContext(MDCBuilder.ACTION, "FETCH")
.addContext("useUid", request.isUseUids())
.addContext("idSet", IdRange.toString(request.getIdSet()))
.addContext("fetchedData", request.getFetch())
.build();
}
}
| 2023-11-19T01:26:59.872264 | https://example.com/article/8388 |
WordPress.org is a blogging platform that has grown and became a content management system (CMS). Hence, its functionality is not limited only for blogging but also in creating and developing multifunctional sites. | 2024-05-05T01:26:59.872264 | https://example.com/article/6572 |
Does hypothermic circulatory arrest or prolonged cardiopulmonary bypass time affect early outcome in reoperative aortic surgery?
Prolonged cardio-pulmonary bypass (CPB) time, usually necessary for reoperations, is known to increase mortality in coronary bypass procedures and aortic reoperations. We investigated if prolonged CPB time and arch reconstruction in reoperations of the thoracic aorta affect in-hospital outcome. Twenty-nine patients underwent reoperations on the thoracic aorta. The reoperations performed were aortic root replacement with composite graft without aortic arch involvement in ten patients, isolated ascending aorta replacement in six patients, aortic arch replacement as a primary procedure in two patients, and aortic arch in conjunction with ascending or descending aorta replacement in 11 patients. Fourteen patients had aortic reoperation with deep hypothermic circulatory arrest (DHCA) and 15 without DHCA. The in-hospital mortality rate was 13.8%. The use deep hypothermic circulatory arrest or CPB time did not affect early outcome. Previous coronary artery bypass procedure was independent predictor of in-hospital mortality. Seven patients required re-exploration for bleeding. One patient suffered from stroke and finally five patients had prolonged ventilation, two requiring tracheostomy. There have been no deaths in the follow-up period. None of the patients has required repeat surgical intervention on the heart or the aorta. The use of DHCA or prolonged CPB time do not affect early outcome in reoperations of the thoracic aorta. | 2023-11-23T01:26:59.872264 | https://example.com/article/9335 |
Q:
Where can i find a good PHP class to export data from html or dataset to excel file with formating?
I am looking for an existing PHP class that export data to an excel file. I also need to ability to create the design so all the reports will look like the web version of the report.
Can some one please lead me to a good and tested class?
A:
To export from to Excel format, take a look at PHPExcel
| 2023-09-07T01:26:59.872264 | https://example.com/article/1037 |
In this Psalm we see the faith of David. We also see imprecatory prayer, where God is asked to obliterate enemies. Modern Christians hate this kind of prayer and try to avoid it. Or, to be precise, they hate it in public but think it in private!
It is like those Christians wh9o say we must not judge. It is a nonsense, because EVERYONE judges. Usually, they pretend not to when talking with their peers, but they mull over plenty of judgment in their heads and hearts. It is inevitable, unless a person is literally brain-dead or unbalanced. We all make judgments every moment of the day! Of course, we may not be judgmental, which is a different thing.
We also see David saying he is right… another thing modern Christians dislike saying. It is a very odd situation, where we have an Almighty God Whose word is always right – but when we act according to that word, we will not say we are right! It is unreal and debilitating. If God is right, and we repeat what He says, then WE must also be right. Logical! To say otherwise is just petty pretence.
David invites God to search his heart. How many of us dare ask God to do that? David could openly say this to God because he was a true man of God, pure and holy, godly in all his words and ways. The fact of sin does not alter that. In a saved person occasional sins do not mean he or she is imperfect, or evil, or unholy. Sin is just a temporary hiccough, not a permanent illness!
We must always be in a position to invite God to look into our hearts. He looks anyway! We cannot hide anything from Him. He knows when we are genuine, and when we do things for the eyes of our peers, just to look good. When we are genuine, and live righteously, He will come immediately to our side when we are in trouble. This He does because it is ordained in eternity. Obedience is the key.
David saw testing as an honour, used by God to purify and strengthen us. Many see trials as awful events given as a punishment, whereas God gives them as a gift, for our wellbeing. How foolish we all are! How lazy, in wanting to be perfect without a perfecting process; in wanting holiness without living holy lives; in wanting everything from God without obedience. It will never happen!
Many Christians today have a feigned sense of their own selves. They refuse to say they are ‘perfect’ when God says we must be; they have a weird anxiety about putting the word ‘I’ before anything, because, they say, it shows a lack of humility; they will not speak to God as David does – saying we are right, because it shows arrogance… What a mixed-up, ignorant, miserable lot we are!
It is time Christians were more honest. Instead of pretending they should not say “I am right” when they ARE right. Why deny it, when God already knows and so does the Christian? Many years ago, when I was in a personal predicament concerning hateful Christians though I was arguing scripturally, I threw my arms into the air one day, and pleaded with God to show me if I was right or not, because my enemies were so adamant and pressing. The reply was instant – whether it was an actual voice or in my head, I cannot remember – “You KNOW you are right.” The response was quiet and authoritative, unexpected, but it stopped my anxiety and self-reproach, and I then stood firm. NEVER say you are wrong, when you speak biblically.
As believers we are meant to be authoritative in Christ, not lambs begging to be slaughtered! And as believers we are perfect – God says so; we must work at it with humble hearts. As for putting ‘I’ before a statement, how else can we refer to what we say? “Mr Williams said that Barry Napier is right”? No ‘I’ there! Placing the word ‘I’ in a statement merely identifies who says something; it does not necessarily mean we are proud or arrogant. David was the least proud person I have come across.
“Hear the right, O LORD”. More correctly, David is asking God to listen to justice and righteousness – which, of course, He always does. So, he is saying “Hear me because what I say is righteous and just”. If what we think, say, and do, is in the will of God (usually defined by scripture), then we are right. Simple as that. We cannot be wrong if we reflect or repeat what God says in His word.
David begs that God will be attentive to his plea, and do something about it; his “cry” or rinnah, being an earnest entreaty. He repeats a similar entreaty with “give ear unto my prayer“. Then he assures God (Who already knows), that what he says does not come “out of feigned lips”… what he was saying was not mirmah, or deceit.
It is a sad fact that most prayers are mirmah, because the Christian does not really mean what he says. He will usually repeat the same old phrases, without them coming from a heart brimming-over with truth or real meaning. How many ‘prayers’ in a prayer meeting are genuine? I would say very few, because prayer meetings are not sanctioned by God, except for those very, very rare occasions when everyone is brought together for a specific serious reason, urgent and given by God. There are also prayers that try to gloss over sin. God knows our hearts! God knew David’s words were genuine, and David reiterated it.
In my work on prayer meetings and prayer, I have said that genuine prayer is prayer that first comes from God into our spirits, and which we then repeat. I have said that only those prayers, from God and to God, are valid. Of course, this receives many retorts… but it does not matter, because I am right! The next verse confirms it…
“Let my sentence come forth from thy presence.” This is highly pertinent to the subject of genuine prayer. David’s “sentence” or mishpat, refers to God’s ‘sentence’, not David’s. It is God’s judgment, or justice, or decision. David merely repeats what firstly comes from God. This is underlined by the words “come forth from”. They come forth from “thy presence”, in Heaven.
David, then, KNOWS he is right, because he has asked God to show him what to say and do. This is the basis of all genuine prayer. (Many pastors are ‘professional’ pray-ers, and so are those ‘prayer warriors’ who love to fill a prayer meeting with their own voices, gushing-over with the usual formula, saying everything and yet meaning nothing. It is relatively easy to have a list of usual phrases in the mind – they sound good in public, but God does not listen to them!)
David relies totally on God’s judgment: “let thine eyes behold the things that are equal.” God’s ‘eyes’ are a reference to His purity and all-knowing. God does not look upon evil, treachery or deceit. So, if God responds to David it is to His own Heavenly words (from His ‘ayin or presence), firstly sent to David to speak. David asks God to tell him what He perceives to be “equal”, meyshar: what is upright and equal or right. The root, yashar, is the opposite to sin – to go straight, be lawful.
David is here saying two things: that what he is pleading before God is just and right, without sin, and, God knows it, whether it is in David or others. God always knows when we think, act or speak truth. Many Christians foolishly and ignorantly try to deceive God with convoluted ‘reasons’ why they want to do or say something, or why they act in a sinful way. Far better to be blunt – because God is! He will shut His ears to such stupidity, and will only listen and act when we repent.
But, David is assured he is speaking only truth: “Thou hast proved my heart”. God tested David and found him holy; his innermost being is godly. God has visited him in the night – when he is not awake and able to deceive, so unable to twist what he really means. God has tried him and not found him wanting. God “shalt find nothing”. Can we say that with confidence about ourselves? If not – why not?
“I am purposed that my mouth shall not transgress”, said David. The reason he did not sin or try to deceive God was a matter of self-discipline. He ‘purposed’ to be upright, zamam – considered and fixed his thoughts on being holy. Do you do this? Do you deliberately tell yourself to be holy and not to lie or deceive? Do you daily train your mind to always be upright and just? Do you always tell yourself to disregard the many temptations to sin? When a temptation to sin comes, do you immediately hit it hard with the mallet of scripture and cast it aside? Do you turn your head, eyes and ears away from such temptations? After all, it is what the Holy Spirit wants.
David assures the Lord that his mouth will not sin, because he speaks to his own soul and to the Holy Spirit daily, stopping his soul from accepting the slightest traces of sin. I know many, many Christians who think this is impossible (which is another way of avoiding God and continuing in sin). Does it mean David, or you and I, will never sin just by training ourselves spiritually? No. It means that if we fall to temptation and sin, we immediately repent and again turn away from it. Repentance covers much that is wrong, by ‘restarting’ our spirits with truth and light; it proves that our minds are alerted to truth and wish only to know truth, even though we occasionally fail.
We must remember that our spirits are brand new, holy before God. We are perfect because of Christ. We purpose not to sin, even though we sometimes fail. It is this inner purpose or decision of inner self, guided by the Spirit, that God looks at when assessing us, not our occasional sins. If we sin and repent, He will see us as holy and untainted, because of His Son’s sacrifice.
Verses 4-7
Concerning the works of men, by the word of thy lips I have kept me from the paths of the destroyer.
Shew thy marvellous lovingkindness, O thou that savest by thy right hand them which put their trust in thee from those that rise up against them.
David continues his plea by saying that when God looks upon his actions (“the works of men”), He will see that David has kept his life safe from sin and Satan by concentrating his whole life on God: “I have kept me from the paths of the destroyer”. This means David was kept pure by observing and obeying “the word of thy lips”.
In this way, he avoided the way of life set before him by the “destroyer”, the violent one, the one who robs. This can mean either his earthly enemies or Satan (who is never called by that name in the Old Testament), or both, for it is Satan who drives both saved and unsaved into sin… the unsaved because they are his prisoners, and the saved because they desire to act wrongly.
David then asks God to support him in his desire to be holy. “Hold up my goings in thy paths, that my footsteps slip not.” David is asking God to keep him fully alert to temptation… most Christians enjoy their sins, so make no effort to get out of them again. They have not fixed their hearts on God and so are easily tempted. But, when we determine to be holy and do everything necessary to be that way, God will carry us forward on the right path, so the destroyer, the enemy of our souls, is kept at bay and cannot harm us. Of course, this is all of God, not us.
When we live holy lives we can call upon God anytime and KNOW He will listen. This is because there is no impediment in our lives to prevent it. “I have called upon thee, for thou wilt hear me, O God.” David is confident God will listen, because he lives as God decrees! So, he can call on God to “incline thine ear unto me, and hear my speech.” God WILL listen and respond when we live righteously.
David asks God to “Shew thy marvellous livingkindness”, because this is God’s enduring response to all who love and obey Him. Therefore, David asks that God will continue to show His love for him, evidenced not only in protection from enemies, but also in His presence in his heart, bringing peace and assurance. To “shew” is to make a distinct impression, separate from everything else. And it is “marvellous” – set apart from the usual ways of mankind and wonderful/illustrious. What is especially ‘marvellous’ is God’s “lovingkindness”, checed: His goodness and faithfulness towards David as a righteous man. God is faithful to all who obey, and is chacad – kind and loving.
If God’s children need him, and are living righteously, they will be upheld and saved by His “right hand” (a symbol of His power) from enemies and troubles, because they put their trust in Him. To ‘trust’ Him is to chacah – flee to Him for protection, to hope and get God’s help. It is a protection open to us all if we obey. This is not Arminianism – it is obedience to what God demands. We are not saved by our works, but by God’s works. When we do what God demands they are holy works; when we do what we decide to do, it is human works and worthless. Know the difference, and you will know God’s love, freedom in Christ, and peace!
Verses 8-12
Keep me as the apple of the eye, hide me under the shadow of thy wings,
From the wicked that oppress me, from my deadly enemies, who compass me about.
They are inclosed in their own fat: with their mouth they speak proudly.
They have now compassed us in our steps: they have set their eyes bowing down to the earth;
Like as a lion that is greedy of his prey, and as it were a young lion lurking in secret places.
We now see a reference to the way God looks upon David, as the “apple of the eye”. Whatever or whoever is loved by God, is called the “apple of his eye” (Zechariah 2:8). Jacob, too, was favoured by God: “He found him in a desert land… he led him about, he instructed him, he kept him as the apple of his eye… So the LORD alone did lead him, and there was no strange god with him.”
Jacob (like David) was righteous, so God gave him everything: “He made him ride on the high places of the earth, that he might eat the increase of the fields…” Then follows a long list of benefits given to Jacob. This is the clue to our own lives – God will keep us, when we obey Him and live honourably. (There are times when He will take us along a seemingly barren way, but this is for our testing and eventual cleansing. This is a privilege not a bad thing). Look to God only and be the apple of His eye!
“Hide me under the shadow of thy wings”. This is a symbol of God’s protection; it is also an indirect reference to Christ, Who was likely the “Spirit of God” in Genesis 1:2, Who “moved upon the face of the waters”, a reference to a mother bird with its wings outstretched. God will completely protect us from dangers and situations if we are faithful to Him.
David had mortal enemies who threatened his very life, they were “wicked” people oppressing him, “deadly enemies” who surrounded him. David was one of the most courageous and fearless men to have lived, yet even he pleaded for God’s mercy and help. He knew that unless he was faithful and God was with him, he would be destroyed instantly.
His enemies were “inclosed in their own fat: with their mouth they speak proudly.” These enemies thought themselves to be something; they were rich (fat) and had great resources, and, like the many kings that come and go, they thought this would be their protection. Thus, they are arrogant and rely on their own means. Such is the enemies’ pride. It is also, sadly, the pride of many Christians, who think they can live without God, or without being holy. (Look beyond the neatly pressed suits and ties, the lovely dresses and handbags, and the perpetual evangelical smiles!)
These enemies, says David, have completely surrounded him and his people. The enemies have “set their eyes bowing down to the earth”, or in modern language, they want to grab all the land they can; “bowing down” means to stretch out, extend. Ever known a time when you were surrounded on all sides by enemies or troubles, and cannot see a way out? Then read the Red Sea miracle again and remember – God is the Master of tough situations! In essence, the situation is irrelevant to God, for He can remove the obstacle with a word, something He predetermined before time began! Look up to God, not down to the earth like your enemies.
In my time (and I suspect in the future) I have been literally stopped from progressing anywhere by my enemies or situation. But, at the exact moment of what I thought would be my demise, God caused the situation or enemy to evaporate before my eyes, with a remarkable and amazing response. You see, we can be amazed, shocked, angry, saddened, frightened… but it does not make any difference to God’s plans; He will do what He does anyway.
Grown lions stalk their prey and young lions copy, hiding their presence so as to surprise their victim. Lions tear you apart and the whole pride eat you. That is what these enemies were like. It is what our enemies are like today. I fear that many Christians cannot see the enemies at their door. They do not realise what is going on, and think all is well, even though watchmen are shouting warnings from the walls of the city. It is a mark of spiritual decline.
Modern Christians in the West are comfortable in their relative wealth and position, so they ignore the truth and the reality of modern life. But, Christians in Africa and other Islamic countries know what to fear and avoid, they know that death and danger lurk, like lions, ready to destroy them. Oh that western Christians could taste of the very real dangers others face every day! It would do their souls good and might turn them back to Christ!
Verses 13-15
From men which are thy hand, O LORD, from men of the world, which have their portion in this life, and whose belly thou fillest with thy hid treasure: they are full of children, and leave the rest of their substance to their babes.
As for me, I will behold thy face in righteousness: I shall be satisfied, when I awake, with thy likeness.
After observing the reality of his situation, David comes up with the answer. Bear in mind that David only prays what God has already placed upon his heart to pray about. Thus, whatever he says is from God in the first place, even if modern Christians hate the idea of praying for the downfall of an enemy.
“Arise, O LORD, disappoint him, cast him down”! The word “arise”, quwm, can be used to refer to a hostile rise, as well as powerful, or to stand up on the side of the faithful. In many texts God shows Himself to be hostile towards enemies of the soul and the body, so do not pretend otherwise.
David asks God to “disappoint” the enemy, qadam, to meet him head-on, to confront him, to go before David, just as the holy cloud and pillar of fire went before the Hebrews. Our God is mighty; He has no equal; when He stands for us, no enemy can win against us. The term also means to fall upon someone with great ferocity. God does these things on our behalf, if we are faithful.
God will cast the enemy down, causing him to acknowledge God and to bow before those they wish to harm; to be subdued. In this way, David would be ‘delivered’ or saved from destruction by the rasha’ – the wicked who loathe God and His people.
This action by God on our behalf, is his “sword”, chereb: meaning He would lay the enemies to waste by killing or subduing them. (Matthew Henry sees it differently). The root, charab, means to make them desolate, to put them to ruin. How many modern Christians are afraid to ask God to completely obliterate their enemies? Instead, afraid to appear unloving before their peers (who make the same silly mistakes), they ‘pray for’ enemies of their souls and bodies. That is, they pray for their wellbeing. But, why? David did not do that, nor does God.
If people are wicked and they hate us, we may call upon God to remove them, by whatever means He wishes to use, including death and crushing. There may be times when we can pray for an enemy at first, or if God allows us to. But, many enemies are so wicked we may only pray for their downfall.
For example, a modern enemy is the homosexual movement, which hates God and His people with a passion. Its members are truly wicked. Therefore, we must pray for their destruction. That is the general rule, for some of us might be prompted to pray for the salvation and wellbeing of an individual homosexual. But, as God says, homosexuals do what is an abomination and are cast aside by Him, we have no right whatever to pray for the wellbeing of all homosexuals.
The same applies to Islam, though not to all Muslims (the case is different for a number of reasons), which must be prayed against strongly, because Islam hates the true God and His people. Only staying close to God will show us who to pray for, and who to pray against.
Men are used by God to bring about His bidding, whether they are enemies or friends. (“From men which are thy hand”). The “men of the world” have “their portion in this life”. That is, the unsaved can see no farther than what they have in this world. Satan makes very sure of that. So, they fight for what they have and hate those who try to stop them.
These people receive the general benefits God gives to all mankind – sun, rain, seasons, food, and so on. All share in this bounty, yet few praise God for it. These unsaved souls have many children to carry out their greedy and sinful wishes, and hope to leave what they gain to their children’s children. I find this a remarkable statement that can apply today to the Islamic movement. It, too, raises many children so that they can overrun every country with Islam. That is, with wickedness.
But, David, conversely, wants only spiritual benefit: “As for me, I will behold thy face in righteousness: I shall be satisfied, when I awake, with thy likeness.” God only wants holiness and goodness from God. Yes, he was also a very rich king, but this did not really interest him. His heart was set on the Lord and on His presence. Nothing else should matter to a Christian – but, unfortunately, many want earthly things more than this. There is nothing wrong with enjoying what God provides, but everything wrong in desiring these things above our spiritual wellbeing.
David says he wants to be completely filled with God’s presence, and with His likeness. When he awakes and when he goes to sleep, he only wants to see God and His holiness. Is this your desire on this earth? | 2023-08-14T01:26:59.872264 | https://example.com/article/8872 |
Trump’s approval rating lowest during first days as President
Washington: Newly-inaugurated US President Donald Trump entered the White House with the lowest approval rating of any American President, a new poll revealed.
According to the Gallup poll issued on Monday, 45 per cent of Americans approved of how the real estate mogul is handling his new job – the same as the per cent of Americans who disapprove, The Hill magazine reported.
The figure is far from that of his predecessor Barack Obama, who in his early days in the Oval Office in 2009 had a 68 per cent approval rating and a disapproval rating of only 12 per cent.
The president with the highest approval rating during his first days in the office was John F. Kennedy, in 1961, with 72 per cent, Efe news reported.
George W. Bush was approved by 57 per cent of Americans in his first days as president in 2001, while Bill Clinton’s approval rating was 58 per cent in 1993.
According to the poll, the worst approval ratings after Trump’s are those of Ronald Reagan and George H. W. Bush in 1981 and 1989 respectively, both with 51 per cent.
Richard Nixon, with a 59 per cent approval rating in 1969; Jimmy Carter with 66 per cent in 1977; and Dwight D. Eisenhower, with 68 per cent, are among those with the highest approval ratings.
The poll did not include approval ratings of former President Lyndon B. Johnson as he took the White House in 1963 after the assassination of President Kennedy and Gerald Ford, who took over after Nixon resigned in 1974.
Gallup conducted the telephone survey of 1,525 people between January 20 and 22. | 2024-07-14T01:26:59.872264 | https://example.com/article/4921 |
ere in 57/5 of a minute?
684
How many millimeters are there in 33.56097um?
0.03356097
What is 18/5 of a litre in millilitres?
3600
What is fourty-six fifths of a millennium in years?
9200
How many millilitres are there in one fifth of a litre?
200
What is 9/10 of a millennium in decades?
90
How many millilitres are there in 1/5 of a litre?
200
Convert 0.953576l to millilitres.
953.576
Convert 1.753077l to millilitres.
1753.077
Convert 833858.5 centuries to years.
83385850
How many seconds are there in 2/15 of a day?
11520
What is 25/8 of a kilogram in grams?
3125
What is 0.394816 decades in centuries?
0.0394816
What is five eighths of a century in months?
750
What is twenty-five halves of a millimeter in micrometers?
12500
What is twenty-nine halves of a microgram in nanograms?
14500
What is 2770.875 kilograms in micrograms?
2770875000000
How many millilitres are there in 1/20 of a litre?
50
How many millimeters are there in 9.528883m?
9528.883
How many months are there in four fifteenths of a decade?
32
How many micrometers are there in 84220.92nm?
84.22092
What is 54/5 of a kilometer in meters?
10800
How many months are there in three fifths of a decade?
72
What is 31/5 of a tonne in kilograms?
6200
What is 46284.62 litres in millilitres?
46284620
How many millilitres are there in 5/8 of a litre?
625
How many litres are there in 7.678669 millilitres?
0.007678669
How many weeks are there in 627.338565 minutes?
0.06223596875
How many micrograms are there in 3/50 of a gram?
60000
How many kilograms are there in 9/10 of a tonne?
900
Convert 4.069059ml to litres.
0.004069059
Convert 0.324473km to millimeters.
324473
How many months are there in one fifth of a century?
240
How many minutes are there in 1/5 of a hour?
12
What is 3/50 of a litre in millilitres?
60
How many microseconds are there in 9420.86 nanoseconds?
9.42086
How many millilitres are there in 0.2297117 litres?
229.7117
Convert 0.5520617 tonnes to nanograms.
552061700000000
What is 3.257699 meters in micrometers?
3257699
What is one tenth of a tonne in kilograms?
100
How many millilitres are there in 3/40 of a litre?
75
Convert 1758.1899 months to years.
146.515825
What is 1468.457 grams in tonnes?
0.001468457
How many kilometers are there in 96061.26 nanometers?
0.00000009606126
What is 5/4 of a milligram in micrograms?
1250
How many decades are there in 147.2892 months?
1.22741
How many milligrams are there in 33/5 of a gram?
6600
What is 2.1762666 minutes in days?
0.00151129625
How many milligrams are there in 1/5 of a gram?
200
Convert 12479.4159 hours to weeks.
74.2822375
How many nanoseconds are there in 21/8 of a microsecond?
2625
How many millilitres are there in 3/40 of a litre?
75
What is one fifth of a litre in millilitres?
200
What is 29/5 of a litre in millilitres?
5800
What is 51/8 of a litre in millilitres?
6375
How many millennia are there in 0.382263 decades?
0.00382263
How many nanograms are there in thirteen quarters of a microgram?
3250
How many micrometers are there in 1/4 of a millimeter?
250
Convert 2.18173 decades to years.
21.8173
What is 711627.2 millennia in years?
711627200
How many centimeters are there in six fifths of a meter?
120
What is 3.0263ml in litres?
0.0030263
Convert 35719.95 litres to millilitres.
35719950
How many litres are there in 41.98747ml?
0.04198747
Convert 666.2431l to millilitres.
666243.1
What is 9/10 of a kilometer in meters?
900
What is 1/5 of a microgram in nanograms?
200
Convert 0.6875799ug to kilograms.
0.0000000006875799
What is 33/5 of a microsecond in nanoseconds?
6600
What is 21/5 of a litre in millilitres?
4200
Convert 36.82613 kilograms to nanograms.
36826130000000
How many millimeters are there in 81457.8cm?
814578
How many nanoseconds are there in 3/32 of a millisecond?
93750
How many grams are there in 26.78205 micrograms?
0.00002678205
What is 957.951 nanoseconds in milliseconds?
0.000957951
What is 49901.64 centuries in years?
4990164
How many grams are there in thirty-one fifths of a kilogram?
6200
Convert 2217.618 litres to millilitres.
2217618
Convert 79804.86kg to nanograms.
79804860000000000
Convert 560003.1 weeks to nanoseconds.
338689874880000000000
What is 5/4 of a day in hours?
30
What is three sixteenths of a minute in milliseconds?
11250
How many nanograms are there in 0.9368574 micrograms?
936.8574
What is 0.8898735 millimeters in meters?
0.0008898735
How many minutes are there in nineteen quarters of a day?
6840
How many centimeters are there in 54/5 of a meter?
1080
Convert 0.0122082l to millilitres.
12.2082
What is 41/2 of a centimeter in millimeters?
205
What is 80035.6g in kilograms?
80.0356
Convert 53531.95 minutes to milliseconds.
3211917000
What is 190.310148 nanoseconds in weeks?
0.00000000000031466625
What is 6/5 of a meter in centimeters?
120
Convert 0.0185694 centimeters to millimeters.
0.185694
How many nanometers are there in 1/4 of a micrometer?
250
What is 53/4 of a century in months?
15900
What is seven halves of a minute in seconds?
210
How many millilitres are there in fifteen quarters of a litre?
3750
What is 227.7285 decades in millennia?
2.277285
What is 987901.1 decades in months?
118548132
Convert 878810.6 litres to millilitres.
878810600
How many tonnes are there in 14.69406 milligrams?
0.00000001469406
How many micrograms are there in eleven eighths of a milligram?
1375
How many kilograms are there in seventy-three quarters of a tonne?
18250
How many weeks are there in 216281.17 days?
30897.31
How many months are there in 1/4 of a year?
3
What is 49/5 of a millennium in decades?
980
What is 11/4 of a milligram in micrograms?
2750
What is 0.8028634 litres in millilitres?
802.8634
Convert 9914.166ml to litres.
9.914166
What is 3.551424l in millilitres?
3551.424
What is 82300.77 decades in years?
823007.7
What is 7.331103 grams in nanograms?
7331103000
How many minutes are there in five quarters of a week?
12600
What is 6/5 of a litre in millilitres?
1200
What is 1/36 of a day in minutes?
40
What is 27/5 of a decade in years?
54
How many millennia are there in 898.2445 centuries?
89.82445
How many months are there in 7.175672 centuries?
8610.8064
What is 4/3 of a decade in months?
160
How many litres are there in 0.6482847 millilitres?
0.0006482847
How many micrograms are there in 3/8 of a milligram?
375
How many milligrams are there in one quarter of a gram?
250
What is eighty-one quarters of a day in hours?
486
Convert 323.9849mg to tonnes.
0.0000003239849
How many millilitres are there in 0.2447183 litres?
244.7183
How many meters are there in 1/4 of a kilometer?
250
How many millilitres are there in 42/5 of a litre?
8400
How many millilitres are there in sixty-seven quarters of a litre?
16750
How many milliseconds are there in 9080.854 weeks?
5492100499200
What is one quarter of a week in minutes?
2520
What is 3/8 of a kilogram in grams?
375
How many years are there in 64912.78 millennia?
64912780
Convert 299857.92 microseconds to minutes.
0.004997632
How many microseconds are there in 1/64 of a second?
15625
What is 1.770156 litres in millilitres?
1770.156
What is 55/2 of a millennium in years?
27500
What is one eighteenth of a hour in seconds?
200
Convert 1118.001 centuries to years.
111800.1
What is 22.834956 months in years?
1.902913
What is 55.98227 millilitres in litres?
0.05598227
How many millilitres are there in 1/20 of a litre?
50
How many millilitres are there in 41/2 of a litre?
20500
How many millilitres are there in thirteen eighths of a litre?
1625
How many millennia are there in 3.074187 decades?
0.03074187
Convert 47972.9ng to kilograms.
0.0000000479729
How many micrometers are there in 1/10 of a centimeter?
1000
What is 260.935 years in millennia?
0.260935
What is 7.926257 days in minutes?
11413.81008
How many micrograms are there in 91/2 of a milligram?
45500
How many months are there in twenty-eight thirds of a century?
11200
What is 1.3354623 months in years?
0.111288525
What is 15462.17l in millilitres?
15462170
What is 1.33296 decades in millennia?
0.0133296
How many months are there in 29/3 of a decade?
1160
How many years are there in one tenth of a decade?
1
Convert 0.9822148 kilometers to millimeters.
982214.8
How many months are there in five ei | 2024-07-02T01:26:59.872264 | https://example.com/article/3853 |
396 So.2d 726 (1981)
DWL, INC., a Florida Corporation, David W. Leadbetter and Nancy Leadbetter, His Wife, Appellants,
v.
Walter E. FOSTER, Jr., Appellee.
No. 80-290.
District Court of Appeal of Florida, Fifth District.
March 11, 1981.
Rehearing Denied April 15, 1981.
*727 R. Michael Kennedy of Kennedy & Hogeboom, South Daytona, for appellants.
B. Paul Katz of Black, Crotty, Sims & Hubka, Daytona Beach, for appellee.
FRANK D. UPCHURCH, Jr., Judge.
Appellants appeal from a summary final judgment holding appellee, an attorney, free of liability for professional malpractice.
Appellee was retained by the Leadbetters to represent them in the purchase of a motel. Foster examined the title and represented appellants at the closing on March 4, 1977. A corporation, D.W.L., Inc., was formed to take title to the motel property and the Leadbetters were sole stockholders.
The motel was encumbered by several mortgages and the closing statement prepared by Foster referred to and included the assumption of six mortgages. Although Foster charged for a title examination, he did not render a written title opinion or otherwise evidence the results of that examination.
Among the mortgages on the closing statement was the "Vutskos" mortgage from Nick and Tula Vutskos to James and Sarah White. Its final paragraph provided:
This mortgage is also made on the express condition that if a certain mortgage recorded in Official Records Book 1444, Page 487, of the Public Records of Volusia County, Florida, which has been assigned to the mortgagees herein goes into default then whatever accrued interest and outstanding principal may, at the option of the holder, be added to this Mortgage and Note. The payment of that amount shall be made equally over the time remaining under the same terms and conditions of this Mortgage and Note at the same interest rate.
The Whites contended that the mortgage (the "White" mortgage referred to in the Vutskos' mortgage quoted above)[1] was in default and demanded payment. The Vutskos contended that it was not a valid debt and asserted they would not pay it. A meeting was held in an attempt to resolve the problem. The depositions used in support of the summary judgment do not reflect a clear understanding of what was *728 proposed. Foster claims that the Vutskos agreed if the Leadbetters would pay the $9,000 due to the Whites, the Vutskos would waive a $15,000 payment due in June. The Leadbetters claim they would be relieved of paying the $15,000 in June in exchange for the $9,000 but would ultimately have to pay it, thereby increasing the purchase price $9,000. Therefore, they elected not to make any further monthly payments and did not make the balloon payment due in June.
In August, 1977, the Vutskos foreclosed their mortgage. Appellants sued Foster for malpractice in failing to disclose the "White" mortgage liability. Appellee moved for summary judgment contending that, as a matter of law, the loss of appellant's motel because of their failure to pay the Vutskos' mortgage constituted an intervening cause, precluding any proximate causation between Foster's omission and appellant's damages.
The sole point on appeal is whether appellant's election not to pay the Vutskos' mortgage constituted an intervening cause to support entry of summary judgment.
A person who has been negligent is not liable for damages suffered by another where some separate force or action is the active and efficient intervening cause, the sole proximate cause or an independent cause. Gibson v. Avis Rent-A-Car Systems, Inc., 386 So.2d 520 (Fla. 1980). However, one who is negligent is not absolved of liability where his conduct sets into motion a chain of events resulting in injury to the plaintiff. Gibson at 522. When an intervening cause is foreseeable by the wrongdoer, his negligence may be considered the proximate cause of the injury notwithstanding the intervening cause. Id.
The appellants paid nothing on the White mortgage. Other than the demand for payment by the Whites, which the Vutskos claimed was not legitimate, appellants suffered no inconvenience because of the mortgage. No suit was filed and their possession of the property was not disturbed.
The loss of the property was directly attributable to their refusal to make further payments. Other avenues to resolve their problem were available to them.[2] Their election to do nothing was the intervening cause of their loss rather than the omission of appellee.
The judgment appealed is therefore affirmed.
ORFINGER, J., and CLARK, HAROLD R., Associate Judge, concur.
NOTES
[1] This mortgage was additional security on another debt between the Vutskos and the Whites.
[2] Appellants made no tender of payment conditioned upon removal of the lien, and made no attempt to defend the Vutskos' foreclosure claiming a set-off against the amount due the Whites.
| 2024-01-12T01:26:59.872264 | https://example.com/article/8440 |
Charge state of lysozyme molecules in the gas phase produced by IR-laser ablation of droplet beam.
Molecules exhibit their intrinsic properties in their isolated forms. Investigations of isolated large biomolecules require an understanding of the detailed mechanisms for their emergence in the gas phase because these properties may depend on the isolation process. In this study, we apply droplet-beam laser-ablation mass spectrometry to isolate protein molecules in the gas phase by IR-laser ablation of aqueous protein solutions, and we discuss the isolation mechanism. Multiply charged hydrated lysozyme clusters were produced by irradiation of the IR laser onto a droplet beam of aqueous lysozyme solutions with various pH values prepared by addition of sodium hydroxide to the solution. The ions produced in the gas phase show significantly low abundance and have a lower number of charges on them than those in the aqueous solutions, which we explained using a nanodroplet model. This study gives quantitative support for the nanodroplet model, which will serve as a fundamental basis for further studies of biomolecules in the gas phase. | 2023-11-28T01:26:59.872264 | https://example.com/article/9660 |
Continuous exposure of nicotine and cotinine retards human primary pterygium cell proliferation and migration.
Pterygium is a triangular-shaped hyperplastic growth, characterized by conjunctivalization, inflammation, and connective tissue remodeling. Our previous meta-analysis found that cigarette smoking is associated with a reduced risk of pterygium. Yet, the biological effect of cigarette smoke components on pterygium has not been studied. Here we reported the proliferation and migration properties of human primary pterygium cells with continuous exposure to nicotine and cotinine. Human primary pterygium cells predominantly expressed the α5, β1, and γ subunits of the nicotinic acetylcholine receptor. Continuous exposure to the mixture of 0.15 μM nicotine and 2 μM cotinine retarded pterygium cell proliferation by 16.04% (P = 0.009) and hindered their migration by 11.93% ( P = 0.039), without affecting cell apoptosis. SNAIL and α-smooth muscle actin protein expression was significantly downregulated in pterygium cells treated with 0.15 μM nicotine-2 μM cotinine mixture by 1.33- ( P = 0.036) and 1.31-fold ( P = 0.001), respectively. Besides, the 0.15 μM nicotine-2 μM cotinine mixture also reduced matrix metalloproteinase (MMP)-1 and MMP-9 expressions in pterygium cells by 1.56- ( P = 0.043) and 1.27-fold ( P = 0.012), respectively. In summary, this study revealed that continuous exposure of nicotine and cotinine inhibited human primary pterygium cell proliferation and migration in vitro by reducing epithelial-to-mesenchymal transition and MMP protein expression, partially explaining the lower incidence of pterygium in cigarette smokers. | 2023-11-23T01:26:59.872264 | https://example.com/article/8426 |
During the next year, we plan to complete studies on the dynamics of DNA in solution by single-clipped photon correlation at large scattering angles. Line-width measurements have been made. The main effort will be on data analysis. Secondly, we hope to finish characterizing the lysine-rich histone fraction in order to examine the effects of aggregates on unassociated histone in solution. Finally, we want to examine the detailed behavior of vesicles under different operating conditions. In order to examine complex systems, we need large amounts of data. Thus, we shall work towards automation of our spectrometers by means of either a calculator or a minicomputer. | 2023-10-08T01:26:59.872264 | https://example.com/article/7994 |
U.S. Attorney General Eric Holder and the Department of Housing and Urban Development (HUD) Secretary Shaun Donovan announced today that the federal government and 49 state attorneys general have reached a landmark $25 billion agreement with the nation’s five largest mortgage servicers to address mortgage loan servicing and foreclosure abuses.
“This agreement - the largest joint federal-state settlement ever obtained - is the result of unprecedented coordination among enforcement agencies throughout the government,” said Attorney General Holder said in a statement. “It holds mortgage servicers accountable for abusive practices and requires them to commit more than $20 billion towards financial relief for consumers. As a result, struggling homeowners throughout the country will benefit from reduced principals and refinancing of their loans.”
It’s a deal that will extract some penalties from the banks — about $25 billion — if all states sign on. In exchange, the banks will get what’s known as a “release,” sort of like an immunity, from lawsuits regarding how they handled some home loans.
Most of the money — $20 billion — would go toward writing down principal payments for homeowners who were not foreclosed upon, but who are struggling now. There could be a million such homeowners eligible. The way it would work is that the banks would have targets they have to meet, in terms of what kinds of loans they would have to modify. But the banks would still have a lot of discretion in who gets what.
And there’s another $5 billion in cash, part of which would go to the states to help fund homeowner assistance programs. Some of the rest would go to homeowners who may have been wrongfully foreclosed upon. For them, it’s up to $2,000 each, which is not much if you lost your home.
But some advocates say today’s settlement is a tiny drop in a big bucket.
“It does not do justice for the millions of homeowners who lost their homes or hold the banks fully accountable for their crimes. For homeowners who were defrauded and lost their homes, $2,000 is too little, too late. It is a paltry down payment toward full relief for homeowners,” read a statement from The New Bottom Line, a coalition of housing advocates.
“Despite its flaws, the settlement announced today is stronger than it would have otherwise been because of grassroots groups and the courageous stance of Attorneys General from California, New York, Nevada, Delaware, and Massachusetts, who fought hard to bring more relief to homeowners and make sure that any settlement does not allow the banks to avoid accountability for fraudulent activity not yet investigated. Due to their work and the work of many allies, momentum is building toward broad-scale relief for homeowners,” The New Bottom Line’s statement went on to say.
The advocates the New Bottom Line say what happens next is critical. What happens next is critical. “This is the President’s chance to show he is a champion for the 99%.”
“The Obama Administration needs to make sure that its task force goes the distance and delivers at least $336 billion in principal reduction on underwater mortgages and $50 billion in restitution for affected homeowners,”
Read this online at http://colorlines.com/archives/2012/02/housing_advocates_say_ag-bank_foreclosure_settlement_is_too_little_too_late.html
Thank you for printing out this Colorlines.com article. If you liked this article, please make a donation today at colorlines.com/donate to support our ongoing news coverage, investigations and actions to promote solutions. | 2024-04-22T01:26:59.872264 | https://example.com/article/2911 |
You Can Use The Following Method For Upgrade BLU Vivo XL2 V0070UU MT6737T Android 6.0 / And If You Want To Hard Reset It By Flashing The StockRom/ In Case If You Are Using Any CustomRom And Want Back To Stock Rom And Official Firmware Or Facing The BootLoop Problem. This Method Is Also Useful For SuddenDeath/Bricked/Not Power And Also After Flashing The Stock Rom IMEINull or UnknownBaseband Problems Can Be Solve.
Download Newest SP Flash Tool– It is a very useful utility for fixing soft brick or Stuck cases especially for the Media-Tek devices. You could flash Stock or Custom Rom’s of your choice. | 2023-11-08T01:26:59.872264 | https://example.com/article/8615 |
Q:
What is wrong with this connection string?
Hai guys,
I use the following connection string
<add name="connectionString" connectionString="server=localhost;user id=root; password=; database=lms; pooling=false;" providerName="MySql.Data.MySqlClient"/>
It gives me the error There is no 'lms'@'%' registered.
My database server is localhost and the user account doesn't have a password..
A:
Here's a working connection string for MySql:
server=localhost;user id=root;password=xxx;database=xxx;pooling=false
Can you connect from the command line (using "mysql")?
Is mysql by any chance bound to a different IP other than localhost (in my.ini)?
If you don't have a password, have you tried leaving off password=?
If that doesn't work, you may have to add a password....
| 2023-11-09T01:26:59.872264 | https://example.com/article/3058 |
Here's my guess, a bit inapropriate, but reasonable for the easter age. The characters are Apes, and I think they're raping Link... That's honestly my guess, but don't take my word for it. And I loved the toad thing XD 10/10 | 2024-06-17T01:26:59.872264 | https://example.com/article/1845 |
The inequality of city-level energy efficiency for China.
This paper proposes a new methodology for measuring energy efficiency inequality based on the Shephard energy distance function and the "double" stochastic meta-frontier. To incorporate the regional inequality, we use three different grouping criteria, geography, city features, and strategic development goals. We also explore whether the different city grouping criteria can influence the energy efficiency. A panel data of 284 cities in China from 2003 to 2013 is used for empirical analysis. The results indicate that the regional heterogeneity has significant impact on the energy efficiency. We find that different grouping criteria affect energy efficiency, especially, the urban feature criteria. These results highlight the importance of choosing a proper grouping criteria in meta-frontier energy efficiency analysis. | 2023-12-01T01:26:59.872264 | https://example.com/article/4236 |
Stephenson signs before deadline
Just before the deadline expired, the Reds signed 2011 first-round pick Robert Stephenson. The right-handed high school pitcher will receive a $2 million bonus.
Stephenson, 18, was the 27th overall selection in the 2011 First-Year Player Draft out of Alhambra High School in Martinez, Calif. During his senior season, he was 7-2 with a 1.33 ERA in 64 innings, and he tossed two no-hitters.
“We got him right there at the end,” Reds senior director of amateur scouting Chris Buckley said just after the 12:01 a.m. ET deadline early Tuesday. “You never want to pick a guy in the first round to not sign him.”
And Stephenson was also happy.
“I’m really excited and definitely relieved to get it done,” Stephenson said by phone. “It was literally at the last minute by the phone waiting for a call.”
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4 Comments
Welcome back, Mark. If you were out of town you missed the best weather of the summer and some of the worst baseball. On the other hand, there was a four game winning streak. On the other other hand, that may just give us time to find a higher ledge to jump off of. Mark, do you think the Reds are really serious about Alonso at third or are they just trying to broaden the trade market?
@maxblue — I do think the Reds are serious. They would like to find a way, any way, to get his bat in the lineup. Whether he can play the position is another matter. I guess we’ll see. Interesting that he’s back in LF today.
Archives
Meta
The following are trademarks or service marks of Major League Baseball entities and may be used only with permission of Major League Baseball Properties, Inc. or the relevant Major League Baseball entity: Major League, Major League Baseball, MLB, the silhouetted batter logo, World Series, National League, American League, Division Series, League Championship Series, All-Star Game, and the names, nicknames, logos, uniform designs, color combinations, and slogans designating the Major League Baseball clubs and entities, and their respective mascots, events and exhibitions. | 2024-02-20T01:26:59.872264 | https://example.com/article/2393 |
The Loners
The Loners may refer to:
The Loners (1972 film), American 1972 film
Loners (2000 film), Czech 2000 film
The Loners (2009 film), Israeli 2009 film
See also
Loner (disambiguation) | 2024-06-28T01:26:59.872264 | https://example.com/article/3437 |
Q:
Parsing a file with hierarchical structure in Python
I'm trying to parse the output from a tool into a data structure but I'm having some difficulty getting things right. The file looks like this:
Fruits
Apple
Auxiliary
Core
Extras
Banana
Something
Coconut
Vegetables
Eggplant
Rutabaga
You can see that top-level items are indented by one space, and items beneath that are indented by two spaces for each level. The items are also in alphabetical order.
How do I turn the file into a Python list that's something like ["Fruits", "Fruits/Apple", "Fruits/Banana", ..., "Vegetables", "Vegetables/Eggplant", "Vegetables/Rutabaga"]?
A:
>>> with open("food.txt") as f:
... res = []
... s=[]
... for line in f:
... line=line.rstrip()
... x=len(line)
... line=line.lstrip()
... indent = x-len(line)
... s=s[:indent/2]+[line]
... res.append("/".join(s))
... print res
...
['Fruits', 'Fruits/Apple', 'Fruits/Apple/Auxiliary', 'Fruits/Apple/Core', 'Fruits/Apple/Extras', 'Fruits/Banana', 'Fruits/Banana/Something', 'Fruits/Coconut', 'Vegetables', 'Vegetables/Eggplant', 'Vegetables/Rutabaga']
| 2023-08-23T01:26:59.872264 | https://example.com/article/8870 |
An electronic approach to the detection of pre-cancer and cancer of the uterine cervix: a preliminary evaluation of Polarprobe.
We report on the testing of a prototype of an electronic device for the detection of cervix cancer and its precursors, known as the Polarprobe. The device monitors three aspects of the cervix tissue; two relate to optical properties and the other to dielectric characteristics. The response to tissue stimulation takes the form of an energy pattern which, in conjunction with spectroscopic discriminants, can be digitized to prepare an algorithm. The pattern algorithms are sufficiently characteristic to be afforded names which correspond to tissue states recognizable as normal or abnormal by the clinician. On a tissue observation basis the previously established recognition algorithms derived from 106 volunteers produced assessments which related strongly to colposcopy/histology diagnoses obtained on 77 additional volunteers. This concordance between colposcopy/histology and Polarprobe diagnoses on this primary analysis subgroup ranged from 85% on low-grade intraepithelial abnormalities, and 90% on high-grade cervical intraepithelial squamous neoplasia, to 99% on invasive cancer. An extrapolation of these results suggests false-positive/false-negative rates in the order of 10% are achievable with the current Polarprobe device. | 2024-05-30T01:26:59.872264 | https://example.com/article/3149 |
Jaunpur, Uttar Pradesh
Jaunpur ( is a city and a municipal board in Jaunpur district in the Indian state of Uttar Pradesh. It is located 228 km southeast of state capital Lucknow.
Jaunpur is located to the northwest of the district of Varanasi in the eastern part of the North Indian state of Uttar Pradesh. Demographically, Jaunpur resembles the rest of the Purvanchal area in which it is located.
History
Jaunpur, historically known as Sheeraz-e-Hind, having its historical dates from 1359, when the city was founded by the Sultan of Delhi Feroz Shah Tughlaq and named in memory of his cousin, Muhammad bin Tughluq, whose given name was Jauna Khan. In 1388, Feroz Shah Tughlaq appointed Malik Sarwar, a eunuch, who is notorious for having been the lover of Feroz Shah Tughlaq's daughter, as the governor of the region. The Sultanate was in disarray because of factional fighting for power, and in 1393 Malik Sarwar declared independence. He and his adopted son Mubarak Shah founded what came to be known as the Sharqi dynasty (dynasty of the East). During the Sharqi period the Jaunpur Sultanate was a strong military power in Northern India, and on several occasions threatened the Delhi Sultanate.2
The Jaunpur Sultanate attained its greatest height under the younger brother of Mubarak Shah, who ruled as Shams-ud-din Ibrahim Shah (ruled 1402-1440). To the east, his kingdom extended to Bihar, and to the west, to Kanauj; he even marched on Delhi at one point. Under the aegis of a Muslim holy man named Qutb al-Alam, he threatened the Sultanate of Bengal under Raja Ganesha.
During the reign of Husain Shah (1456–76), the Jaunpur army was perhaps the biggest in India, and Husain decided to attempt a conquest of Delhi. However, he was defeated on three successive attempts by Bahlul Khan Lodi. It is a dominant trend in modern historiography of the period that this defeat was a cause of a large number of eunuchs in the military ranks. Finally, under Sikandar Lodi, the Delhi Sultante was able to reconquer Jaunpur in 1493, bringing that sultanate to an end.
The Jaunpur Sultanate was a major center of Urdu and Sufi knowledge and culture. The Sharqi dynasty was known for its excellent communal relations between Muslims and Hindus, perhaps stemming from the fact that the Sharqis themselves were originally indigenous converts to Islam, as opposed to descendants of Persians or Afghans. Jaunpur's independence came to an end in 1480, when the city was conquered by Sikander Lodhi, the Sultan of Delhi. The Sharqi kings attempted for several years to retake the city, but ultimately failed.
Although many of the Sharqi monuments were destroyed when the Lodis took the city, several important mosques remain, most notably the Atala Masjid, Jama Masjid (now known as the Bari (big mosque) Masjid) and the Lal Darwaza Masjid. The Jaunpur mosques display a unique architectural style, combining traditional Hindu and Muslim motifs with purely original elements. The old bridge over the Gomti River in Jaunpur dates from 1564, the era of the Mughal Emperor Akbar. The Jaunpur Qila, a fortress from the Tughlaq era, also remains in good form.
Jaunpur district was annexed into British India based on the Permanent settlement of 1779, and thus was subject to the Zamindari system of land revenue collection. During the Revolt of 1857 the Sikh troops in Jaunpur joined the Indian rebels. The district was eventually reconquered for the British by Gurkha troops from Nepal. Jaunpur then became a district administrative center.
Present state
Jaunpur is the district headquarters. The district has 2 Lok Sabha and 9 Vidhan Sabha constituencies.
Demographics
As per 2011 Indian Census, Jaunpur NPP had population of 180,362 of which male and female were 93,718 and 86,644 respectively, that is a sex ratio of 1000 males per 924 females. Child population in the age range of 0-6 years was 22,710. The total number of literates in Jaunpur was 128,050, which constituted 71% of the population with male literacy of 75.2% and female literacy of 66.5%. The effective literacy rate of 7+ population of Jaunpur was 81.2%, of which male literacy rate was 86.1% and female literacy rate was 75.9%. The Scheduled Castes and Scheduled Tribes population was 12,703 and 195 respectively. There were 26216 households as of 2011.
Rivers
Gomti, Sai, Varuna, Pili, and Basuhi are the five rivers which make its land fertile.
Transportation
Rail
Jaunpur is well-connected with all major cities of India thanks to Indian Railways. It has four major railway stations: Jaunpur City Railway Station(JOP) and (JNU), Shahganj Junction (SHG), Janghai Junction, Kerakat railway station (KCT). Zafarabad (ZBD) also a railway station where's many train routes are diverted i.e. Allahababd, Varanasi, Lucknow Via Sultanpur, Lucknow via Shahganj, Ghazipur via Jaunpur junction.
Road
Jaunpur is well-connected to Lucknow, Gorakhpur, Varanasi, Allahabad and other cities like Azamgarh, Mirzapur, Janghai, Sultanpur, Kerakat, Ghazipur etc. Mariahu NH-56, SH-36 are the roadways connecting all major cities to Jaunpur.
Jaunpur to Babatpur NH-56 is now 4-lane highway.
Education
University
Veer Bahadur Singh Purvanchal University, formerly Purvanchal University, is in Jaunpur. It was established in 1987 as a residential-cum-affiliating university and is named after Vir Bahadur Singh, former chief minister of Uttar Pradesh.
Institutes
Kutir Post Graduate College, established in 1971.
Jawahar Navodaya Vidyalaya, 21 km south from the district headquarters on Lumbini - Duddhi Road in Katghara Village near Mariahu Tehsil.
Industries
GSG, GS Green Enterpriese Katehari- Leduka Jaunpur was established in March 2017 by the Govt. of Uttar Pradesh, under U.P. Industrial Area Development Act, 1976 to facilitate concentrated effort on Industrial development of eastern Uttar Pradesh.
In its 1st phase of activity, the authority has a fully developed growth center area on 10 acres of land, under growth center scheme of Govt. of India. Hawkins Cookers Limited company has one of the three manufacturing plants in India at Jaunpur to manufacture pressure cookers and cookware.
SIDA (Satharia Industrial Development Authority)
Satharia Industrial Development Authority was established in November 1989 by the Govt. of Uttar Pradesh, under U.P. Industrial Area Development Act, 1976 to facilitate concentrated effort on Industrial development of eastern Uttar Pradesh.
In its 1st phase of activity, the authority has a fully developed growth center area on 508 acres of land, under a growth center scheme of Govt. of India.
Virtually all kind of industrial, commercial and social infrastructural facilities, such as Medical, Educational, Residential, Roads, Transportation, drainage, Telecommunication, dedicated industrial power 33/11 KV supply, post office, bank, water supply, community center, shopping center, field hostel etc., have been fully established and are operative.
Local products
Under One District, One Product (ODOP) Scheme 2018 of the UP Govt., perfume and carpet industry have been selected for Jaunpur district.
Local Media
Mostly all major English, Hindi and Urdu dailies including Times of India, Hindustan Times, The Hindu, Dainik Jagran, Amar Ujala, Hindustan, Rashtreey Sahara, Inquilab, Hausla News available in Jaunpur. Hindi and Urdu dailies also have their bureaus in the city. Almost all major Hindi TV news channel have stringers in the city.a Hindi newspaper Tarunmitra is also published from Jaunpur.
Landmarks
There are a number of tourist attractions in Jaunpur including monuments, and holy places.
Monuments
Shahi Bridge
Shahi Quila Jaunpur Fort
Religious Sites
Atala Masjid, Jaunpur
Jama Masjid, Jaunpur
Lal Darwaza Masjid, Jaunpur
Sheetala Chaukia Dham Mandir Jaunpur
Notable people
Ashok Bhushan
Banarasidas
Harivansh Singh
Hasan Abidi
Indu Prakash Singh
Lalji Singh
Mohammad Akram Nadwi
Muhammad Jaunpuri
Parasnath Yadava
Ravi Kishan
Sharadindu Bandyopadhyay
Syed Wazir Hasan
Tribhuvan Ram
Yadavendra Dutt Dubey
References
External links
Category:Jaunpur
Category:Cities and towns in Jaunpur district
Category:Cities in Uttar Pradesh | 2024-05-31T01:26:59.872264 | https://example.com/article/1458 |
Before the draft I put out my series of Draft Tiers. Tier one was the players I believed would immediately make two positions better. Lions first round pick Jarrad Davis was among those I put in that group. Tier Two were players I believed would immediately start for the Lions from the moment they walked in the door. Rather than a straight copy of my impact tiers, this is a list of the top 35 remaining players for Lions day two selection, most of whom made those lists. Every one of these players will be a starter in the NFL in my opinion.
Lions Day Two Draft Selections: The Best of The Rest
Chidobe Awuzie A toolbox corner capable of playing any coverage well. Cordrea Tankersley A ball-hawking press corner, but not lost in other coverage types. Joe Mixon The best RB in the draft, but also, the most controversial pick. Obi Melifonwu The Draft’s premier workout warrior, but he can also play. Dalvin Cook Off the field issues are the reason he is still on the board. Forrest Lamp The best offensive lineman in this draft, immediately a great guard. Buddah Baker Hard hitting but slightly undersized safety. Alvin Kamara Dynamic return ability, and explosive one cut runner. Zay Jones The best hands in the draft. good speed, decent size. Kevin King Big and athletic corner used to being the guy across the field from a great CB. Dan Feeney A high end interior lineman that would finish off the Lions overhaul. Akhelo Witherspon This corner has ideal height, and athleticism. He gets his hands on balls. Carl Lawson The best pass rusher left in the draft, better than a couple that were taken already. Tarell Basham The most promising pass rusher in the draft, May become better than some who have already been taken. Amara Darboh Excellent hands, big bodied, and good speed are why a team might want him. Malik McDowell Inconsistent effort and bad interviews, but a very talented lineman. Fabian Moreau He was a very good corner but the injuries are concerning Josh Jones Aggressive play making safety. Freakishly good athlete. Caleb Brantley Interior pass rusher that gets the job done vs the run too. Tyus Bowser Flamethrower off the edge, but also able to handle coverage a bit. Jordan Willis The left defensive end type the Lions need across from Ziggy Ansah Marcus Maye Field general type safety that kept Florida’s talented group organized. Cooper Kupp He’s a smart receiver who understands his limitations and works within them to get the best results. Derek Rivers Raw small-school pass rusher that has the traits to become a game-changer. Adam Shaheen Raw small-school tight end that has the traits to become a game-changer Tyler Elflein Polished interior offensive lineman. Snaps it directly to the QB without a glance, every time. Like clockwork. Chris Wormley Big and athletic Michigan lineman. May be able to do more than asked in college Justin Evans Athletic safety prospect. More of a hitter than a form tackler. Montravious Adams Thick three-technique with an explosive first step off the ball. Dalvin Tomlinson He’s a very similar player to A’Shawn Robinson, but a bit more burst. Zach Cunningham Slick coverage linebacker with insane hype he wouldn’t match, but a great value in round three. Curtis Samuel Able to fill in as a RB, but likely going to make his living downfield and returning kicks. Rasul Douglas A big-bodied corner who may need to transition to safety. Alex Anzalone Injuries are the thing that have held Anzalone back from being among the elite linebackers of this class. Nathan Peterman If you’re looking for a day two quarterback, this is the best one. I don’t think the Lions are, but if they were…
Those are my top 35 players who remain on the board. I will be disappointed if the Lions day two choices aren’t on this list. | 2024-07-24T01:26:59.872264 | https://example.com/article/8392 |
PROJECT SUMMARY/ABSTRACT Arterial thrombotic diseases such as ischemic heart disease are the leading cause of disability and death in the United States. Platelet adhesion and formation of thrombotic platelet aggregates at the site of a ruptured atherosclerotic plaque or damaged endothelium under arterial blood flow is essential in the pathogenesis of arterial thrombosis. Under high or disturbed flow conditions, the initial interaction between platelets and the vessel wall is primarily mediated by von Willebrand factor (vWF) and platelet glycoprotein Iba (GPIba), which subsequently leads to platelet content release, aggregation, and activation of the coagulation. These mechanisms, which are critical for both hemostasis and thrombosis, are targets of current FDA-approved antiplatelet therapies. Although they are effective, all have the life-threatening side effect of causing bleeding, which significantly limits their clinical use. To address this unmet need, it is critical to further elucidate insights into mechanisms essential for thrombosis but dispensable for hemostasis. Recent published data from several independent labs show that platelet CLEC-2 (C-type lectin-like receptor 2) is important in arterial thrombosis. However, how CLEC-2 regulates arterial thrombosis is unknown. The lectin-domain of CLEC-2 is known to bind to sialylated O-glycans. Our preliminary data showed that CLEC-2 interacts with GPIba in a sialylation-dependent manner. Furthermore, our preliminary results reveal that CLEC-2 promotes GPIba- mediated activation of integrin ?IIb?3, which is critical for arterial thrombus growth and stability in vivo. Importantly, blocking CLEC-2 function does not prolong the bleeding time in vivo. Therefore, we hypothesize that CLEC-2 is critical for GPIba-mediated platelet activation that is required for arterial thrombus growth and stability. To test this, we will 1) test the hypothesis that CLEC-2 regulates GPIba-mediated platelet activation through interaction between its lectin-like domain and sialylated O-glycans of GPIba as GPIba is heavily modified by sialylated O-glycans; 2) determine if/how CLEC-2 stabilizes the arterial thrombus by facilitating GPIba-mediated integrin aIIbb3 activation using mouse and human arterial thrombosis models. CLEC-2 and GPIba are expressed at similar high levels on murine platelets, and both receptors are essential in arterial thrombosis. However, the mechanisms underlying their role in arterial thrombosis have been either elusive (GPIba) or unknown (CLEC-2). Our proposed study will provide new mechanistic insights into these outstanding questions in the field. It may lead to the development of a new effective and safe anti-thrombosis therapy. | 2024-05-15T01:26:59.872264 | https://example.com/article/1082 |
Tracheal pH monitoring: a pilot study in tracheostomy dependent children.
1. Determine the feasibility of measuring tracheal pH with a novel non-aqueous probe designed for oropharyngeal pH monitoring. 2. Correlate clinical and subclinical laryngopharyngeal reflux aspiration events with esophageal pH measurements. Five children with chronic indwelling tracheostomies undergoing routine endoscopy and pH probe monitoring at a tertiary care pediatric aerodigestive center between October 2007 and January 2008 were identified for this prospective feasibility pilot study. The non-aqueous Restech Dx-pH probe was subsequently affixed to each child's tracheostomy with the probe tip confirmed to be within the tracheal lumen. Esophageal and tracheal probe pH measurements were subsequently recorded until the child was unable to tolerate the study or 24 h elapsed. Tracheal pH tracings were compared directly to esophageal pH tracings. Esophageal biopsy and bronchoalveolar lavage data were reviewed for each child. 3/5 children tolerated the tracheal probe for greater than 18 h. Adequate tracheal pH tracings were demonstrated for all children while the probe was in position. Mean baseline tracheal pH was 7.8. One child demonstrated direct correlation between acidic esophageal reflux events and decreased tracheal pH. Esophageal biopsy confirmed the presence of active inflammation consistent with reflux in this child. Tracheal pH can be accurately recorded with the Restech Dx-pH probe. The technology may allow further investigations to determine the impact of gastroesophageal refluxate aspiration and empiric antireflux therapy in children with aerodigestive symptoms. | 2024-07-31T01:26:59.872264 | https://example.com/article/5073 |
Experimental chronic Chagas' disease myocarditis is an autoimmune disease preventable by induction of immunological tolerance to myocardial antigens.
The protozoan Trypanosoma cruzi causes chronic Chagas' disease myocarditis (CCDM) in infected mammals. The pathogenesis of CCDM, however, is still unclear. Indirect evidence for either parasite- or heart-specific immune responses playing a pathogenic role is available. In this work, the participation of autoimmunity in the development of CCDM is demonstrated in mice in which immunological tolerance to heart antigens was induced or strengthened prior to their infection by T. cruzi. Tolerance was induced by heart antigen administration in the presence of complete Freund's adjuvant and anti-CD4 antibodies. Tolerized mice developed less intense CCDM than control non-tolerized animals that had received only anti-CD4 and adjuvant. This result confirms the important notion that tolerance to self, and in particular to heart antigens, may be reinforced/induced in normal animals, and raises the possibility that analogous interventions may prevent the development of CCDM in millions of T. cruzi -infected human beings. | 2024-05-08T01:26:59.872264 | https://example.com/article/8675 |
About this page
This is the page with our 4.3 release notes. It should be final now that the 4.3 version itself has been released. However, if you spot any missing or incorrect information, then please let us know. Thanks in advance for your help!
Writer
Raise limit of characters in paragraphs
Raise the 16bit (65,535) characters limitation of Writer paragraphs to 32bit (2,147,483,647). Especially useful in locales where there is a requirement to record minutes of meetings in a single paragraph. tdf#30668, i#17171 (Caolán McNamara)
A paragraph with more than 64k characters
Moved Navigation buttons
The Navigation buttons have been moved from below the scrollbar to the Find bar (Samuel Mehrbrodt, UX-Advise Team)
Before After
Increase/decrease font size buttons
Removed the 72 pt limitation of the Increase font button. tdf#73414 (Maxim Monastirsky, Caolán McNamara)
Also added Increase/decrease font functionality to drawing objects. commit (Maxim Monastirsky)
DrawingML import/export
Brand new drawingML-based DOCX import/export filter for shapes and TextFrames. For more details, see this blog entry. (Miklos Vajna)
Import and export of nested comments in the ODF, DOC, DOCX and RTF filters. i#123792 (Oliver-Rainer Wittmann - Apache: ODF filter and DOCX import part, Miklos Vajna: DOCX export and RTF/DOC filter parts)
Nested comments in a file imported from RTF.
Proportion image scaling
Images are now scaled proportionally by default, free resizing is available holding ⇧ Shift . tdf#71669 (Tomaž Vajngerl)
Solarized blue for Non-printing characters
Non-printing Characters are shown with "Solarized blue" color (currently not available on macOS). tdf#68071 (Tomaž Vajngerl)
Relative text frame anchoring improvements
Multiple relations are now supported for relative text frames. For more details, see this blog entry. (Miklos Vajna)
Relative textframes: relative from page or paragraph.
Vertical alignment for text frames
Vertical alignment of text (and other content) is now supported for text frames. This can be set under the "Options" tab. (Zolnai Tamás)
Vertical alignment for text frames
Comments can now be printed next to the text in the right margin as they appear on screen. Each page is scaled down in order to make space for the comments to fit on the underlying paper size. tdf#36815 (Caolán McNamara)
New 'Place in margins' option Sample output pdf with comments in margin
The character properties of all comments can be set at the same time now in order to reformat all comments in a document at the same time. (Caolán McNamara)
New 'Format all comments' option
Unicode-compliant soft hyphen handling
Soft hyphens can result non-standard hyphenation, according to the Unicode standard, and (soft hyphen based) hyphenation dialog window suggests these hyphenation points, too. tdf#44314 (László Németh)
Non-standard hyphenation support in user-defined dictionaries
In the user-defined dictionaries, now it is possible to use a [] block instead of the = sign to specify character changes before the hyphenation break. Possible character changes:
Extra characters, for example tug[g]gumi results the correct hyphenation “tugg- gummi” of the Swedish word “tuggummi”.
Character removing specified by a digit, for example paral·[1]lel results correct hyphenation “paral- lel” of the Catalan word “paral·lel”, removing one character before the break point.
Both removed and extra characters, for example cafee[2é]tje results correct hyphenation “café- tje” of the Dutch word “cafeetje”, removing two characters before the break point, and adding an extra one.
Note: also it is possible to complete the hyphenation of Dutch, Norwegian, Swedish, Catalan, Hungarian without the modification of the TeX-like hyphenation patterns, using a default shared user-defined dictionary file. (László Németh)
New non-standard hyphenation support in user-defined dictionaries
LibreLogo
Improvements of LibreLogo, the Logo-like programming environment of LibreOffice for graphic design and education:
Several user interface fixes
New PENTRANSPARENCY, FILLTRANSPARENCY commands to set transparency after PENCOLOR, FILLCOLOR usage
A transparent circle with 50% transparent outline (the orange part is the overlapping of the circle and its outline). Source code: PENSIZE 100 PENCOLOR “GOLD” PENTRANSPARENCY 50 FILLCOLOR “RED” FILLTRANSPARENCY 50 CIRCLE 450
Color and transparency gradients are now supported via FILLCOLOR and FILLTRANSPARENCY commands. (introduction)
Example for LibreLogo color gradient support. Code: PENUP REPEAT 100 [ FILLCOLOR [ANY, ANY] CIRCLE 20 + RANDOM 130 POSITION ANY ]
For additional information, see the new portal for LibreLogo news and examples: LibreLogo.org
Calc
Smarter highlighting of cell in a formula
Border highlight on multiple instances of the same cell, when selecting a formula, now get same color. After calculating a long formula, the cells can be easily referenced with the formula, as they get the same color i.e., the highlight of the cell and the name of the cell in the formula. tdf#52461 (Rachit Gupta)
Before After
Number selected rows and columns in status bar
When selecting cells, the number of selected rows and columns is shown in the status bar. tdf#64290 (Manmeet Singh)
See the number of selected rows and columns in the status bar.
Sheet tab area: when expanding the space available for sheet tabs make better use of that. (Michael Meeks)
Start cell edit with content of cell above
Allow starting of cell edit with the content of the cell above it as its initial content. It is bound to the Ctrl + ' (single quote) key by default. (Note: On some locales this keyboard shortcut may conflict with the system default shortcuts. If the default shortcut does not work due to conflict, bind it to a different shortcut). (Kohei Yoshida)
Starting cell edit with the formula from the above cell.
User selectable text conversion models
Under Tools ▸ Options ▸ LibreOffice Calc ▸ Formula in Detailed calculation settings ▸ Custom ▸ Details the user can select how textual cell content shall be treated in arithmetic operations. See also this blog entry for some details. tdf#37132 and tdf#75834 related (Eike Rathke)
Pivot Table layout improvement
"Data" field is now on columns by default, and can be moved to rows if needed. This makes it much faster to generate useful pivot tables from large data sources. tdf#77927 (Tomaž Vajngerl)
Before version 4.3, it was only possible to generate pivot table with data field on rows.
Start from LO 4.3, it's also possible to generate pivot table with data field on columns.
Formula engine
Added GAMMA.DIST, GAMMA.INV and GAMMALN.PRECISE spreadsheet functions for Excel interoperability. tdf#71936 (Winfried Donkers)
Added LOGNORM.DIST, LOGNORM.INV, NORM.DIST, NORM.INV, NORM.S.DIST and NORM.S.INV spreadsheet functions for Excel interoperability. tdf#72158 (Winfried Donkers)
Added T.DIST, T.DIST.2T, T.DIST.RT, T.INV, T.INV.2T and T.TEST spreadsheet functions for Excel interoperability. tdf#72793 (Winfried Donkers)
Added PERCENTILE.EXC, PERCENTILE.INC, PERCENTRANK.EXC, PERCENTRANK.INC, QUARTILE.EXC, QUARTILE.INC, RANK.EQ and RANK.AVG spreadsheet functions for Excel interoperability. tdf#73146 (Winfried Donkers)
Added MODE.SNGL, MODE.MULT, NEGBINOM.DIST and Z.TEST spreadsheet functions for Excel interoperability. tdf#72197 (Winfried Donkers)
Added FLOOR.PRECISE, CEILING.PRECISE and ISO.CEILING spreadsheet functions for Excel interoperability. tdf#71720 (Winfried Donkers, Eike Rathke)
Added NETWORKDAYS.INTL and WORKDAY.INTL spreadsheet functions for Excel interoperability. tdf#73147 (Winfried Donkers)
Added ERF.PRECISE and ERFC.PRECISE spreadsheet functions for Excel interoperability. tdf#73149 (Winfried Donkers)
Enable CoinMP solver
Previously LibreOffice shipped the lpsolve solver, now we can build both the lpsolve and coin-mp solvers. (Matúš Kukan)
Statistics Wizard (alternative to Excel's Add-in "Analysis ToolPak")
In Statistics Wizard Data ▸ Statistics
added Two factor Analysis of Variance (ANOVA) (Tomaž Vajngerl)
added F-test. tdf#74663 (Tomaž Vajngerl)
added t-test. tdf#74668 (Tomaž Vajngerl)
Random number generation
In random number generation dialog box Edit ▸ Fill ▸ Random Number, now user can optionally limit the number of decimal places in the generated random number. tdf#76718 (Tomaž Vajngerl)
The new rounding option for random number generation
Impress and Draw
Number of Pages
Hidden slides are no longer included in the “Number of pages” counting field, to avoid confusion. tdf#74383 (J. Fernando Lagrange)
Fit slide to window
Add an icon to the statusbar to allow fitting the current slide to window with a single click. (Caolán McNamara)
Fit slide to current window
Slide Pane selected/unselected slides with mouse over
It is now possible to distinguish between selected and unselected slides when the mouse over highlight activates. rhbz#1096295 (Caolán McNamara)
Before, Selected or Unselected After, Unselected After, Selected
3D models
LibreOffice now supports inserting 3D models in the glTF format into presentations (using libgltf). To use this feature, go to Insert ▸ Object ▸ 3D Model. Currently this option is available for Windows and Linux. (Zolnai Tamás, Jan Holesovsky, Markus Mohrhard).
Static model: Duck
Animated model: Monster
Monster 3D model
Limited support for 3D models in *.dae and *.kmz formats (using collada2gltf). (Zolnai Tamás, Matúš Kukan).
For more information about 3D model support see this blog post.
Base
LibreOffice bundles a new version of Access2Base, see Scripting / Base for details.
Chart
Property Mapping
Added property mapping functionality for charts, allowing to change data series properties based on spreadsheet values. For more details see this blog entry (Markus Mohrhard)
The new Property mapping dialog
Core
Accessibility
On Windows, IAccessible2 is now the only assistive technology support option. Support for the Java Accessibility Bridge has been removed, and turning on experimental features is no longer necessary in the Advanced options to enable assistive technology support.
Added new, specialized roles for specific text, spreadsheet and presentation documents. tdf#39944 (blog post) (Jacobo Aragunde)
Improve mapping of ATK and LibreOffice roles, matching new(ish) ATK roles with existing UNO ones. tdf#39944 (blog post) (Jacobo Aragunde)
Expose the role change between a heading and a paragraph through a new UNO accessibility event. tdf#35105 (blog post) (Jacobo Aragunde)
Remove unnecessary text-attributes-changed events when typing. tdf#71556 (Jacobo Aragunde)
Notify misspelled words to accessibility. tdf#71558 (Jacobo Aragunde)
Use quick help text as the accessible name for toolbar buttons if not explicitly set. tdf#74681 (Jacobo Aragunde)
VCL (GUI Toolkit)
Major refactoring and cleanup of the VCL code (Chris Sherlock)
Options / General
CUPS, fax machines and spadmin
LibreOffice will now autodetect that fax4CUPS printers are fax machines and prompt for the fax number to use when you print to them. Multiple numbers, separated by commas, can be entered.
Other printer drivers that contain custom options which can take arbitrary text or numbers are now supported. So to set the phone number for printer drivers for fax machines that utilize a custom option for that purpose the number can be entered in the device tab of the printer properties.
The graphical utility spadmin is now removed in favor of these new features and the operating system's standard printer administration tools. (Caolán McNamara)
Filters
Improved PDF import
Improved OOXML support
Initial import support for OOXML Strict in the DOCX, XLSX and PPTX formats. For more details, see this blog entry. (Markus Mohrhard, Miklos Vajna)
Theme fonts support: detect and render the proper fonts and preserve font theme attributes. Details in this blog entry. (Jacobo Aragunde)
Preserve theme colors on fonts, paragraphs and table cells. (Jacobo Aragunde, blog entry)
Preserve style attribute on shapes and tables. (Jacobo Aragunde)
Preserve line and fill theme colors on shapes, including color transformations. (Jacobo Aragunde, blog entry)
Preserve gradient shape fill, although the render is not accurate the gradient information is completely preserved on export. (Jacobo Aragunde, blog entry)
Save embedded spreadsheets, presentations, etc. in docx documents. (Jacobo Aragunde)
Improved Standard Document Tags support: fix export of date and checkbox controls, fix import of combobox controls reusing dropdown control and preserve the other kinds of tags. (Jacobo Aragunde)
Preserve effects on shapes and pictures, including 3D effects and artistic effects. (Jacobo Aragunde, blog entry)
Artistic effects in Writer
Improved handling of Writer track changes in groupshape text. (Miklos Vajna, blog entry)
Group shape with change tracking text in Writer
Shape adjustment names are now exported according to the specification. tdf#73215 (Miklos Vajna)
VML import now handles optional command parameters. commit (Miklos Vajna)
Improved drawingML export of pattern fill for shapes. commit (Miklos Vajna)
DOCX import now handles explicit horizontal merges of table cells. tdf#65090 (Miklos Vajna)
DOCX import now handles floating tables anchored inside tables. tdf#74357 (Miklos Vajna)
New import filters
Microsoft Works spreadsheets and databases (Laurent Alonso)
A host of legacy Mac formats (Laurent Alonso) spreadsheets: BeagleWorks, ClarisWorks, Claris Resolve, GreatWorks, MacWorks, Wingz vector and bitmap images: BeagleWorks, ClarisWorks, GreatWorks, MacPaint, MacWorks, SuperPaint
GUI
Available since 4.3.1 There was a leftover 1 px border around the Start Center, which is now removed. core commit 2b2d1bbaf9af0ec177e27fd930cd63c6bfdc2ab9 (Adolfo Jayme Barrientos)
There was a leftover 1 px border around the Start Center, which is now removed. core commit 2b2d1bbaf9af0ec177e27fd930cd63c6bfdc2ab9 (Adolfo Jayme Barrientos) Available since 4.3.1 The background color was tweaked and unified with that of the rulers, streamlining and improving the default look. tdf#51534, tdf#79278 (Michael Meeks, Adolfo Jayme Barrientos)
The rulers harmonize with the background again; the darker color helps to focus on the document and reduces eye strain.
Refreshed Tango icons
The default Tango icon set has received a general update, including the addition of new icons for the Sidebar. (Alexander Wilms, Miroslav Mazel)
Native background rendering on macOS
Native rendering of toolbars background on macOS. tdf#69358 (Joren De Cuyper, Jan Holesovsky, Tor Lillqvist)
Native toolbar background
Color pickers improvements
Line color picker now uses a color palette instead of a list. tdf#46839 (Maxim Monastirsky)
Before After
Several color pickers were converted to split buttons, making it possible to apply the last used color with one mouse click. This includes: Font color (Impress, Draw), Font color of drawing objects (Writer, Calc), Line color, 3D Extrusion color. commit (Maxim Monastirsky)
Start Center improvements
Preview of all file types in start center, not only ODF. tdf#72469 (Jan Holesovsky)
Selectively delete Recent Documents (Jan Holesovsky)
Selectively delete Recent Documents
Initial HiDPI support
Some HiDPI support for Linux and Windows, most of the patches have been backported to 4.2.3 (Keith Curtis, Jan Holesovsky, Caolán McNamara, Andrzej Hunt)
Progressbar for DOCX documents
DOCX import now has a progressbar. tdf#58044 (Miklos Vajna)
Progressbar while opening a DOCX file.
Localization
Font support
Available since 4.3.1 We now ship Adobe’s Source Sans Pro 2.0, which includes a greatly expanded range of characters. It now supports the Cyrillic, Greek and IPA writing systems, tweaks several diacritic marks and adds the new Russian Rupee sign ( ₽ , U+20BD , included since Unicode 7.0). tdf#81095 (András Tímar)
New languages/locales in language list
Available for character attribution and spell-checking.
Added Maninkakan, Eastern, Latin [emk-Latn-GN]. tdf#74672 (Eike Rathke)
Added Avar [av-RU]. tdf#75161 (Eike Rathke)
Added Cree, Plains, Latin [crk-Latn-CN] and Syllabics [crk-Cans-CN]. tdf#73973 (Eike Rathke)
New languages/locales with locale data
Available as default document language and for locale specific formatting.
Added Lengo [lgr-SB] locale data. tdf#72512 (pcunger, Eike Rathke)
Added Moore [mos-BF] locale data. tdf#78647 (David Delma, Eike Rathke)
Added French (Côte d'Ivoire) [fr-CI] locale data. tdf#79348 (David Delma, Eike Rathke)
Added French (Mali) [fr-ML] locale data. tdf#79349 (David Delma, Eike Rathke)
Added French (Senegal) [fr-SN] locale data. tdf#79350 (David Delma, Eike Rathke)
Added French (Benin) [fr-BJ] locale data. tdf#79351 (David Delma, Eike Rathke)
Added French (Niger) [fr-NE] locale data. tdf#79352 (David Delma, Eike Rathke)
Added French (Togo) [fr-TG] locale data. tdf#79353 (David Delma, Eike Rathke)
Adding a new language tag
In character attribution dialogues the language list box (of the Western text font if CJK or CTL are enabled) is now a combo box with an edit field where the user can specify a valid BCP 47 language tag to define a text language attribute if the language they wants to assign is not available from the selectable list. (Eike Rathke)
Performance
Algorithm of reordering sorted data has been overhauled. Sorting of large data set is now substantially faster. (Kohei Yoshida, Michael Meeks)
Importing OOXML documents with lots of relations is much faster. (Michael Meeks)
Much accelerated DOCX hyperlink import. tdf#76563 (Miklos Vajna)
Scripting / Base
Access2Base new version
LibreOffice bundles Access2Base V1.1.0, a simplified API for scripting of Base (and database forms stored in Writer, Calc, ... documents) in the Basic programming language. It is more concise and easier to learn than the cross-language standard UNO API. The current version allows dynamic data access from any Basic macro, including, just as an example, from a user-defined function invoked in a Calc cell formula. (Jean-Pierre Ledure)
Feature removal / deprecation
Exporting to the OpenOffice.org 1.0 XML file format was removed; users are recommended to save in ODF, which is a perfect substitute that is better in all respects. Import of old files is still possible. (Bryan Quigley)
The Sidebar in Draw doesn't have an "Insert Shapes" panel anymore. tdf#73070 (Rob Snelders)
API changes
Removed configuration options
C++ UNO language binding and URE libraries
All inline C++ functions that took a sal_Bool parameter by value or returned sal_Bool have been changed to use bool instead. This should effectively be transparent to client code, and potentially helps static analyzers produce better diagnostics.
parameter by value or returned have been changed to use instead. This should effectively be transparent to client code, and potentially helps static analyzers produce better diagnostics. cppu::Enterable::v_isValid returns bool instead of int core commit 81cb6a7fbc315d3287e7a485b73a1b66dd4478ef
instead of core commit 81cb6a7fbc315d3287e7a485b73a1b66dd4478ef Removed the cppu::loadSharedLibComponentFactory override with rPrefix parameter, intended only for internal use anyway. core commit 2f7b329297c65d75f428d389a53b5822e38b0ec5
override with parameter, intended only for internal use anyway. core commit 2f7b329297c65d75f428d389a53b5822e38b0ec5 Removed rtl/allocator.hxx , intended only for internal use anyway. core commit a908e4eb41b83d051232f9e551e779e77c9a9c4f
, intended only for internal use anyway. core commit a908e4eb41b83d051232f9e551e779e77c9a9c4f Removed the obsolete functions originally underlying osl/diagnose.h before that got rebased onto sal/log.hxx core commit 97354578d7195bce927f0c00c4e2ae9cd7344776
OSL macro clean up
Remove dead support for nonexisting UNO “array” and “union” concepts
Removed functionality of
typelib_static_array_type_init function
function typelib_typedescription_newArray function
function typelib_typedescription_newUnion function
function typelib_ArrayTypeDescription struct
struct typelib_UnionTypeDescription struct
struct getCppuArrayType * inline functions
core commit a2c464868aca4bb38aa8afff635da56942b597ac
UNO API changes
Removing XInitialization from a service implementations
Deprecating com.sun.star.lang.XTypeProvider.getImplementationId
Implementations should just always return an empty sequence, and clients should be prepared to routinely obtain empty sequences (which already could have happened in the past) or (better) not call this method at all. core commit dd1050b182260a26a1d0ba6d0ef3a6fecc3f4e07
Other
Platform Compatibility
Windows
Updated build environment on Windows (Windows Server 2012R2 with Visual Studio 2012).
Known Issue: there are problems with running the Windows release on older CPUs that lack support for SSE2 instructions, see tdf#82430.
Affected CPUs include Intel Pentium III and older, and all AMD 32-bit CPUs (Athlon XP and older).
Mac
macOS 32 bits build and version 10.6 and 10.7 are deprecated.
Most Annoying Bugs
The following annoying bugs were not fixed in time and will be addressed in the regular bug fix releases: | 2023-11-19T01:26:59.872264 | https://example.com/article/7433 |
Q:
Geotools conditional Style based on attribute
How do I style different elements of a layer differently, depending on the value of an attribute?
For example, I have time zone data which includes an attribute associating an integer from 1 to 8 to each time zone, for the purposes of colouring the time zones on a map. How can I associate a style to each value of the attribute, and use it to colour the time zones in different colours?
A:
This answer is for Geotools 9.2
Below is an example which you can adopt, see below for some ideas how to apply it to your requirements.
The example is about polygons. It has different styles for selected and visible features and for small and large scales:
protected final StyleFactory styleFactory =
CommonFactoryFinder.getStyleFactory(GeoTools.getDefaultHints());
protected final FilterFactory2 filterFactory =
CommonFactoryFinder.getFilterFactory2();
protected Rule createLayerRule
( Color outlineColor
, float strokeWidth
, Color fillColor
, float opacity
, Filter filter
, double minScaleDenominator
, double maxScaleDenominator)
{
Stroke stroke =
outlineColor != null
? styleFactory.createStroke
( filterFactory.literal(outlineColor)
, filterFactory.literal(strokeWidth)
, filterFactory.literal(opacity))
: null;//Stroke.NULL;
Fill fill =
fillColor != null
? styleFactory.createFill
( filterFactory.literal(fillColor)
, filterFactory.literal(opacity))
: null;//Fill.NULL;
PolygonSymbolizer symbolizer =
styleFactory.createPolygonSymbolizer(stroke, fill, null);
return createRule(filter, minScaleDenominator, maxScaleDenominator, symbolizer);
}
// IDs of visible features, programmatically updated.
protected final Set<FeatureId> visibleFeatureIDs = new HashSet<FeatureId>();
// IDs of selected features, programmatically updated.
protected final Set<FeatureId> selectedFeatureIDs = new HashSet<FeatureId>();
protected Style createLayerStyle()
{
Filter selectionFilter = filterFactory.id(selectedFeatureIDs);
Filter visibilityFilter = filterFactory.and
( Arrays.asList
( filterFactory.not
(selectionFilter)
, filterFactory.id(visibleFeatureIDs)
)
);
FeatureTypeStyle fts = styleFactory.createFeatureTypeStyle
( new Rule[]
{
// hope constants below are self explaining
createLayerRule
( SELECTED_OUTLINE_COLOR
, STROKE_WIDTH_LARGE_SCALE
, SELECTED_FILL_COLOR
, SELECTED_OPACITY
, selectionFilter
, STYLE_SCALE_LIMIT
, Double.NaN)
, createLayerRule
( UNSELECTED_OUTLINE_COLOR
, STROKE_WIDTH_LARGE_SCALE
, UNSELECTED_FILL_COLOR
, UNSELECTED_OPACITY
, visibilityFilter
, STYLE_SCALE_LIMIT
, Double.NaN)
, createLayerRule
( SELECTED_OUTLINE_COLOR
, STROKE_WIDTH_SMALL_SCALE
, SELECTED_FILL_COLOR
, SELECTED_OPACITY
, selectionFilter
, Double.NaN
, STYLE_SCALE_LIMIT)
, createLayerRule
( UNSELECTED_OUTLINE_COLOR
, STROKE_WIDTH_SMALL_SCALE
, UNSELECTED_FILL_COLOR
, UNSELECTED_OPACITY
, visibilityFilter
, Double.NaN
, STYLE_SCALE_LIMIT)
}
);
Style style = styleFactory.createStyle();
style.featureTypeStyles().add(fts);
return style;
}
// layer creation
FeatureLayer someMethode()
{
...
FeatureLayer layer = new FeatureLayer
( dataStore.getFeatureSource()
, createLayerStyle()
, "Zipcodes"
);
...
return layer;
}
// style update if visible or selected features have changed
void someOtherMethod(FeatureLayer layer)
{
... // update selectedFeatureIDs or visibleFeatureIDs
layer.setStyle(createLayerStyle());
}
Of course optimizations are possible and welcome.
For your requirement the following may help:
You need 8 rules (see createRule(..) above), if you want to have one style for all scales (or 16 for small and large scales).
Define 8 filters using FilterFactory.equals(Expression, Expression) where first expression is of type AttributeExpressionImpl and second of type LiteralExpressionImpl
Be aware that there is another method equal (without s) in FilterFactory2
| 2024-01-20T01:26:59.872264 | https://example.com/article/7849 |
LaCrosse (LAC) virus, an arbovirus of the California group, will be further studies in its natural hosts the mosquito Aedes triseriatus and the chipmunk Tamias striatus to determine if either host selects for plaque variants. Viremic blood from experimentally infected chipmunks will be fed to mosquitoes. Total virus populations and selected plaque size variants of virus from both hosts will be compared for differences in mouse neuroviralence, mosquito infectivity, temperature stability and antigenic character. Plaque size, neurovirulence and antigenic character of LAC virus isolates from different areas will be compared to determine if this virus is geographically variable. Studies on medium-sized mammals as potential maintenance or disseminating hosts of LAC virus will include field surveys to detect naturally acquired antibody. Red foxes (Vulpes fulva) will be placed in enzootic foci as sentinels to determine frequency of natural infection. Foxes will also be tested for susceptibility to oral infection by LAC virus. Chipmunks and snowshoe hares (Lepus americanus) will be inoculated with 1) LAC virus, 2) the closely-related snowshoe hare virus, & 3) reassortants (derived from co-infection of cells with both agents). This experiment will determine if the reassortants can infect the natural hosts of the parent viruses. | 2023-11-20T01:26:59.872264 | https://example.com/article/9279 |
Buy Dishonored The Brigmore Witches CD Key Compare Prices
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Dishonored: The Brigmore Witches is an action–adventure video game developed by Arkane Studios and published by Bethesda Softworks. It is the successor to Dishonored:The Knife of Dunwall.
Continuing from where The Knife of Dunwall left off, The Brigmore Witches once again places you in the role of Daud, a legendary assassin, offering three more levels, two new factions to face and new gadgets and powers to utilize and an ending that changes not only your fate, but also influences the fate of the city.
Brigmore Witches introduces new sets of powers. gadgets. and weapons for a doubled exciting action adventure. Explore more of Dunwall and infiltrate territories to free captives who can help you out on your journey. The outcome of your quest depends on your skills and the decisions you make. It is high time to conclude Daud’s journey. The Brigmore Witches await your reckoning.
Dishonored: The Brigmore Witches brings about a satisfying conclusion to the Dishonored narrative, and like Knife of Dunwall before it, not only augments the over-arching story, but stands on its own.
STEAM CD KEY : Use the Steam Key Code on Steam Platform to download and play Dishonored Brigmore Witches. You must login to your Steam Account or create one for free. Download the (Steam Client HERE). Then once you login, click Add a Game (located in the bottom Left corner) -> Activate a Product on Steam. There type in your CD Key and the game will be activated and added to your Steam account game library. | 2024-07-25T01:26:59.872264 | https://example.com/article/9618 |
Introduction
============
Transition metal catalyzed cross coupling is one of the most powerful and versatile tools for C--C bond formation.[@cit1] In general, cross coupling occurs between two complementary functional groups: an organometallic group (Mg, Zn, Sn or B) and an organic halide (Cl, Br, I). In polymer chemistry, cross coupling reactions are particularly important for the synthesis of π-conjugated polymers.[@cit2] Kumada catalyst transfer polycondensation (KCTP) was first developed based on Kumada-type cross coupling.[@cit3] Other examples of catalyst transfer polycondensation utilize Negishi, Suzuki, Stille and Murahashi-type couplings.[@cit3b],[@cit4] These represent the best routes to well-defined, high molecular weight π-conjugated polymers.[@cit5] Important considerations for these polymerizations include catalyst design, monomer structure, and the utilization of additives.[@cit5b],[@cit6] Since the discovery of the quasi-living synthesis of polythiophenes, considerable effort has been devoted to understanding the underlying reaction mechanisms and expanding the scope of applicable monomers. Nickel([ii]{.smallcaps})diphosphine catalysts, such as 1,2-bis-(diphenylphosphino)propane nickel([ii]{.smallcaps}) chloride (Ni(dppp)Cl~2~) and 1,2-bis-(diphenylphosphino)ethane nickel([ii]{.smallcaps}) chloride (Ni(dppe)Cl~2~), are most frequently used for the controlled synthesis of electron-rich conjugated polymers, and their polymerizations are often used as model systems for studying the mechanism of KCTP.[@cit7]
While considerable progress has been made in identifying new functional groups for cross coupling polymerizations, aromatic halides continue to play an irreplaceable role.[@cit2a] When selecting the halogen, one must typically consider synthetic accessibility, monomer stability, and relative bond strengths (Ar--Cl \> Ar--Br \> Ar--I). This has led to the predominance of brominated monomers today due to their ease of synthesis, relatively good stability, and intermediate bond strength of brominated species. Aryl chlorides and aryl iodides also afford their own advantages and see significant use in a few select cases, but their polymerizations are less studied. For example, 2-chloro-5-chloromagnesio-3-hexylthiophene can be polymerized with an *N*-heterocyclic carbene nickel catalyst, but not with the more commonly used nickel([ii]{.smallcaps})diphosphine catalysts.[@cit8] In the early stages of polythiophene development, iodine was the halogen of choice. Wudl and coworkers reported that Kumada coupling polymerization of 2,5-diiodothiophene affords high-quality unsubstituted polythiophenes.[@cit9] The first synthesis of stable and soluble poly(3-alkylthiophenes) (P3ATs) was demonstrated by Elsenbaumer and coworkers using 3-alkyl-2,5-diiodothiophene as a monomer precursor.[@cit10] However, a comprehensive understanding of the role of the halogens in KCTP remains elusive.
Herein we report the first systematic comparison of the polymerizations of thiophenes bearing different halogens (Cl, Br and I). We find that reaction kinetics and chain-growth behaviour vary significantly for different halogens with the polymerization influenced in previously unreported and unexpected ways. *In situ*^31^P NMR shows that the catalyst resting state is dependent on the halogen identity and DFT calculations indicate that the activation energy of transmetalation increases from Cl to Br to I. These results provide a critical understanding of the role of halogens and the inhibition effect of magnesium salts in KCTP. The significant mechanistic influence of LiCl as an additive in polymerizing an iodinated monomer is also studied. All of our experimental evidence shows that the halides play a noninnocent role in the context of KCTP. Finally, we demonstrate how these new insights can be used to guide future monomer design for obtaining higher quality and more precise π-conjugated polymers.
Results and discussion
======================
The monomers chosen for this study are 2-chloro-5-iodo-3-(3,7-dimethyloctyl)thiophene, 2-bromo-5-iodo-3-(3,7-dimethyloctyl)thiophene, 2,5-dibromo-3-(3,7-dimethyloctyl)thiophene, and 2,5-diiodo-3-(3,7-dimethyloctyl)thiophene. The branched 3,7-dimethyloctyl (DMO) side chain is used to ensure that all resulting polymers are sufficiently soluble in common organic solvents. Electrophilic substitution reactions with the corresponding *N*-halosuccinimides were used to synthesize all dihalogenated thiophene derivatives (Scheme S1, ESI[†](#fn1){ref-type="fn"}). All monomers were characterized using ^1^H NMR, ^13^C NMR, and mass spectroscopy. Geminal coupling (^2^*J*~H--H~ = --14.08 Hz) is observed for the protons at the 1-position of the DMO side chain due to the chiral centre at the 3-position.[@cit11] For example, in 2,5-dibromo-3-(3,7-dimethyloctyl)thiophene, the two methylene protons on the side chain adjacent to the heterocycle are split into two large doublets of doublets flanked by a smaller doublet of doublets on either side (Fig. S1, ESI[†](#fn1){ref-type="fn"}).
KCTP involves two principal synthetic manipulations: (1) generation of the active monomer by a Grignard metathesis step;[@cit12] and (2) initiation and polymerization by application of the catalyst. In our current studies, we strived to eliminate the influence of the Grignard metathesis reactions on the following polymerizations. Generally, monomer activation is carried out by treating a dihalogenated monomer with 0.98 equivalent of *i*-PrMgCl.[@cit13] For 2-chloro-5-iodo-3-(3,7-dimethyloctyl)thiophene and 2-bromo-5-iodo-3-(3,7-dimethyloctyl)thiophene Grignard activation will occur exclusively at the 5-position \[denoted as XMg-Th-**Cl** and XMg-Th-**Br** (I/Br), respectively\]. For 2,5-dibromo-3-(3,7-dimethyloctyl)thiophene and 2,5-diiodo-3-(3,7-dimethyloctyl)thiophene metathesis occurs primarily at the 5-position \[∼80%, denoted as XMg-Th-**I** and XMg-Th-**Br** (Br/Br), respectively\] with a small amount 2-position (∼20%), however this minor species is not a polymerizable monomer due to steric constraints.[@cit14]
When designing studies to test the influence of halogens on KCTP the catalyst must be carefully considered. The Ni(dppe)Cl~2~ pre-catalyst is known to be sparingly soluble in THF, resulting in sluggish initiation that could potentially complicate kinetic studies. To address this issue, pre-initiation with five equivalents of monomer[@cit7a] and utilization of a THF-soluble *o*-tolyl functionalized Ni(*o*-tolyl)(dppe)Cl external initiator[@cit15] were both tested as alternative rapid initiation routes. Pre-initiation was found to yield pronounced tailing and several sets of end groups in the resulting polymers. Conversely, the use of an external initiator led to polymers with a unimodal molecular weight distribution and well-defined end groups (Fig. S2, ESI[†](#fn1){ref-type="fn"}). Since the Ni(*o*-tolyl)(dppe)Cl external initiator leads to better quality polymers it was used in all of the subsequent polymerization studies.
The polymerization of XMg-Th-**Br** (I/Br) proceeds rapidly at room temperature after addition of the external initiator. All evidence supports a controlled chain-growth mechanism. Notably the monomer consumption reaches 80% within one minute ([Fig. 1](#fig1){ref-type="fig"}). Crude polymer samples were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS).[@cit16] All aliquots collected during the polymerization have a unimodal size distribution and shift entirely to higher molecular weight regions (Fig. S3, ESI[†](#fn1){ref-type="fn"}). The degree of polymerization (DP) increases linearly as a function of monomer conversion without deviation (Fig. S4, ESI[†](#fn1){ref-type="fn"}). Analogous to the brominated monomer, the polymerization of XMg-Th-**Cl** is also complete within minutes. However, low molecular weight and broad dispersity (Fig. S5, ESI[†](#fn1){ref-type="fn"}) both indicate a non-living polymerization when changing the halogen from Br to Cl.[@cit7d],[@cit8]
{#fig1}
In contrast, XMg-Th-**I** has vastly slower polymerization kinetics. The DP increases linearly with monomer consumption (Fig. S6, ESI[†](#fn1){ref-type="fn"}), consistent with chain-growth character. Surprisingly, the polymerization proceeds quickly at the start but then slows down considerably as it progresses ([Fig. 1](#fig1){ref-type="fig"}). Overall, the polymerization of XMg-Th-**I** is much slower than both XMg-Th-**Br** (I/Br) and XMg-Th-**Cl**, with only 60% of the monomer being consumed after 100 minutes. Considering that kinetic differences could arise from XMg-Th-**Br** (I/Br) and XMg-Th-**Cl** both exclusively metathesizing on one side of the asymmetric monomer, while a mixture of activated regioisomers are possible for the diiodinated monomer metathesis, we further investigated the polymerization of XMg-Th-**Br** (Br/Br) to directly compare between halogen-symmetric monomers. The polymerization rate measured for XMg-Th-**Br** (Br/Br) was comparable to that using XMg-Th-**Br** (I/Br) (Fig. S7, ESI[†](#fn1){ref-type="fn"}). This indicates that the halogen at 2-position of the activated monomer is accountable for the difference in polymerization kinetics, and not the monomer activation process or the presence of an unreactive regioisomer.
The KCTP catalytic cycle involves four steps: transmetalation (TM), reductive elimination (RE), ring walking (RW) and oxidative addition (OA) ([Scheme 1](#sch1){ref-type="fig"}).[@cit6c],[@cit16] After the addition of Ni(*o*-tolyl)(dppe)Cl external initiator, one active monomer is transmetalated to the Ni centre forming the Ni([ii]{.smallcaps})-thienyl-(*o*-tolyl) complex **2**. Reductive elimination (RE) occurs to form a new carbon--carbon bond and the Ni catalyst remains associated as Ni(0)-π complex **3**. To achieve a chain-growth mechanism, the Ni(0) catalyst migrates intramolecularly to the terminal carbon--halogen bond followed by oxidative addition (OA) affording Ni([ii]{.smallcaps})-thienyl halide complex **1**. The four consecutive steps of the catalytic cycle continue until the active monomers are consumed and the catalyst then rests as the Ni([ii]{.smallcaps})-thienyl halide complex **1**.
![Proposed mechanism for Kumada catalyst transfer polycondensation. \[OA\]: oxidative addition; \[TM\]: transmetalation, \[RE\]: reductive elimination; \[RW\]: ring walking. The green circle represents an *o*-tolyl group.](c8sc04808h-s1){#sch1}
After the polymerizations of XMg-Th-**Cl** and XMg-Th-**I**, two peaks are observed by ^31^P NMR in a region anticipated for the Ni([ii]{.smallcaps})-thienyl halide complex **1** ([Fig. 2](#fig2){ref-type="fig"}). Surprisingly, we find that the spectra of the post-polymerization complexes are identical in these two cases (48 and 62 ppm, [Fig. 2a and c](#fig2){ref-type="fig"}). After the polymerizations of XMg-Th-**Br** (I/Br) these two peaks are also observed, along with two additional up-field shifted peaks (43 and 59 ppm, [Fig. 2b](#fig2){ref-type="fig"}). We assign the signals at 48 and 62 ppm to Ni([ii]{.smallcaps})-thienyl iodide and the signals at 43 and 59 ppm to Ni([ii]{.smallcaps})-thienyl bromide.[@cit7a] Further support of this assignment is provided when magnesium iodide was added to the polymerization of XMg-Th-**Br** (I/Br) after collecting the post-polymerization spectrum. This experiment causes two of the original peaks (43 and 59 ppm) to disappear and two peaks with the same chemical shifts as those found after the polymerizations of XMg-Th-**Cl** and XMg-Th-**I** (48 and 62 ppm) to strengthen ([Fig. 2d](#fig2){ref-type="fig"}).
{#fig2}
The unexpected presence of Ni([ii]{.smallcaps})-thienyl iodide after polymerizing XMg-Th-**Cl** or XMg-Th-**Br** (I/Br) is a result of halogen exchange (HE) between the original Ni([ii]{.smallcaps})-thienyl chloride or Ni([ii]{.smallcaps})-thienyl bromide and an iodide source, formed through either the decomposition of isopropyl iodide[@cit14] or the nucleophilic substitution reaction between *i*-PrMgCl and isopropyl iodide in the course of the metathesis. This observation indicates the preferential formation of Ni([ii]{.smallcaps})-thienyl iodide when iodide is present ([Fig. 2](#fig2){ref-type="fig"}). This observation seems to contradict the halide affinity for Ni([ii]{.smallcaps}) diphosphine complexes (Cl \> Br \> I).[@cit17] However, it should be noted that these halides are counterions of Mg^2+^. For instance, when only free halides are considered, density functional theory (DFT) calculations show that the equilibrium favors the formation of Ni([ii]{.smallcaps})-thienyl chloride by 93 kJ mol^--1^. When magnesium salts are considered instead, the equilibrium favors the formation of Ni([ii]{.smallcaps})-thienyl iodide by 17 kJ mol^--1^ ([Scheme 2](#sch2){ref-type="fig"}). This tendency is likely due to the much stronger interactions between Mg^2+^ (hard acid) and chloride (hard base).[@cit18]
{#sch2}
Distinct spectra are also observed during *in situ*^31^P NMR spectroscopic studies carried out on the polymerizations. For reference, the ^31^P NMR spectrum of the external initiator has two doublets centred at 32 and 53 ppm (*J*~pp~ = 40 Hz, Fig. S8, ESI[†](#fn1){ref-type="fn"}). Once mixed with a monomer solution the ^31^P NMR spectrum rapidly changes depending on the type of activated monomer. We first evaluated XMg-Th-**Br** (I/Br), where two proximate, broad multiplets (47--48 ppm) were observed to be indicative of two phosphorus nuclei in similar chemical environments ([Fig. 3b](#fig3){ref-type="fig"}). We assign the catalyst resting state to Ni([ii]{.smallcaps})-dithienyl complex **2** ([Scheme 1](#sch1){ref-type="fig"}), which is consistent with a previous report by McNeil and coworkers that RE is the rate-determining step for this polymerization.[@cit7a]
{#fig3}
In the case of the XMg-Th-**Cl** polymerization, the Ni([ii]{.smallcaps})-dithienyl complex **2** is observed, however an additional distinct and sharp singlet appears around 50 ppm ([Fig. 3a](#fig3){ref-type="fig"}), which is indicative of phosphorus nuclei in an identical chemical environment. The observed singlet does not match any intermediates in the catalytic cycle (complex **1--4** in [Scheme 1](#sch1){ref-type="fig"}) suggesting that some of the active catalyst is diffusing away from the propagating polymer chain, likely due to the difficult OA or other side reactions.[@cit7a],[@cit17] This is consistent with a mixture of polymers with different end-group compositions being observed in this polymerization (Fig. S9, ESI[†](#fn1){ref-type="fn"}).[@cit15b],[@cit19] We therefore conclude that the catalyst rests as dissociated Ni(phosphine) complex and Ni([ii]{.smallcaps})-dithienyl complex **2** in the polymerization of XMg-Th-**Cl**.
The greatest mixture of intermediates is observed when polymerizing XMg-Th-**I**. The major signals (48 and 62 ppm) are assigned to Ni([ii]{.smallcaps})-thienyl iodide complex **1** ([Scheme 1](#sch1){ref-type="fig"}, [Fig. 3c](#fig3){ref-type="fig"}), and match the signals observed after polymerization. In addition, one set of minor signals is attributed to the formation of Ni([ii]{.smallcaps})-(*o*-tolyl) iodide (41 and 57 ppm), which is confirmed experimentally by a separately prepared Ni complex (Fig. S8, ESI[†](#fn1){ref-type="fn"}) and can only be formed by HE between the added external initiator and an iodide source. We can therefore conclude that the catalyst rests mostly as Ni([ii]{.smallcaps})-thienyl iodide complex **1** in the polymerization of XMg-Th-**I** based on its stronger NMR signals.
Thus far, we have established the halogen-dependence of catalyst resting states by ^31^P NMR, and that TM becomes more difficult when iodide is used. This raises the question of how halogen atoms influence TM.[@cit20] Activation energies (AE) for TM of a fully dissociated monomer calculated by DFT increase from 44 kJ mol^--1^ (Cl) to 59 kJ mol^--1^ (Br) to 79 kJ mol^--1^ (I) indicating the greater difficulty of TM going from Cl to Br to I ([Fig. 4](#fig4){ref-type="fig"}). There are two possible explanations for this increase in AE. First, this trend can be interpreted as a result of increased steric congestion around the Ni centre. Steric mapping shows that the percent buried volume (%*V*~Bur~) around the Ni centre in complex **1** increases moving from Cl to Br to I (Fig. S10, ESI[†](#fn1){ref-type="fn"}).[@cit21] Alternatively, weaker Mg--I interactions serve to further increase the AE for I (soft base) compared to Br and Cl.
{#fig4}
Significant product inhibition is also observed in the iodothiophene polymerization ([Fig. 1](#fig1){ref-type="fig"}). To investigate these effects, a series of polymerizations were carried out with different additives. The polymerization decelerates when adding increasing amounts of magnesium chloride (Fig. S11, ESI[†](#fn1){ref-type="fn"}) and accelerates when adding an increasing amount of *o*-tolyl magnesium chloride (Fig. S12, ESI[†](#fn1){ref-type="fn"}). Due to the inhibitive effect of adding of MgCl~2~ to the polymerization, we can rule out the influence of a Schlenk equilibrium which would be expected to increase the percentage of Grignard form.[@cit22] We therefore hypothesize that the produced magnesium salts, which are a product of TM, form a more stable complex with the Grignard reagents which decreases the reactivity of the activated monomers.[@cit23] As the polymerization proceeds, the concentration of magnesium salt builds up and decelerates the polymerization to a large extent. These different features over the course of the polymerization are also observed when polymerizing 2,5-diiodo-3-(3,7-dimethyloctyl)selenophene (Fig. S13, ESI[†](#fn1){ref-type="fn"}) and 2,5-diiodo-3-(3-ethylheptyl)tellurophene[@cit24] showing the general nature of these findings. In contrast, when *o*-tolyl magnesium chloride serves as a sacrificial reagent to coordinate with produced magnesium salts in solution, the polymerization rate increases. This is the first study to emphasize the role of product inhibition in KCTP, which is consistent with the distinct polymerization kinetics observed.
This suggests that the polymerization of XMg-Th-**I** is very sensitive to product complexation in solution. Previous reports have demonstrated that the actual structure of Grignard reagents is far more complicated than the generic formula R-MgX indicates and LiCl is believed to de-aggregate these complex aggregates.[@cit25]*In situ*^31^P NMR shows that when a turbo Grignard (*i*-PrMgCl·LiCl) is used for iodinated monomer metathesis, the catalyst resting state changes from Ni([ii]{.smallcaps})-thienyl iodide complex **1** to Ni([ii]{.smallcaps})-dithienyl complex **2** (Fig. S14, ESI[†](#fn1){ref-type="fn"}). McNeil and coworkers have previously reported that LiCl has no influence on the catalyst resting state in polymerizations of XMg-Th-**Br** (Br/Br).[@cit7a] In contrast, here we demonstrate the unique mechanistic influence of LiCl as an additive in KCTP to accelerate the TM of an iodinated monomer, where the catalyst otherwise rests as pre-TM complex **1**. Combined with *in situ*^31^P NMR studies and DFT calculations, this further proves that the distinct kinetic features originate from the iodine atom and Grignard aggregation, together with magnesium by-product inhibition.
We previously reported that 3-(2-ethylhexyl)-5-chloromagnesio-2-iodotellurophene polymerizes very slowly (requiring over 12 hours to complete), and is accompanied by early chain termination and re-initiation under typical KCTP conditions.[@cit24] It is well known that branched side chains increase monomer bulkiness and slow down the overall polymerization.[@cit26] The present study shows that iodine also contributes to slowing down the polymerization to a large extent. This led us to wonder whether the use of bromine instead of iodine would improve the polymerization of 2-ethylhexyltellurophene. We therefore synthesized the asymmetric monomer 2-bromo-3-(2-ethylhexyl)-5-iodotellurophene, (Scheme S2, ESI[†](#fn1){ref-type="fn"}). A test polymerization targeting DP = 30 was attempted and found to give a unimodal molecular distribution, low polydispersity (*Đ* = 1.2) and high yield (85%) ([Fig. 5a](#fig5){ref-type="fig"}). The MALDI-TOF/MS spectrum shows only one set of end groups corresponding to *o*-tolyl and H ([Fig. 5b](#fig5){ref-type="fig"}). All evidence strongly supports a controlled chain growth mechanism. This successful polymerization emphasizes the importance of the halogen functionality, particularly for monomers with bulky side chains.
{#fig5}
Conclusions
===========
In summary, we have discovered the important role that halogens and magnesium salts play in Kumada catalyst transfer polycondensation. Non-living behaviour is observed in the polymerization of a chlorinated monomer, while both brominated and iodinated monomers are polymerized in a controlled manner but with distinct kinetics. *In situ*^31^P NMR reveals that the catalyst resting state changes from a Ni([ii]{.smallcaps})-dithienyl complex to a Ni([ii]{.smallcaps})-thienyl iodide complex when Br is replaced with I. The addition of LiCl leads to a change in catalyst resting state when polymerizing the iodinated monomer, highlighting the significant mechanistic influence of LiCl in KCTP. Based on these studies, a new tellurophene monomer with a bulky side chain is designed and demonstrated to undergo controlled polymerization for the first time. These insights are likely not limited to controlled polymerizations utilizing cross-coupling reactions, but are potentially more widely applicable to Kumada cross coupling reactions in general.
Conflicts of interest
=====================
There are no conflicts to declare.
Supplementary Material
======================
Supplementary information
######
Click here for additional data file.
D. S. S. is grateful from support from the NSERC of Canada, The Canadian foundation for Innovation, the Ontario research fund and the Ontario Centres of Excellence. S. Y. is grateful for the support of Colin Hahnemann Bayley Fellowship. This research was enabled in part by support provided by SHARCNET and Compute Canada.
[^1]: †Electronic supplementary information (ESI) available. See DOI: [10.1039/c8sc04808h](10.1039/c8sc04808h)
| 2024-04-23T01:26:59.872264 | https://example.com/article/3159 |
Kenya to close refugee camps, displacing over 600,000
Kenya will close all refugee camps, a move that would displace more than 600,000 people living there, the government announced.
The decision taken on Friday includes Dadaab, the largest such camp in the world. It is home to more than 300,000 people on the Kenya-Somalia border, CNN reported on Saturday.
The government is shutting down the camps because of “very heavy” economic, security and environmental burdens, senior Interior Ministry official Karanja Kibicho said in a statement.
“Kenya, having taken into consideration its national security interests, has decided that hosting of refugees has come to an end,” Kibicho said, pointing to threats, such as the terror group Al-Shabaab.
Kenya announced the closure of refugee camps last year for the same reasons but backed down in the face of international pressure. Most of the camp residents come from Somalia, which has been torn by civil war.
At the time, government officials were not clear where they expected the refugees to go, other than somewhere into Somalia and out of Kenya.
While it is not immediately clear if or when a closure might happen, the interior ministry said it has already disbanded the department of refugee affairs as a first step.
Kenya will close all refugee camps, a move that would displace more than 600,000 people living there, the government announced.
The decision taken on Friday includes Dadaab, the largest such camp in the world. It is home to more than 300,000 people on the Kenya-Somalia border, CNN reported on Saturday.
The... | 2024-06-04T01:26:59.872264 | https://example.com/article/7713 |
Introduction {#s1}
============
Many infants and children receive different types of surgery or diagnostic procedure every year. Recent animal and clinical studies have demonstrated extended or multiple exposures to inhaled anesthetics during brain development can induce neuronal apoptosis and increase the risk of cognitive abnormalities during adulthood (Jevtovic-Todorovic et al., [@B28]; Zhu et al., [@B60]; DiMaggio et al., [@B14]; Cheng et al., [@B11]; Wu et al., [@B53]). Isoflurane, as a common volatile anesthetic, has been implicated in long-term developmental neurotoxicity and cognitive deficits (Stratmann et al., [@B43]).
The mechanisms of isoflurane-induced developmental neurotoxicity are probably multifactorial. First, neonatal exposure to isoflurane can result in neuronal apoptosis (Lei et al., [@B34]), which affects the normal development of neuronal networks, and leads to long-term neurocognitive decline. The underlying molecular mechanisms include the inhibition of N-methyl-aspartate (NMDA) receptor, activation of γ-aminobutyric acid (GABA) receptor (Fredriksson et al., [@B16]), dysregulation of intracellular calcium homeostasis (Wei et al., [@B52]), mitochondrial perturbations (Zhang et al., [@B57]), downregulation of BNDF (Zhang et al., [@B55]) and neuroinflammatory pathways (Wang et al., [@B49]). Second, early anesthesia exposure can disturb synapse development and potentially lead to abnormalities in synaptic plasticity (Huang et al., [@B22]). Moreover, a recent study has demonstrated that anesthetic suppression of postnatal neurogenesis is associated with deficits in hippocampus-dependent learning and memory function (Kang et al., [@B30]). Notably, the synaptic plasticity and neurogenesis of neurons can be controlled by the ubiquitin-proteasome system (UPS; Zhou et al., [@B59]). However, whether ubiquitination activity is related to anesthesia-induced neurotoxicity is unknown.
Anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase, and its co-activator, Cdh1, are important components of the UPS. In proliferating cells, APC/C-Cdh1 can prevent premature S phase entry through limiting the accumulation of cyclins in G1 (Li and Zhang, [@B35]). Neurons are post-mitotic cells. Previous studies have demonstrated that Cdh1 is highly expressed in neurons (Gieffers et al., [@B18]). Further studies have indicated that APC/C-Cdh1 is involved in axonal growth and patterning, neuronal differentiation, neurogenesis and synaptic development in the central nervous system (Almeida, [@B1]; Zhou et al., [@B59]). Almeida et al. ([@B2]) found that Cdh1 phosphorylation by cyclin-dependent kinases (Cdks) promotes post-mitotic neurons re-entry into the cell cycle and mediates excitotoxicity in neurodegenerative disease. Additionally, Cdh1 is essential in maintaining the replicative lifespan of neurons and in hippocampus-dependent cognitive functions (Li et al., [@B36]). Therefore, we hypothesized that APC/C-Cdh1 could be involved in isoflurane-induced neurotoxicity and cognitive deficits in the developing brain.
In this study, we first examined the change in Cdh1 expression and neuronal apoptosis in the hippocampus of developing rats and, *in vitro*, in primary neurons after exposure to 2% isoflurane for 6 h. We then administered a Cdh1-encoding lentivirus into the hippocampus of rat pups and primary cultured neurons. The effect of Cdh1 overexpression on neuronal apoptosis and the impairment of learning and memory ability induced by isoflurane in developing rats were evaluated.
Materials and Methods {#s2}
=====================
Animals {#s2-1}
-------
All experimental procedures were approved by the Huazhong University of Science and Technology Ethics Committee for Care and Use of Laboratory Animals. Protocols were in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. Postnatal 1- or 7-day Sprague-Dawley rats of both sexes were supplied by Tongji Medical College Experimental Animal Center. They were housed in a temperature-controlled room with a 12-h light/dark-cycle.
Primary Hippocampal Neuron Culture {#s2-2}
----------------------------------
Rat hippocampal neurons were derived from newborn (within 24 h) Sprague-Dawley rats as previously described (Beaudoin et al., [@B5]). Briefly, hippocampal tissues were dissected, gently minced, and trypsinized. The digestion was stopped by adding DMEM/F12 medium containing 10% fetal bovine serum (FBS). Culture plates were coated with 100 mg/mL Poly-L-lysine. Neurons were cultured at a concentration of 5 × 10^5^ cells/mL onto dishes or coverslips. Then, the medium was changed to neurobasal medium containing B27 supplement (Gibco, USA). We added cytosine arabinoside (10 μM) to the medium to arrest the growth of non-neuronal cells on the second day *in vitro*. Half of the cell medium was replaced every 3 days.
Anesthesia Procedure {#s2-3}
--------------------
The anesthesia protocol was established according to previous reports (Boscolo et al., [@B7]; Wang et al., [@B50]) with some modifications. Rat pups at postnatal day 7 (P7) and cultured neurons were placed in a tightly sealed translucent plastic chamber, which was continuously flushed with fresh gas at 37°C. Rat pups at P7 are susceptible to anesthesia-induced developmental neurotoxicity (Yon et al., [@B54]). We administered 6 h of isoflurane based on previous studies (Sanchez et al., [@B41]; Boscolo et al., [@B7]). The concentration of isoflurane was maintained at 2%. The isoflurane group of rat pups inhaled isoflurane in a gas mixture of 30% oxygen (O~2~) and 70% nitrogen (N~2~). For cultured neurons, isoflurane was flushed in a gas consisting 95% O~2~ and 5% CO~2~ on day 7 *in vitro* (7 DIV). A Datex Capnomac Ultima gas analyzer (Datex Ohmeda, USA) was used to monitor the gas flow (2 L/min). The animals in the control group were handled as the isoflurane-treated animals, except that no isoflurane was added. All rat pups were allowed to breathe spontaneously.
To determine the adequacy of ventilation, arterial blood obtained from the left cardiac ventricle was sampled at the end of anesthesia administration for blood gas analysis as previously described (Jevtovic-Todorovic et al., [@B28]). There were no obvious signs of metabolic or respiratory distress in the isoflurane compared with the control rats (data not shown). Rat pups assigned for Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were euthanized immediately post-anesthesia. The hippocampi of rats were removed immediately for biochemical studies.
Lentivirus Treatment {#s2-4}
--------------------
Cdh1-encoding lentivirus vector was constructed in a previous study (Qi et al., [@B40]). The encoding sequence of the rat Cdh1 gene (NM_001108074.1) was synthesized chemically. Then, it was fused into the pGC-FU vector through genetic recombination. The lentivirus construct expressing green fluorescent protein (GFP) only (pGC-FU-GFP) was used as a control. The lentiviral package used in our experiments was commercially supplied by GeneChem Inc. (China) and previously used in our laboratory (Qi et al., [@B40]; Lv et al., [@B37]). The titer of Cdh1-encoding lentivirus was 1.0 × 10^9^ transduction units (TU)/mL. Neurons and animals were divided into four groups: control (Con) group; isoflurane (Iso) group; Iso + Lenti-Cdh1-GFP group, and Iso + Lenti-GFP group.
GFP expression visualized under a fluorescence microscope was used to determine the optimal multiplicity of infection (MOI) and infection duration. Neurons in the Iso + Lenti-Cdh1-GFP group or the Iso + Lenti-GFP group were transfected with the Cdh1-encoding lentivirus or control lentivirus, respectively, for 10 h at an MOI of 10 on 4 DIV. The medium was then replaced with standard culture medium. Isoflurane exposure was performed 72 h after lentivirus transfection. On 7 DIV, all test neurons were exposed to 2% isoflurane for 6 h. All experiments were repeated three times.
For rat pups (*n* = 16 for each group) in the Iso + Lenti-Cdh1-GFP group and the Iso + Lenti-GFP group, lentivirus (1.5 μL) was directly microinjected into the bilateral hippocampus of rats at postnatal day 3 using a 32-gauge needle (Hamilton Co., Reno, NV, USA; microliter no. 701 RN, 10 μL). The experimental protocol has been described previously (Fitting et al., [@B15]). The set of coordinates used for the bilateral hippocampus were: −2.0 mm anterior to the Bregma, ±1.6 mm lateral to the Bregma and −2.5 mm dorsal from the dura. The injection lasted 2 min, and the needle was withdrawn over 10 min to prevent reflux. The incision was closed with surgical glue. After two injections, the pups were warmed under a heat lamp before being returned to their cages. Isoflurane exposure was then performed 4 days after lentivirus injection. Rat pups assigned for western blot and TUNEL assays were euthanized immediately post-anesthesia, while the remaining rats (*n* = 10 for each group) were placed back to their cages for behavioral tests.
TUNEL Staining {#s2-5}
--------------
After euthanasia with pentobarbital injection (100 mg/kg, intraperitoneal), the brains were collected and treated with 4% paraformaldehyde (PFA) in PBS. Neurons were washed with D-Hanks and then fixed with PBS containing 4% formaldehyde for 30 min. TUNEL assay was performed using the *in situ* cell Death Detection Kit (Roche Inc., USA) following the manufacturer's instructions. Briefly, after TUNEL-staining according to the protocols, sections were subsequently incubated with 4′,6-diamidino-2-phenylindole (DAPI)-containing medium for 10 min. The TUNEL-positive cells were identified by a blind investigator via fluorescence microscopy (Leica Microsystems, Germany). Then, the data were analyzed by another blind investigator. We defined the apoptotic index as the average number of TUNEL-positive cells in six views of slices.
Western Blot Analysis {#s2-6}
---------------------
After isoflurane exposure, the bilateral hippocampus tissues were dissected. Total protein from the hippocampus and neuronal cultures were harvested in RIPA lysis buffer (Beyotime Biotechnology, Shanghai, China), and mixed with phenylmethylsulfonyl fluoride protease inhibitor. Neurons were extracted from three wells in a culture plate. Separation and extraction of the cytoplasmic and nuclear proteins of hippocampal neurons were performed following the Tissue Protein Extraction Kit (Boster Biological Technology, Shanghai, China). Levels of protein were determined by using a BCA assay kit (Boster Biological Technology). Equal amounts of protein were subjected to electrophoresis via 10% sodium dodecyl sulfate-polyacrylamide gel and then transferred to 0.45-μm polyvinylidene difluoride (PVDF) membranes. After blocking with 5% defatted milk powder in TBST, membranes were incubated overnight at 4°C with primary antibodies: mouse anti-β-actin (1:500; Boster Biological Technology), rabbit anti-Cdh1 (1:1000; Abcam), rabbit anti-Skp2 (1:500; ABclonal), rabbit anti-cyclin B1 (1:1000; ABclonal), rabbit anti-SnoN (1:1000; Abcam), rabbit anti-Bax (1:1000; Cell Signaling Technology, Danvers, MA, USA), rabbit anti-Bcl-2 (1:1000; Cell Signaling Technology), rabbit anti-total Caspase-3 (1:1000; Cell Signaling Technology), or rabbit anti-cleaved-Caspase-3 (1:1000; Cell Signaling Technology). Membranes were rinsed with TBST, incubated with a horseradish peroxidase-conjugated secondary antibody (1:5000; Boster Biological Technology) for 1.5 h at room temperature. After rinsing with TBST three times, bands were detected with an enhanced chemiluminescence kit (Thermo Scientific, Waltham, MA, USA). Signals were digitally scanned with a Chemi-Doc XRS imaging system (Bio-Rad, Hercules, CA, USA). The relative protein levels were normalized to that of the housekeeping gene, β-actin.
Quantitative Real-Time PCR {#s2-7}
--------------------------
The levels of Cdh1 mRNA were examined via SYBR green-based quantitative RT-PCR. Total RNA was isolated from the rat hippocampi using Trizol reagent (Invitrogen, Carlsbad, CA, USA) according to the previous manufacturer's instructions. The reaction solution was composed of cDNA template, forward/reverse primers, and SYBR green I Master Mix (Invitrogen, Carlsbad, CA, USA). The primers used to amplify Cdh1 and β-actin were as follows: *Cdh1*: forward: 5′-GAACCGCAAAGCCAAGGAT-3′, reverse: 5′-CTTGTGCTCTGGGGTGGAT-3′; β-actin: forward: 5′-CACGATGGAGGGGCCGGACTCATC-3′, reverse: 5′-TAAAGACCTCTATGCCAACACAGT-3′. Reverse transcription and real-time reverse transcription PCRs were performed in triplicate. Fold-change was calculated using the ΔΔCT method to estimate the amount of target mRNA.
Open-Field Test {#s2-8}
---------------
The open-field test was performed 21 days after isoflurane-treatment according to previously described protocols (Wang et al., [@B51]). On P28, rats (*n* = 10 for each group) were placed individually in a black box for 30 s in the dark for habituation. Then, each rat was allowed to explore from the center of the box for 10 min in dark. During the procedure, the behavior of the rat pups was recorded by using a video tracking system placed right above, which could automatically measure the distance traveled and the amount of time spent in the center area. When each test was completed, the inner wall of the chamber was wiped with 95% ethyl alcohol to prevent the influence of olfactory cues.
Morris Water Maze Test {#s2-9}
----------------------
The morris water maze (MWM) test was performed 26 days after isoflurane-treatment as previously described, with some modifications (Ju et al., [@B29]). Rats (*n* = 10 for each group) were subjected to four trials per day over five consecutive days to evaluate the rats' spatial memory between distant cues and the escape platform from P31 to P36. A circular platform (submerged 1.5 cm, not visible) was placed at one of the four quadrants (named the target quadrant \[T\]), and the remaining quadrants were defined by the relative location to the T quadrant: opposite (O), left (L) and right (R) quadrants. The release position was randomly predetermined. Each rat was given 60 s to locate the hidden platform. If the rat failed to find the platform within 60 s, it would be manually guided to the platform and allowed to stay on it for 15 s. The time to reach the platform could reflect the function of spatial learning and was named latency. The swimming paths were recorded by a digital video camera placed right above the tank. Immediately after the last training session (P36), the platform was removed, and a 60-s-probe trial was performed. Rats started to swim in the same quadrant facing the pool wall. The number of times the rats crossed the area where the platform was located in the target quadrant and the swimming time in each quadrant were recorded by a digital video camera positioned right above the center of the water maze. The recording data were further analyzed by using the DigBehav System (Jiliang Software Co., Shanghai, China).
Statistical Analysis {#s2-10}
--------------------
All data are presented as mean ± standard error of the mean (SEM). The SPSS software (Version 17.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. One-way analysis of variance (ANOVA), followed by Turkey honest significant difference (HSD) test and student's *t*-test were used as appropriate for comparisons between different groups. Group comparisons in the spatial training sessions of the MWM test were analyzed by two-way repeated ANOVA, in which "Days of testing" was treated as the "within-subjects" factor and "Groups" was used as the "between-subjects" factor. Values of *P* \< 0.05 were considered statistically significant.
Results {#s3}
=======
Exposure of Postnatal 7-Day Rat Pups to Isoflurane Leads to Cdh1 Downregulation and Neuronal Apoptosis in the Hippocampus {#s3-1}
-------------------------------------------------------------------------------------------------------------------------
First, we assessed whether isoflurane at the concentration used in our experiment could induce neuronal apoptosis in the developing rats. As shown in Figure [1A](#F1){ref-type="fig"}, the number of TUNEL-positive cells significantly increased in the isoflurane group compared to that in the control group in the hippocampal CA1 region after anesthesia with 2% isoflurane for 6 h. Consistently, western blotting showed that isoflurane-treatment lead to a significant elevation of pro-apoptotic proteins (cleaved caspase-3 and Bax), while the expression of the anti-apoptotic protein Bcl-2 decreased after anesthesia (*P* = 0.006 for cleaved caspase-3, *P* = 0.017 for Bax and *P* = 0.004 for Bcl-2; Figure [1B](#F1){ref-type="fig"}). Additionally, isoflurane reduced the total level of Cdh1 in the developing hippocampus, as assessed by western blotting (*P* = 0.018, Figure [1C](#F1){ref-type="fig"}). We further analyzed Cdh1 activity according to subcellular localization. The results showed that the amount of Cdh1 in the cytosol was significantly higher in the isoflurane group than in the control group (*P* = 0.021, Figure [1D](#F1){ref-type="fig"}), while the level of Cdh1 in the nucleus was reduced after isoflurane-treatment (*P* = 0.032, Figure [1E](#F1){ref-type="fig"}). These results suggest the translocation of Cdh1 from the nucleus to the cytosol during isoflurane-treatment. In addition, together with the downregulation of the total level of Cdh1, several downstream substrates (skp2, snoN and cyclin B1) were accumulated, indicating inactivity of Cdh1 (*P* \< 0.05, Figure [1C](#F1){ref-type="fig"}).
{#F1}
Cdh1 Is Downregulated during Isoflurane-Induced Neuronal Apoptosis *in Vitro* {#s3-2}
-----------------------------------------------------------------------------
To further confirm the effects of isoflurane on neuronal apoptosis and Cdh1 activity, cultures of hippocampal neurons were exposed to isoflurane (2%, 6 h). Consistent with the results obtained *in vivo*, isoflurane-treatment alone led to significant neuronal cell death (Figure [2A](#F2){ref-type="fig"}). Western blot indicated an increase in the expression of cleaved caspase-3 and Bax proteins and a decreased level of Bcl-2 protein in the isoflurane-treatment group compared with the control group (*P* \< 0.05, Figure [2B](#F2){ref-type="fig"}). Furthermore, Cdh1 level was decreased after exposure to isoflurane (*P* = 0.039), and the expression of downstream substrates of Cdh1 (skp2, snoN and cyclin B1) was enhanced in the isoflurane group compared with the control group (*P* \< 0.05, Figure [2C](#F2){ref-type="fig"}). Altogether, these data further indicated that downregulation of Cdh1 activity is correlated with isoflurane-induced neuronal apoptosis.
{#F2}
Lentivirus-Mediated Cdh1 Over-expression Reduces Isoflurane-Induced Neuronal Apoptosis *in Vitro* {#s3-3}
-------------------------------------------------------------------------------------------------
To test whether Cdh1 upregulation would protect against isoflurane-induced developmental neurotoxicity, a lentivirus encoding Cdh1 was administered before isoflurane-treatment. For *in vitro* experiments, we chose an MOI of 10 as the optimal MOI to infect neurons on 4 DIV for 10 h; cells were treated with isoflurane 72 h after transfection. The expression of Cdh1 was effectively upregulated by Cdh1-encoding lentivirus in the Iso + Lenti-Cdh1-GFP group compared with the Iso group, while the accumulation of cyclin B1 was significantly reduced at the same time (*P* = 0.003 for Cdh1 and *P* \< 0.05 for cyclin B1, lane 3, Figure [3A](#F3){ref-type="fig"}). Additionally, the number of TUNEL-positive cells was significantly decreased in the Iso + Lenti-Cdh1-GFP group, while there was no statistical difference in the number of apoptotic neurons between the Iso and Iso + Lenti-GFP groups (Iso + Lenti-Cdh1-GFP and Iso + Lenti-GFP group vs. Iso group, *P* \< 0.001 and *P* = 0.638, Figures [3B,C](#F3){ref-type="fig"}). In addition, the activation of cleaved caspase-3 and Bax in the Iso group was abolished after transfection of the Cdh1-encoding lentivirus in the Iso + Lenti-Cdh1-GFP group. Moreover, Bcl-2 expression was enhanced in the Iso + Lenti-Cdh1-GFP group, while it was reduced in the Iso group (*P* \< 0.05, lane 3, Figure [3D](#F3){ref-type="fig"}).
{#F3}
Bilateral Intra-Hippocampal Injection of Cdh1-Encoding Lentivirus Decreases Isoflurane-Induced Neuronal Apoptosis in the Developing Hippocampus {#s3-4}
-----------------------------------------------------------------------------------------------------------------------------------------------
To further confirm the effects of Cdh1 overexpression on isoflurane-induced neuronal apoptosis, the lentivirus was stereotactically injected into bilateral CA1 of the hippocampus in rat pups. The expression of GFP was detected by immunofluorescence microscopy. The results showed that GFP was mainly expressed in the cytoplasm in the Iso + Lenti-GFP group, while it was expressed in the nucleus in the Iso + Lenti-Cdh1-GFP group, as GFP was fused to Cdh1 in the vector (Figure [4A](#F4){ref-type="fig"}). Western blotting and real-time PCR showed that Cdh1 expression was enhanced in the Iso + Lenti-Cdh1-GFP group compared with the Iso and Iso + Lenti-GFP group (*P* \< 0.05, Figures [4B,C](#F4){ref-type="fig"}). The upregulation of downstream substrates of Cdh1 induced by isoflurane were reversed (*P* \< 0.05, Figure [4D](#F4){ref-type="fig"}; lane 3). The number of TUNEL-positive cells in the hippocampal CA1 area was decreased by Cdh1 overexpression in the Iso + Lenti-Cdh1-GFP group (Iso + Lenti-Cdh1-GFP group vs. Iso group, *P* \< 0.001; Iso vs. control group, *P* \< 0.001; Figures [5A,B](#F5){ref-type="fig"}). Quantification of the western blot revealed that the administration of Cdh1-encoding lentivirus expectedly decreased the expression of pro-apoptotic proteins (cleaved caspase-3 and Bax) and rescued the anti-apoptotic protein Bcl-2 protein level (*P* \< 0.05, lane 3, Figure [5C](#F5){ref-type="fig"}). Together, these results suggest that Cdh1 overexpression protected hippocampal neurons from apoptosis induced by isoflurane anesthesia in the developing brain.
{#F4}
{#F5}
Cdh1 Overexpression Attenuates Isoflurane-Induced Long-Term Cognitive Deficits {#s3-5}
------------------------------------------------------------------------------
To investigate whether Cdh1 overexpression could protect against isoflurane-induced cognitive impairment in developing rats, a behavioral study was conducted (Figure [6A](#F6){ref-type="fig"}).
{#F6}
Compared with the control group, rats did not show abnormal locomotor and anxiety-like behavior in the isoflurane group, assessed on the basis of the distances traveled by the rats (control vs. Iso group, *P* = 0.226, Figure [6B](#F6){ref-type="fig"}) and the time spent in the center (control vs. isoflurane, *P* = 0.379, Figure [6C](#F6){ref-type="fig"}) during the open-field test, indicating that there were no physical and emotional depression between the experimental and control rats in terms of locomotor activity.
Hippocampal pyramidal neurons in the CA1 area are essential for spatial learning and memory. In the place trials, no difference was observed in terms of swimming speeds (control vs. Iso group: *P* \> 0.05 from day 1 to day 5, Figure [6D](#F6){ref-type="fig"}), consistent with the results obtained for locomotor activity. However, rats in the isoflurane group and Iso + Lenti-GFP group apparently spent more time in finding the submerged platform than the control group rats from trial day 2 to day 4 (control vs. Iso and Iso + Lenti-GFP group: *P* = 0.048 and 0.011, second trial; *P* = 0.009 and 0.031, third trial; *P* = 0.011 and 0.009, fourth trial; Figure [6E](#F6){ref-type="fig"}). The rats had shorter escape latency in the Iso + Lenti-Cdh1-GFP group than in the Iso group or Iso + Lenti-GFP group from trial day 2 to day 4 (*P* = 0.038 and 0.036, second trial; *P* = 0.018 and 0.047, third trial; *P* = 0.007 and 0.006, fourth trial; Figure [6E](#F6){ref-type="fig"}). In the probe test, rats from the Iso and Iso + Lenti-GFP groups showed a reduction in the number of platform crossing and time spent in the target quadrant compared with the control group (*P* = 0.002 and 0.001, respectively, Figure [6F](#F6){ref-type="fig"}). In addition, animals in the Iso + Lenti-Cdh1-GFP group exhibited increased number of crossing and time spent in the target quadrant compared to rats from the Iso and Iso + Lenti-GFP groups (*P* = 0.003 and 0.001 for crossing; *P* = 0.04 and 0.046 for time, Figures [6F,G](#F6){ref-type="fig"}). Furthermore, the typical swimming paths of each group are shown in Figure [6H](#F6){ref-type="fig"}. Collectively, these data suggested that Cdh1 overexpression alleviated the learning and memory deficits caused by isoflurane exposure in the developing rats, but did not influence locomotor activity.
Discussion {#s4}
==========
Our findings demonstrated that exposure to 2% isoflurane for 6 h induces neuroapoptosis and significantly reduces Cdh1 expression, coinciding with the accumulation of several of its downstream substrates (skp2, snoN and cyclin B1). Additionally, Cdh1 overexpression attenuated the neuroapoptosis induced by isoflurane exposure. Furthermore, through intra-hippocampal injection of lentivirus encoding Cdh1, we observed that overexpressing Cdh1 in the developing hippocampus ameliorated the learning and memory impairments caused by isoflurane anesthesia. To our knowledge, this is the first study to investigate the role of APC-Cdh1 in isoflurane neurotoxicity, and our results suggest that Cdh1 is associated with isoflurane-induced neurotoxicity.
Generally, the immature rat brain is most vulnerable to neuronal apoptosis induced by anesthesia during the process of synaptogenesis (Jevtovic-Todorovic et al., [@B27]). High concentration or long duration of anesthetics exposure could lead to significant neurotoxicity. The minimum alveolar concentration (MAC) of isoflurane was 2.7% in P7 Sprague-Dawley rats (Istaphanous et al., [@B24]). In this study, we employed a moderate dose of isoflurane (2%), which is within the clinically used dosage during pediatric anesthesia (Cameron et al., [@B10]). Short exposures to a low concentration of isoflurane did not cause cell damage (Zhao et al., [@B58]). A single anesthesia exposure before the age of 36 months among healthy children did not result in differences in IQ scores in later childhood, compared with healthy siblings with no anesthesia exposure (Sun et al., [@B45]). Therefore, we determined 6 h as the exposure time based on previous studies (Lei et al., [@B34]). Consistent with a previous study (Zhang et al., [@B56]), our results demonstrated that isoflurane exposure increases the number of apoptotic cells in the hippocampal CA1 area and in cultured neurons. In addition, disruption of the balance between anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax occurs, which ultimately stimulates caspase-3 and neuronal apoptosis.
Different methods can be used to evaluate the activity of APC. APC can be activated by combination with Cdh1. APC/C-Cdh1 displayed high ubiquitination activity in the purified brain. In the central nervous system, Cdh1 is highly expressed in post-mitotic neurons, and Cdh1 downregulation by RNA interference can reduce APC/C-Cdh1 activity (Konishi et al., [@B31]; Almeida et al., [@B2]). Another indirect method is to evaluate the level of APC substrates (Gieffers et al., [@B18]). In addition, Cdh1 phosphorylation and the following nuclear export lead to inactivity of APC/C-Cdh1 (Jaquenoud et al., [@B25]). In our study, Cdh1 total protein level was decreased after isoflurane exposure. Meanwhile, the expression of downstream substrates of APC/C-Cdh1 (skp2, snoN and cyclin B1) increased after isoflurane anesthesia, indicating that the ubiquitination activity of APC/C-Cdh1 was inhibited. Furthermore, Cdh1 was highly expressed in the nuclear of hippocampal neurons in the control group, whereas, in the isoflurane group, the expression of Cdh1 in the nucleus decreased, while that in the cytoplasm increased. These results demonstrated that the activity of APC/C-Cdh1 was downregulated during isoflurane-induced neuronal apoptosis in the developing brain. We only studied Cdh1 activity by measuring its location and the change of substrates, a direct method which correlates Cdh1 activity with the observed Cdh1 effect might be better for this study. Further studies are needed to address this point.
To further refine the role of Cdh1 in developmental isoflurane neurotoxicity, a lentivirus encoding Cdh1 was applied in our study. Lentiviral vectors can mediate transfer into any neuronal cell types and allow sustained expression without immune response in the developing mouse brain and primary neuron culture (Sun and Gan, [@B44]; Artegiani and Calegari, [@B4]). We previously constructed the lentivirus and successfully overexpressed Cdh1 in the nervous system (Lv et al., [@B37]; Hu et al., [@B20]). In the current study, we employed a recombinant Cdh1-encoding lentiviral vector to overexpress Cdh1 in the hippocampal neurons 3 days before isoflurane-treatment. GFP-positive signal was detected in the cytoplasm and nucleus of hippocampal neurons in developing rats. Western blot analysis and real-time PCR indicated that Cdh1 was overexpressed, indicating the effective transfection of Cdh1-encoding lentivirus.
Growing evidence has demonstrated that impaired function of APC/C-Cdh1 and accumulation of its substrates are involved in neurodegenerative diseases (Fuchsberger et al., [@B17]). APC/C-Cdh1 is involved in excitotoxicity, oxidative stress, and ectopic cell-cycle re-entry. APC/C-Cdh1 can cause aberrant stabilization and accumulation of cyclin B1 during excitotoxic damage (Maestre et al., [@B38]). Stabilized cyclin B1 binds and activates Cdk1, and accumulation of cyclin B1-Cdk1 complex continues to phosphorylate the anti-apoptotic protein Bcl-xL and leads to neuronal death (Veas-Pérez de Tudela et al., [@B47]). Bax, a member of the Bcl-2 family, can also be regulated by APC-Cdh1 through degradation of the Bax activation enhancer (modulator of apoptosis protein 1; Lee et al., [@B33]; Huang et al., [@B23]). Isoflurane induces neuron apoptosis through the Bcl-2 family protein-mediated mitochondrial pathway of apoptosis (Zhang et al., [@B56]). Therefore, we assessed changes in cyclin B1 and Bcl-2 family proteins expression after Cdh1 overexpression and isoflurane anesthesia. Overexpression of Cdh1 not only decreased the accumulation of cyclin B1 *in vitro*, but also diminished the number of TUNEL-positive cells after isoflurane anesthesia. Consistently, the imbalance of Bcl-2 family proteins tended toward stabilization. Moreover, the caspase-3 activation induced by isoflurane was inhibited by Cdh1 overexpression. Therefore, Cdh1 overexpression protected hippocampal neurons against isoflurane-induced apoptosis.
It has been demonstrated that progressive neuronal death is a consequence of aberrant re-entry into the cell cycle of post-mitotic neurons in many neurodegenerative diseases (Herrup, [@B19]; Veas-Pérez de Tudela et al., [@B48]). Inhibition of Cdh1 has been reported to mediate aberrant cell cycle entry of post-mitotic neurons, leading to apoptotic cell death. Cdh1 depletion in post-mitotic neurons can trigger cyclin B1-mediated entry into S-phase (Almeida et al., [@B2]). Moreover, Cdk5 phosphorylates Cdh1 on at least three phosphorylation sites, subsequently leading to cyclin B1 stabilization (Maestre et al., [@B38]). Notably, a recent study reported that neonatal isoflurane exposure caused aberrant Cdk5 stabilization (Wang et al., [@B50]). Therefore, the upstream partner of Cdh1 involved in isoflurane-induced neuronal apoptosis could be Cdk5. The downstream partner of Cdh1 could stabilize cyclin B1 to avoid re-entry into the cell cycle, thereby inducing apoptotic cell death. Further studies are needed to determine the relationship of Cdk5 activity and Cdh1 subunit expression in developmental isoflurane cytotoxicity.
Neonatal exposure to isoflurane anesthesia in rats produces neurobehavioral defects persisting into adulthood (Jevtovic-Todorovic et al., [@B28]; Zhu et al., [@B60]; Coleman et al., [@B12]). Neuroapoptosis occurs in cognition-related brain regions (such as the hippocampi) and produces an adverse impact on the fundamental development of neuronal networks, which leads to long-term neurocognitive decline. Many studies have supported the role of hippocampal neuroapoptosis in cognitive dysfunction (Jevtovic-Todorovic et al., [@B28]; Boscolo et al., [@B8]; Wu et al., [@B53]). Similarly, our results indicated that Cdh1 overexpression not only reduced isoflurane-induced hippocampal neuroapoptosis, but also alleviated the learning and memory deficits induced by isoflurane in developing rats.
Besides neuroapoptosis, other factors contribute to cognitive deficits associated with isoflurane exposure during brain development. Some studies support the notion that hippocampal synaptic plasticity disturbance (Uchimoto et al., [@B46]) and developmental neurogenesis suppression (Jevtovic-Todorovic, [@B26]; Kang et al., [@B30]) play important role in cognitive impairment induced by postnatal anesthesia exposure. APC/C-Cdh1 is important in contributing to synaptic development and transmission. Previous studies have reported that removing neuronal Cdh1 early in the development resulted in impaired hippocampal long-term potentiation (LTP) and deficits in behavioral flexibility during the updating of memories (Pick et al., [@B39]). Furthermore, conditional knockout of Cdh1 profoundly impaired the induction of long-term depression (LTD) in CA1 hippocampal neurons (Huang et al., [@B21]). Deletion of Cdh1 disrupted synapse development in the cortex and hippocampus (Bobo-Jiménez et al., [@B6]). In addition, recent studies have demonstrated that functional APC/C-Cdh1 ubiquitin ligase is required for developmental neurogenesis (Delgado-Esteban et al., [@B13]). These results indicated that downregulation of Cdh1 may be associated with the molecular mechanism of synaptic plasticity disturbance and neurogenesis suppression induced by isoflurane. However, further studies are needed to clarify the involvement of synaptic plasticity in anesthetic neurotoxicity.
Many preclinical and clinical studies focused exclusively on cognitive function and learning disability as the primary outcomes after anesthesia exposure at a young age. We examined the effect of isoflurane on postnatal rats in terms of other functional outcomes such as locomotor and anxiety-like explorative activity. Similar to a clinical study in children (Sun et al., [@B45]), there was no statistical difference in motor/processing speed after a single anesthesia exposure. It was reported that children before 2 years old repeatedly exposed to anesthesia resulted in higher risk of attention-deficit/hyperactivity disorder (Sprung et al., [@B42]). Although our preliminary behavioral studies suggest alleviation of learning deficits and no alteration of anxiety by overexpression of Cdh1 in isoflurane-treated rats, more cohorts and tests are needed to confirm our observations reported here. Therefore, cautions should be taken to generalize the results until further data becomes available.
This study has some limitations. First, we detected the effect of anesthesia alone on cognitive deficits in developing brain. However, it is impossible to administer anesthetics to children without surgery or examination in clinical practices. In fact, a surgical procedure can increase cytokine levels, and alter gene expression and neural plasticity, compared with administration of anesthesia alone (Broad et al., [@B9]). Second, we did not consider the gender-related effects and used mixed gender rats in our experiments. Previous studies have indicated that isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females (Lee et al., [@B32]), but the effect of gender on anesthetic-induced developmental neurotoxicity remains poorly understood. Third, we performed DAPI + TUNEL to represent the apoptosis of neurons, the neuronal maker NeuN might be better to detect neuron cell death. In addition, we assume that the TUNEL-positive cells do not express Cdh1 but we are currently unable to provide prove for it.
In conclusion, this is the first study to investigate the role of the UPS in anesthesia-induced neurotoxicity and bring a new prospect for neuroprotection in developmental anesthesia. Our study demonstrates that Cdh1 is downregulated in isoflurane-induced neuroapoptosis, leading to long-term cognitive deficits in rats. Cdh1 overexpression can prevent isoflurane-induced developmental neurotoxicity.
Author Contributions {#s5}
====================
KW, LL and WY conceived and designed the experiments. XL, KW, RH and BZ were responsible for performing experiments. RH, LL, LW and CZ contributed to acquiring and analyzing data. XL, KW and WY analyzed data. XL and WY interpreted data and complete the manuscript. Authors included in our article agreed with the final manuscript.
Conflict of Interest Statement {#s6}
==============================
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.** This study is supported by grants from the National Natural Science Foundation of China (no. 81000476 to WY) and a 2015 Youth Arch Foundation from Hubei University of Chinese Medicine (LL).
[^1]: Edited by: Davide Cervia, Università degli Studi della Tuscia, Italy
[^2]: Reviewed by: Kevin Donald Broad, UCL Institute of Ophthalmology, United Kingdom; Edgar Richard Kramer, Medical Research Council Harwell (MRC), United Kingdom
[^3]: ^†^These authors have contributed equally to this work.
| 2024-04-17T01:26:59.872264 | https://example.com/article/4903 |
Adjuvant radiotherapy in the treatment of pediatric myxopapillary ependymomas.
Assess the role of radiotherapy (RT) in the management of primary and recurrent myxopapillary ependymoma (MPE). We conducted a retrospective review of patients with MPE treated at the Montreal Children's Hospital/McGill University Health Centre between 1985 and 2008. Seven children under the age of 18 were diagnosed and treated for MPE. All patients were treated with surgery to the primary site. Three patients underwent subtotal resection (STR) and received adjuvant post-operative RT. Only one patient who had spinal drop metastases received post-operative RT to the lumbosacral region following complete resection of the primary tumor. After a median follow up of 78 months (range 24-180 months), all patients were alive with controlled disease. The single patient treated with gross total resection (GTR) and adjuvant local radiation remained recurrence free. One of the three patients treated with STR and adjuvant RT had disease progression that was controlled with re-resection and further RT. Two of the three patients treated with surgery alone developed local and disseminated recurrent spinal disease that was controlled by salvage RT. Our data support the evolving literature which suggests that GTR alone provides suboptimal disease control in MPE. In our patients, RT resulted in control of residual, metastatic and/or recurrent disease. Routine adjuvant RT may improve outcomes in pediatric MPE. | 2024-05-06T01:26:59.872264 | https://example.com/article/6909 |
Cook the spaghetti using the package directions; drain. Melt the butter in a large skillet over medium heat. Add the garlic, shrimp and mushrooms. Saute for 5 minutes or until the shrimp turn pink. Add the cooked spaghetti, Romano cheese, salt and pepper and stir carefully with a large spoon until combined. | 2023-08-03T01:26:59.872264 | https://example.com/article/4398 |
Vance Cemetery
Vance Cemetery is a cemetery at the end of Vance Cemetery Road in Weaverville, North Carolina. The cemetery opened in 1813 when the namesake David Vance, Sr. was buried. His will stated that he was to be buried above his peach orchard. David Vance, Sr. was the grandfather of Zebulon Baird Vance, the Civil War Governor of North Carolina. The cemetery is still functioning today. There are a large number of children buried in the cemetery, victims of the Spanish flu.
References
Category:Cemeteries in North Carolina | 2024-05-24T01:26:59.872264 | https://example.com/article/9075 |
Introduction {#s1}
============
Information processing within neocortical and hippocampal circuits relies upon complex interactions between glutamatergic excitatory projection neurons and GABAergic inhibitory neurons. Coordinated cell--cell communication amongst and between these two neuronal populations is essential to maintain a delicate balance between excitatory and inhibitory signaling within the brain and is subject to dynamic regulation by many neuromodulatory substances such as various neuropeptides and nitric oxide (NO) (Krimer and Goldman-Rakic, [@B75]; Baraban and Tallent, [@B9]; Somogyi and Klausberger, [@B127a]). Disruption of this excitatory-inhibitory balance often precipitates pathological disorders such as epilepsy, autism, and schizophrenia (McBain and Fisahn, [@B96]; Rubenstein and Merzenich, [@B123]; Levitt et al., [@B84a]; Batista-Brito et al., [@B13]; Lewis et al., [@B85]; Marin, [@B93]). Understanding normal brain functions and the bases of these pathologies requires thorough characterization of telencephalic neurons and their development. For GABAergic neurons this has proven particularly difficult due to their remarkable diversity. Indeed a prerequisite in determining the circuit properties of this cell group is to first define each specific class of interneuron that populates the telencephalon. Helpful criteria for such classification were recently established by the Petilla inteneuron nomenclature group (PING). These include morphological, electrophysiological and molecular properties (Petilla Interneuron Nomenclature Group et al., [@B109a]). Among the established subtypes of interneurons the subpopulation expressing neuronal nitric oxide synthase (nNOS) was recently shown to represent the most prevalent interneuron subpopulation in the hippocampus (Fuentealba et al., [@B49]). Though historically these cells had received relatively little attention a wave of recent studies have implicated interneurons expressing nNOS in important physiological processes such as the homeostatic regulation of sleep (Kilduff et al., [@B73]), neurovascular coupling to control neocortical blood flow (Cauli et al., [@B22]; Cauli and Hamel, [@B21]; Perrenoud et al., [@B106] in this issue), and synaptic integration of adult born neurons (Overstreet and Westbrook, [@B103]). Moreover, these interneurons may contribute to pathological states related to dysfuntion of NO production/release as has been documented in neuronal death and epilepsy (Gholipour et al., [@B58]). Despite the common expression of nNOS there exists considerable heterogeneity within this cohort of interneurons yielding even further subdivision and overlap with other subpopulations defined by criteria unrelated to nNOS expression. During the past decade studies focusing on the developmental origins (place and date of birth) and genetic programs underlying fate specification have produced additional criteria that help make sense of interneuron diversity. In this review we will summarize recent advances in the characterization of neocortical and hippocampal nNOS expressing interneurons with particular emphasis on the genetic programs governing their genesis and specification. We will also briefly review the current understanding of circuit roles played by interneurons expressing nNOS in the development and plasticity of the hippocampus and neocortex.
GABAergic neurons expressing neuronal nitric oxide synthase in the juvenile or mature hippocampus and neocortex
===============================================================================================================
Using a combination of intracellular recoding, dye filling, single cell RT-PCR, NADPH-diaphorase (NADPH-d) reactivity and immunostaining with various antibodies against calcium binding proteins, neuropeptides and nNOS, several groups have shown that nNOS GABAergic neurons can be subdivided into several hippocampal and neocortical sub-populations that are summarized in Tables [1](#T1){ref-type="table"} and [2](#T2){ref-type="table"} and Figure [3](#F3){ref-type="fig"} (see below).
######
**Characteristics of rodent hippocampal GABAergic neurons expressing neuronal nitric oxide synthase**.
**Markers** **Morphology location** **Axonal targeting on pyramidal neurons** **Firing pattern[^\*^](#TN1){ref-type="table-fn"}** **Transcription factors or lineage markers** **Place of genesis[^£^](#TN2){ref-type="table-fn"}**
---------------------- ------------------------------------------------------------------------------------------------------------------ ---------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------- -----------------------------------------------------------------------------------------------------------
nNOS^+^/NPY^+^ Multipolar[^1^](#TN3){ref-type="table-fn"}^,^[^2^](#TN4){ref-type="table-fn"}^,^[^3^](#TN5){ref-type="table-fn"} Dendrite[^1^](#TN3){ref-type="table-fn"}^,^[^2^](#TN4){ref-type="table-fn"}^,^[^3^](#TN5){ref-type="table-fn"} Late spiking[^3^](#TN5){ref-type="table-fn"} Nkx2.1/Lhx6[^3^](#TN5){ref-type="table-fn"}^,^[^4^](#TN6){ref-type="table-fn"} MGE[^3^](#TN5){ref-type="table-fn"}^,^[^4^](#TN6){ref-type="table-fn"}^,^[^5^](#TN7){ref-type="table-fn"}
(IVCs) s.r.; s.p.; s.o. Non-adapting AEP/POA?
nNOS^+^/NPY^+^ Multipolar[^3^](#TN5){ref-type="table-fn"}^,^[^6^](#TN8){ref-type="table-fn"}^,^[^7^](#TN9){ref-type="table-fn"} Dentritic shaft[^6^](#TN8){ref-type="table-fn"}^,^[^7^](#TN9){ref-type="table-fn"} Late spiking[^3^](#TN5){ref-type="table-fn"}^,^[^5^](#TN7){ref-type="table-fn"}^,^[^6^](#TN8){ref-type="table-fn"} Nkx2.1/Lhx6[^3^](#TN5){ref-type="table-fn"}^,^[^4^](#TN6){ref-type="table-fn"} MGE[^3^](#TN5){ref-type="table-fn"}^,^[^4^](#TN6){ref-type="table-fn"}^,^[^5^](#TN7){ref-type="table-fn"}
(NGFCs) neurogliaform Blood vessels Non-adapting CoupTFII AEP/POA ?
s.l.m./s.r. bd
s.l.m./s.m. bd
nNOS^+^/VIP^+^/CR^+^ Bipolar[^8^](#TN10){ref-type="table-fn"} s.p. SOM^+^ neurons[^8^](#TN10){ref-type="table-fn"} of the s.o. Non-LS[^3^](#TN5){ref-type="table-fn"} CoupTFII[^4^](#TN6){ref-type="table-fn"} CGE[^3^](#TN5){ref-type="table-fn"}^,^[^4^](#TN6){ref-type="table-fn"}
5-HT~3A~[^4^](#TN6){ref-type="table-fn"} LGE ?
AEP/POA ?
nNOS^+^/PV^+^ Basket? Granule cell layer? Fast spiking? Nkx2.1? MGE?
DG specific
Firing pattern elicited from intracellular injections of depolarizing currents.
AEP, entopeduncular area; CGE, caudal ganglionic eminence; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; POA, preoptic area; s.l.m.; stratum lacunosum molecular; s.m.; startum molecular; s.o.; stratum oriens; s.p.; stratum pyramidale; s.r.; stratum radiatum.
*Fuentealba et al., [@B49]*,
*Somogyi et al., [@B128]*,
*Tricoire et al., [@B138]*,
*Tricoire et al., [@B139]*,
*Jaglin et al., [@B66]*,
*Price et al., [@B115]*,
*Zsiros and Maccaferri, [@B158]*,
Freund and Buzsáki, [@B48].
######
**Characteristics of rodent neocortical GABAergic neurons expressing neuronal nitric oxide synthase**.
**Markers** **% cells within nNOS-type II** **Morphology** **Axonal targeting** **Firing pattern[^\*^](#TN11){ref-type="table-fn"}** **Transcription factors or lineage markers** **Place of genesis**
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------- -------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------ ----------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------
Highly Long projection[^1^](#TN12){ref-type="table-fn"}^,^[^2^](#TN13){ref-type="table-fn"} Blood vessels[^1^](#TN12){ref-type="table-fn"}^,^[^2^](#TN13){ref-type="table-fn"} Late spiking[^3^](#TN14){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"} Nkx2.1/Lhx6[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}^,^[^5^](#TN16){ref-type="table-fn"} MGE[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}^,^[^5^](#TN16){ref-type="table-fn"}
nNOS^+^SOM^+^/NPY^+^[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}^,^[^5^](#TN16){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"}^,^[^7^](#TN18){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"} Neurons[^1^](#TN12){ref-type="table-fn"}^,^[^2^](#TN13){ref-type="table-fn"} Adapting[^3^](#TN14){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"}
(nNOS-type I)
Lightly nNOS^+^ 55 Neurogliaform[^3^](#TN14){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"} Blood vessels ? Adapting[^3^](#TN14){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"} Nkx2.1/Lhx6[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"} MGE[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}
NPY^+^[^3^](#TN14){ref-type="table-fn"}^,^[^5^](#TN16){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"}^,^[^9^](#TN20){ref-type="table-fn"} Dentritic shaft 5-HT~3A~[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"} CGE/AEP[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}
(nNOS-type II)
Lightly nNOS^+^ PV^+^ or SOM^+^[^3^](#TN14){ref-type="table-fn"}^,^[^5^](#TN16){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"}^,^[^10^](#TN21){ref-type="table-fn"} (nNOS-type II) 35 Multipolar[^3^](#TN14){ref-type="table-fn"} Blood vessels ? Proximal dendrites Soma Axonal initial segment Fast spiking[^3^](#TN14){ref-type="table-fn"} Nkx2.1/Lhx6[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"} MGE[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}
Lightly nNOS 10 Bipolar[^3^](#TN14){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"} Blood vessels ? Adapting[^3^](#TN14){ref-type="table-fn"} 5-HT~3A~[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"} AEP/PO? [^3^](#TN14){ref-type="table-fn"}
VIP^+^/CR^+^[^3^](#TN14){ref-type="table-fn"}^,^[^5^](#TN16){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"}^,^[^8^](#TN19){ref-type="table-fn"} Double-bouquet[^3^](#TN14){ref-type="table-fn"}^,^[^6^](#TN17){ref-type="table-fn"} Soma CGE[^3^](#TN14){ref-type="table-fn"}^,^[^4^](#TN15){ref-type="table-fn"}
(nNOS-type II) SVZ/Ctx?
Firing pattern elicited from intracellular injections of depolarizing currents: AEP, entopeduncular area; CGE, caudal ganglionic eminence; Ctx, cortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; POA, preoptic area; SVZ, subventricular zone.
*Tomioka et al., [@B137]*,
*Higo et al., [@B62]*,
*Perrenoud et al., [@B105]*,
*Magno et al., [@B91]*,
*Jaglin et al., [@B66]*,
*Perrenoud et al., [@B106]*,
*Kubota et al., [@B78]*,
*Karagiannis et al., [@B72]*,
*Oláh et al., [@B102]*,
Vruwink et al., [@B147].
GABAergic neurons expressing neuronal nitric oxide synthase in the hippocampus
------------------------------------------------------------------------------
The hippocampus is subdivided in two main anatomical areas, the dentate gyrus (DG) and the cornu ammonis (CA). The CA region is classically further divided into CA1--4. In this section of the review, we will mainly focus on results obtained in CA1 where interneuron diversity has been best characterized but will detail other areas when data are available. As in the neocortex, nNOS expressing neurons comprise primarily inhibitory GABAergic neurons although nNOS immunoreactivity is also found in CA1 pyramidal cells. In these glutamatergic excitatory cells staining intensity in mature brain is much weaker than in interneurons and nNOS is observed preferentially in dendritic spines (Burette et al., [@B17]). Hippocampal nNOS expressing interneurons differ from their neocortical homologs in that they are much more abundant and the level of nNOS expression is more homogenous (Jinno and Kosaka, [@B68]). Indeed, while neocortical nNOS^+^ interneurons may be subdivided based on intensity of nNOS immunoreactivity (see next section), no such distinction exists in the hippocampus. Furthermore, a recent study revealed that interneurons expressing nNOS comprise the most abundant interneuron subpopulation in the hippocampus, in contrast to neocortical observations where parvalbumin (PV) expressing interneurons are considered to be the most abundant interneuron subtypes (Fuentealba et al., [@B49]). Like in the neocortex, nNOS expressing interneurons are found in all hippocampal layers of CA and in the DG. One study in the mouse has shown that the density of nNOS interneurons is higher in the septal/dorsal part compared to the temporal/ventral part of the hippocampus (Jinno and Kosaka, [@B68]).
In rats and mice, at least five interneuron subpopulations have been described to express nNOS: (1) the neurogliaform cells (NGFC), (2) Ivy cells (IvC), (3) interneurons co-expressing the vasoactive intestinal peptide (VIP) and calretinin (CR), (4) interneurons expressing PV and (5) projection cells. This latter subtype of nNOS^+^ cells has been shown to accumulate close to the subiculum (Freund and Buzsáki, [@B48]). The subpopulation coexpressing nNOS and PV principally resides in the DG (Dun et al., [@B36]; Jinno and Kosaka, [@B68], [@B69]). However species differences between rat and mouse have been noted as co-expression of nNOS and PV in rat DG is much lower than in mouse (Dun et al., [@B36] for rat; Jinno and Kosaka, [@B68] for mouse). Additionally, a subset of somatostatin (SOM) expressing interneurons in CA1, CA3, and DG areas has been shown to express nNOS (Jinno and Kosaka, [@B69]). Similar to the case with PV, species differences have been encountered with nNOS/SOM coexpression being higher in rat than mouse (Dun et al., [@B36] for rat; Jinno and Kosaka, [@B69] for mouse). Examples of the morphology and firings of three of these cell groups are provided in Figure [1](#F1){ref-type="fig"}.
![**Examples of IvC, NGFC, and VIP^+^/nNOS^+^ interneurons. (A)** Neurolucida reconstructions of biocytin-filled cells (black, dendrite; red, axon). **(B)** Voltage responses of cells shown in **(A)** to three current step injections (-200 pA, just suprathreshold, and twice the current for just suprathreshold). Adapted from Tricoire et al. ([@B138]).](fncir-06-00082-g0001){#F1}
Neurogliaform and ivy cells
---------------------------
Hippocampal NGFCs derive their name from their neocortical homologs with which they share common morphological features. NGFC bodies are typically found in stratum lacunosum moleculare (slm) and its border with s. radiatum (sr) of CA1-3, as well as within s. moleculare of the DG (Vida et al., [@B145]; Price et al., [@B115], [@B116]; Elfant et al., [@B38]; Karayannis et al., [@B72a]; Szabadics et al., [@B133]; Armstrong et al., [@B5]; Krook-Magnuson et al., [@B76]; Markwardt et al., [@B94]). Their soma is relatively small in comparison with those of other interneuron subtypes such as somatostatin^+^ (SOM^+^) and PV^+^ interneurons. NGFCs exhibit a multipolar dendritic network with a high degree of ramification close to the soma without any privileged orientation. The axonal arborization is extremely dense with extensive ramification within the local network and usually radiates beyond the spatial boundaries of the dendritic field (Price et al., [@B115]; Tricoire et al., [@B138]). In addition, both fields are restricted to slm and typically penetrate very little into the sr. However, several studies reported that the axons of CA1 NGFCs may penetrate s. moleculare of the DG (Price et al., [@B115]; Fuentealba et al., [@B50]; Tricoire et al., [@B138]). Similarly axons of DG NGFCs can cross the hippocampal fissure and penetrate into slm of nearby CA1 and subiculum (Armstrong et al., [@B5]).
Closely related to NGFCs, are the recently described hippocampal IvCs (Fuentealba et al., [@B49], [@B50]; Tricoire et al., [@B138], [@B139]; Krook-Magnuson et al., [@B76]) and the existence of an equivalent interneuron subpopulation in the neocortex is a matter of debate. These cells were first reported by Peter Somogyi\'s group and named for the English Ivy-like appearance of their axons which profusely branch close to their origin providing dense thin branches with numerous small varicosities (Fuentealba et al., [@B49]; Somogyi et al., [@B128] in this issue). In contrast to NGFCs, the cell bodies and processes of IvCs are found in s. oriens, s. pyramidale and sr without infiltrating slm (Fuentealba et al., [@B49]; Tricoire et al., [@B138]). However, recent results indicate that IvCs whose soma is located in sr regularly send axons and dendrites to some extent in slm. (Somogyi et al., [@B128] in this special issue and Szabo et al., [@B134]).
From a molecular point of view, NGFCs and IvCs express several common markers/receptors resulting in convergent neurochemical profiles for these two nNOS^+^ interneurons subtypes. The neuropeptide Y (NPY) has been found to colocalize with nNOS in both NGFCs and IvCs (Fuentealba et al., [@B49]; Tricoire et al., [@B138]; Somogyi et al., [@B128] in this issue). However, NPY is not specific to nNOS^+^ interneurons as it is also frequently coexpressed with SOM and PV in yet other distinct interneuron subpopulations (Klausberger and Somogyi, [@B74]). Whereas IvC and NGFC subpopulations of CA constitute a distinct population from PV and SOM expressing subpopulation, nNOS and PV often colocalize in the DG. The alpha1 GABAA receptor subunit is also frequently encountered in IvCs and nNOS^+^ NGFCs (Fuentealba et al., [@B49]; Tricoire et al., [@B138]) but, like NPY, it cannot be considered as a specific marker of IvCs or NGFCs as it is also expressed in other interneuron subtypes (Baude et al., [@B14]). More recently, the delta GABAA receptor subunit that underlies tonic inhibition was demonstrated to preferentially localize to NGFC/IvC interneurons (Oláh et al., [@B102]). However this subunit is not specific of interneurons and is also found in excitatory granule cells in DG (Wei et al., [@B149]). IvCs and NGFCs are inhibited by mu opioid agonists, such as DAMGO, consistent with the expression of mu opioid receptors (MORs) on both interneuron subpopulations (Krook-Magnuson et al., [@B76]). Interestingly, MORs are also found in PV^+^ interneurons in CA1. This expression pattern is distinct from that observed in neocortex where MORs are found on interneurons co-expressing VIP and cholecystokinin (CCK) (Férézou et al., [@B42]). The microtubule associated protein alpha actinin 2 has been shown to be selective for NGFCs and IvCs in rat hippocampus (Price et al., [@B115]; Fuentealba et al., [@B49]). It is not clear if it is also the case in mouse hippocampus. In rat, the chicken ovalbumin upstream promoter transcription factor II (CoupTFII) is frequently observed in both IvCs and NGFCs (Fuentealba et al., [@B50]), whereas in mouse it is rarely found in IvCs despite frequent expression in NGFCs (Tricoire et al., [@B138]). So far reelin appears to be the only marker that is differentially expressed between IvCs and NGFCs although this marker is also commonly found in SOM^+^ interneurons (Alcántara et al., [@B3]). Indeed, reelin has been detected in NGFCs but not in IvCs (Fuentealba et al., [@B50]; Somogyi et al., [@B128] in this issue).
In CA1, IvCs receive their main excitatory inputs from CA1 and CA3 pyramidal cells (Fuentealba et al., [@B49]; Somogyi et al., [@B128] in this issue) while NGFCs receive excitatory inputs from the entorhinal cortex via the temporo-ammonic pathway and from CA3 via the Schaffer collateral pathway (Price et al., [@B115]). Both cell subpopulations inhibit down-stream targets via GABAA receptors. However, in addition, NGFCs generate long lasting postsynaptic inhibitory currents through the activation of GABAB receptors on their postsynaptic targets (Price et al., [@B115], [@B116]). Interestingly, NGFCs are highly interconnected via both electrical and chemical synapses (Price et al., [@B115]; Zsiros and Maccaferri, [@B158]). In contrast, IvCs have thus far only been found to signal via chemical synapses on postsynaptic cells (Fuentealba et al., [@B49]). In terms of neuronal activity, IvCs and NGFCs exhibit very similar electrophysiological properties regarding their passive membrane and firing properties (Tricoire et al., [@B138]). For example, they all show a late spiking phenotype, i.e., a delay to generate action potentials when challenged by just suprathreshold current injection (Price et al., [@B115]; Zsiros and Maccaferri, [@B158]; Tricoire et al., [@B138]). None of these cell types exhibit adaptation of firing frequency at threshold stimulation. However, upon stronger stimulation, they all switch to an adaptive spiking profile (Tricoire et al., [@B138]). Nonetheless, *in vivo* recordings in anesthetized rats revealed that IvCs and NGFCs exhibit different firing characteristics during rhythmic hippocampal activities. NGFCs fire at the peak of theta oscillations detected extracellularly in s. pyramidale, whereas IvCs fire at the trough of these oscillations (Fuentealba et al., [@B50]; Lapray et al., [@B79]).
VIP^+^/CR^+^/nNOS^+^ interneurons in CA1-3
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The third interneuron subpopulation expressing nNOS consists of a subset of VIP^+^/CR^+^ interneurons (Jinno and Kosaka, [@B68]; Tricoire et al., [@B138]). This population is specialized to innervate other GABAergic cells exclusively. To date, three types of interneuron-specific (IS) interneurons have been described on the basis of their anatomical and neurochemical features (Acsády et al., [@B1],[@B2]; Gulyás et al., [@B61]). Among them, nNOS has been found in the IS-3 subset (Tricoire et al., [@B138]). These cells have somas located in stratum pyramidale (s.p.) or in stratum radiatum (s.r.) close to the pyramidal layer, dendritic fields that are vertically oriented, and a primary axon descending to emit several horizontally oriented branches at the s.o.-alveus border. Consistent with their axonal morphology, they constitute a major local source of inhibition to SOM^+^ O--LM cells (Acsády et al., [@B1],[@B2]; Gulyás et al., [@B61]; Chamberland et al., [@B23]). Electrophysiologically, they exhibit an irregular firing pattern when depolarized with current injection which differs from the late spiking and more regular firing profile of IvC/NGFC (Tricoire et al., [@B138]). The position of these neurons in the hippocampal network in terms of input is still to be determined.
PV^+^/nNOS^+^ interneurons in DG
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The expression pattern of nNOS in the DG differs from that observed in CA areas. Indeed, nNOS is found in about 20% of PV^+^ interneurons (Jinno and Kosaka, [@B68]) whereas there was no overlap between nNOS and PV expression in CA areas. While PV^+^ interneurons in DG are well characterized in terms of morphology and neurophysiology (Bartos et al., [@B11]), so far no study has examined if nNOS^+^/PV^+^ cells represent a specific interneuron subpopulation compared to other DG PV^+^ interneurons. Briefly, PV^+^ interneurons exhibit a fast spiking firing profile, which means that they are able to generate a train of action potentials at high frequency and little to no accommodation when injected with depolarizing current. Action potentials in these neurons are much shorter in duration that those in IvC/NGF (Tricoire et al., [@B139]) and their axons preferentially target the perisomatic region of granule cells making them ideally suited to rapidly regulate DG output.
GABAergic neurons expressing neuronal nitric oxide synthase in the neocortex
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In the cerebral cortex, nNOS GABAergic neurons comprise an average of 20% of the neocortical GABAergic population (Kubota et al., [@B77]; Gonchar and Burkhalter, [@B60]; Magno et al., [@B91] and Perrenoud et al., [@B105] in this issue). Classically, two types of GABAergic nNOS^+^ neurons have been distinguished at the histochemical level (Figure [2](#F2){ref-type="fig"}). The first one corresponds to the subpopulation of GABAergic neurons expressing high levels of nNOS and NADPH-d activity, the so called "nNOS-type I" that display fast-spiking and adapting properties. They account for 0.5--2% of the neocortical GABAergic population (Kubota et al., [@B77]; Gonchar and Burkhalter, [@B60]; Magno et al., [@B91] and Perrenoud et al., [@B105] in this issue). In these neurons nNOS is associated with SOM and NPY expression and immunoreactivity as well as with the substance P receptor NK1 (Kubota et al., [@B78]). Further, it was recently shown that these neurons are depolarized by substance P application (Dittrich et al., [@B34] in this issue). They mainly correspond to projection neurons that are sparsely distributed in all neocortical layers but preferentially located in lower layer VI (Perrenoud et al., [@B105] in this issue; Magno et al., [@B91] in this issue) and to a lesser extent in superficial layers. Using NADPH-d activity these GABAergic neurons were recently shown to send long (\>1.5 mm in the mouse) thick axonal fascicles running between the gray and white matter in cat and mouse neocortex invading both the corpus callosum and the fimbria (Tomioka et al., [@B137]; Higo et al., [@B62]). Their projections innervate both GABAergic neurons and pyramidal neurons and they are suspected to interconnect the two controlateral hemispheres as well as the archi- and paleo-cortex. Interestingly, nNOS-type I cells were recently shown to be selectively activated during sleep as they showed c-Fos accumulation during sleep recovery following sleep deprivation (Gerashchenko et al., [@B57]). Kilduff et al. proposed that nNOS-type I GABAergic neurons could synchronize EEG activity across neocortical regions (detailed in the last chapter; Kilduff et al., [@B73]).
![**Immunolabeling for nNOS in a neocortical sections of GAD67:GFP mouse strain showing the two nNOS populations. (A)** Fluorescence picture showing immunohistochemical expression of nNOS. **(B)** Expression pattern of GFP. **(C)** Overlay of **(A)** and **(B)**. nNOS-type I neurons display strong immunolabeling (open arrows) and a large soma whereas nNOS-type II (arrows) are weakly stained and display smaller soma. Note that all nNOS-positive neurons are GABAergic. Scale bar: 30 μm. Unpublished caption obtained from preparations used for the study presented by Perrenoud et al. ([@B105]).](fncir-06-00082-g0002){#F2}
![**nNOS expressing interneurons in cortex and hippocampus.** Scheme summarizing the molecular profiles of neocortical and hippocampal nNOS^+^ interneurons. This diagram is based on previous report (Tricoire et al., [@B138], [@B139]) and on Perrenoud et al. ([@B105] in this issue).](fncir-06-00082-g0003){#F3}
The second classically defined subpopulation of neocortical nNOS expressing GABAergic neurons exhibits weak nNOS soma staining and low NADPH-d activity. This group corresponds to "nNOS-type II" cells that were initially reported in the primate (Yan et al., [@B157]; Smiley et al., [@B126]) but have more recently been described in rodents (Cho et al., [@B24a]; Kubota et al., [@B78]). In rodents nNOS-type II GABAergic neurons comprise an average of 17% of the neocortical GABAergic population (Kubota et al., [@B78]; Magno et al., [@B91] and Perrenoud et al., [@B105] in this issue) and have often been underestimated due to the difficulty of their visualization. These cells mainly concentrate into the superficial layers II--III and in deep layers V--VI. Although poorly described "nNOS-type II" cells appear to form a heterogeneous cell population regarding the neuronal markers they co-express and the few electrophysiological properties that have been reported. Indeed, a fraction of "nNOS-type II" cells was reported to express SOM and another PV (Kubota et al., [@B78]; Vruwink et al., [@B147]) with both of these distinct subsets emerging clearly in the cluster analysis (Karagiannis et al., [@B72]). Another subpopulation of nNOS-type II neurons comprises the group of adapting neurogliaform interneurons that mediates slow GABAergic inhibition of pyramidal cells and interneurons (Karagiannis et al., [@B72]; Oláh et al., [@B102]). Indeed, in their classification of NPY^+^ interneurons Karragiannis and colleagues revealed that a fraction of interneurons expressing NPY^+^, but not PV, SOM, or VIP, and displaying adapting firing properties with neurogliaform morphologies could be further subdivided into two groups one expressing NPY "only" and another that accounts for 50% of the neurogliaform cluster in which NPY is co-expressed with nNOS (Karagiannis et al., [@B72]). In addition this cluster also included neurons expressing nNOS only but sharing electrophysiological and morphological similarities with adapting NPY interneurons.
More recently, Perrenoud et al performed a multiparametric analysis of "nNOS-type I" and "nNOS-type II" cells that intended to clarify nNOS expressing cell classification schemes and shed light on the physiological relevance of the different subgroups (Perrenoud et al., [@B105] in this issue). This multiparametric analysis used an unsupervised classification of nNOS expressing GABAergic neurons and demonstrated clear segregation of nNOS cells into four clusters. One group contained GABAergic nNOS neurons co-expressing SOM and NPY that might correspond to the well-described population of nNOS-type I interneurons (Karagiannis et al., [@B72]; Kubota et al., [@B78]). Electrophysiologically these cells displayed adapting discharges fired long duration spikes followed by fast AHPs and had significantly slower membrane time constants than other interneurons. The three other clusters presumably corresponded to subpopulations of nNOS-type II interneurons. One cluster consisted of a population of interneurons co-expressing nNOS and CR and/or VIP that was to our knowledge not reported before. They were characterized by high input resistances, low firing threshold, adapting discharges to threshold and saturating current injections and they fired at significantly lower maximal frequencies than other neurons. A second cluster included a population of interneurons coexpressing nNOS and NPY with the exclusion of other classical markers (except CCK) that might correspond to neurogliaform interneurons. On an electrophysiological basis these NPY^+^/nNOS^+^ neurons were characterized by medium range input resistances. They displayed action potential discharges that were accelerating at threshold, adapting at saturation and a significantly larger accommodation of spike amplitude than in other clusters. In addition, these GABAergic neurons displayed long duration spikes followed by significantly slower AHPs than observed in other neurons. The third cluster included nNOS^+^ interneurons expressing PV or SOM that are mainly located in the infragranular layers. These neurons displayed several unique electrophysiological characteristics. They had depolarized membrane potentials and short time constants. Moreover, these cells showed little or no adaptation at threshold, fired at significantly higher maximal rates, and displayed significantly faster spike and AHP dynamics than other neurons.
Development of telencephalic interneurons
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In rodents numerous studies have demonstrated that telencephalic interneurons mainly derive from subpallial territories (Figure [4](#F4){ref-type="fig"}). Pioneering *in vitro* studies and phenotypical descriptions of mutant mice lacking germinal zones that showed reduced interneuron numbers in the neocortex and hippocampus suggested that telencephalic interneurons expressing SOM and PV originate from the medial ganglionic eminence (MGE) and/or the preoptic area (POA) (Lavdas et al., [@B80]; Sussel et al., [@B132]; Wichterle et al., [@B150]; Pleasure et al., [@B110]; Wonders and Anderson, [@B151]; Batista-Brito and Fishell, [@B12]; Vitalis and Rossier, [@B146]). Indeed, in mice deficient for Nkx2.1, a transcription factor expressed in MGE and POA, the MGE appears to undergo a respecification into an LGE-like region and SOM and PV interneurons are dramatically reduced in the cortex and hippocampus. (Sussel et al., [@B132]; Pleasure et al., [@B110]; Figure [5](#F5){ref-type="fig"}). More recently, it was demonstrated that Nkx2.1 was necessary for the expression of Lhx6, a Lim homeobox transcription factor that is specifically expressed in the MGE and needed for the specification of MGE-derived interneurons (Liodis et al., [@B88]; Du et al., [@B35]). Grafting experiments and the use of transgenic mice often in association with "Cre-Lox strategy" have refined these analyses and confirmed that in the cerebral cortex fast spiking PV interneurons (Xu et al., [@B155]; Butt et al., [@B19], [@B18]; Wonders et al., [@B152]) originate preferentially from the ventral part of the MGE (MGEv). By contrast, similar studies revealed that neocortical bursting and adapting SOM interneurons arise preferentially from the dorsal part of the MGE (MGEd) (Butt et al., [@B19]; Miyoshi et al., [@B97]). In the cerebral cortex, Martinotti cells co-expressing SOM and CR were further shown to be derived from the most dorsal MGE territory (LGE4 as named in Flames et al., [@B45]) that expresses the transcription factor Nkx6.2 (Fogarty et al., [@B46]). While initial *in vitro* experiments revealed that the CGE produces mainly CR expressing interneurons (Xu et al., [@B155]), more recent studies have demonstrated a much larger contribution of this region in generating telencephalic interneuron diversity (Butt et al., [@B19]; Fogarty et al., [@B46]; Miyoshi et al., [@B97]; Lee et al., [@B83]; Vucurovic et al., [@B148]). Indeed, together these studies showed that telencephalic (hippocampal and neocortical) interneurons expressing VIP, CR, and a subpopulation of neocortical neurogliaform interneurons expressing NPY (Lee et al., [@B83]; Tricoire et al., [@B138], [@B139]; Vucurovic et al., [@B148]) are all CGE-derived. Interneurons arising from CGE pogenitors all appear to express the 5-HT receptor type 3A (5-HT~3A~) (Lee et al., [@B83]; Vucurovic et al., [@B148]) and the transcription factor Gsh2 (Fogarty et al., [@B46]) while lacking Nkx2.1, Nkx6.2, and Lhx6 (Flames et al., [@B45]). However, it should be noted that the entopeduncular region (AEP), also defined as the more ventral extension of the MGE (Flames et al., [@B45]) co-expresses 5-HT~3A~, NKx2.1, and Lhx6. Homochronic grafting of the AEP has revealed that this region does not appear to contribute importantly to the genesis of neocortical neurons expressing 5-HT~3A~. By contrast, these experiments have shown that the AEP generates subpopulations of 5-HT^+^~3A~ hippocampal interneurons (Vucurovic et al., [@B148]; Jaglin et al., [@B66]).
{#F4}
{#F5}
Besides contributions from the MGE, CGE, and AEP other regions have been implicated in the genesis of neocortical and hippocampal interneurons such as the preoptic regions and the neocortex. Recently, homochronic graftings of dorsal preoptic territories (POA1) have revealed that Nkx5.1^+^ progenitors generate neocortical interneurons expressing NPY^+^ with the exclusion of other markers classically used to discriminate interneurons populations (Gelman et al., [@B56]). The anatomical features and firing patterns of these neurons in the neocortex suggested they represent an additional subset of neurogliaform interneurons (Gelman et al., [@B56]). Further, Gelman et al have shown that the Dbx1-derived progenitors arising from the ventral POA (POA2) contribute to the genesis of various interneurons including fast spiking PV^+^, SOM^+^, multipolar late spiking NOS^+^, neurogliaform, and bituftued/bipolar irregular spiking VIP/CR interneurons that mainly populate deep neocortical layers and hippocampal subfield (Gelman et al., [@B55a]).
Together these studies have successfully correlated the place of genesis and the contribution of specific transcription factors or molecular markers with a preferential interneuron phenotype and location. Specific guidance molecules are preferentially expressed in different subterritories and participate to the targeting of specific interneuron subpopulations. Recent studies suggest that motility and guidance of interneurons depend on several molecular cues that are already differentially expressed in ganglionic eminences and neocortical compartments (Powell et al., [@B112]; Polleux et al., [@B111]; Pozas and Ibanez, [@B113]; Kanatani et al., [@B70]; López-Bendito et al., [@B90]). However, other mechanisms have been shown to participate in the correct positioning of specific classes of interneurons. Indeed, the selective cell death of specific interneurons during early postnatal development may contribute to remove those that are abnormally positioned or not appropriately integrated in neocortical circuits (De Marco García et al., [@B33]). For instance it has recently been shown that reelin^+^ and CR^+^, but not VIP^+^, interneurons depend on neocortical activity for their correct migration and positioning (De Marco García et al., [@B33]).
In addition to the embryonic genesis of neocortical interneurons recent studies have also shown that during the three first postnatal weeks the neocortex produces CR-positive interneurons (Cameron and Dayer, [@B20]; Inta et al., [@B64]; Riccio et al., [@B120]). Such postnatally generated populations may participate in distinct physiological processes including the appropriate targeting of callosal projections.
Origin of interneurons expressing nNOS
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Origin of hippocampal interneurons expressing nNOS
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As mentioned above, hippocampal nNOS^+^ interneurons differ from their neocortical homologs in terms of neuronal diversity and distribution among hippocampal subfields and layers. Therefore specific studies have addressed their embryonic origin using lineage analysis, conditional fate-mapping, and loss of function (Fogarty et al., [@B46]; Tricoire et al., [@B138], [@B139]; Figure [6](#F6){ref-type="fig"}). Using an Nkx2.1-Cre driver line in combination with different Cre-dependant GFP reporter lines, it has been shown that IvCs and nNOS^+^/NGFCs derive essentially from the MGE. This was also supported by the expression of Lhx6 in these subpopulations (Tricoire et al., [@B139]; Figure [6](#F6){ref-type="fig"}). Accordingly, when a CGE preferred tamoxifen dependant driver line was used (Mash1-CreER, Miyoshi et al., [@B98]), very few fate-mapped neurons expressed nNOS (Tricoire et al., [@B138]). These few nNOS expressing CGE-derived neurons typically exhibited morphologies and distributions consistent with VIP^+^/CR^+^ interneurons rather than IvCs and NGFCs. Moreover, conditional loss of Nkx2.1 function (constitutive knock out die at birth) caused an almost complete loss of nNOS^+^ GABAergic neurons in the hippocampus except for few bipolar interneurons in s.p. reminiscent of the VIP^+^/CR^+^ interneurons revealed in the CGE reporter (Tricoire et al., [@B138]; Figures [6A,B](#F6){ref-type="fig"}). In parallel, analysis of a GAD65-GFP transgenic line that labels a subset of CGE-derived interneurons (López-Bendito et al., [@B90a]) further confirmed that some VIP^+^ interneurons also express nNOS. Their electrophysiological and morphological properties were different from those of IvCs and NGFCs but were reminiscent of the IS-3 cell type that inhibits a subset of SOM^+^ interneurons located in stratum oriens (s.o.) that project in turn to the stratum lacunosum molecular (Freund and Buzsáki, [@B48]; Chamberland et al., [@B23]).
![**Embryonic origin of nNOS^+^ hippocampal interneurons. (A)** Images illustrating the coexpression of GFP and nNOS in the Nkx2.1Cre:RCE (left) and GAD65-GFP (right) mouse lines. Scale bar: 25 μm. **(B)** Nkx2.1 is necessary for the specification of nNOS^+^ interneurons. Top, *In situ* hybridization against Lhx6 transcripts on hippocampus of control (left) and mutant (right) P15 mice after conditional loss of Nkx2.1 function at E10.5. Scale bar: 200 μm. Bottom, Immunohistochemical expression patterns of nNOS in CA1 of control and mutant mice. Scale bar: 50 μm. Adapted from Tricoire et al. ([@B138], [@B139]).](fncir-06-00082-g0006){#F6}
Surprisingly, the lineage analysis also revealed that classically defined NGFCs can be subdivided into two groups with nNOS^+^/NGFCs being derived from the MGE and nNOS-/NGFCs arising from CGE progenitors (Tricoire et al., [@B138], [@B139]). This contrasts with findings in the neocortex where the CGE is the dominant source of NGFCs (Butt et al., [@B19]; Miyoshi et al., [@B97], [@B98]) and of nNOS-type II interneurons (Perrenoud et al., [@B105] in this issue). The surprising lack of nNOS in the CGE-derived subset of NGFCs may partially explain the reduced levels of nNOS in the neocortex compared to the hippocampus (Yan and Garey, [@B156]; Lee and Jeon, [@B81]). The striking difference between hippocampal and neocortical NGFCs suggests that interneuron precursors could be fated early during embryogenesis to reside in either the hippocampus or neocortex, perhaps reflecting differential sensitivities to specific sorting factors like chemokines (Li et al., [@B86]; López-Bendito et al., [@B90]) that promote migration of nNOS^+^/NGFC and IvC precursors into the hippocampus. Alternatively, these cells may adopt a different fate depending on whether they integrate into the hippocampus or neocortex due to differential expression of morphogenic molecules within these local environments.
Origin of neocortical interneurons expressing nNOS
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Investigations into the developmental origins of neocortical GABAergic neurons expressing nNOS are only in their infancy due to the fact that this population in the juvenile brain is largely heterogeneous and thus poorly defined. This is especially true for nNOS-type II interneurons that display low NADPH-d activity and nNOS-immunoreactivity making them difficult to identify histologically. The study presented by Perrenoud et al. in this special issue is to our knowledge the first study to specifically characterize neocortical interneurons expressing nNOS using a multiparametric approach and to elucidate their developmental origins (see Table [1](#T1){ref-type="table"}). The first group identified is homologous to previously described nNOS-type I cells being relatively homogeneous comprised of nNOS^+^ GABAergic cells that coexpress SOM and display fast-spiking properties (Perrenoud et al., [@B105] in this issue; see above). These properties clearly suggest that they belong to a subgroup of well-defined SOM^+^ interneurons that were previously shown to derive from the MGE. Indeed, Perrenoud et al. demonstrate that all members of this subgroup express Lhx6 in agreement with two recent studies---presented in this issue---that have used various transgenic mouse lines to clarify the origin of nNOS expressing interneurons (Jaglin et al., [@B66]; Magno et al., [@B91]). Interestingly, it was recently shown that the specification of a large fraction of nNOS-type I neurons required the Lhx6-mediated activation of Sox6 for proper specification (Batista-Brito et al., [@B13]; Jaglin et al., [@B66]). Indeed, deletion of Sox6 in Lhx6 expressing cells suppressed SOM expression in nNOS-type-I neurons and altered their morphology by decreasing process complexity (Jaglin et al., [@B66]). In contrast to this first cluster, nNOS-type II cells displayed considerable heterogeneity segregating into three clusters with embryonic origins in both the MGE and the CGE/AEP territories. Indeed, not all nNOS-type II cells express Lhx6 (Jaglin et al., [@B66] in this issue; Perrenoud et al., [@B105]). A subpopulation of nNOS-type II cells express 5-HT~3A~, a CGE/AEP marker, and colocalization between nNOS, 5-HT~3A~, and VIP was observed (average 10% of the 5-HT~3A~ population; Perrenoud et al., [@B105],[@B106] in this issue). These cells are mainly localized in the superficial layers where they may participate in neuro-vascular coupling. Another group of cells expressing nNOS and NPY but not SOM may derived from MGE and CGE territories and could correspond to neurogliaform cells located in the most superficial layers where they may bidirectionally regulate blood flow. The recent genesis of a transgenic line expressing a tamoxifen inducible Cre recombinase under the control of the nNOS promoter (nNOS-CreER) will help to analyze the physiological roles that these populations may play (Taniguchi et al., [@B135]).
Primates and human telencephalon: specific aspects of GABAergic development
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Rodents, specifically mice, are of great interest due to the availability of transgenic models (Taniguchi et al., [@B135]) that allow for thorough dissection of the genetic programs needed for interneuron development and specification. However, it is difficult to relate neocortical development in mice to the much longer timescale and complexity of primate development (Uylings et al., [@B140]; Rakic, [@B117]). Indeed, comparative studies across species indicate that the first postnatal week in mice corresponds broadly to gestational days 85--130 in macaques and to 110--170 in humans (Clancy et al., [@B26]). The much longer timescale in these higher order species is certainly due to the important brain expansion in size and therefore to the increasing distance of subpalial and pallial territories and concerns the place of origins of telencephalic interneurons (see Molnar et al., [@B99]; Rakic, [@B117]). Indeed, while the vast majority of telencephalic GABAergic neurons originate from supallial territories in rodents (see above), in humans (from 5 to 15 gestational weeks) and primates this is only the case for the first generated ones that mainly arise from MGE (Letinic et al., [@B84]; Jakovcevski et al., [@B67]; Zecevic et al., [@B157a]). Later, neurogenesis occurs in dorsal pallial territories and presumably in the CGE (Petanjek et al., [@B107],[@B108]; Jakovcevski et al., [@B67]). Indeed, it is known that late proliferations from pallial territories mainly generate CR^+^ interneurons that are more numerous in humans and primates than in rodents and display distinct morphologies in each species (Jones, [@B69a]; Rakic, [@B117]).
Recently, analysis of interneuron densities in postmortem brain tissue from humans suffering from holoprosencephaly associated with agenesis of GE showed a strong correlation between massive reductions in Nkx2.1 expression and depletion of nNOS/NPY/SST^+^ and PV^+^ interneurons (Fertuzinhos et al., [@B43]). These observations suggest that, like in mice, these populations of putative nNOS-type I cells are generated in the GE. Despite the fact that nNOS-type II largely outnumbered nNOS-type I neurons in primate and human brains their place of genesis has not been analyzed in these species.
Development and maturation of neocortical and hippocampal interneurons expressing nNOS
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The pattern of nNOS immunoreactivity in the rodent telencephalon undergoes sterotyped changes during development. From embryonic day 13 (E13) to the first postnatal day (P0), a period of intense neuronal migration, nNOS is strikingly expressed by distinct cells types. Indeed, cells migrating in the marginal zone displaying Cajal-Rezius like morphologies express nNOS (Santacana et al., [@B125]). In addition, by E15 in rats, nNOS labeling is clearly seen in the ganglionic eminence and the AEP/PO region (Figure [2A](#F2){ref-type="fig"} in Santacana et al., [@B125]) suggesting that nNOS could also label the early populations of GABAergic neurons that continue to express nNOS at mature stages. Later on, from E17 to E19, in rats, neurons displaying leading processes oriented along the intermediate zone or toward the pial surface, presumably migrating neurons were reported to express nNOS (Santacana et al., [@B125]). However, it is not clear whether they correspond solely to GABAergic neurons or to subpopulations of GABAergic and glutamatergic neurons.
In rat visual cortex, nNOS^+^ neurons appear as early as postnatal day 1 in the intermediate (white matter) and subplate (layers V and VI) regions as small and undifferentiated neurons. Differences in intensity of nNOS immunoreactivity (later mentioned as type I and type II neurons) become evident as early as P7 (Chung et al., [@B25]; Kanold and Luhmann, [@B71]). nNOS GABAergic neurons reach their typical morphology in the second postnatal week and appear in all layers. Neurons in layers V and VI precede those in the superficial layers in acquiring their final morphology. By P30, NADPH-d active neurons are no longer detected in layer I suggesting they die off or migrate to deeper layers residing only transiently in layer I (Lüth et al., [@B90b]).
In rat barrel cortex, an area that integrates sensory inputs coming from the whiskers, between P10 and P90, the neuropilic distributions of NADPH-d and cytochrome oxidase (CO) activities exhibit a remarkable similarity. NADPH-d activity is denser in barrel hollows, regions that receive somatotopic sensory thalamic inputs, and is less active in barrel septa (Furuta et al., [@B51]). The number of NADPH-d active neurons increases significantly in the barrel fields between P10 and P23, with a peak at P23. The dendritic arborizations of NADPH-d active neurons become more elaborate during barrel development. At all ages evaluated, the number of NADPH-d^+^/NOS^+^ cells, mostly type I cells, was always higher in the septa than in the barrel hollows (Vercelli et al., [@B143]; Freire et al., [@B47]).
In the hippocampus, nNOS is transiently expressed in the pyramidal cell layer between P3 and P7 (Chung et al., [@B25]). While NADPH-d reactive soma and processes are present from the day of birth until adulthood in Ammon\'s horn, expression of NOS is delayed in the DG appearing only by the end of the first postnatal week (Moritz et al., [@B101]).
Role of nNOS and NO in development, maturation, and plasticity
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Production of nitric oxide by neuronal nitric oxide synthase
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NO is a free radical gas that can move rapidly across plasma membranes in anterograde and retrograde directions to act presynaptically, postsynaptically or within the cell that has produced it. NO is generated following the activation of NO synthases (Bredt and Synder, [@B16]; Daff, [@B31]). So far three NOS isoforms have been identified, two of which, endothelial (eNOS) and the neuronal (nNOS), are constitutively expressed while the third one is inducible and rarely present under basal conditions. Each NOS subtype has distinct functional and structural features. Depending on the neuronal cell type and the mode of neuronal excitation, nNOS, which is a Ca2^+^/calmodulin-regulated enzyme, can be activated by Ca^2+^ influx through N-methyl-D-aspartate (NMDA) receptors or other calcium permeable channels (i.e., the ionotropic 5-HT~3A~ receptor; Rancillac et al., [@B118]; see also Perrenoud et al., [@B106] in this issue). Alternatively, calcium liberated from intracellular stores such as the endoplasmic reticulum (i.e., through activation of metabotropic receptors coupled to activation of Gq protein) may promote nNOS activity. Arginine transported into the cell by the anion-cation tranporter is oxidised by nNOS into citrulline in a nicotinamide adenine dinucleothide phosphate (NADPH)-dependant manner (Snyder et al., [@B127]) generating NO that is considered to be stable in physiological conditions for approximately 1--2 s (1 s half-life; Garthwaite, [@B54]). Within cells, NO has the capacity to trigger several transduction pathways. The most well-known involves activation of guanylyl cyclase (Arnold et al., [@B6]) leading to the conversion of GTP into cGMP and subsequent activation of protein kinase G (PKG). PKG activity in turn promotes Erk activation and the induction of various immediate early genes such as c-fos, Arc, and BDNF. Indeed, in neuronal cultures NOS inhibition attenuates bicuculine-induced activation of Erk as well as the rise in c-Fos, Egr-1, and Arc that are all implicated in experience-dependant plasticity in the barrel cortex. Moreover, although NOS inhibition does not affect the phosphorylation of CREB it decreases accumulation of the CREB coactivator TORC1 (Gallo and Iadecola, [@B53]; Figure [7](#F7){ref-type="fig"}). Activation of the NO/cGMP pathway is implicated in various neurophysiological processes including neuronal development, synaptic modulation, learning and memory. In addition several cGMP-independent effects of NO related to nervous system function have been reported. For instance, various presynaptic targets for NO have been identified such as SNAP25, synthaxin Ia, n-Sec 1, neurogranin as well as the postsynaptic targets ADP ribosyltransferase and NMDA receptors (Gallo and Iadecola, [@B53]). Finally, excessive NO production is potentially neurotoxic but this aspect is beyond the scope of this revue (Steinert et al., [@B129]).
![**Synthesis of nitric oxide and transduction cascades.** Neuronal nitric oxide synthase (nNOS) is activated by a calcium-dependant calmodulin. NOS produces nitric oxide (NO) upon oxidation of arginine into citrulline. NO diffuses and act on presynaptic or postsynaptic targets. A well-known pathway of NO is through the activation of guanylyl cyclase (GC) that activates a protein kinase G (PKG) leading to Erk activation and the stabilization of TORC1 a CREB co-activator. CAT, cation and anion transporter; PL. M, plasma membrane. Adapted from Gallo and Iadecola ([@B53]).](fncir-06-00082-g0007){#F7}
Role of nNOS and NO during early development
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Numerous papers and reviews have described the role of nNOS and NO in various neuronal populations during development. Here, we will briefly focus on some of the best understood roles for NO/nNOS in neurons at early stages. nNOS or NADPH-d activity are transiently expressed in the embryonic hippocampal and neocortical anlagen during the peak of neurogenesis and the period of developmental synaptogenesis (Bredt and Snyder, [@B16a]). It has been shown that NO acts as a paracrine messenger in newly generated neurons to control the proliferation and differentiation of mouse brain neural progenitor cells (NPC). Treatments with the NO synthase inhibitor L-NAME or the NO scavenger hemoglobin increase cell proliferation and decrease the differentiation of NPCs into neurons (Barnabé-Heider and Miller, [@B10]). Interestingly, a similar role of NO was demonstrated in the subventricular zone of adult mice, a region that retains the capacity to generate neurons at mature stages (Xiong et al., [@B154]; Cheng et al., [@B24]; Matarredona et al., [@B95]). Both BDNF and epidermal growth factor (EGF) have been largely implicated in these events (Barnabé-Heider and Miller, [@B10]; Matarredona et al., [@B95]).
In addition to regulating neurogenesis, NO has also been implicated in the formation of cerebral maps. This role has been largely investigated and demonstrated in the visual system where NO induces synaptic refinement or elimination of immature synaptic connections at retino-collicular and retino-thalamic levels (Cramer et al., [@B26a], [@B26b]; Wu et al., [@B153a], [@B153]; Cramer and Sur, [@B27]; Cuderio and Rivadulla, [@B29]; Vercelli et al., [@B142]). However, outside of retino-collicular and retino-thalamic organization, NO appears dispensible for the establishment of patterned neocortical maps since animals receiving daily injection of nitroarginine prior to and during the period of ocular dominance column formation, as well as nNOS knockout mice, display normal organization of the somatosensory cortex and barrel field plasticity (Van der Loos and Woolsey, [@B141]; Finney and Shatz, [@B44]). Nevertheless, though apparently not instructive, NO may still participate in establishing and refining neocortical connectivity. Indeed, when NADPH-d activity is altered in the barrel field, as observed in mice lacking NMDAR1 specifically in neocortical neurons, abnormal segregation of thalamocortical axons occurs (Iwasato et al., [@B65]; Lee et al., [@B82]). In these animals thalamocortical axons display fewer branch points in layer IV and abnormally expansive thalamocortical arbors, a feature that corresponds to a rudimentary whisker-specific pattern. These results suggest that NO could promote thalamocortical sprouting and participates in the consolidation of synaptic strength in layer IV of the primary somatosensory cortex.
Finally, it has been shown that between P6 and P10 in rodents, NO also affects neuronal gap-junction coupling. Indeed, Rörig and colleagues have shown that following preincubation with sodium nitroprusside (an NO donor), the number of gap-junction coupled neurons decreased (Rörig and Sutor, [@B121],[@B122]; Roerig and Feller, [@B120a]). In the developing neocortex, gap-junctions represent a transient metabolic and electrical communication system occurring between glutamatergic or GABAergic neurons belonging to the same radial column. Thus, NO mediated regulation of gap junctions has the capacity to affect electrical coupling, synchronization of metabolic states and, coordination of transcriptional activity amongst connected neurons.
Role of nNOS and NO in microcircuits plasticity
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The idea that NO might modulate synaptic transmission, first proposed in 1988 by Garthwaite and colleagues (Garthwaite et al., [@B55b]), has been confirmed in several brain regions including the hippocampus, striatum, hypothalamus, and locus coeruleus (Prast and Philippu, [@B114]). Indeed, studies using NO donors suggest that release of several transmitters, including acetylcholine, catecholamines, glutamate and GABA are regulated by endogenous NO. As a gaseous very weakly polar molecule without net electric charge and due to its small size, NO can diffuse readily across cell membranes. However, the high reactivity of NO as a free radical limits activity to within a micrometer of its site of synthesis allowing for synapse specificity in modulating presynaptic function (Garthwaite, [@B54]).
In acute hippocampal slices from neonatal rat, NO signaling was found to decrease GABAergic and glutamatergic postsynaptic currents, whereas network calcium imaging indicated that inhibition or stimulation of NO signaling enhanced or suppressed synchronous network events, respectively (Cserép et al., [@B28]). The regulation of GABAergic and glutamatergic synaptic transmission in early postnatal development, NO is considered particulalrly critical for fine-tuning synchronous network activity in the developing hippocampus (Cserép et al., [@B28]). In more mature hippocampus NO regulates LTP at the Schaffer collateral/CA1 synapses and acts as a retrograde messenger (for review see Malenka and Bear, [@B92]; Lisman and Raghavachari, [@B89]). This occurs via the activation of postsynaptic NMDA receptors, synthesis of NO by NOS expressed in pyramidal cells and then retrograde activation of guanylate cyclase located in axon terminals (See Feil and Kleppisch, [@B41] for detailed intracellular mechanisms). In contrast, in the cerebellum NO serves as an anterograde messenger that is produced in parallel fiber terminals or cerebellar interneurons and then diffuses to the postsynaptic Purkinje cell to induce LTD through a cGMP-dependent mechanism (for review see Feil et al., [@B40]).
Role of NO and interneurons expressing nNOS in hippocampal and neocortical network
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Studies investigating synaptic modulation by NO have typically considered it to be derived from NOS localized in pyramidal cell postsynaptic densities. However, as described above, nNOS is largely expressed in GABAergic interneurons. Even if NO can modulate GABAergic transmission, it is still unclear if the NO released by interneurons principally regulates transmitter release or instead participates in other homeostatic processes such as regulation blood flow or neuronal excitability (Iadecola et al., [@B63]). Indeed bath application of an NO donor onto acute rat neocortical slices cause dilation of blood vessels (Cauli et al., [@B22]) and this hemodynamic change can similarly be elicited electrical stimulation of a single neocortical nNOS expressing interneuron (Cauli et al., [@B22]). Such tight coupling between neuronal activity of interneurons expressing nNOS and vasomotricity has also been reported in other brain structures such as cerebellum where pharmacological or electrical stimulation of stellate cells, which strongly express nNOS, induces vasodilation by release of NO that can be measured using NO-sensitive electrode (Rancillac et al., [@B118]). Given this interneuron mediated regulation of brain blood perfusion, it is interesting to note that most of nNOS^+^ interneurons also coexpress NPY which is a potent vasoconstrictor (Dacey et al., [@B30]; Cauli et al., [@B22]). Consistently, we have shown that activation of serotonin type 3 receptors which are present on nNOS-type II interneurons co-expressing NPY and/or VIP (Vucurovic et al., [@B148]; Perrenoud et al., [@B105] in this issue), induces both vasodilation and vasoconstriction (Perrenoud et al., [@B106] in this issue) via direct release of NO and NPY respectively. Therefore, it appears that both neocortical and hippocampal NGFCs, which coexpress NPY and nNOS, likely exert dual control over cerebral blood flow. To resolve these conflicting observations we propose that NPY, which is likely released at axon terminals, controls blood vessel tone distally from the cell body while NO released by the somato-dendritic compartment acts more proximally via volume transmission. These differential effects would permit fine-tuning of energy and oxygen supply by creating locally a microsphere with increased blood perfusion consequently to increased neural activity (Estrada and DeFelipe, [@B39]).
Regarding excitability, NO can regulate several conductances via the cGMP/PGK pathway in central neurons (Garthwaite, [@B54]). Indeed the hyperpolarization activated current that serves as a pacemaker to generate rhythmic activity amongst thalamic neurons (Pape and Mager, [@B104]) is regulated by NO (Biel et al., [@B15]). NO also acts on several potassium conductances such as the delayed rectifier Kv3 channels (Rudy and McBain, [@B124]). It has been shown that NO donors inhibit both Kv3.1 and Kv3.2 channels in CHO cells via activation of the cGMP/PKG pathway (Moreno et al., [@B100]). Such inhibition of Kv3 current has also been observed in the central nervous system via volume transmission in the auditory brain stem and the hippocampus (Steinert et al., [@B130], [@B131]). It is interesting to note that Kv3 channels are responsible for the short duration of action potentials in auditory neurons as well as in hippocampal/neocortical PV^+^ and SOM^+^ interneurons (Atzori et al., [@B8]; Tansey et al., [@B136]; Lien and Jonas, [@B87]). NO-mediated modulation of Kv3 would therefore regulate the spike timing of these neurons (Lien and Jonas, [@B87]).
Recently, the role of NO in sleep regulation has been challenged. Indeed, the group of Kilduff has shown that long range projecting nNOS-type I GABAergic neurons are specifically activated during sleep by demonstrating that these cells specifically accumulate c-Fos during sleep rebound following sleep deprivation (Gerashchenko et al., [@B57]). The mechanism behind this activation is not completely understood. However, it is suspected that during the waking period NPY^+^/SOM^+^/nNOS^+^ GABAergic neurons (putative nNOS-type I) are inhibited by neuromodulatory afferents driving arousal such as acetylcholine, noradrenaline, serotonin, and histamine and that they would be activated when arousal systems are depressed when sleep-promoting substances are released (i.e., adenosine, cytokines, growth hormone, releasing hormone, and cortistatin). Once activated nNOS neurons could synchronize EEG activity across neocortical regions through the release of NO, GABA or NPY. Interestingly it has been reported that nNOS knockout mice spend more time than controls in slow wave sleep as monitored by EEG. This suggests that nNOS-type I GABAergic neurons may regulate sleep homeostasis (Kilduff et al., [@B73]). However additional experiments remain to be performed to fully address this point.
Conclusion and perspectives
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The development and plasticity of nNOS^+^ interneurons needs to be confronted with more general questions that are central to understand interneurons development and specification. One important issue to address is to determine the extent to which interneurons are fully specified by their place and time of genesis. In other words are these cells hard wired from the progenitor stage or allowed a certain degree of "developmental plasticity" after the last division of the progenitors to adapt to their migratory and ultimately circuit environment? At mature stages interneuron subtypes are characterized by a combination of: (1) their laminar position within different circuits; (2) specific combinations of neurochemical markers; (3) their basic morphology; and (4) their electrophysiological features including passive membrane properties, spiking behavior and synaptic connectivity. Various studies including some highlighted above have shown that these criteria are largely dictated by an interneuron\'s site and time of genesis. However, some studies have also pointed to a role for the cellular environment an interneuron ultimately occupies in refining these properties such as their stratification (i.e., CR- and reelin-positive interneurons) and their expression of certain activity regulated markers like NPY. In this respect it should be mentioned that the expression of nNOS appears to be developmentally regulated in various neuronal populations and could be modulated by cellular targets in subpopulations of interneurons (i.e., in an activity-dependent manner). Thus, although challenging, it will be important to determine whether nNOS interneurons are guided to their final location early on, like most interneurons, or are eliminated if inaccurately positioned or if they stop expressing/fail to induce nNOS. An understanding of subtle differences in the genetic makeup/molecular characteristics of divergent nNOS interneuron cohorts may provide insight into these issues. The recent generation and use of Cre reporter animals in association with other techniques have been successfully used to determine the embryonic origin and birthdating of nNOS type I and type II interneurons revealing for the first time their heterogeneity and specificities (lineage and characteristics displayed at mature stage; in this issue). The increasing array of transgenic models and genetic tools available (i.e., optogenetic) will help advance the pace of this research.
Interestingly, the unique features that have been shown to depend on neuronal activity (Verhage et al., [@B144]) for wiring and plasticity are the density and strength of GABAergic innervations. It remains to be established if and how NO could participate in the maturation and refinement of axonal and/or dendritic arborization of specific classes of interneurons.
Conflict of interest statement
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Thierry Gallopin, Hélène Geoffroy, Quentin Perrenoud and Armelle Rancillac of the "sleep neuronal networks" team for constant and fruitful interactions. We thank Gord Fishell and Renata Batista-Brito and, Nicoletta Kessaris for sharing the results of their studies before publication. We thank Kenneth Pelkey for suggestions to improve the manuscript. Financial support was provided by the CNRS, ESPCI ParisTech and INSERM.
[^1]: Edited by: Bruno Cauli, CNRS and UPMC, France
[^2]: Reviewed by: Karri P. Lamsa, University of Oxford, UK; Bernardo Rudy, New York University School of Medicine, USA
| 2023-09-06T01:26:59.872264 | https://example.com/article/9333 |
Methylation is a hot topic in the field of epigenetics whether it’s occurring on the cytosines of DNA or its histone protein friends. With a relatively well-known set of enzymes, methylation marks are dynamically modified in order to regulate gene expression.
However, the revisiting of a RNA modification discovered in the 70’s has come to show that post-translational modifications to RNA have the potential to influence the epigenetic landscape just as well.
Methylation of N6-methyladenine (m6A) is the most prevalent internal modification on mRNA and long non-coding RNA. Recently, Dr. Cuan He’s team at the University of Chicago (Go Bulls) have made some groundbreaking discoveries. Here are the highlights of their recent findings:
The AlkB family of dioxygenases, specifically Alkbh5 and FTO , are capable of oxidatively reversing the methylation of m 6 A and serve as novel RNA demethylases.
and , are capable of oxidatively reversing the methylation of m A and serve as novel RNA demethylases. These enzymes participate in a variety of biological pathways and are widely expressed across multiple tissues.
Alkbh5 is most highly expressed in the testis and a knockout in mice resulted in impaired male fertility due to compromised spermatogenesis.
is most highly expressed in the testis and a knockout in mice resulted in impaired male fertility due to compromised spermatogenesis. They also observed increased m 6 A levels in mRNA isolated from the knockout mouse organs.
A levels in mRNA isolated from the knockout mouse organs. Interestingly, their RNA-Seq results indicated altered gene expression in the cells of testes from their knockout mice, thus showing that the loss of the m6A demethylase influences gene expression and results in compromised spermatogenesis.
Given the genome wide observance of m6a by other groups, these finding challenge our conventional perceptions of where epigenetic marks occur. Ultimately, it appears that RNA modifications are not only reversible, but given their dynamic nature they have important regulatory functions that are yet to be fully appreciated.
Read all about it in RNA Biology, April 2013 | 2023-09-16T01:26:59.872264 | https://example.com/article/2689 |
Video audio processing devices typically go to a standby state when power is turned off by remote control. In the standby state, only minimum necessary circuit elements (for example, a standby microcomputer) are provided with power, and the others (for example, a video signal decoder, an audio signal decoder, etc.) are not provided with power. This allows the device to be ready for use more quickly as compared to when the main power is turned on, while lowering power consumption.
Various dedicated signal processors or signal processing blocks (for example, a TS (Transport Stream) decoder, a video decoder, an audio decoder, etc.) are particularly incorporated into digital television broadcast receivers or the like. There are various compression coding methods for video and audio signals. Thus, in order to be compatible with all of those methods, each signal processing block loads a program into an internal instruction memory thereof and operates. Such programs are stored in an auxiliary storage, such as a flash memory, and are retained even if power is not supplied.
When the video audio processing device returns from the standby state, a program stored in the auxiliary storage is first loaded into a CPU that controls each signal processing block, and the CPU starts operating. Thereafter, programs for the respective signal processing blocks are read from the auxiliary storage by the CPU and then loaded into the instruction memories in the respective signal processing blocks. And when the loading of the programs into the signal processing blocks is complete, each signal processing block is activated by the CPU, and the video audio processing device returns to a normal operational state. For example, in the case of a digital television broadcast receiver, broadcast contents are displayed on the screen. Therefore, an improvement of performance relating to access to the auxiliary storage is an important factor in achieving a quick return from the standby state. A technique has been conventionally known in which performance relating to access to a flash memory, in particular, performance relating to write access, is improved to enhance the speed of the entire system (see Patent Document 1, for example). Patent Document 1: Japanese Unexamined Patent Application Publication No. 2005-529399 | 2023-11-23T01:26:59.872264 | https://example.com/article/8765 |
Neil Patrick Harris is a married man!
The Tony winner, 41, and David Burtka, 39, tied the knot on Saturday in Italy. The couple, parents to twins Gideon and Harper, began dating more than 10 years ago.
Both grooms wore custom Tom Ford tuxedos. Their friend and mentor, How I Met Your Mother producer and director Pam Fryman, officiated the ceremony.
And talk about a wedding singer—Elton John performed at the reception!
"We happily confirm that Neil Patrick Harris and David Burtka were married in Italy in an intimate ceremony surrounded by their close friends and family," a rep for NPH said.
"Guess what? @DavidBurtka and I got married over the weekend. In Italy. Yup, we put the 'n' and 'd' in 'husband'," the newlywed tweeted Monday. | 2023-09-27T01:26:59.872264 | https://example.com/article/1379 |
This is from Hamodia:
An invitation to several chareidi youths to join in his son’s wedding has cost the mayor of the Palestinian Authority-controlled village of Dir Kadis his job. The four Jews, whom the mayor claims were invited to “embarrass” him, were seen in a widely distributed video singing and dancing at the wedding, clearly as welcome guests — and as a result, the mayor has been fired and removed from his position on the PA’s Education Committee, Haaretz reported Sunday.
The incident took place last Wednesday, as the son of Radi Nasser was wed. Four Jews, residents of Modiin Ilit (Kiryat Sefer), attended the wedding in the nearby village. The son worked with the Jews in Modiin Ilit, and apparently invited them to the wedding. Footage of the event shows a happy circle of dancers, with the Jews hoisted on the shoulders of the guests as they celebrated the event.
But when the footage hit social media sites, the recriminations began. The Fatah movement, of whom Nasser was a member, condemned the dancing, saying that it was “insulting” to Palestinians. Nasser was summarily thrown out of Fatah. Editorials in PA newspapers reiterated the “insult” narrative, saying that Palestinians should not be inviting “representatives of the occupation” to their events.
Nasser attempted to deny that he invited the youths. “They were invited by garage workers at the entrance of the village who fix the Jews’ cars,” he said, adding that they were put up to it by his political enemies, and that he had the youths thrown out of the wedding when he found out what was happening. But the denials fell on deaf ears — at least in part because he is seen dancing with them.
Fatah said that a no-confidence meeting would be held to remove Nasser from office and that the names of the Jewish attendees would be passed on to the Palestinian security forces. | 2024-07-03T01:26:59.872264 | https://example.com/article/9716 |
Sumi Inklings is a competitive Splatoon 2 duo.
I wanted the logo to reflect the organic stroke of a brush dipped in sumi ink while also staying stylistically consistant with the game.
I also created promotional material to be shared on social media including an editorial illustration of team members Raizor and Emipri and the "Splat Match" template used for finding potential teammates and trading player info. | 2024-07-26T01:26:59.872264 | https://example.com/article/8851 |
The Potential Effect of Epidural Anesthesia on Mesenteric Injury after Supraceliac Aortic Clamping in a Rabbit Model.
Epidural anesthesia is known to increase blood flow by producing vasodilatation on mesenteric circulation. In this experimental study, we aim to examine the effect of epidural anesthesia on mesenteric ischemic-reperfusion (IR) injury induced by supracoeliac aortic occlusion in a rabbit model. Twenty-eight male white New Zealand rabbits were assigned into 4 separate groups, with 7 rabbits in each group: group I, control group; group II, IR-only group; group III, IR plus epidural anesthesia group; group IV, epidural anesthesia-only group. IR model was produced by clamping supraceliac aorta with an atraumatic vascular clamp for 60 min, followed by reperfusion for 120 min. An epidural catheter was placed via Th12-L1 intervertebral space by using open technique before aortic clamping in those assigned to epidural anesthesia. IR injury was assessed using blood markers interleukin-6 and IMA and tissue markers superoxide dismutase and malondialdehyde. Also histopathological examination was performed to evaluate the degree of injury. All biochemical markers in group II were significantly elevated in comparison with the other 3 groups (p < 0.05). This was paralleled by a more severe histopathological injury in IR- only group (group II). The group receiving IR plus epidural anesthesia (group III) had lower biochemical marker levels as compared with the IR-only group (group II). Mesenteric IR injury that can occur during abdominal aorta surgery can be reduced by epidural anesthesia, which is commonly used during or after major operations for pain control. Controlled clinical studies are required to evaluate these findings. | 2024-02-27T01:26:59.872264 | https://example.com/article/4507 |
Dress Pattern for 6 to 8 Inch Dolls
Here are the pattern pieces for the dress for 6 to 8 inch dolls. It should fit Vogue Ginny Dolls, American Girl Mini dolls and any other dolls of similar body type.
This dress is slightly more involved to make than my usual designs. The skirt has two layers, one of fabric and one of very fine tulle, or netting. This gives the skirt a little body and stiffness. Thee is also more lace trim than i usually put on my dresses, but this is such a tiny, sweet little dress that I wanted it to be a real "confection".
This pattern is my original design and may not be used commercially.
To make this dress you'll want to choose fabric that has a very small pattern, since the dress is so small. Small calico prints are ideal.
Materials
1/4 yard of fabric is probably enough to make four of these dresses
a 2.75 inch by 17.5 inch rectangle of fine weight tulle
Approximately 1 yard of pre-gathered, single edge lace trim, about 1/2 inch wide
Matching thread
Velcro dots.
For the skirt, cut a rectangle, from your fabric, that is 2.75 inches by 17.5 inches. Cut a second rectangle of the same size from the fine tulle.
To copy the pattern by hand you can create a 1/2 inch grid by measuring every half inch and making a pencil dot all the way down and across, on all four sides of a piece of 8 1/2 by 11 inch paper. Then use your ruler or straight edge to connect the dots with your pencil. Then draw the pattern lines into each square of your grid, exactly as they are shown in my design.
The most popular dress on the Doll Making Site, The Spring Dress for 18 Inch Dolls, is included as well as 5 other outfits, underwear, and accessories such as jewelry, a bag, a knitted hat and scarf, and the new scrub suit. There are also patterns for slender Magic Attic type dolls as well as full-bodied American Girl dolls and an antique Saucy Walker doll from the 1950's.
If you love 18 inch dolls, and want a collection of patterns for a wardrobe, all in one handy Ebook, this is for you! All these patterns are available on the Doll Making site, but I have brought them all together in one book for ease of finding and using them. Make Clothes for 18 Inch Dolls. | 2023-11-24T01:26:59.872264 | https://example.com/article/4737 |
Thalamus-related anomalies as candidate mechanism-based biomarkers for psychosis.
Identification of reliable biomarkers of prognosis in subjects with high risk to psychosis is an essential step to improve care and treatment of this population of help-seekers. Longitudinal studies highlight some clinical criteria, cognitive deficits, patterns of gray matter alterations and profiles of blood metabolites that provide some levels of prediction regarding the conversion to psychosis. Further effort is warranted to validate these results and implement these types of approaches in clinical settings. Such biomarkers may however fall short in entangling the biological mechanisms underlying the disease progression, an essential step in the development of novel therapies. Circuit-based approaches, which map on well-identified cerebral functions, could meet these needs. Converging evidence indicates that thalamus abnormalities are central to schizophrenia pathophysiology, contributing to clinical symptoms, cognitive and sensory deficits. This review highlights the various thalamus-related anomalies reported in individuals with genetic risks and in the different phases of the disorder, from prodromal to chronic stages. Several anomalies are potent endophenotypes, while others exist in clinical high-risk subjects and worsen in those who convert to full psychosis. Aberrant functional coupling between thalamus and cortex, low glutamate content and readouts from resting EEG carry predictive values for transition to psychosis or functional outcome. In this context, thalamus-related anomalies represent a valuable entry point to tackle circuit-based alterations associated with the emergence of psychosis. This review also proposes that longitudinal surveys of neuroimaging, EEG readouts associated with circuits encompassing the mediodorsal, pulvinar in high-risk individuals could unveil biological mechanisms contributing to this psychiatric disorder. | 2024-05-31T01:26:59.872264 | https://example.com/article/1333 |
Effects of lithium and valproate on hippocampus citrate synthase activity in an animal model of mania.
Some studies suggest that mitochondrial dysfunction may be related to the pathophysiology of bipolar disorder. In this work, we evaluated the activity of citrate synthase in rats, and the effects of the treatment with mood stabilizers (lithium and valproate) on the enzyme activity. In the first experiment (reversal treatment), amphetamine or saline were administered to rats for 14 days, and between day 8 and 14, rats were treated with either lithium, valproate or saline. In the second experiment (prevention treatment), rats were pretreated with lithium, valproate or saline, and between day 8 and 14, rats were administered amphetamine or saline. In reversal and prevention models, amphetamine administration significantly inhibited citrate synthase activity in rat hippocampus. In amphetamine-pretreated animals, valproate administration reversed citrate synthase activity inhibition induced by amphetamine. In the prevention model, pretreatment with lithium prevented amphetamine-induced citrate synthase inhibition. Our results showed that amphetamine inhibited citrate synthase activity and that valproate reversed and lithium prevented the enzyme inhibition. | 2024-02-13T01:26:59.872264 | https://example.com/article/4466 |
Martin McGuinnesss official driver has proven remarkably accident-prone.
Figures released under the Freedom of Information Act have led to fresh questions about a DUP change to the rules which allows Sinn Fein to use its own drivers but pay them from public funds.
Mr McGuinness’s ministerial driver has been at fault for four accidents since 2011, costing the public purse £1,517 in repair bills. He was responsible for two accidents in March of this year, costing more than £600 of damage each time.
On a further two occasions, the car was damaged due to vandalism, with the satellite navigation system being stolen in July 2014.
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Earlier this month, the TUV leader Jim Allister uncovered that new Sinn Fein Finance Minister Máirtín Ó Muilleoir is paying his own driver £34,000-a-year, a figure which is believed to be identical to that for every other Sinn Fein ministerial driver.
Five years ago, the News Letter revealed that at that point Mr McGuinness’s ministerial driver had been involved in more crashes than all the other ministerial drivers put together.
The vehicle had been involved in five accidents in five years.
In 2009 alone, the £15,000 Skoda Superb vehicle — which among its safety features has electronic parking assistance and nine airbags — was involved in three crashes.
By contrast, first minister Peter Robinson’s car had not been involved in any accidents since the restoration of devolution in four years earlier.
During that period, Sinn Fein ministerial drivers were involved in six crashes, while only one civil service driver had been involved in an accident during the same period.
Sinn Fein has always declined to use civil service drivers and instead employed its own operatives.
In 2007 the then DUP Finance Minister, Peter Robinson, ruled that if Sinn Fein wanted to use its own drivers then it would have to pay for them from party funds.
But in 2011, that decision was overturned by the then Finance Minister Sammy Wilson, although the new rules were not announced and only emerged after a Freedom of Information battle by this newspaper.
At the time, a A Department of Finance source said that the arrangement had been one of the factors which broke the budget deadlock between Sinn Fein, who initially were opposed to any budget cuts.
Documents released under FoI showed that Mr Wilson did not want to allow Sinn Fein to get public funds for their drivers, in line with his public statement that he wanted ministers to share cars and thereby cut the cost of the fleet, but the executive decided that the change should be made.
Official Stormont guidelines now appear to leave the door open for any minister from any party to employ their own driver and pay them from their department’s budget. It is not clear what, if any, recruitment procedures are followed for the hiring of Sinn Fein drivers. The guidelines say: “Ministerial drivers shall normally be civil servants at the appropriate grade. “Any alternative arrangements must be justified by a proportionate business case and be in accordance with employment law.”
The latest figures which show that Sinn Fein ministerial drivers are far more prone to crashing that their civil service counterparts mean that the system of Stormont chauffeurs should be reviewed, the Ulster Unionists have said.
Fermanagh and South Tyrone MP Tom Elliott said that Sinn Fein should at the very least advertise the driving posts so that members of the public could apply for the jobs.
Mr Elliott said: “This calls into question Sinn Fein being allowed to have their own drivers. At best, they seem accident prone. Some might say, they`re downright careless.
“I understand that Civil Service drivers have to have some form of advanced driving skills. Does anyone even know what skills or training these publicly paid Sinn Fein drivers have to have to get a job? The fact that the jobs are not even advertised, and the drivers are wholly unaccountable to anyone but Sinn Fein, is just another example of the Executive Office failing in its duty to use taxpayers’ money openly and transparently.
“It’s time to review it. If the public purse is going to supply the vehicles and pay for the damage every time a Sinn Fein driver prangs a car...then the public has a right to know what level of training these people receive. Sinn Fein should apply some transparency to their driving pool, and tell the public how they can get a driving job.” | 2024-06-10T01:26:59.872264 | https://example.com/article/1514 |
Introduction {#s1}
============
Gustatory receptor (*Gr*) genes comprise a large fraction (∼50%) of the Drosophila chemosensory receptor gene superfamily [@pone.0001513-Robertson1], encoding 7-transmembrane (7TM) proteins involved in taste and smell. Most Drosophila *Grs* are very divergent, sometimes showing as little as 8% amino acid identity to each other [@pone.0001513-Robertson1]. Much of the diversity of the chemoreceptor family has evolved through widespread and repeated whole-gene duplications, followed by functional divergence of those duplicates that do not degrade to pseudogenes [@pone.0001513-Nozawa1], [@pone.0001513-Guo1]. Another mechanism that enlarges the eukaryotic protein repertoire in general is alternative splicing. Although this is currently thought to be rare among chemosensory receptor loci [@pone.0001513-Hill1], [@pone.0001513-Robertson2], three *D. melanogaster Gr* genes (*Gr23a, Gr28b*, *Gr39a*) are notable in that they have been shown to undergo alternative splicing, together coding for 11 proteins, or 16% of all gustatory receptors in the species [@pone.0001513-Robertson1], [@pone.0001513-Clyne1]. Analysis of the *Gr* repertoire in 12 Drosophila species allowed us to identify the orthologues of the *Gr39a* genes in these species [@pone.0001513-Gardiner1]. This locus showed an unusual pattern of structural changes compared with other *Grs*. Here we investigate in detail the evolution of the *Gr39a* gene using a comparative, bioinformatic approach.
Located on the left arm of the second chromosome of *D. melanogaster*, the *Gr39a* gene has four large exons (*A*, *B*, *C* and *D*), each including coding sequences for six transmembrane domains, followed by three small exons that together encode the seventh transmembrane domain and COOH-terminus [@pone.0001513-Clyne1]. Any one of the large exons may be spliced to the smaller exons, generating four different 7TM protein products. These are expressed in the main taste organs of *D. melanogaster*, the labellum (Gr39aA, Gr39aB, Gr39aC, Gr39aD), though some are also expressed in the thorax (Gr39aC, Gr39aD), abdomen (Gr39aC) and wings (Gr39aD) [@pone.0001513-Clyne1]. The function of *Gr39a* is unknown, but its close phylogenetic affinity with the *D. melanogaster* male specific pheromone receptor *Gr68a* [@pone.0001513-Bray1] suggests a possible involvement in pheromone recognition [@pone.0001513-Amrein1].
We have annotated the orthologs of *D. melanogaster Gr39a* in eleven other recently sequenced Drosophila species [@pone.0001513-Drosophila1], representing a wide range of phylogenetic divergence from *D. melanogaster* ([Figure 1A](#pone-0001513-g001){ref-type="fig"}, [@pone.0001513-Drosophila1]). Of these species, nine (*D. melanogaster, D. simulans, D. sechellia, D. yakuba*, *D. erecta*, *D. ananassae*, *D. pseudoobscura*, *D. persimilis* and *D. willistoni*) are in the subgenus *Sophophora*, and the remaining three (*D. mojavensis*, *D. virilis* and *D. grimshawi*) are within the subgenus *Drosophila*. The two subgenera are estimated to have diverged from each other 40--60 million years ago [@pone.0001513-Russo1], [@pone.0001513-Tamura1]. Lower level groups and subgroups have been identified within the subgenera ([Figure 1A](#pone-0001513-g001){ref-type="fig"}). We examined the structural and potentially functional differences between the *Gr39a* genes across these twelve species. We identified a new large exon, exon *E*, found in most species but lost in the melanogaster lineage. After an analysis in which we employ phylogenomic approaches more usually used to examine gene evolution, we propose a model of the evolution of *Gr39a*. We conclude that, despite strong purifying constraints on the *Gr39a* locus overall, the exons that are prone to duplication or pseudogenisation show evidence of relaxed selection which probably facilitated "subfunctionalization" of the duplicated exon copies. Evidence of positive selection also suggests "specialization" and/or neofunctionalization of tandemly duplicated exons has occurred, though potential new functions are currently unknown.
{#pone-0001513-g001}
Results {#s2}
=======
Chemosensory receptor repertoires among different insects show great divergence, for instance only a few orthologous groups were identified when the complete olfactory and gustatory receptor repertoires of the fruit fly, honeybee and mosquito were compared [@pone.0001513-Hill1], [@pone.0001513-Robertson2], [@pone.0001513-Fox1]. Robertson and Wanner [@pone.0001513-Robertson2] suggest that the exons *Gr39aA-D* of *Drosophila melanogaster* form an orthologous group with seventeen *Gr* genes of *Anopheles gambiae* (*AgGr9a*-*n*, *AgGr10*, *AgGr11*, and *AgGr12*), but the evidence of the orthology is lacking due to the very weak bootstrap support for this clade. In *Apis mellifera*, the orthologs of *Gr39a* were not identified [@pone.0001513-Robertson2]. The *Drosophila* exons are related among themselves by duplications, which seem to have occurred after the *Drosophila*-*Anopheles* split.
We were able to uncover complex structural changes that have occurred to *Gr39a* since the subgenera *Drosophila* and *Sophophora* diverged. The gene structure of *Gr39a* described for *D. melanogaster,* with four large exons *A, B, C,* and *D* followed by three small constitutive exons [@pone.0001513-Clyne1], is peculiar to the species of the melanogaster subgroup only ([Figure 1A](#pone-0001513-g001){ref-type="fig"}). In this subgroup, the first exon *A* has either accumulated frame shift mutations or significantly degraded in two species: *D. sechellia* and *D. erecta*, respectively. Each large exon contains its own start codon and 5′ splice signal allowing the locus to encode several protein products independent of the mutational alteration of the ORF in one of the exons, so we would expect the exons *B, C* and *D* to be expressed in *D. sechellia* and *D. erecta*. Species of the melanogaster subgroup have also lost an ancestral exon *E,* first described here and identified as a degraded copy in *D. ananassae*, an intact exon in the species of the obscura group, *D. willistoni, D. mojavensis* and *D. grimshawi*, and an exon with two frame-shift mutations in *D. virilis* ([Figure 1A](#pone-0001513-g001){ref-type="fig"}). In support of this interpretation, a search for evidence of exon *E* in the melanogaster subgroup revealed the presence of short sequences that code for about 100 amino acids alignable with the truncated exon *E* of *D. ananassae* and intact exon *E* of *D. pseudoobscura*.
The Bayesian-MCMC phylogeny of *GR39a* exons and their homologues is summarized in [Figure 2](#pone-0001513-g002){ref-type="fig"}. The posterior probabilities shown in [Figure 2](#pone-0001513-g002){ref-type="fig"} appear to lack significant bias as estimates of the probabilities of the clade, conditional on the data, model and priors: average standard deviation of split frequencies was 0.0060 at the start of the final MCMC sample (close to the ideal value of zero), and lag-1 ACF for lnL in the two MrBayes runs was 0.014 (P\>0.05) and 0.036 (P\>0.05).
{#pone-0001513-g002}
Exon *E* occupies a basal position within a clade including exons *C* and *D* ([Figure 2](#pone-0001513-g002){ref-type="fig"}). The reconciliation of the species tree and phylogenetic tree of exons *E, C* and *D* by the Notung program [@pone.0001513-Durand1] showed two events of exon duplication (duplication of exon *E* and subsequent origin of exons *D* and *C* before the subgenera *Sophophora* and *Drosophila* split) and three independent events of exon loss ([Figure 3](#pone-0001513-g003){ref-type="fig"}). This prediction supports the loss of exon *E* in the melanogaster group, and suggests the loss of exon *C* in *D. willistoni* and the subgenus *Drosophila*, but we did not find any evidence of the presence of exon *C* in these species.
{#pone-0001513-g003}
Closely related to each other, exons *B* and *A* were found in all species, *B* as a single copy exon, while exon *A* underwent multiple duplications in several lineages ([Figure 1A](#pone-0001513-g001){ref-type="fig"}). The relationships among copies of exon *A* are complex. We found three copies of exon *A* in the obscura and willistoni groups, seven copies (two pseudo- and five intact exons) in *D. mojavensis*, six intact copies in *D. virilis* and four in *D. grimshawii* ([Figure 1A](#pone-0001513-g001){ref-type="fig"} and [Figure 2](#pone-0001513-g002){ref-type="fig"}). Some exon copies are very recent and/or experienced gene conversion, others are likely to be of more ancient origin, possibly suggesting losses as well as gains. Such extensive exon duplication in an alternatively spliced chemoreceptor gene is an apparently unique case-analyses of the other alternatively spliced gustatory (*Gr23a, Gr28b*) and olfactory (*Or46a, Or69a*) receptor genes revealed a more conservative structure. Thus, the structure of *Gr23a,* with two large alternatively spliced exons, is preserved in all species examined. We found only cases of species-specific degradation or loss of some exons in the *Gr28b, Or46a* and *Or69a* genes due to accumulation of frame shifts, premature stop codons and large deletions (for example, *Gr28bA* in *D. sechellia*, *Gr28bD* and *E* in *D. grimshawii, Or69aC* in *D. sechellia* and *D. melanogaster*).
The presence of sequence motifs that specify six transmembrane domains was detected in all the large exons of *Gr39a*; the last three small exons are present in all species and encode for the seventh transmembrane domain ([Figure 1A](#pone-0001513-g001){ref-type="fig"}). We analysed the splicing structure of *Gr39a* in all species. The location of splice sites is conserved throughout the genes examined ([Figure 1B](#pone-0001513-g001){ref-type="fig"}). All large exons (except the pseudo-exons *A* in *D. sechellia* and *D. erecta*) and two conserved small exons contain the 5′ donor-splice motif \[AG\]↑**GT**(NNGT), while the first 3′ acceptor-splice motif (C~n~T~n~)NC**AG**↑\[GC\] appears at the beginning of the block of three conserved small exons ([Figure 1B](#pone-0001513-g001){ref-type="fig"}). This structure supports a model of mutually exclusive alternative splicing, when a single large exon is spliced with the small conserved exons and the other large exons are excluded as part of an intron.
The estimated *ω* values for the whole gene and its large exons were all substantially lower than 1 ([Table 1](#pone-0001513-t001){ref-type="table"}) suggesting that all parts of the gene are subject to strong purifying selection, however weaker selective constraints act on exon *E* and the duplicated exon *A* (*ωE* = 0.27 and *ωA* = 0.24; c.f. ∼0.17).
10.1371/journal.pone.0001513.t001
###### PAML analysis of selection on the *Gr39a* gene and its tandemly duplicated large exons (*A, B, C, D, E*).
{#pone-0001513-t001-1}
Region *N* *ω*M0 Test for positive selection
-------- ----- ------- ----------------------------- ---------------------------- --------------------------
Gr39a 12 0.19 \- \- \-
Gr39aA 10 0.24 NS \- \-
Gr39aB 12 0.14 P\<0.011 P\<0.0001(*ω*Dgri\>1) P\<0.05 (*ω*\<1)
P\<0.003 (Dvir+Dmoj*ω*\>1)
Gr39aC 8 0.19 NS \- P\<0.016 (*ω*Dsec = 1.4)
Gr39aD 12 0.18 NS \- P\<0.05 (*ω*\<1)
Gr39aE 6 0.27 NS \- \-
*N*, number of sequences tested
*ωM0*, estimates of the overall ratio (*ω*) of nonsynonymous substitution rate to the synonymous substitution rate
NS--not significant
Species abbreviation: Dgri--*D. grimshawii*; Dvir--*D. virilis*; Dmoj--*D. mojavensis*; Dsec--*D. sechellia*
Evidence of expression of *Gr39a* in *D. melanogaster* [@pone.0001513-Clyne1], strong selective constraints, and preservation of the transmembrane domain structure and splice signals all suggest that *Gr39a* is a functionally active gene. The estimates of the coefficient of functional divergence (*θ)* [@pone.0001513-Gu1]--[@pone.0001513-Gu3] between the protein isoforms of *Gr39a* are generally high (0.4936--0.6432) ([Table 2](#pone-0001513-t002){ref-type="table"}) and comparable with estimates of *θ* for highly functionally diverged duplicated genes [@pone.0001513-Gu1] and duplicated *Grs* in Drosophila species ([Table S2](#pone.0001513.s002){ref-type="supplementary-material"}). These results suggest functional divergence between exons *B, C, D,* and *E*. Interestingly, when we analysed functional divergence between isoforms *B* and *A*, including the single copies of *A* from each species that were considered to be conserved orthologs of *A* of *D. melanogaster*, we detected very low values of *θ* between *A* and *B* (*θ* = 0.1408, not significantly different from zero), providing no evidence that these exons have diverged in their function, but rather suggesting that replacement mutations are due to neutral evolution. However, the inclusion of the duplicate isoforms of *A* of *D. mojavensis*, *D. virilis* and *D. grimshawii* increased *θ* to 0.28--0.38 (P\<0.0001), when the *A* and *B* clusters were compared. The comparison of the *A* isoforms of *Sophophora* versus the *A* isoforms of *D. mojavensis, D. virilis* and *D. grimsshawii* also provided evidence of functional divergence between them (*θ* ranged from 0.27 to 0.49, P\<0.004--0.002). We also observed low divergence between exons *C* and *D*, possibly indicating similar functions.
10.1371/journal.pone.0001513.t002
###### Estimates of functional divergence between the large exons (*A*, *B, C, D, E*) of the *Gr39a* gene.
{#pone-0001513-t002-2}
A/B A/E A/C A/D B/E B/C B/D E/C E/D C/D
-------- -------- -------- -------- -------- -------- -------- -------- -------- -------- --------
*θ* 0.1408 0.6352 0.5360 0.6432 0.5575 0.5312 0.5944 0.5235 0.4936 0.2928
*α* 2.1806 3.4014 2.9970 2.6127 1.9484 1.6205 1.6260 2.8306 2.3156 2.0193
SE *θ* 0.0873 0.1439 0.1348 0.1016 0.1097 0.1073 0.0812 0.1677 0.0984 0.1091
LR *θ* 2.5998 19.460 15.795 40.038 25.790 24.479 53.458 9.7441 25.144 7.2000
P NS 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.002 0.0001 0.007
*θ*-maximum likelihood estimate for the coefficient of functional divergence
*α-*maximum likelihood estimate for the gamma shape parameter for rate variation among sites
SE *θ-*standard error of the estimate of *θ*
LR *θ*-likelihood-ratio statistic for comparison of alternative hypothesis *θ*\>0 against the null hypothesis of *θ* = 0
P--probability (NS--not significant)
We tested the main regions of the *Gr39a* gene for signs of positive selection using several models in PAML. Application of the site and branch-site models detected positive selection on exon *B* (P\<0.011) in the subgenus *Drosophila* during the diversification of *D. grimshawi*, *D. mojavensis* and *D. virilis* ([Table 1](#pone-0001513-t001){ref-type="table"}). Only 1.2% of sites of exon *B* underwent positive selection with *ω* = 2.4; sites *28T, 60T, 68S* and *193D*. We applied branch models to test variation in *ω* in exons *B, C* and *D* on phylogenetic lineages within the melanogaster group (we excluded exon *A*, because it degraded in two melanogaster group species). *ω* exceeded 1 (the neutral expectation) in exon *C* of *D. sechellia* (*ω* = 1.43). Analyzing exon *C*, we also found an increase in *ω* in *D. simulans* (*ω = *0.8138) and *D. melanogaster* (*ω = *0.7554). To examine this further, pairwise comparisons of the *d~N~* (nonsynonymous substitution rate) and *d~S~* (synonymous substitution rate) of the exons *C, B, D* (excluding exon *A*, because it degraded in *D. sechellia*) and small conserved exons were carried out in *D. sechellia* vs. *D. melanogaster,* and *D. simulans* vs. *D. melanogaster* ([Figure 4A](#pone-0001513-g004){ref-type="fig"}) (comparing closely related species excludes potential problems of accounting for multiple hits at the synonymous sites and saturation). At the conserved small exons the *d~S~* rates exceeded the *d~N~* rates approximately ten times, indicating very strong negative selection against nonsynonymous mutations ([Figure 4A](#pone-0001513-g004){ref-type="fig"}). We found signs of a slight increase in the *d~S~* and *d~N~* rates in exon *D* of *D. sechellia*, and also an increase in the *d~N~* rates of exon *C* in *D. sechellia* and *D. simulans*, while the *d~S~* rates of exon *C* were relatively stable compared with the *d~S~* rates in exons *B* or *D*. Thus, the *d~S~* rates of exons *B* and *D* were nearly three times higher than their *d~N~* rates, while in the exon *C* the substitution rate at the synonymous sites was about twice higher than that at the nonsynonymous sites ([Figure 4A](#pone-0001513-g004){ref-type="fig"}). For comparison, we also analysed the *d~S~, d~N~* rates and the *ω* ratio *(d~N~/d~S~)* amongst the exons *A, B, C, D* and small conserved exons between *D. melanogaster* and *D. yakuba* ([Figure 4B](#pone-0001513-g004){ref-type="fig"}). Along with the increase of the *ω* in the exon *C*, we found similar patterns in exon *A*, in both cases changes of *ω* happened due to an increased rate of nonsynonymous substitution.
{#pone-0001513-g004}
Discussion {#s3}
==========
About 10% of Drosophila genes contain tandemly duplicated exons, many of which are believed to be involved in mutually exclusive alternative splicing events [@pone.0001513-Letunic1]. Of the chemosensory receptor gene family, which contains around 120 genes, only three gustatory (*Gr23a, Gr28b, Gr39a*) and two olfactory (*Or46a, Or69a*) receptor genes have tandemly duplicated exons, which have been shown to undergo alternative splicing [@pone.0001513-Robertson1]. Among these genes, *Gr39a* is a unique case of rapid evolution through exon duplication and divergence, and in some cases exon loss.
Several structural changes have occurred to *Gr39a*, including the loss of exon *C* in *D. willistoni* and the species of *Drosophila* subgenus, and multiple duplications of exon *A* in *D. pseudoobscura, D. persimilis, D. willistoni, D. mojavensis, D. virilis* and *D. grimshawii*, around the time of the *Drosophila-Sophophora* division. The species of the melanogaster group have lost the ancestral exon *E*, also pseudogenisation of exon *A* has occurred in *D. sechellia* and *D. erecta*. McBride and Arguello [@pone.0001513-McBride1] also reported pseudogenisation of parts of the *Gr* repertoire in these last two species and related this to the ecological specialisation shown by these species [@pone.0001513-Gardiner1]. Evidence for strong purifying constraints on *Gr39a* supports its status as a functional gene. We found evidence of functional divergence between exons *B, E, C* and *D*. However, based on the low level of functional divergence between the exons *C* and *D*, it is likely that they have similar functions, even though both exons have persisted over a long evolutionary period. In *D. melanogaster*, both exons are expressed in the labellum and thorax, but also show spatial delimition with Gr39aC being expressed in the abdomen and Gr39aD in the wings [@pone.0001513-Clyne1]. The increase of the nonsynonymous substitution rate we detected in *Gr39aC* of *D. simulans* and, especially, in the specialist *D. sechellia* must indicate exon diversification.
We found little evidence of functional divergence between exons *A* and *B*. Curiously, exon *A* is multiply duplicated in all lineages except the melanogaster group, where it was lost in the two specialist species. The duplicates of exon *A* present in *D. mojavensis, D. virilis* and *D. grimshawii* show evidence of functional divergence from exon *B*, as well as from exon *A* of the *Sophophora* subgenus. We also detected positive selection acting on *Gr39aB* in the *Drosophila* subgenus. The extensive creation of new copies of exon *A* and signs of positive selection acting on *Gr39aB* in the *Drosophila* subgenus could indicate functional diversification of the *Gr39aA* and *Gr39aB* in these species.
Increased functional diversity results from extensive whole gene duplication in some cases, creating gene families, whereas in other cases it evolves through alternative splicing. Curiously, although the results of these two processes are similar, they are inversely correlated at the genomic level and it is unclear what conditions lead to one rather than the other [@pone.0001513-Talavera1]. There are several hypotheses proposed to explain the functional diversification of duplicated genes which presumably also apply to exon duplication. According to Ohno\'s hypothesis, most gene duplicates, being functionally redundant, are eliminated from the genome (nonfunctionalization), except for rare occasions when beneficial mutations could lead to a new gene function (neofunctionalization) [@pone.0001513-Ohno1]. Another model predicts dividing the functions between the duplicate and the original copy (subfunctionalization) [@pone.0001513-Lynch1]. Both models assume that relaxation or a lack of selection on the duplicate allows the acquisition of novel replacement mutations and/or changes in expression pattern. According to Hughes [@pone.0001513-Hughes1], "specialization" of duplicates to different functions of the bi-functional ancestral gene can occur through positive selection. This model assumes a bi-functional nature of the ancestral gene, though in the case of already extensive gene families, different loci will already have similar functions but a degree of specialization (such as detecting related ligands). It has been shown that many chemoreceptors can recognize more than one ligand [@pone.0001513-Hallem1], suggesting their bi- or multi-functional nature. Duplication of such genes can facilitate the specialization of daughter genes and changes in expression, for instance in more restricted sets of tissues, can further drive specialization [@pone.0001513-Hughes1]. For tandemly duplicated exons, Kondrashov and Koonin [@pone.0001513-Kondrashov1] favour the "specialization" model of the duplicated exons, assuming that if both duplicated exons are translated immediately after duplication, both will be subject to stabilizing selection, which excludes the possibility of short-term relaxation or lack of selection required to allow accumulation of replacement mutations. Alternatively, adaptation of alleles to different functions or sub-functions might start even before duplication [@pone.0001513-Proulx1], thereby facilitating neofunctionalisation after duplication.
Despite our expectations that large alternatively spliced exons of the *Gr39a* would experience similar selective constraints and stabilizing selection, we found evidence of relaxation in the selective constraints on exon *A* (which is prone to duplication) and exon *E*. Exon *E* is either present as a single copy or lost in some lineages, while exon *A* has multiply duplicated in most species. We found evidence of functional divergence between the copies of *A* amongst the species of two subgenera, and we suggest that the exon divergence probably occurred through relaxation of selective constrains on this exon, which implies subfunctionalization of the duplicates according to Lynch and Force [@pone.0001513-Lynch1] or neofunctionalization according to Ohno\'s hypothesis [@pone.0001513-Ohno1]. The selective constraints that act on other large exons (*B, C* and *D*) are relatively constant. We detected signals of positive selection on the *Gr39aB* in the *Drosophila* subgenus and possibly on *Gr39aC* in some species of the melanogaster group. Exon *B* is present as a single copy in all Drosophila species examined; the signature of positive selection which we detected on this exon indicates an adaptive mode of its evolution. The ancient duplicates *Gr39aC* and *Gr39aD* have functionally diverged, but experience similar selective constrains. We suggest the participation of positive selection in their divergence. We found some evidence of an increase of the nonsynonymous substitution rate in several species of the melanogaster group with the strongest signal in the specialist *D. sechellia*. This observation might support Hughes\'s model of "specialization" of duplicates [@pone.0001513-Hughes1] or the idea that positive selection can lead to a completely new function (neofunctionalization).
Materials and Methods {#s4}
=====================
Annotation of the orthologs of *D. melanogaster Gr39a* genes was performed for the other 11 Drosophila species whose genome sequences are publicly available [@pone.0001513-Drosophila1] using a combination of Blast [@pone.0001513-Altschul1], GeneWise [@pone.0001513-Birney1] and manual curation [@pone.0001513-Gardiner1]. Annotations ([Table S1](#pone.0001513.s001){ref-type="supplementary-material"}, [Figure S1](#pone.0001513.s003){ref-type="supplementary-material"}) and proteins alignment ([Figure S2](#pone.0001513.s004){ref-type="supplementary-material"}) are available as Supplemental data. [Figure S1](#pone.0001513.s003){ref-type="supplementary-material"} contains sequences of genes from the start codon to stop including introns, and also contains coding sequences (open reading frames, ORFs) in which introns are represented as gaps. The resulting sets of *Gr39a* sequences were multiply aligned at the codon level using ClustalW [@pone.0001513-Thompson1] on translations, followed by Protal2dna (K. Schuerer, C. Letondal; <http://bioweb.pasteur.fr>). Coding sequences identified were tested for the presence of transmembrane domains in their product using the TMHMM2.0 program [@pone.0001513-Krogh1]. For comparison of the *Gr39a* locus with other Drosophila gustatory (*Gr23a, Gr28b*, *Gr39a)* and olfactory (*Or46a, Or69a*) receptor genes that are known to undergo alternative splicing, we also identified their orthologs in the same set of species following the same procedure.
The phylogeny of *Gr39a* nucleotide sequences, with *Gr68aDmel* and *Gr32aDmel* as outgroups, was reconstructed by Bayesian Markov chain Monte Carlo (MCMC) analysis using MrBayes-3.1.2 [@pone.0001513-Ronquist1] with the HKY+4Γ model; default priors on branch lengths, rate parameters and tree topology; and two runs, each with one chain of 30,000,000 generations sampled every 50,000 generations. The first 250 trees sampled in each run were discarded as burn-in, leaving a final MCMC sample of 702 trees. Convergence was assessed using the average standard deviation of split frequencies, output by MrBayes. Independence within the sample was assessed using autocorrelation in tree log-likelihoods of the 351 trees from each run [@pone.0001513-Pagel1], obtained with the ACF function of Minitab v14.20 (Minitab, inc.). The majority-rule consensus of the final MCMC sample was taken to be the phylogeny of *Gr39a*.
We used Notung 2.1 [@pone.0001513-Durand1] to reconcile the "gene" tree (in our case, exon tree) and the species tree. Notung maps duplication and loss events onto branches of the species tree by reconstructing ancestral states according to parsimony rules. The topology of the species tree ([Figure 1A](#pone-0001513-g001){ref-type="fig"}) was obtained from [@pone.0001513-Drosophila1].
The structural and potentially functional divergence of the large exons of *Gr39a* was explored using DIVERGE v1.04 [@pone.0001513-Gu1]. The approach applied in DIVERGE was developed for the analysis of the functional divergence of duplicated genes which, from an evolutionary perspective, we assume also applies to duplicated exons. This approach was also suggested to be useful for studying functional divergence after speciation events, domain shuffling, lateral gene transfer etc. [@pone.0001513-Gu1]. Briefly, after gene (or exon) duplication, the evolutionary rate (*λ*) at an amino acid site may increase, leading to a functional divergence in the early stage after duplication, followed later by purifying constraints acting to maintain the novel function(s) [@pone.0001513-Gu1]. If the evolutionary rates between the original (*λ~1~*) and duplicate (*λ~2~*) stay the same or change proportionally over time, the coefficient of rate correlation (*r~λ~*) between them will be 1. A decrease of the *r~λ~* indicates differences in the evolutionary rates between the original and the duplicate copy, and a measure of such divergence is assigned as *θ = 1−r~λ~*, where *θ* is a coefficient of functional divergence [@pone.0001513-Gu1]. *θ* = 0 indicates no functional divergence, and an increase in *θ* from 0 to 1 shows increasing functional divergence from weak to extremely strong [@pone.0001513-Gu1]. The significance of *θ* is assessed using the likelihood ratio statistic, *LR*, defined as where *H* ~0~ is the likelihood of the model representing the null hypothesis (here, a model in which *θ* is constrained to equal zero) and *H* ~1~ is the likelihood of a more general model, representing the alternative hypothesis (*θ* is allowed to vary). *LR* was converted to a P-value on the assumption that the null distribution of *LR* is χ^2^ with degrees of freedom (d.f.) equal to the difference in the number of free parameters between *H* ~1~ and *H* ~0~ (here, d.f. = 1) [@pone.0001513-Gu1], [@pone.0001513-Cox1]. We estimated *θ* between the encoded protein isoforms Gr39aA, Gr39aB, Gr39aC, Gr39aD and Gr39aE, excluding the last transmembrane domain specified by three conserved exons. Because exon *A* duplicated in most lineages, we performed several comparisons of the Gr39aA isoforms. Initially, we compared the Gr39aA isoforms with Gr39aB, Gr39aC, Gr39aD and Gr39aE, by including only single copies of *A* from each species that were considered to be conserved orthologues to the *A* of *D. melanogaster* on the basis of the highest similarity score calculated by GeneWise, then repeated this test by excluding *D. grimshawi* whose copies of A scored similar values in GeneWise. We then repeated the analysis including duplicates of Gr39aA of one of the species where exon A duplicated (*D. pseudoobscura*, *D. persimilis*, *D. willistoni, D. mojavensis*, *D. virilis* and *D. grimshawi*) and compared these with Gr39aB. We also compared the Gr39aA of the *Drosophila* subgenus with the Gr39aA isoforms of the *Sophophora* subgenus.
The "M0" model of *codeml* in the PAML computer package [@pone.0001513-Yang1] was used to determine the average selective constraint on the whole gene, and also separately for its exons (*B, C, D, E* and the set of exons *A*, which comprised from the copies of *A* that were considered to be conserved orthologues to the *A* of *D. melanogaster*), through estimation of the ratio of the normalized nonsynonymous substitution rate (*d~N~*) to normalized synonymous substitution rate (*d~S~*), or *ω = d~N~/d~S~*. *ω*\>1 is considered strong evidence of positive selection for amino acid replacements whereas *ω*≈0 indicates purifying selection, while *ω* = 1 conforms to a neutral expectation [@pone.0001513-Yang2]. To test for positive selection on orthologous exons, we used a range of tests in which two models are compared, again by means of *LR*. The models permit detecting episodes of positive selection acting on a fraction of sites ("site" models) or on particular phylogenetic lineages ("branch" models), as well as a combination of both ("branch-site" models). The strength of evidence for site, branch and branch-site models was assessed by comparing *codeml* models "M8" with "M7", "Mfree" with "M0", and "M2" with "M1", respectively. Model M7 allows several site classes with *ω* drawn from a *β* distribution and fixed between 0 and 1, while M8 adds another class of sites with *ω*\>1 [@pone.0001513-Yang1]. Branch models allow testing variation in *ω* among different branches of a phylogeny [@pone.0001513-Yang1]. The simplest model, M0, assumes one *ω* for all branches, while the "free-ratio" or Mfree model allows different *ω* for all branches [@pone.0001513-Yang1]. We used M0 and Mfree to estimate *ω* for the exons *B, C* and *D* in the melanogaster group (we excluded exon *A* because it had degraded in two species of the melanogaster group). Finally, branch-site models can detect episodic events of adaptive evolution on specific sites in different branches of a phylogeny [@pone.0001513-Yang1]. In the M1 model, there are four classes of sites with ω fixed below 1, while M2 allows a fraction of sites to have *ω*\>1 on user-selected ("foreground") branches [@pone.0001513-Yang1]. For converting *LR* to a P-value, for M8 vs M7, d.f. = 2; for Mfree vs M0 in this study, d.f. = 8; for M1 vs M0, d.f. = 1. Finally, the pairwise comparison of the *d~S~* and *d~N~* rates was performed using *codeml* option runmode = −2 [@pone.0001513-Yang1].
Supporting Information {#s5}
======================
######
Annotation and description of the identified Gr39a genes
(0.02 MB XLS)
######
Click here for additional data file.
######
The estimates of the functional divergence amongst Drosophila gustatory receptors
(0.02 MB XLS)
######
Click here for additional data file.
######
The nucleotide sequences of the identified Gr39a genes
(0.23 MB TXT)
######
Click here for additional data file.
######
The Gr39a multiple protein sequence alignment
(10.06 MB TIF)
######
Click here for additional data file.
The genomic sequences of *D. erecta, D. ananassae, D. mojavensis, D. virilis* and D. *grimshawi* were provided by Agencourt Bioscience Corporation. The genomes of *D. simulans* and *D. yakuba* were sequenced by Washington University (St. Louis), while *D. sechellia* and *D. persimilis* by the Broad Institute. Baylor University provided the data for the *D. pseudoobscura* genome. *D. melanogaster* genome was provided by the Berkeley Drosophila Genome Project and Celera. The authors are indebted to Christoph Echtermeyer for assistance with graphics and an anonymous reviewer for useful comments.
**Competing Interests:**The authors have declared that no competing interests exist.
**Funding:**This work was supported by the Natural Environment Research Council UK, grant NE/C003187/1. DB was supported by a Research Councils UK Academic Fellowship.
[^1]: Conceived and designed the experiments: RB WJ MR. Performed the experiments: AG. Analyzed the data: DB AG. Wrote the paper: RB DB AG WJ MR.
| 2024-05-05T01:26:59.872264 | https://example.com/article/5349 |
Portugal opposition wants bailout renegotiation
LISBON (Reuters) - The opposition Socialists demanded a renegotiation of Portugal's bailout terms on Friday, raising a hurdle to a cross-party pact the president says is needed to end the euro zone country's dependence on international funding next year.
Prime Minister Pedro Passos Coelho and Socialist leader Antonio Jose Seguro said they are ready to discuss a deal, but analysts say their divergence on painful austerity policies linked to the bailout could make it hard to resolve the crisis.
"We have to abandon austerity politics. We have to renegotiate the terms of our adjustment program," Seguro told parliament. "The prime minister has to recognize publicly that his austerity policies have failed."
The political turmoil has already forced Lisbon to request a delay in the eighth review of the bailout by its creditors, initially due to start on Monday, until the end of August or early September.
The delay drove up yields on Portuguese government bonds, which move inversely with prices, with 10-year yields surging 90 basis points on Friday to 7.87 percent.
President Anibal Cavaco Silva threw the country into disarray this week by rejecting the premier's bid to heal a rift in the ruling coalition via a cabinet reshuffle, calling for a cross-party agreement to last until the end of the bailout program in June 2014, to be followed by early elections.
The Socialists have blamed the government's austerity drive under the 78-billion-euro bailout for pushing Portugal into its biggest economic slump since the 1970s and unemployment to record levels of around 18 percent.
AGREEMENT SEEN DIFFICULT
"More time is something which we have always fought for. More time so our adjustment curve is not so steep and we can relieve sacrifices families and businesses have to make," Seguro, whose party lead in opinion polls, said.
The Socialists had lobbied Cavaco Silva to call a snap election immediately, a move which the president rejected, saying it would significantly increase the risk of Portugal being forced to request a second bailout.
"As things stand today, I don't think there is any possibility of the Socialists reaching a deal with the coalition without any concessions from the government as they will not back the continuation of policies which they reject," said Filipe Garcia, head of Informacao de Mercados Financeiros consultants in Porto.
"There have to be concessions, especially as the Socialists prefer a (snap) election to an agreement," he added.
The resignation of Foreign Minister Paulo Portas, who also leads the junior coalition partner CDS-PP, over Passos Coelho's austerity policies last week triggered the crisis.
The premier said his government was still in office with full powers and the country could overcome the crisis under the president's plan. Political talks to resolve the situation are set to continue in coming days.
"What happened should not have happened, and we have to show that it will not happen again," Passos Coelho told lawmakers.
The small opposition Green Party said it would present a motion of no confidence to parliament. The motion, expected next week, is unlikely to succeed but with political events moving quickly it will be watched closely.
Portugal's debt agency said earlier on Friday it would only return to regular bond issuance in the second half of 2013 "if market conditions are conducive".
Analysts said that even if parties reach a deal, Portugal's reform progress could suffer.
"Under the president's plan, Mr Passos Coelho would be politically crippled," Nicholas Spiro, Managing Director at Spiro Sovereign Strategy in London, said in a research note.
"The Socialists would rapidly lose support and the reform drive would grind to a screeching halt." | 2024-07-30T01:26:59.872264 | https://example.com/article/5670 |
Q:
Unable to deconstruct product type after simplifying in OCaml
I have this simple code in OCaml:
type int_pair = int * int;;
type a = A of int_pair;;
let extract (A x) = x;;
Testing my extract function, it appears to work:
# extract (A (1,2));;
- : int_pair = (1, 2)
I simplify it, so it only needs one type:
type a' = A' of int * int;;
let extract' (A' x) = x;;
But I get the error:
Error: The constructor A' expects 2 argument(s),
but is applied here to 1 argument(s)
The funny thing is, I can construct values of a'...
# A' (1,2);;
- : a' = A' (1, 2)
...I just can't deconstruct them. Why?
A:
You need to use
type a' = A' of (int * int)
This is one of the tricky places in OCaml type specification.
There are two different types involved that are subtly different:
type one_field = F1 of (int * int)
type two_fields = F2 of int * int
In the type one_field there's a single field that's a pair of ints. In the type two_fields there are two fields each of which is an int. The tricky thing is that the constructor looks identical:
# F1 (3, 5);;
- : one_field = F1 (3, 5)
# F2 (3, 5);;
- : two_fields = F2 (3, 5)
These two types are distinct, and are in fact represented differently in memory. (The two-field variant actually takes less space and is slightly faster to access.)
| 2024-04-24T01:26:59.872264 | https://example.com/article/8906 |
from tornado import web, gen
from .constants import OK, NO_CONTENT
from .resources import Resource
from .exceptions import MethodNotImplemented, Unauthorized
import weakref
import inspect
try:
from tornado.concurrent import is_future
except ImportError:
is_future = None
if is_future is None:
"""
Please refer to tornado.concurrent module(newer than 4.0)
for implementation of this function.
"""
try:
from concurrent import futures
except ImportError:
futures = None
from tornado.concurrent import Future
if futures is None:
FUTURES = Future
else:
FUTURES = (Future, futures.Future)
is_future = lambda x: isinstance(x, FUTURES)
@gen.coroutine
def _method(self, *args, **kwargs):
"""
the body of those http-methods used in tornado.web.RequestHandler
"""
yield self.resource_handler.handle(self.__resource_view_type__, *args, **kwargs)
class _BridgeMixin(object):
"""
This mixin would pass tornado parameters to restless,
and helps to init a resource instance
"""
def __init__(self, *args, **kwargs):
super(_BridgeMixin, self).__init__(*args, **kwargs)
# create a resource instance based on the registered class
# and init-parameters
self.resource_handler = self.__class__.__resource_cls__(
*self.__resource_args__, **self.__resource_kwargs__
)
self.resource_handler.request = self.request
self.resource_handler.application = self.application
self.resource_handler.ref_rh = weakref.proxy(self) # avoid circular reference between
class TornadoResource(Resource):
"""
A Tornado-specific ``Resource`` subclass.
"""
_request_handler_base_ = web.RequestHandler
"""
To override ``tornado.web.RequestHandler`` we used,
please assign your RequestHandler via this attribute.
"""
def __init__(self, *args, **kwargs):
super(TornadoResource, self).__init__(*args, **kwargs)
self.request = None
"""
a reference to ``tornado.httpclient.HTTPRequest``
"""
self.application = None
"""
a reference to ``tornado.web.Application``
"""
self.ref_rh = None
@property
def r_handler(self):
"""
access to ``tornado.web.RequestHandler``
"""
return self.ref_rh
@classmethod
def as_view(cls, view_type, *init_args, **init_kwargs):
"""
Return a subclass of tornado.web.RequestHandler and
apply required setting.
"""
global _method
new_cls = type(
cls.__name__ + '_' + _BridgeMixin.__name__ + '_restless',
(_BridgeMixin, cls._request_handler_base_,),
dict(
__resource_cls__=cls,
__resource_args__=init_args,
__resource_kwargs__=init_kwargs,
__resource_view_type__=view_type)
)
"""
Add required http-methods to the newly created class
We need to scan through MRO to find what functions users declared,
and then add corresponding http-methods used by Tornado.
"""
bases = inspect.getmro(cls)
bases = bases[0:bases.index(Resource)-1]
for k, v in cls.http_methods[view_type].items():
if any(v in base_cls.__dict__ for base_cls in bases):
setattr(new_cls, k.lower(), _method)
return new_cls
def request_method(self):
return self.request.method
def request_body(self):
return self.request.body
def build_response(self, data, status=OK):
if status == NO_CONTENT:
# Avoid crashing the client when it tries to parse nonexisting JSON.
content_type = 'text/plain'
else:
content_type = 'application/json'
self.ref_rh.set_header("Content-Type", "{}; charset=UTF-8"
.format(content_type))
self.ref_rh.set_status(status)
self.ref_rh.finish(data)
def is_debug(self):
return self.application.settings.get('debug', False)
@gen.coroutine
def handle(self, endpoint, *args, **kwargs):
"""
almost identical to Resource.handle, except
the way we handle the return value of view_method.
"""
method = self.request_method()
try:
if not method in self.http_methods.get(endpoint, {}):
raise MethodNotImplemented(
"Unsupported method '{}' for {} endpoint.".format(
method,
endpoint
)
)
if not self.is_authenticated():
raise Unauthorized()
self.data = self.deserialize(method, endpoint, self.request_body())
view_method = getattr(self, self.http_methods[endpoint][method])
data = view_method(*args, **kwargs)
if is_future(data):
# need to check if the view_method is a generator or not
data = yield data
serialized = self.serialize(method, endpoint, data)
except Exception as err:
raise gen.Return(self.handle_error(err))
status = self.status_map.get(self.http_methods[endpoint][method], OK)
raise gen.Return(self.build_response(serialized, status=status))
| 2024-01-08T01:26:59.872264 | https://example.com/article/9026 |
Nitrate toxicosis in beef and dairy cattle herds due to contamination of drinking water and whey.
Four cases of rarely reported nitrate toxicosis due to contamination of drinking water or whey were recorded in 2 beef and 2 dairy cattle herds. In the cases associated with water contamination, water containing ammonium nitrate as a fertilizer for irrigating orchards accidentally entered drinking water troughs for cattle through malfunctioning 1-way valves. The whey contamination in 1 instance was caused by transportation in containers which contained traces of concentrated ammonium nitrate; the 2nd case was induced by whey derived from the production of a specialty cheese produced by the incorporation of nitrate. Mortality occurred in 2 herds and abortions in the 2 other herds. Affected cows responded well to treatment, but some animals remained in a deteriorated physical condition for several months. | 2023-09-29T01:26:59.872264 | https://example.com/article/4566 |
Corresponding Author
**Jenifer L. Bratter is an assistant professor in the Department of Sociology at the Rice University, P.O. Box 1892‐MS 28, 6100 Main Street, Houston, TX 77005 (E-mail address: jlb1@rice.edu).
Rosalind B. King is a Health Scientist Administrator in the Demographic and Behavioral Sciences Branch at the Center for Population Research, National Institute of Child Health and Human Development, 6100 Executive Boulevard, Room 8B07, MSC 7510, Bethesda, MD 20892‐7510 (E-mail address: kingros@mail.nih.gov). | 2023-10-13T01:26:59.872264 | https://example.com/article/4612 |
Q:
How can I return a human readable time range?
I used the code below to return a number, but it's not human readable. How do I convert it to a x hours x mins x second format?
ruby-1.9.2-p0 > Time.now.end_of_day() -Time.now
=> 31612.235963075
A:
Use distance_of_time_in_words(Time.now, Time.now.end_of_day)
| 2024-02-18T01:26:59.872264 | https://example.com/article/5581 |
About
Mission statement:
"North Omak Elementary exists to prepare students to participate in a democratic society by ensuring that all students meet or exceed district, state, and federal learning requirements annually in a safe and secure environment." John R. "Jack" Schneider, Principal
School Song:
(Tune: Twinkle Twinkle Little Star)We are North Stars; see us shine. Safety and teamwork are our pride.We keep positive attitudes.And respect our friends and school.With all of these, we earn success.We are North Stars; we’re the best!
North School Rules:
1. Be Kind and Respectful2. Make Good Decisions3. Solve Problems
Non-Discrimination and Affirmative Action Notification:
Non-Discrimination StatementOmak School District does not discriminate in any programs or activities on the basis of sex, race, creed, religion, color, national origin, age,veteran or military status, sexual orientation, sexual expression or identity, disability, or the use of a trained dog guide or service animal and provides equal access to the Boy Scouts and other designated youth groups. The following employees have been designated to handle questions and complaints of alleged discrimination: Civil Rights Coordinator and Title IX Coordinator: LeAnne Olson, (509) 826-7687, lolson@omaksd.org ; and Section 504 Coordinator: John Holcomb, (509) 826-8342, johnholcomb@omaksd.org , P.O. Box 833, Omak, WA 98841. | 2024-05-23T01:26:59.872264 | https://example.com/article/2409 |
These fine grain cork pads are perfect for protecting your cupboards, drawers, cabinets etc. The self-adhesive backing makes it fast and easy to simply peel and stick! Our cork pads are the perfect solution for protecting your furniture from scratches and dents and stick to any hard surface including wood, laminate, ceramic, vinyl, and hardwood floors.
$59.84 USD
Product Description
These fine grain cork pads are perfect for protecting your cupboards, drawers, cabinets etc. The self-adhesive backing makes it fast and easy to simply peel and stick! Our cork pads are the perfect solution for protecting your furniture from scratches and dents and stick to any hard surface including wood, laminate, ceramic, vinyl, and hardwood floors. | 2024-07-24T01:26:59.872264 | https://example.com/article/4804 |
Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites.
To characterize the interaction of coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca(2+) influx results established that coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC50's in μM) sequence: (-)-ibogamine (0.62±0.23)∼(+)-catharanthine (0.68±0.10)>(-)-ibogaine (0.95±0.10)>(±)-18-methoxycoronaridine [(±)-18-MC] (1.47±0.21)>(-)-voacangine (2.28±0.33)>(±)-18-methylaminocoronaridine (2.62±0.57 μM)∼(±)-18-hydroxycoronaridine (2.81±0.54)>(-)-noribogaine (6.82±0.78). A good linear correlation (r(2)=0.771) between the calculated IC50 values and their polar surface area was found, suggesting that this is an important structural feature for its activity. The radioligand competition results indicate that (±)-18-MC and (-)-ibogaine partially inhibit [(3)H]imipramine binding by an allosteric mechanism. Molecular docking, molecular dynamics, and in silico mutation results suggest that protonated (-)-18-MC binds to luminal [i.e., β4-Phe255 (phenylalanine/valine ring; position 13'), and α3-Leu250 and β4-Leu251 (leucine ring; position 9')], non-luminal, and intersubunit sites. The pharmacophore model suggests that nitrogens from the ibogamine core as well as methylamino, hydroxyl, and methoxyl moieties at position 18 form hydrogen bonds. Collectively our data indicate that coronaridine congeners inhibit hα3β4 AChRs by blocking the ion channel's lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites. | 2023-09-17T01:26:59.872264 | https://example.com/article/8730 |
Neuromuscular adaptations following prepubescent strength training.
Underlying mechanisms of prepubescent strength gains following resistance training are speculative. The purpose of this investigation was to determine the effects of 8 wk of resistance training on muscular strength, integrated EMG amplitude (IEMG), and arm anthropometrics of prepubescent youth. Sixteen subjects (8 males, 8 females) were randomly assigned to trained or control groups. All subjects (mean age = 10.3 yr) were of prepubertal status according to the criteria of Tanner. The trained group performed three sets (7-11 repetitions) of bicep curls with dumbbells three times per week for 8 wk. Pre- and posttraining measurements included isotonic and isokinetic strength of the elbow flexors, arm anthropometrics, and IEMG of the biceps brachii. Planned comparisons for a 2 x 2 (group by test) ANOVA model were used for data analysis. Significant isotonic (22.6%) and isokinetic (27.8%) strength gains were observed in the trained group without corresponding changes in arm circumference or skinfolds. The IEMG amplitude increased 16.8% (P < 0.05). The control group did not demonstrate any significant changes in the parameters measured. Early gains in muscular strength resulting from resistance training prepubescent children may be attributed to increased muscle activation. | 2024-03-21T01:26:59.872264 | https://example.com/article/2987 |
Now Commenting On:
Phillips relishes chance to interact with Reds fans
COLUMBUS, Ohio -- Second baseman Brandon Phillips is the second-longest tenured Reds player, having arrived in a trade in April 2006.
No one on the roster has more experience than Phillips when it comes to Reds Caravan trips. Each winter since his arrival in Cincinnati, Phillips has never missed a chance to hop on the bus and do the annual tour of the region.
"I don't feel like I'm better than anybody else," Phillips said on Saturday. "I like to go on the caravan to help the Reds fan base out. Regardless of how much money I've made, I want them to know me as a guy that loves the fans. I'm all about the fans. If there were no fans, there would be nobody in the stands."
Phillips, 31, and the rest of the caravan's northern leg -- Minor League catcher Tucker Barnhart, former Reds player Todd Benzinger, assistant general manager Bob Miller and broadcasters Marty Brennaman and Chris Welsh -- found plenty of fans waiting to see them on Saturday morning in Columbus.
At Nationwide Arena, the home of the NHL's Blue Jackets, an estimated 1,000 people filled an expansive concourse to see a Reds Caravan stop. Many wanted to see Phillips, a two-time All-Star and three-time Gold Glove winner who won his first Silver Slugger Award after last season.
As often happens during larger caravan stops, the Reds held a brief question and answer session with the fans before the featured group signed hundreds of autographs.
"That's why I love these things," Phillips said. "I want the fans to get to know me as a person and not just as player. It's another way to give back to the fans that come here and support us. You don't really know how big Reds country is until you go out on a caravan. They're in West Virginia, Indiana and all of these small towns. It's just awesome to see these guys."
Barnhart, who will likely starts the 2013 season at Double-A Pensacola, sees Phillips as an example for younger players in how he relates with the fans.
"A guy at Brandon's level, he doesn't have to do this," Barnhart said. "I think he thoroughly enjoys it and interacting with the fans and stuff. He genuinely cares about all of these fans. It's fun to see."
The Northern leg, which Brennaman also dubbed "The Rock Star Tour," has made stops in Parkersburg, W.Va., and Athens, Ohio, among other places the past couple of days and still had visits planned for Lima and Dayton in Ohio. Snowy weather on Friday forced the cancellation of a couple of other visits.
"All of the stops have been good, especially the main stops," Phillips said. "We played laser tag in Parkersburg. It was fun. It's always a great group. Every stop we have, we just have a blast."
About 200 people were waiting outside at 9 a.m. before the doors opened at Nationwide Arena.
The Reds normally make their Columbus caravan stops at a local mall, but were invited to use the arena. Had there not been the NHL lockout that forced its cancellation, this would have been the weekend of the league's All-Star Game. Instead, with the lockout recently ended, there is a regular-season game Saturday night.
"I think it's a more central location, and we have a great relationship with the Blue Jackets," said Michael Anderson, the Reds' public relations manager. "We are able to accommodate more people here. They were gracious enough to let us have the event here in the morning before they have a game in the evening."
Mark Sheldon is a reporter for MLB.com. Read his blog, Mark My Word, and follow him on Twitter @m_sheldon. This story was not subject to the approval of Major League Baseball or its clubs. | 2024-01-30T01:26:59.872264 | https://example.com/article/4978 |
// Distributed under the terms of the MIT license
// Test case submitted to project by https://github.com/practicalswift (practicalswift)
// Test case found by fuzzing
func < {
case
let {
class a {
let f = {
struct d {
class
case ,
| 2024-02-17T01:26:59.872264 | https://example.com/article/3028 |
Q:
c++ remove vertex from a graph
3he following compiles using boost.1.46.1
#include <boost/graph/adjacency_list.hpp>
struct Node {
int id;
};
struct Edge {
int source;
int target;
int weight;
};
int main() {
/* an adjacency_list like we need it */
typedef boost::adjacency_list<
boost::setS, // edge container
boost::listS, // vertex container
boost::bidirectionalS, // directed graph
Node, Edge> Graph;
typedef boost::graph_traits<Graph>::vertex_descriptor Vertex;
Graph gp1;
std::cout << "Number of vertices 1: " << boost::num_vertices(gp1) << std::endl;
Vertex v1 = boost::add_vertex(gp1);
Vertex v2 = boost::add_vertex(gp1);
std::cout << "Number of vertices 2: " << boost::num_vertices(gp1) << std::endl;
gp1[v1].id = 3;
gp1[v2].id = 4;
Graph gp2(gp1);
std::cout << "Number of vertices 3: " << boost::num_vertices(gp2) << std::endl;
boost::remove_vertex(v2, gp2);
std::cout << "Number of vertices 4: " << boost::num_vertices(gp1) << std::endl;
std::cout << "Number of vertices 5: " << boost::num_vertices(gp2) << std::endl;
boost::graph_traits<Graph>::vertex_iterator it, end;
for (boost::tie( it, end ) = vertices(gp2); it != end; ++it) {
if ( gp2[*it].id == 3 ) {
boost::remove_vertex(*it, gp2);
}
}
std::cout << "Number of vertices 6: " << boost::num_vertices(gp1) << std::endl;
std::cout << "Number of vertices 7: " << boost::num_vertices(gp2) << std::endl;
return 0;
}
How does gp2 know about v2 when removing it at: "boost::remove_vertex(v2, gp2)"
and why does the number of vertices of gp1 decrease by 1?
Why does it give a segmentation fault at: "boost::remove_vertex(*it, gp2)"
and how can I fix it?
A:
Note that sehe's solution only applies to graphs with a VertexList=listS, and in particular not to graphs with VertexList=vecS. Also note that in general you can't store either vertex descriptors or iterators and delete them later, because of this from the Boost Graph Library webiste:
void remove_vertex(vertex_descriptor u, adjacency_list& g)
... If the
VertexList template parameter of the adjacency_list was vecS, then all
vertex descriptors, edge descriptors, and iterators for the graph are
invalidated by this operation. The builtin vertex_index_t property for
each vertex is renumbered so that after the operation the vertex
indices still form a contiguous range [0, num_vertices(g)). ...
A:
You are modifying the vertex collection while iterating it.
Collect the vertices to be removed first, then remove them. Or use the followingpattern:
// Remove all the vertices. This is OK.
graph_traits<Graph>::vertex_iterator vi, vi_end, next;
tie(vi, vi_end) = vertices(G);
for (next = vi; vi != vi_end; vi = next) {
++next;
remove_vertex(*vi, G);
}
Sample taken from this page: http://www.boost.org/doc/libs/1_47_0/libs/graph/doc/adjacency_list.html (which is what google returns when you look for remove vertices boost graph)
Edit
Translated that quickly into your sample:
boost::graph_traits<Graph>::vertex_iterator vi, vi_end, next;
boost::tie(vi, vi_end) = vertices(gp2);
for (next = vi; vi != vi_end; vi = next) {
++next;
if (gp2[*vi].id == 3)
remove_vertex(*vi, gp2);
}
Output:
Number of vertices 1: 0
Number of vertices 2: 2
Number of vertices 3: 2
Number of vertices 4: 1
Number of vertices 5: 2
Number of vertices 6: 1
Number of vertices 7: 1
No more crashes :)
| 2024-07-31T01:26:59.872264 | https://example.com/article/9087 |
Hydraulic suspension systems with hydraulic shock absorbers or dampers are known and commonly used on most vehicles. A shock absorber is a mechanical device designed to smooth out or dampen shock impulses, and dissipate kinetic energy. Shock absorbers, or merely called shocks, are also known as dampers and dashpots. Pneumatic and hydraulic shock absorbers commonly take the form of a cylinder with a sliding piston inside. The cylinder is filled with a liquid (such as hydraulic fluid) or air. Shock absorbers may include cushions and/or springs. The shock absorber's function in the suspension system of a vehicle is to absorb or dissipate energy acting on the vehicle. While shock absorbers may also serve the purpose of limiting excessive suspension movement, their intended main purpose is to dampen spring oscillations. Shock absorbers use valving of oil and gases to absorb excess energy from the springs. Vehicles typically employ both hydraulic shock absorbers and coil springs or torsion bars. In such a suspension system, “shock absorber” typically refers specifically to the hydraulic piston that absorbs and dissipates (i.e. dampens) vibration.
One requirement with hydraulic suspension systems in vehicles is that they require enough ride height, or ground clearance, to dampen or absorb the terrain being traveled over. The ride height of the vehicle, or the ground clearance of the vehicle, may be relatively small for smaller vehicles and vehicles intended to be driven on smooth surfaces like roads. However, with larger vehicles, like trucks and sports utility vehicles (i.e. SUVs), and vehicles that are designed to be driven off road and over uneven terrain, like military vehicles, the ride height or ground clearance required by the suspension system can be much larger.
One problem discovered in association with a large ride height or the required ground clearance of the vehicle could be the transportation or shipment of the vehicles. For example, if the vehicle needs to be shipped in a container, like the cargo unit of a truck, train, boat, airplane or helicopter, the vehicle may not fit into the container because the vehicle is too tall. As such, there is clearly a need to lower the ride height of a vehicle in order to transport the vehicle in a container, like the cargo unit of a truck, train, boat, airplane or helicopter. Another problem associated with a large ride height or large ground clearance of a vehicle is it may not be ideal for traveling on smoother roads where higher speeds and cornering are desired. For example, multi-purpose vehicles like trucks, SUVs, and even military vehicles come standard with large ride heights or large ground clearances in order for the vehicles to maneuver over uneven terrain or off-road purposes. However, these vehicles are also driven on smooth surfaces like roads at high speeds where cornering may be required. In these situations a lower ride height would be ideal but the vehicle's suspension must still function and dampen the forces acting on the vehicle. As such, it is clear that there is a need for such multi-purpose vehicles to have suspension systems that may be lowered while still functioning to dampen forces acting on the vehicle at a lowered position.
One known solution to lowering the ride height of a vehicle for purposes like transportation is to use mechanical struts to lock the vehicle at a lowered position. The problem with this mechanically locked solution is that it does not allow for the vibrations of the container to be dampened by the suspension system, or the hydraulic dampers, as they are locked into place. Thus, the vibrations of the shipping container, whether it be the vibrations of the truck, train, boat, plain or helicopter go directly into the vehicle which has been discovered to cause damage to the vehicle being shipped. In addition, these mechanical struts clearly would not work for lowering the ride height of the multi-purpose vehicles described previously. Other problems with these mechanical struts that lock the vehicle down is that they are difficult to install and take time and power to lower the vehicle. This may not be ideal for some situations, like military transportation, where time and efficiency are of the essence. As such, there is clearly a need to provide a system for lowering the ride height of a vehicle that still provides damping forces to the vehicle while it is lowered and is quick and easy to operate.
The instant invention is designed to address at least some of the above mentioned problems. | 2023-09-08T01:26:59.872264 | https://example.com/article/1934 |
.
n, -4, -2
Let n(q) = -q**2 - 6*q + 5. Suppose 0 = -3*j - 14 - 4. Let l be n(j). Sort l, 4, -2 in ascending order.
-2, 4, l
Let v = -2 + -1. Suppose -151*p = -150*p + 5. Sort 5, v, p in ascending order.
p, v, 5
Let u(b) = -4 - 3 + b + 0 + 5. Let c be u(5). Let k be ((-3)/2)/(c/(-4)). Sort k, 3, 0 in descending order.
3, k, 0
Let d(a) = 6*a**3 - 2*a**2 + 1. Suppose 7 = 3*s + w, 5*s + 5 = 2*s + 2*w. Let m be d(s). Put 1, m, -4 in descending order.
m, 1, -4
Let p = 9 - 5. Let o = p - 8. Put -2, 4, o in decreasing order.
4, -2, o
Let m = 35 + -33. Sort 0.4, -5, m, 1 in increasing order.
-5, 0.4, 1, m
Let t be (4/(-3))/((-30)/45). Put -5, 3, t in ascending order.
-5, t, 3
Let b = -70 - 29. Let u = 399/4 + b. Let c = 9 - 11. Sort u, 2, c in increasing order.
c, u, 2
Suppose 2*r + 5*k = -10 - 4, -10 = 4*r + k. Sort -26, 3, r, 1 in increasing order.
-26, r, 1, 3
Let g = -27 - -19. Sort g, 2, -3 in descending order.
2, -3, g
Let s be (-64)/6*3/(-2). Suppose 9 = 5*g - s. Suppose 6 = 2*t, -4 + 21 = 5*r + 4*t. Sort r, g, -4 in decreasing order.
g, r, -4
Suppose 5*j = -3*f - 13, 5 = -j - 3*j + 3*f. Suppose -g + 7 = h - 4*g, 3*h = 2*g + 14. Put j, 1, h in ascending order.
j, 1, h
Let v = -79/235 - 3/47. Sort v, 11, -4, 0.5 in increasing order.
-4, v, 0.5, 11
Suppose -2*h + 15 = 3*y, 0 = -4*h + y - 5*y + 20. Let f = -1 + h. Let n = -4.5 + 7.5. Put n, f, 2 in descending order.
n, 2, f
Let u = 97/12 + -33/4. Put 1, u, 0.1 in ascending order.
u, 0.1, 1
Suppose 0 = 5*u - 4 - 6. Suppose 0 = -4*m + 2*m - u. Put -2, -3/7, m in descending order.
-3/7, m, -2
Suppose 3*n - 4 = 4*n. Let s = 7 - 4. Suppose 0 = -3*f + 5*g - 40, s*f + g + g + 5 = 0. Sort n, f, -2 in descending order.
-2, n, f
Let w(x) = x + 3*x**3 + 0*x**3 + 2*x - 2*x**3 - 6*x**2 + 6. Suppose -2*y + 5*g + 9 = -11, -2*y + 8 = g. Let a be w(y). Sort 5, a, 0.
a, 0, 5
Suppose 4*u - 14*u = 30. Let t be 2/6 + (-16)/3. Sort 2, t, u in decreasing order.
2, u, t
Let a = 23 - 18. Sort -4, a, -6 in decreasing order.
a, -4, -6
Suppose -w - 3*w + 5*z = 4, 4*w - 4*z = 0. Let t be 2/4*-2*-1. Put 5, w, t in decreasing order.
5, w, t
Suppose j - 3 = 4*j. Sort 3, j, -2 in increasing order.
-2, j, 3
Let m = 17 - 16. Put m, 3, -3 in ascending order.
-3, m, 3
Let r be ((1 + -5)/2)/1. Let n(w) = -w**2 + 11*w - 4. Let h be n(10). Sort r, 2, h in descending order.
h, 2, r
Let f = -2236/21 + 8902/35. Let b = f + -148. Let l = 0 + -1. Sort l, 2, b in decreasing order.
2, b, l
Suppose 5*f = -0*q - 5*q + 40, -4*q - f + 20 = 0. Put q, -1, -4 in descending order.
q, -1, -4
Let l = 5 + -2. Sort -2, l, 2.
-2, 2, l
Let x be 6/(-18) - 7/6. Sort -0.9, x, 1/3 in ascending order.
x, -0.9, 1/3
Let q = 49 - 50. Put q, -4, 0, 5 in descending order.
5, 0, q, -4
Let d be ((-6)/(-9))/((-2)/3). Suppose -5*f = -6*f. Put d, -3, f in decreasing order.
f, d, -3
Let w = 17 + -15. Sort -4, -2, w in increasing order.
-4, -2, w
Let k = 7 + -4. Suppose 2*n + 2 = -4*q, -n - k*q = n + 3. Let v = 2 - n. Sort v, -1, 0 in decreasing order.
v, 0, -1
Suppose 2*g - 125 = -3*g. Let i be (-2)/5 + 20/g. Put -5, 2/17, i in ascending order.
-5, 2/17, i
Let f = -0.01 - 0.49. Sort f, 0, 3 in descending order.
3, 0, f
Suppose 9 + 16 = -5*z - 5*h, -2*z + 5*h = 17. Put z, -2, 3 in decreasing order.
3, -2, z
Let b = -5.11 - -0.11. Let l = 234 + -233.6. Sort b, l, -1 in decreasing order.
l, -1, b
Let j = 0.053 + 7.747. Let v = 7.93 - -0.07. Let g = j - v. Sort -2, g, 5.
-2, g, 5
Let s be ((-11)/(-22))/(1/(-2)) - -6. Sort -1, 1, s, 2 in descending order.
s, 2, 1, -1
Let y = -9 - -12. Let o(g) = -g - 1. Let s be o(-1). Put s, y, 2 in ascending order.
s, 2, y
Suppose -6*u = -3*u. Suppose -5*n + 1 = t - u, -3*n - 3*t = -3. Suppose -2*w + 12 = 2*w. Put n, 4, w in decreasing order.
4, w, n
Suppose -4*r + r - 9 = 0. Suppose 7*j + 48 = 19*j. Put j, r, 5 in ascending order.
r, j, 5
Suppose -4*g = -30 + 10. Sort -13, -3, g in increasing order.
-13, -3, g
Let j(x) = -x**2 - 4*x + 5. Let z be j(-4). Let m(c) = c. Let a be m(3). Suppose -20 = a*b - 5. Put z, 0, b in decreasing order.
z, 0, b
Let t be 0*(4 - 33/9). Suppose -5*r + 66 = 3*v - 2*r, -5*r = -4*v + 88. Suppose -4*g + 2 = v. Sort t, g, 4 in decreasing order.
4, t, g
Suppose -4*j - v = -5*j - 4, j = 5*v - 24. Let c = 6 - 5.7. Let y = -1.7 - c. Sort y, j, 1/4 in ascending order.
y, 1/4, j
Let k = 27 + -29. Put 0.2, -2/9, k in descending order.
0.2, -2/9, k
Let o = 8 + -4. Let y = -4/29 - -110/377. Sort -0.3, o, y in decreasing order.
o, y, -0.3
Let c(p) = p**2 + 7*p + 1. Let g be c(-7). Put g, -4, 2 in decreasing order.
2, g, -4
Suppose 2*l - j - 3*j = -10, -j - 8 = 3*l. Let u = l - -5. Suppose -u*m - m = 0. Put -3, -1, m in increasing order.
-3, -1, m
Let g(l) = l**2 + 6*l - 6. Let o = -25 + 18. Let u be g(o). Sort u, -2, -4 in ascending order.
-4, -2, u
Let c(s) = -s + 2. Let r be c(4). Sort r, -1, 4 in ascending order.
r, -1, 4
Let x be ((-9)/6)/(6/10). Sort -1, -1/5, x in ascending order.
x, -1, -1/5
Let v = 14 - 15. Sort -10, v, -1/5, 4.
-10, v, -1/5, 4
Let m be (-35)/((2/4 + -1)*-2). Sort 2, -3, m in increasing order.
m, -3, 2
Let d be (-6)/(-18) - (-1)/(-3). Suppose d = -0*l - l + 5. Put -1, l, 3 in decreasing order.
l, 3, -1
Let f = 6 - 4. Let b be 8/(-12)*(f + 1). Suppose -v + 4 = -1. Sort -1, b, v in ascending order.
b, -1, v
Let c = 1.9 + -2.35. Let g = 0.05 - c. Sort -2/5, g, -2 in descending order.
g, -2/5, -2
Let i = 236/21 - 35/3. Sort 2/9, i, -0.4 in ascending order.
i, -0.4, 2/9
Let z = 29 + -25. Put -4, 1, 5, z in ascending order.
-4, 1, z, 5
Let z be (0 + 0)*4/(-4). Let b = 4 + -9. Put b, z, -3 in descending order.
z, -3, b
Let n = 1.3 + -5.3. Let m = 3.6 + n. Sort -0.5, 5, m in ascending order.
-0.5, m, 5
Let s(i) = 2*i**2 + 2*i + 1. Let r be s(-1). Let u be 4/2 + (0 - r). Put 1/3, 5, u in descending order.
5, u, 1/3
Let v = 6.16 + -0.16. Let c = 0.878 + 0.122. Sort -0.2, c, v.
-0.2, c, v
Let y = 9 - 15. Let o = 5.5 - 4.5. Put o, 0.3, y in descending order.
o, 0.3, y
Let s = 0.6 - -3.4. Let a = -2 + s. Let r = a - 2.4. Put r, 5/3, 1 in ascending order.
r, 1, 5/3
Let l = 10.72 + -11. Let j = l + -0.02. Put j, -2/9, 2 in ascending order.
j, -2/9, 2
Let s = -3/5 + 6/5. Put 3/7, -8, s, 2/11 in increasing order.
-8, 2/11, 3/7, s
Let w be -3 - (-7)/((-28)/(-48)). Let a(t) = -t**3 + 9*t**2 - t + 11. Let m be a(w). Put 4, m, 5 in increasing order.
m, 4, 5
Suppose 0 = r + r + 4*q, 5*q + 4 = -2*r. Let o(l) = 3*l + 11 + r*l + l**3 + 0*l**2 - 2*l + 9*l**2. Let j be o(-8). Sort -2/9, -3/7, j in decreasing order.
j, -2/9, -3/7
Let s = -17.4 - 0.6. Let r = 0.02 - -12.98. Let t = s + r. Sort t, -0.5, -3/8 in descending order.
-3/8, -0.5, t
Suppose 3*r = -3 - 9. Let t(d) = -d**2 + 7*d - 1. Let a be t(7). Sort 4, a, r in descending order.
4, a, r
Suppose 5*r + 20 = 0, 0 = 2*z - z + 3*r + 9. Suppose 5*d + 16 = -3*q, -3*q - z*d = 15 - 3. Sort 4, 5, q in ascending order.
q, 4, 5
Let n(s) = -s**3 + s + 3. Let p be n(0). Suppose -7 = -3*t + 8. Sort t, p, 2 in ascending order.
2, p, t
Suppose 8 = -12*t + 10*t. Put -10, 3, -1/3, t in descending order.
3, -1/3, t, -10
Let x = -13.64 - -1.64. Sort x, -0.3, 0 in increasing order.
x, -0.3, 0
Let u(o) = -3*o**3 + 4*o + 3. Let i be u(-1). Sort i, -0.3, -4, -2/17.
-4, -0.3, -2/17, i
Let n = 3 - 1. Let y(x) = -x**3 + 4*x**2 + 4. Let g be y(4). Sort -4, n, g in increasing order.
-4, n, g
Let f = 5 - 5.4. Let o = 0.6 - 0.8. Let t = -0.5 + -1.5. Put o, f, t in descending order.
o, f, t
Let w = 4.38 + -2.38. Let b = 3 - 2. Sort w, 0.2, b in ascending order.
0.2, b, w
Let c = -1.8 + 2. Let x = 3.4 + -4.4. Sort c, 0.4, x in descending order.
0.4, c, x
Suppose -7*f = -15 - 13. Sort 2, f, -4.
-4, 2, f
Let l = 1 + -1.3. Let w = -12.6 - -12.4. Let i = 43/111 - 2/37. Sort l, w, i.
l, w, i
Let k(l) = -2*l. Let q(b) = 15*b + 6. Let o(h) = -14*k(h) - 2*q(h). Let f be o(-8). Sort 5, f, 2.
2, f, 5
Let j(v) = v - 2. Let z be j(2). Suppose 0 = -5*f + 8 - 3, -3*k + 3*f - 3 = z. Let w be (-1*2 - k) + 1. Put w, 3, 2 in descending order.
3, 2, w
Let s = 0.8 + -0.7. Suppose -v - v - 6 = 0. Sort v, 1, s.
v, s, 1
Let h be (-1 + 0 - -6) + -11. Put 5, 3, h, -5 in decreasing order.
5, 3, -5, h
Let t = -21 - -22.3. Let b = 1 - t. Sort b, 1/2, -4.
-4, b, 1/2
Let v(j) be the first derivative of -j**3/3 - j**2/2 - 3. Let | 2023-10-04T01:26:59.872264 | https://example.com/article/9748 |
Q:
Help with a db_select() not returning results when it *should*
I'm having trouble figuring out why the db_select() is not returning any results. Long story short, if I pass the results of $results->execute() through a foreach ($results as $result), I don't get any results. If I take the generated SQL and go directly to command line or phpMyAdmin (substituting manually for the placeholders) I get the expected result. I feel like I have to just be overlooking something - I'm hoping fresh eyes can point it out for me.
Here is the select:
$results = db_select('product_charges_override', 'pc');
$results->join('products', 'p', 'p.product_id = pc.product_id');
$results->fields('pc', array('uid', 'product_id', 'override_count', 'redemption_count', 'coupon_code'))
->fields('p', array('human_name'))
->condition('pc.coupon_code', $coupon_code);
$results->execute();
Here is the result of dpq($results):
SELECT pc.uid AS uid, pc.product_id AS product_id, pc.override_count AS override_count, pc.redemption_count AS redemption_count, pc.coupon_code AS coupon_code, p.human_name AS human_name FROM {product_charges_override} pc INNER JOIN {products} p ON p.product_id = pc.product_id WHERE (pc.coupon_code = :db_condition_placeholder_0)
Here is the relevant Where statement from just var_dump($results):
protected 'where' =>
object(DatabaseCondition)[136]
protected 'conditions' =>
array
'#conjunction' => string 'AND' (length=3)
0 =>
array
'field' => string 'pc.coupon_code' (length=14)
'value' => string 'ugd2pl8z92j9' (length=12)
'operator' => string '=' (length=1)
protected 'arguments' =>
array
':db_condition_placeholder_0' => string 'ugd2pl8z92j9' (length=12)
protected 'changed' => boolean false
protected 'queryPlaceholderIdentifier' => string '52e7fdf78bbd25.63959182' (length=23)
public 'stringVersion' => string ' (pc.coupon_code = :db_condition_placeholder_0) ' (length=48)
And, finally, the query as I run it from the command line (notice the '{' and '}' have been removed, as well as the placeholder replaced with the value from the 'where' object). Those are the only things I replaced from the results of dpq().
SELECT pc.uid AS uid, pc.product_id AS product_id, pc.override_count AS override_count, pc.redemption_count AS redemption_count, p.human_name AS human_name FROM product_charges_override pc INNER JOIN products p ON p.product_id = pc.product_id WHERE (pc.coupon_code = 'ugd2pl8z92j9')
And an export from phpMyAdmin of the query results:
/**
* Export to PHP Array plugin for PHPMyAdmin
* @author Geoffray Warnants
* @version 0.2b
*/
//
// Database "mats_theme"
//
// mats_theme.product_charges_override
$product_charges_override = array(
array('uid'=>null,'product_id'=>7,'override_count'=>5,'redemption_count'=>0,'human_name'=>'Fleet Forum Registration')
);
A:
I'm not assigning $results->execute() to anything - that's why I can't iterate over the results. Answer was provided by a local mailing list that I sent this link to.
So, solution is $results = $results->execute(). Of course, the query should be renamed to something like, $query;
| 2024-06-11T01:26:59.872264 | https://example.com/article/9697 |
The present invention is described with respect to its use on riding lawn mowers, particularly self-propelled machines fitted with rotating blades for cutting turf grasses. In the most favored typical design, the rider sits atop a three or four wheeled machine, while one or more blades rotate about a vertical axis within a mower deck mounted at the underside of the machine, to cut grasses as the machine moves across the surface being mowed.
In many typical riding mowers, the cutter deck is configured as either a ground-following deck or a floating deck. A ground-following deck typically rides on either two or four caster wheels and follows the contours of the ground. A floating deck is hung between the front and rear wheels and beneath the chassis by chains, links or other devices, being adapted to rise up when skids, wheels, rollers and the like attached to the underside of the deck make contact the lawn surface. Generally, the intent for such deck suspension system is to avoid continuing contact with the earth surface. The distance of the cutter deck from the earth surface is determined by the elevation of the chassis. When the mower crosses an earth-surface rise which is relatively severe, that is, short in horizontal length compared to the wheel base of the mower and great in height compared to the pre-set elevation of the mower deck, the deck frequently makes contact with the earth surface. Then, it is intended that the deck rises or "floats" upwardly, so the rotary blades do not hit the earth surface. Such designs work well for many kinds of unevenness, but scalping for certain earth surfaces and mower movements is still a problem. Even if there is no scalping, a variation of the height of the cutter deck relative to the earth surface is not wanted, as it varies the height of the cut grass.
Many typical prior art mowers have the wheels rigidly attached to the chassis. Thus, unevenness in the earth surface imparts a lot of up and down chassis motion. Some prior art mowers employ center-pivoting axles which somewhat reduce the vertical motion of the chassis when one wheel encounters unevenness. The related applications describe a preferred transmission steerable mower which has rear drive wheels which are independently driven and spring suspended from the chassis, and which has free pivoting caster front wheels, mounted at the outer ends of a pivotable axle or subframe. The cutter deck is suspended between the front and rear wheels.
Mowers with improved spring suspension systems reduce the amount of chassis motion when one or both drive wheels of a mower encounter unevenness in the surface being mowed. Drive wheel traction is improved. However, depending on the particulars of any non-rigid suspension system, the chassis is enabled to roll relative to the earth surface, such as, for example, when the mower is sharply turning or when the mower is traversing a steep hillside. When a mower rolls, a floating cutter deck moves closer to the earth surface and there can be a tendency for scalping of the turf by the cutter deck. An improvement in one of the related applications connects the cutter deck with the rear wheels, thereby ensuring that the cutter deck moves relative to the wheels and ground instead of relative to the chassis of the mower.
A problem still exists with the independent suspension system of the related applications. For heavier weight riders or mower accessories, such as grass catchers, the spring used in the suspension system limits the suspension. Rider discomfort occurs when the spring bottoms out. In addition, the collapsed spring can create coil bind which drastically reduces the life of the spring. Merely substituting a stiffer spring for the existing spring causes a harder ride when the load is light. A suspension that works effectively with a wide range of weight variations is therefore needed. | 2023-12-26T01:26:59.872264 | https://example.com/article/2517 |
---
abstract: 'Spin-transfer torque (STT) provides key mechanisms for current-induced phenomena in ferromagnets. While it is widely accepted that STT involves both adiabatic and non-adiabatic contributions, their underlying physics and range of validity are quite controversial. By computing microscopically the response of conduction electron spins to a time varying and spatially inhomogeneous magnetic background, we derive the adiabatic and non-adiabatic STT in a unified fashion. Our result confirms the macroscopic theory \[Phys. Rev. Lett. **93**, 127204 (2004)\] with all coefficients matched exactly. Our derivation also reveals a benchmark on the validity of the result, which is used to explain three recent measurements of the non-adiabatic STT in quite different settings.'
author:
- Ran Cheng
- Qian Niu
title: 'Microscopic derivation of spin-transfer torque in ferromagnets'
---
The interplay between current and magnetization is currently the central topic of spintronics [@ref:Spintronics]. When a current flows through a ferromagnetic metal, it becomes spin-polarized due to local exchange coupling between conduction electron spins and local magnetic moments. In turn, spin angular momentum is transferred to magnetization through the mechanism known as spin-transfer torque (STT) [@ref:BegerSlonczewski; @ref:STT], which is a consequence of spin conservation. STT provides key mechanisms for numerous intriguing phenomena in ferromagnets, such as current-driven domain wall motion [@ref:DWDynamics1; @ref:DWDynamics2], spin wave excitations [@ref:SW1; @ref:SW2], *etc*. In both fundamental studies and device designs, STT-driven magnetization dynamics has aroused enormous attention in the past two decades [@ref:STTReview1; @ref:STTReview2], and it is becoming the core issue of spintronics. However, the fundamental physics underlying STT is far from clear.
At present, STT is believed to be divided into adiabatic (reactive) and non-adiabatic (dissipative) contributions. While the former has been derived microscopically via different approaches [@ref:BegerSlonczewski; @ref:AdiabaticSTT1], the latter has only been justified macroscopically through spin conservation [@ref:STT; @ref:Fitting; @ref:SpinMHD] and Galilean invariance [@ref:GalileonInv], whose microscopic origin is under intense debates. In many recent efforts, microscopic theories have been developed in generic ways [@ref:NonAdiabaticSTT1; @ref:NonAdiabaticSTT2; @ref:NonAdiabaticSTT3; @ref:NonAdiabaticSTT4; @ref:NonAdiabaticSTT5] and in specific contexts [@ref:MomentumTransfer; @ref:EuropModel; @ref:ClassicalModel; @ref:DWSTTModel], but their coefficients do not lead to a consensus. Meanwhile, some others even cast doubt on the existence of the non-adiabatic STT [@ref:CastDoubt]. From an experimental point of view, measurements of this torque are not in agreement [@ref:Exp1; @ref:Exp2; @ref:NarrowDW], and the magnitude is sensitive to spin-orbit interaction [@ref:Miron] and impurity doping [@ref:Lepadatu].
In this Letter, a microscopic derivation of the magnetization dynamics induced by STT is provided. Based on the *s-d* model [@ref:STT], we first calculate the response of a conduction electron spin to a time varying and spatially inhomogeneous magnetic background $\bm{M}(\bm{r},t)$, and we obtain the non-equilibrium local spin accumulation $\delta\bm{m}$ (perpendicular to $\bm{M}(\bm{r},t)$) by integration over the conduction band. Due to the exchange coupling between *s*-band electrons and *d*-band magnetic moments, the back-action exerted on $\bm{M}(\bm{r},t)$ by the current is proportional to $\delta\bm{m}\times\bm{M}$, where the adiabatic and non-adiabatic STTs naturally appear on an equal footing. Our result (Equation ) justifies the macroscopic model [@ref:STT] with all coefficients matched exactly. Our derivation also provides a benchmark on the validity of the result, which is used to explain three experimental results: why the non-adiabatic STT on narrow domain walls [@ref:NarrowDW] shows deviations from Eq. , why Eq. is still valid even when an extraordinarily large non-adiabatic STT is achieved [@ref:Miron], and why the non-adiabatic STT is enhanced by impurity doping while the damping is not affected [@ref:Lepadatu].
We adopt the *s-d* model where electron transport is due to the itinerant *s*-band. It will be treated separately from the magnetization, which mostly originates from the localized *d*-band. The conduction electrons interact with the magnetization through the exchange coupling described by the following Hamiltonian $$\begin{aligned}
H_{ex}=\frac{SJ_{ex}}{M_s}\bm{s}\cdot\bm{M}(\bm{r},t) \label{eq:Hamiltonian}:\end{aligned}$$ where $\bm{s}$ is the (dimensionless) spin of a conduction electron, $|\bm{M}(\bm{r},t)|=M_s$ is the saturation magnetization, and $S$ denotes the magnitude of background spins. The coupling strength $J_{ex}$ can be as large as an $\mathrm{eV}$ in transition metals and their alloys, so that if $\bm{M}(\bm{r},t)$ varies slowly in space and time, conduction electron spins will follow the background profile when the system is in thermal equilibrium, which is known as the adiabatic limit. However, when an external current is applied to the system, a small non-equilibrium spin accumulation $\delta\bm{m}$ transverse to local $\bm{M}(\bm{r},t)$ is induced. It is this $\delta\bm{m}$ that exerts STT on the background magnetization.
To compute $\delta\bm{m}$, we first study the spin response of an individual conduction electron to the background $\bm{M}(\bm{r},t)$ when current is applied. From Eq. , we know that *local* spin-up (majority) and spin-down (minority) bands are separated by a large gap $\Delta\equiv SJ_{ex} =\mathcal{E}_{\downarrow}-\mathcal{E}_{\uparrow}$, and the associated spin wave functions are denoted by $|\!\uparrow\!(\bm{r},t)\rangle$ and $|\!\downarrow\!(\bm{r},t)\rangle$. The electron is described by a coherent wave packet centered at $(\bm{r}_c,\bm{k}_c)$ [@ref:Niu; @ref:Ran] $$\begin{aligned}
|W\rangle=\!\int\mathrm{d}^3\bm{k}\ w(\bm{k})e^{i\bm{k}\cdot\bm{r}}|\bm{k}\rangle[c_a|\!\uparrow\!(\bm{r}_c,t)\rangle+c_b|\!\downarrow\!(\bm{r}_c,t)\rangle],\end{aligned}$$ where $w(\bm{k})$ is a profile function that satisfies $\int\mathrm{d}\bm{k}\bm{k}|w(\bm{k})|^2=\bm{k}_c$; $|\bm{k}\rangle$ is the periodic part of the *local* Bloch function; and $c_a$, $c_b$ are superposition coefficients. Since $|\!\uparrow\!(\bm{r}_c,t)\rangle$ and $|\!\downarrow\!(\bm{r}_c,t)\rangle$ form a set of local spin bases with the quantization axis being $\bm{n}(\bm{r}_c,t)=\bm{M}(\bm{r}_c,t)/M_s$, we can construct a local frame moving with $\bm{M}(\bm{r}_c,t)$, where the coordinates are labeled by $\bm{n}$, $\hat{e}_{\theta}$, and $\hat{e}_{\phi}$ in Fig. \[Fig:Spin\]. The electron spin expressed in this local frame reads $$\begin{aligned}
\bm{s}&=\{s_1, s_2, s_3\}=\eta^{\dagger}\bm{\sigma}\eta \notag\\
&=\{2\mathrm{Re}(c_a c_b^*),\ -2\mathrm{Im}(c_a c_b^*),\ |c_a|^2-|c_b|^2\}, \label{eq:localspin}\end{aligned}$$ where $\bm{\sigma}$ is a vector of Pauli matrices, and $\eta=[c_a,c_b]^{\mathrm{T}}$ is regarded as the spin wave function in the local basis.
![(Color online) Eigenstates of Eq. form a set of local spin bases, and define a local frame that moves with $\bm{n}=\bm{M}/M_s$. Components of the conduction electron spin $\bm{s}$ (red) in the local frame are denoted by $s_1$, $s_2$, and $s_3$. In the tangential plane with normal $\bm{n}$, we make a coordinate transformation from $\hat{e}_\theta$ and $\hat{e}_\phi$ to $\dot{\bm{n}}$ and $\bm{n}\times\dot{\bm{n}}$ so that everything expressed in the new basis is physical. \[Fig:Spin\]](Spin.eps){width="0.95\linewidth"}
The equations of motion are obtained from the universal Lagrangian $L=\langle W|i\hbar\partial_t-H|W\rangle$ through the variational principle [@ref:Niu], which involves not only the dynamics of $\bm{r}_c$ and $\bm{k}_c$, but also the dynamics between the two (well separated) spin bands. The latter represents spin evolution with respect to the local magnetization $\bm{M}(\bm{r},t)$ and exhibits fast rotating character due to the large gap $\Delta$. It should be distinguished with adiabatic dynamics between degenerate bands [@ref:Ran]. Due to the space-time dependence of the local spin basis, Berry gauge connections are induced in the effective Lagrangian (Appendix A) $$\begin{aligned}
L=i\hbar\eta^{\dagger}\dot{\eta}+\eta^\dagger[\dot{\bm{r}}_c\!\cdot\!\bm{A}+\Phi]\eta+\hbar\bm{k}_c\!\cdot\!\dot{\bm{r}}_c-\frac12s_3\Delta-\mathcal{E}_0, \label{eq:Lagrangian}\end{aligned}$$ where $\mathcal{E}_0=\frac12(\mathcal{E}_{\uparrow}(\bm{k}_c)+\mathcal{E}_{\downarrow}(\bm{k}_c))$ denotes the average value of local band energy; the gap $\Delta$ couples only with $s_3$, which resembles a *local* Zeeman energy. The Berry connections have both a spatial component, $$\begin{aligned}
\bm{A}=i\hbar
\begin{bmatrix}
\langle\ \uparrow|\nabla|\uparrow\ \rangle && \langle\ \uparrow|\nabla|\downarrow\ \rangle \\
\langle\ \downarrow|\nabla|\uparrow\ \rangle && \langle\ \downarrow|\nabla|\downarrow\ \rangle
\end{bmatrix}\end{aligned}$$ as a vector potential (note that $\nabla=\frac{\partial}{\partial\bm{r}_c}$), and temporal component, $$\begin{aligned}
\Phi=i\hbar
\begin{bmatrix}
\langle\ \uparrow|\partial_t|\uparrow\ \rangle && \langle\ \uparrow|\partial_t|\downarrow\ \rangle \\
\langle\ \downarrow|\partial_t|\uparrow\ \rangle && \langle\ \downarrow|\partial_t|\downarrow\ \rangle
\end{bmatrix}\end{aligned}$$ as a scalar potential. The local spin wave functions are taken to be $|\!\uparrow\rangle=[e^{-i\frac{\phi}2}\cos\frac{\theta}2, \ e^{i\frac{\phi}2}\sin\frac{\theta}2]^\mathrm{T}$ and $|\!\downarrow\rangle=[-e^{-i\frac{\phi}2}\sin\frac{\theta}2, \ e^{i\frac{\phi}2}\cos\frac{\theta}2]^\mathrm{T}$, where $\theta=\theta(\bm{r}_c,t)$ and $\phi=\phi(\bm{r}_c,t)$ are spherical angles specifying the direction of $\bm{M}(\bm{r}_c,t)$, whose total time derivatives are $\dot{\theta}=\dot{\bm{r}}_c\cdot\nabla\theta+\partial_t\theta$ and $\dot{\phi}=\dot{\bm{r}}_c\cdot\nabla\phi+\partial_t\phi$. Then the Berry connection terms can be unified into a $2\times2$ matrix $$\begin{aligned}
\dot{\bm{r}}_c\!\cdot\!\bm{A}+\Phi=\frac{\hbar}2
\begin{bmatrix}
\cos\theta\dot{\phi} && -\sin\theta\dot{\phi}-i\dot{\theta}\ \\
-\sin\theta\dot{\phi}+i\dot{\theta} && -\cos\theta\dot{\phi}
\end{bmatrix}.\end{aligned}$$ It is worth mentioning that freedom exists in the choice of local spin wave functions, which leads to the gauge freedom of the Berry gauge connection. More graphically, a specified set of spin wave functions corresponds to a particular choice of local frame in Fig. \[Fig:Spin\], and the relative orientation of the local frame can be rotated about $\bm{n}$ by gauge transformations, thus is not physical. But everything will be expressed in terms of gauge invariant quantities in the end.
Regarding Eq. , the spin dynamics is obtained through the variational principle $\delta L/\delta\eta=0$. After some manipulations (Appendix B) we obtain $$\begin{aligned}
\begin{bmatrix}
\dot{s}_1\\ \dot{s}_2\\ \dot{s}_3
\end{bmatrix}
\!=\!\begin{bmatrix}
0 & \cos\theta\dot{\phi}-\dfrac1{\tau_{_{ex}}} & -\dot{\theta} \\
-\cos\theta\dot{\phi}+\dfrac1{\tau_{_{ex}}} & 0 & -\sin\theta\dot{\phi} \\
\dot{\theta} & \sin\theta\dot{\phi} & 0
\end{bmatrix}\!
\begin{bmatrix}
s_1\\ s_2\\ s_3
\end{bmatrix}, \label{eq:spindynamics}\end{aligned}$$ where $\tau_{_{ex}}=\hbar/\Delta$ is defined as the exchange time. Eq. describes the coherent spin dynamics in the local frame moving with $\bm{M}(\bm{r}_c,t)$. However, spin relaxation as a non-coherent process should also be taken into account. In real materials spin relaxation is very case dependent, but regardless of the underlying mechanism, it adds a term $-\frac1{\tau_{sf}}(\bm{s}-\bm{s}_{eq})$ to Eq. , where $\tau_{sf}$ is the mean spin-flip time and $\bm{s}_{eq}=\{0,0,1(-1)\}$ is the local equilibrium spin configuration for the majority (minority) band $\mathcal{E}_{\uparrow}(\mathcal{E}_{\downarrow})$. Eq. should be solved numerically in general, but an approximation can be made based upon the following considerations: the large gap $\Delta$ results in an extremely small $\tau_{_{ex}}$ (typically of the order of $10^{-14}\sim10^{-15}s$). Thus on the time scale marked by $\tau_{_{ex}}$, the change of magnetization is negligible, *i.e.*, magnitudes of $\partial_t\bm{M}$ and $(\dot{\bm{r}}_c\!\cdot\!\nabla)\bm{M}$ are much smaller than $M_s/\tau_{ex}$. To this end, we define two small parameters $\varepsilon_1=\tau_{ex}\sin\theta\dot{\phi}$ and $\varepsilon_2=\tau_{ex}\dot{\theta}$ which satisfy $\sqrt{\varepsilon_1^2+\varepsilon_2^2}=\hbar|\dot{\bm{M}}|/(M_s\Delta)\ll1$. On the same time scale, variations of $\varepsilon_1$ and $\varepsilon_2$ are even higher order small quantities, thus it is a good approximation to treat $\varepsilon_1$ and $\varepsilon_2$ as constants, by which Eq. becomes a set of first order differential equations with a constant coefficient matrix. As a result, it can be solved analytically. Given the initial condition $\bm{s}=\bm{s}_{eq}$, the solution of Eq. for the majority band is obtained in its original form in Appendix B, which, when maintaining up to the lowest order in $\varepsilon_{1,2}$, becomes the following:
\[eq:solutions\] $$\begin{aligned}
s_1(t)&=\frac{\varepsilon_1-\xi\varepsilon_2}{1+\xi^2}-\frac{e^{-\xi\tilde{t}}}{1+\xi^2}[\varepsilon_1(\cos\tilde{t}+\xi\sin\tilde{t}) +\varepsilon_2(\sin\tilde{t}-\xi\cos\tilde{t})], \\
s_2(t)&=-\frac{\xi\varepsilon_1+\varepsilon_2}{1+\xi^2}-\frac{e^{-\xi\tilde{t}}}{1+\xi^2}[\varepsilon_1(\sin\tilde{t}-\xi\cos\tilde{t}) -\varepsilon_2(\cos\tilde{t}+\xi\sin\tilde{t})], \\
s_3(t)&=1+\frac{e^{-\xi\tilde{t}}}{1+\xi^2}(\varepsilon_1^2+\varepsilon_2^2)[\cos\tilde{t}+\xi\sin\tilde{t}],\end{aligned}$$
where $\tilde{t}=t/\tau_{_{ex}}$ is the scaled time, and $\xi=\tau_{ex}/\tau_{sf}$ (this is usually known as the $\beta$ parameter in the literature).
As stated above, magnetization dynamics occurs on a time scale $T$ much larger than $\tau_{ex}$, thus the number $N=T/\tau_{ex}\gg1$. This allows us to take a time average of the electron spin by defining $\langle s_i\rangle=\frac{1}{T}\int_0^Ts_i(t)\mathrm{d}t$. Then all time dependent terms in Eq. will be negligible, because according to the following expressions
\[eq:approximation\] $$\begin{aligned}
&\frac{1}{T}\int_0^T\mathrm{d}t\ e^{-\xi\tilde{t}}\cos\tilde{t}=\frac{\xi+e^{-N\xi}(\sin N-\xi\cos N)}{N(1+\xi^2)} \notag\\
&\qquad\qquad\qquad<\frac{1}{N}\left[\frac{\xi+\sqrt{1+\xi^2}}{1+\xi^2}\right]\le\frac{1}{N}\frac{3\sqrt{3}}{4}, \\
&\frac{1}{T}\int_0^T\mathrm{d}t\ e^{-\xi\tilde{t}}\sin\tilde{t}=\frac{1-e^{-N\xi}(\xi\sin N+\cos N)}{N(1+\xi^2)} \notag\\
&\qquad\qquad\qquad<\frac{1}{N}\left[\frac{1+\sqrt{1+\xi^2}}{1+\xi^2}\right]\le\frac{2}{N},\end{aligned}$$
no matter how large $\xi$ is, their upper bounds are suppressed by $N\gg1$. Thus only time-independent terms of Eq. survive after the time averaging:
\[eq:averagespin\] $$\begin{aligned}
\langle s_1\rangle&=\frac{\varepsilon_1-\xi\varepsilon_2}{1+\xi^2}, \\
\langle s_2\rangle&=-\frac{\xi\varepsilon_1+\varepsilon_2}{1+\xi^2}, \\
\langle s_3\rangle&=1.\end{aligned}$$
If we write the spin as $\bm{s}=\bm{s}_{eq}+\delta\bm{s}$, then $\delta\bm{s}=\langle s_1\rangle\hat{e}_\theta+\langle s_2\rangle\hat{e}_\phi$. For the minority band, Eq. only differs by an overall minus sign. To express $\delta\bm{s}$ in terms of gauge invariant quantities, we need to make a coordinate transformation which corresponds to a rotation of basis in the tangential plane depicted in Fig. \[Fig:Spin\] $$\begin{aligned}
\begin{bmatrix}
\dot{\bm{n}} \\ \bm{n}\times\dot{\bm{n}}
\end{bmatrix}
=\frac{\Omega}{\tau_{ex}}
\begin{bmatrix}
\varepsilon_2 & \varepsilon_1 \\
-\varepsilon_1 & \varepsilon_2
\end{bmatrix}
\begin{bmatrix}
\hat{e}_\theta \\ \hat{e}_\phi
\end{bmatrix},\end{aligned}$$ where $\Omega=|\dot{\bm{n}}|$. Then we obtain $$\begin{aligned}
\delta\bm{s}_{\uparrow,\downarrow}&=\mp\frac{\tau_{ex}}{1+\xi^2}[\bm{n}\times\dot{\bm{n}}+\xi\dot{\bm{n}}] \notag\\
&=\mp\frac{\tau_{ex}}{1+\xi^2}[\bm{n}\times\frac{\partial\bm{n}}{\partial t}+\xi\frac{\partial\bm{n}}{\partial t} \notag\\
&\qquad\qquad\qquad +\bm{n}\times(\dot{\bm{r}}_c\!\cdot\!\nabla)\bm{n}+\xi(\dot{\bm{r}}_c\!\cdot\!\nabla)\bm{n}], \label{eq:delspin}\end{aligned}$$ where $\dot{\bm{n}}=\partial_t\bm{n}+(\dot{\bm{r}}_c\!\cdot\!\nabla)\bm{n}$ has been used and $\dot{\bm{r}}_c=-\frac{\partial\mathcal{E}_{\uparrow,\downarrow}}{\hbar\partial\bm{k}_c}$ is the center of mass velocity. The local non-equilibrium spin accumulation is obtained by integration $$\begin{aligned}
\delta\bm{m}=\mu_B\int\mathrm{d}\mathcal{E}[\mathscr{D}_{\uparrow}(\mathcal{E})g_{\uparrow}(\mathcal{E})\delta\bm{s}_{\uparrow}+\mathscr{D}_{\downarrow}(\mathcal{E})g_{\downarrow}(\mathcal{E})\delta\bm{s}_{\downarrow}], \label{eq:delm}\end{aligned}$$ where $\mu_B$ is the Bohr magneton, $\mathscr{D}_{\uparrow,\downarrow}(\mathcal{E})$ is the density of states, and $g_{\uparrow,\downarrow}(\mathcal{E})$ represents the distribution function. In a weak electric field $\bm{E}$ and zero temperature, we have $g_{\uparrow,\downarrow}(\mathcal{E})=f_{0\uparrow,\downarrow}(\mathcal{E})+e\tau_{0\uparrow,\downarrow}\bm{E}\!\cdot\!\frac{\partial \mathcal{E}_{\uparrow,\downarrow}}{\hbar\partial\bm{k}_c}\frac{\partial f_{0\uparrow,\downarrow}}{\partial \mathcal{E}}$ where $f_{0\uparrow,\downarrow}(\mathcal{E})$ is the Fermi distribution function without electric field and $\tau_{0\uparrow,\downarrow}$ is the relaxation time. It should be noted that when the mean spin-flip time $\tau_{sf}$ is assumed to be independent of energy, it is equivalent to introducing it either in solving the Boltzmann equation or in Eq. , and we have chosen the latter. Our target now is to relate $\delta\bm{m}$ to the charge current $$\begin{aligned}
\bm{j}_e=-\frac{e}{\hbar}\int\delta\mathcal{E}\left[\mathscr{D}_{\uparrow}(\mathcal{E})g_{\uparrow}(\mathcal{E})\frac{\partial\mathcal{E}_{\uparrow}}{\partial\bm{k}_c} +\mathscr{D}_{\downarrow}(\mathcal{E})g_{\downarrow}(\mathcal{E})\frac{\partial\mathcal{E}_{\downarrow}}{\partial\bm{k}_c}\right]. \notag\end{aligned}$$ Regarding Eq. and Eq. , terms involving electric field $\bm{E}$ and $\tau_{0\uparrow,\downarrow}$ can be expressed in terms of $\bm{j}_e$. After some simple algebra, we obtain $$\begin{aligned}
\delta\bm{m}&=\frac{\tau_{ex}}{1+\xi^2}\left[-\frac{n_0}{M_s^2}\bm{M}\times\frac{\partial\bm{M}}{\partial t}-\frac{\xi n_0}{M_s}\frac{\partial\bm{M}}{\partial t}\right. \notag\\
&\left.+\frac{\mu_B P}{eM_s^2}\bm{M}\times (\bm{j}_e\cdot\nabla)\bm{M}+\frac{\xi\mu_B P}{eM_s}(\bm{j}_e\cdot\nabla)\bm{M}\right], \label{eq:centralresult}\end{aligned}$$ where $P=(n_{\uparrow}^{F}-{n_\downarrow}^{F})/(n_{\uparrow}^{F}+{n_\downarrow}^{F})$ is the spin polarization with $n_{\uparrow(\downarrow)}^{F}$ being the electron density of the two bands at the Fermi level, and $n_0=\mu_B\int\mathrm{d}\mathcal{E}[\mathscr{D}_{\uparrow}(\mathcal{E})f_{0\uparrow}(\mathcal{E})-\mathscr{D}_{\downarrow}(\mathcal{E})f_{0\downarrow}(\mathcal{E})]$ is the local equilibrium spin density of conduction electrons, which represents the *s*-band contribution to the total magnetization. For the *s-d* model, the magnetization is mainly attributed to the *d*-band electrons, thus the ratio $n_0/M_s$ should be very small. For example, in typical ferromagnetic metals (Fe, Co, Ni and their alloys), $n_0/M_s\sim10^{-2}$. Eq. reproduces Eq. (8) in Ref. \[\], but the above derivation is purely microscopic, and the four terms of Eq. can be traced back to the four terms in Eq. , respectively.
From Eq. , the STT exerted on the background magnetization $\bm{M}(\bm{r},t)$ is $\bm{T}=(1/\tau_{_{ex}}M_s)\delta\bm{m}\times\bm{M}$, which should be added to the Landau-Lifshitz-Gilbert equation: $\partial\bm{M}/\partial t=\gamma\mathrm{\bm{H}}_{_{eff}}\times\bm{M}+(\alpha/M_s)\bm{M}\times\partial\bm{M}/\partial t+\bm{T}$, where $\gamma$ is the gyromagnetic ratio, $\mathrm{\bm{H}}_{_{eff}}$ is the effective magnetic field, and $\alpha$ is the Gilbert damping parameter. The final form of magnetization dynamics becomes $$\begin{aligned}
\frac{\partial\bm{M}}{\partial t}&=\tilde{\gamma}\mathrm{\bm{H}}_{_{eff}}\times\bm{M}+\frac{\tilde{\alpha}}{M_s}\bm{M}\times\frac{\partial\bm{M}}{\partial t} \notag\\
&\quad+\frac{1}{1+\eta}\left[(\bm{u}\cdot\nabla)\bm{M}-\xi\frac{\bm{M}}{M_s}\times(\bm{u}\cdot\nabla)\bm{M}\right], \label{eq:finalresult}\end{aligned}$$ where $\bm{u}=P\bm{j}_e\mu_B/eM_s(1+\xi^2)$ is the effective electron velocity, and $\eta=(n_0/M_s)/(1+\xi^2)$ is a dimensionless factor. The renormalized gyromagnetic ratio and Gilbert damping parameter are $$\begin{aligned}
\tilde{\gamma}=\frac{\gamma}{1+\eta},\quad\tilde{\alpha}=\frac1{1+\eta}[\alpha+\eta\xi], \label{eq:renormalize}\end{aligned}$$ where the renormalization originates from the first two terms of Eq. (or Eq. ), and they are determined by the local equilibrium spin density $n_0$ which exists even in the absence of current. Eqs. and confirm the results of previous macroscopic theory [@ref:STT].
Our microscopic derivation relies on two assumptions: local equilibrium can be defined, and $\bm{M}$ is nearly constant on the time scale marked by $\tau_{ex}$. The former requires diffusive transport which is usually the case in transition metals and their alloys; the latter, however, is only true when the characteristic length of the texture $l$ (*e.g.*, the domain wall width) satisfies $l\gg v_F\tau_{ex}$ where $v_F$ is the Fermi velocity, otherwise the solution Eqs. and are invalid. In a recent experiment [@ref:NarrowDW], people measured the non-adiabatic torque on very narrow domain walls ($1\sim10\mathrm{nm}$) and found disagreement with Eq. . A rough estimate using $v_F\sim3\times10^5\mathrm{m/s}$ and $\Delta\sim1\mathrm{eV}$ tells us that $v_F\tau_{ex}$ is of the order of many angstroms, thus a domain wall of a few $\mathrm{nm}$ wide cannot be considered as $l\gg v_F\tau_{ex}$. In that case, our local solution is no longer a good approximation, because the time-dependent terms in Eq. become important and the averaging in Eq. is no longer good. As a result, STT may exhibit non-local behavior and also oscillatory patterns in space.
The parameter $\xi$ determines the relative strength of the non-adiabatic torque with respect to the adiabatic torque. It is very material dependent and tunable in many different ways [@ref:Miron; @ref:Lepadatu]. But according to Eq. and Eq. , the result is valid *regardless* of the value of $\xi$; only $N=T/\tau_{ex}\gg1$ is sufficient to guarantee the negligence of the time dependent terms of Eq. . This can be used to explain a recent experiment in which $\xi$ is as large as $1$ [@ref:Miron], while the observed domain wall velocity is still fitted using the form of Eq. . However, we should mention that large $\xi$ is usually accompanied by large spin-orbit coupling, which brings about spin-orbit torque in addition to the non-adiabatic torque [@ref:SOTorque1; @ref:SOTorque2]. This is an important issue that draws people’s attention very recently, but goes beyond the scope of this paper.
In another experiment, $\xi$ is enhanced by increasing impurity doping (which decreases $\tau_{sf}$), but the damping is basically not affected [@ref:Lepadatu]. This can be easily understood through Eq. : since $n_0/M_s\sim10^{-2}$ is very small within the *s-d* model description, $\eta$ is a small quantity, hence $\tilde{\alpha}$ could only be slightly renormalized even if $\xi$ has a sizable change.
A final remark concerns the spin motive force [@ref:Shengyuan] $\bm{E}_{SMF}=\frac{\hbar}{2e}\bm{n}\cdot(\partial_t\bm{n}\times\nabla\bm{n})$, which is small but should be taken into consideration in a strict sense. As a result, the electric field should be replaced by the effective field $\bm{E}_{eff}=\bm{E}+\bm{E}_{SMF}$ in deriving Eq. from Eqs. and . This creates an additional contribution to the renormalized $\tilde{\alpha}$, which has been studied recently via a quite different route [@ref:GenDamping].
We thank Maxim Tsoi, Elaine Li, Allan MacDonald, Xiao Li, Gregory Fiete, and Karin Everschor for helpful discussions. This work is supported by DOE (DE-FG03-02ER45958, Division of Materials Science and Engineering), the MOST Project of China (2012CB921300), NSFC (91121004), and the Welch Foundation (F-1255).
Set $|u\rangle=c_a|\!\uparrow\!(\bm{r}_c,t)\rangle+c_b|\!\downarrow\!(\bm{r}_c,t)\rangle$, the wave packet is $|W\rangle=\!\int\!\mathrm{d}^3\bm{k}w(\bm{k})e^{i\bm{k}\cdot\bm{r}}|\bm{k}\rangle|u\rangle$, where $w(\bm{k})$ is the profile function satisfying two conditions: $\int\mathrm{d}\bm{k}|w(\bm{k})|^2=1$ and $\int\mathrm{d}\bm{k}\bm{k}|w(\bm{k})|^2=\bm{k}_c$ with $\bm{k}_c$ being the center of mass momentum. Then following a quite standard procedure [@ref:Niu], the effective Lagrangian becomes $$\begin{aligned}
L=i\hbar\langle u|\frac{\mathrm{d}u}{\mathrm{d}t}\rangle+\hbar\bm{k}_c\cdot\dot{\bm{r}}_c-\langle u|H_{ex}|u\rangle.\end{aligned}$$ Due to the orthogonality $\langle\uparrow|\downarrow\rangle=0$, the energy term becomes $\langle u|H_{ex}|u\rangle=|c_a|^2\mathcal{E}_{\uparrow}+|c_b|^2\mathcal{E}_{\downarrow}$. From Eq. , we known that $s_3=|c_a|^2-|c_b|^2$ and $|c_a|^2+|c_b|^2=1$, thus we have the following: $$\begin{aligned}
\langle u|H_{ex}|u\rangle &=\frac{1+s_3}2\mathcal{E}_{\uparrow}+\frac{1-s_3}2\mathcal{E}_{\downarrow} \notag\\ &=\frac{\mathcal{E}_{\uparrow}+\mathcal{E}_{\downarrow}}2+s_3\frac{\mathcal{E}_{\uparrow}-\mathcal{E}_{\downarrow}}2=\mathcal{E}_0+\frac12s_3\Delta. \label{eq:energy}\end{aligned}$$ To compute the Berry connection term, we notice that $$\begin{aligned}
|\frac{\mathrm{d}u}{\mathrm{d}t}\rangle=&\dot{c}_a|\uparrow\rangle+\dot{c}_b|\downarrow\rangle \notag\\
&+\left[c_a(\dot{\bm{r}}_c\!\cdot\!\nabla+\partial_t)|\uparrow\rangle+c_b(\dot{\bm{r}}_c\!\cdot\!\nabla+\partial_t)|\downarrow\rangle\right],\end{aligned}$$ where $\nabla=\frac{\partial}{\partial\bm{r}_c}$. Multiply by $\langle u|$ we have $$\begin{aligned}
\langle &u|\frac{\mathrm{d}u}{\mathrm{d}t}\rangle=(c_a^*\dot{c}_a+c_b^*\dot{c}_b) \notag\\
&+|c_a|^2\langle\uparrow|\dot{\bm{r}}_c\!\cdot\!\nabla +\partial_t|\uparrow\rangle+c_a^*c_b\langle\uparrow|\dot{\bm{r}}_c\!\cdot\!\nabla+\partial_t|\downarrow\rangle \notag\\
&+|c_b|^2\langle\downarrow|\dot{\bm{r}}_c\!\cdot\!\nabla+\partial_t|\downarrow\rangle +c_ac_b^*\langle\downarrow|\dot{\bm{r}}_c\!\cdot\!\nabla+\partial_t|\uparrow\rangle.
\label{eq:udu}\end{aligned}$$ Now define the Berry connection ($2\times2$) matrices $$\begin{aligned}
\bm{A}(\bm{r}_c,t)=i\hbar
\begin{bmatrix}
\langle\ \uparrow|\nabla|\uparrow\ \rangle && \langle\ \uparrow|\nabla|\downarrow\ \rangle \\
\langle\ \downarrow|\nabla|\uparrow\ \rangle && \langle\ \downarrow|\nabla|\downarrow\ \rangle
\end{bmatrix}, \label{eq:connA}
\\
\Phi(\bm{r}_c,t)=i\hbar
\begin{bmatrix}
\langle\ \uparrow|\partial_t|\uparrow\ \rangle && \langle\ \uparrow|\partial_t|\downarrow\ \rangle \\
\langle\ \downarrow|\partial_t|\uparrow\ \rangle && \langle\ \downarrow|\partial_t|\downarrow\ \rangle
\end{bmatrix},
\label{eq:connPhi}\end{aligned}$$ which play the roles of a vector potential and a scalar potential, respectively. From Eqs. , , , and we obtain the effective Lagrangian, $$\begin{aligned}
L=i\hbar\eta^{\dagger}\dot{\eta}+\eta^\dagger[\dot{\bm{r}}_c\!\cdot\!\bm{A}+\Phi]\eta+\hbar\bm{k}_c\!\cdot\!\dot{\bm{r}}_c-\frac12s_3\Delta-\mathcal{E}_0,\end{aligned}$$ where $\eta=[c_a,c_b]^{\mathrm{T}}$, thus Eq. is justified. The local spin wave functions are chosen to be $$\begin{aligned}
|\uparrow\ \rangle=
\begin{bmatrix}
e^{-i\frac{\phi}2}\cos\frac{\theta}2\\
e^{i\frac{\phi}2}\sin\frac{\theta}2
\end{bmatrix},\qquad
|\downarrow\ \rangle=
\begin{bmatrix}
-e^{-i\frac{\phi}2}\sin\frac{\theta}2\\
e^{i\frac{\phi}2}\cos\frac{\theta}2
\end{bmatrix},
\label{eq:spinwavefunctions}\end{aligned}$$ where $\theta$ and $\phi$ are spherical angles specifying the direction of local magnetization $\bm{M}(\bm{r},t)$, hence they are functions of space and time. Using Eq. , the Berry connections and can be written in a unified $2\times2$ matrix, $$\begin{aligned}
\mathscr{A}(\bm{r}_c,t)&\equiv\dot{\bm{r}}_c\!\cdot\!\bm{A}(\bm{r}_c,t)+\Phi(\bm{r}_c,t) \notag\\
&=\frac{\hbar}2
\begin{bmatrix}
\cos\theta\dot{\phi} && -\sin\theta\dot{\phi}-i\dot{\theta}\ \\
-\sin\theta\dot{\phi}+i\dot{\theta} && -\cos\theta\dot{\phi}
\end{bmatrix},\end{aligned}$$ where $\dot{\theta}=\dot{\bm{r}}_c\cdot\nabla\theta+\partial_t\theta$ and $\dot{\phi}=\dot{\bm{r}}_c\cdot\nabla\phi+\partial_t\phi$ are total time derivatives. It should be noted that the choice of Eq. is not unique, which gives rise to the gauge freedom of the Berry potential.
Decomposing the Berry potential $\mathscr{A}$ in terms of Pauli matrices $\mathscr{A}=\sigma_i\mathcal{A}_i$ (adjoint representation), we have $$\begin{aligned}
\{\mathcal{A}_1,\mathcal{A}_2,\mathcal{A}_3\}= \frac12\mathrm{Tr}[\bm{\sigma}\mathscr{A}]=\frac12\{-\sin\theta\dot{\phi},\ \dot{\theta},\ \cos\theta\dot{\phi}\}, \label{eq:adjointA}\end{aligned}$$ where $\mathrm{Tr}[\sigma_i\sigma_j]=2\delta_{ij}$ has been used.
Taking the variation of the Lagrangian with respect to $\eta$, we obtain the evolution of the spin wave function in the local frame, $$\begin{aligned}
i\hbar\dot{\eta}=
i\hbar\frac{\mathrm{d}}{\mathrm{d}t}
\begin{bmatrix}
c_a \\ c_b
\end{bmatrix}
=-\mathscr{A}
\begin{bmatrix}
c_a \\ c_b
\end{bmatrix}+\frac{\Delta}2
\begin{bmatrix}
c_a \\ -c_b
\end{bmatrix}. \label{eq:etadyn}\end{aligned}$$ From Eq. and its complex conjugate, we derive spin dynamics in the local frame $$\begin{aligned}
i\hbar\frac{\mathrm{d}}{\mathrm{d}t}\bm{s}&=i\hbar\frac{\mathrm{d}}{\mathrm{d}t}(\eta^\dagger\bm{\sigma}\eta) =i\hbar(\dot{\eta}^\dagger\bm{\sigma}\eta+\eta^\dagger\bm{\sigma}\dot{\eta}) \notag\\
&=(\eta^\dagger\mathscr{A}\bm{\sigma}\eta-\eta^\dagger\bm{\sigma}\mathscr{A}\eta) \notag\\
&\qquad+\frac{\Delta}{2}\left([-c_a^*,c_b^*]\bm{\sigma}\eta+\eta^\dagger\bm{\sigma}
\begin{bmatrix}
c_a \\ -c_b
\end{bmatrix}\right)
\label{eq:ds}.\end{aligned}$$ To put Eq. into a simple and elegant form, we should write it down component by component. The third component of Eq. reads: $$\begin{aligned}
i\hbar\dot{s}_3&=\eta^\dagger \mathcal{A}_i[\sigma_i,\sigma_3] \eta+\frac{\Delta}{2}(-|c_a|^2-|c_b|^2+|c_a|^2+|c_b|^2) \notag\\
&=-2i\hbar\eta \varepsilon_{3ij}\mathcal{A}_i\sigma_j \eta+0 = 2i\hbar \varepsilon_{3ij}s_i\mathcal{A}_j, \label{s3}\end{aligned}$$ where $\varepsilon_{ijk}$ is the total antisymmetric tensor. The first component reads: $$\begin{aligned}
i\hbar\dot{s}_1&=\eta^\dagger \mathcal{A}_i[\sigma_i,\sigma_1] \eta+\Delta(c_ac_b^*-c_a^*c_b) \notag\\
&=-2i\hbar\eta \varepsilon_{1ij}\mathcal{A}_i\sigma_j \eta+2i\Delta\mathrm{Im}[c_ac_b^*] \notag\\
&= 2i\hbar\varepsilon_{1ij} s_i\mathcal{A}_j-i\Delta s_2, \label{s1}\end{aligned}$$ and the second component reads: $$\begin{aligned}
i\hbar\dot{s}_2&=\eta^\dagger \mathcal{A}_i[\sigma_i,\sigma_2] \eta+i\Delta(c_ac_b^*+c_a^*c_b) \notag\\
&=-2i\hbar\eta \varepsilon_{2ij}\mathcal{A}_i\sigma_j \eta+2i\Delta\mathrm{Re}[c_ac_b^*] \notag\\
&= 2i\hbar\varepsilon_{2ij} s_i\mathcal{A}_j +i\Delta s_1. \label{s2}\end{aligned}$$ Now we are able to combine Eqs. , , in a matrix form: $$\begin{aligned}
\begin{bmatrix}
\dot{s}_1\\ \dot{s}_2\\ \dot{s}_3
\end{bmatrix}
\!=\!\begin{bmatrix}
0 & \cos\theta\dot{\phi}-\dfrac{\Delta}{\hbar} & -\dot{\theta} \\
-\cos\theta\dot{\phi}+\dfrac{\Delta}{\hbar} & 0 & -\sin\theta\dot{\phi} \\
\dot{\theta} & \sin\theta\dot{\phi} & 0
\end{bmatrix}\!
\begin{bmatrix}
s_1\\ s_2\\ s_3
\end{bmatrix}, \label{eq:derivecentral}\end{aligned}$$ where Eq. has been used. Define $\tau_{ex}=\hbar/\Delta$ as the exchange time, Eq. is justified.
As $\sin\theta\dot{\phi}$, $\cos\theta\dot{\phi}$, and $\dot{\theta}$ can be treated as constants on the time scale marked by $\tau_{ex}$, Eq. can be solved analytically. Adding the relaxation term, the solution is obtained upon the initial condition $\bm{s}=\bm{s}_{eq}=\{0,0,1\}$ for the majority band,
$$\begin{aligned}
s_1(t)&=\frac1{\Omega^2+1/\tau_{sf}^2}\left\{ \frac1{\tau}\sin\theta\dot{\phi}-\frac1{\tau_{sf}}\dot{\theta}-e^{-t/\tau_{sf}}\left[ \frac1\tau\sin\theta\dot{\phi}\left(\cos\Omega t+\frac1{\Omega\tau_{sf}}\sin\Omega t\right)+\Omega\dot{\theta}\left(\sin\Omega t-\frac1{\Omega\tau_{sf}}\cos\Omega t \right) \right] \right\}, \notag\\
s_2(t)&=\frac{-1}{\Omega^2+1/\tau_{sf}^2}\left\{ \frac1{\tau}\dot{\theta}+\frac1{\tau_{sf}}\sin\theta\dot{\phi}+e^{-t/\tau_{sf}}\left[ \Omega\sin\theta\dot{\phi}\left(\sin\Omega t-\frac1{\Omega\tau_{sf}}\cos\Omega t\right)-\frac1\tau\dot{\theta}\left(\cos\Omega t+\frac1{\Omega\tau_{sf}}\sin\Omega t \right) \right] \right\}, \notag\\
s_3(t)&=\frac1{\Omega^2+1/\tau_{sf}^2}\left\{ \frac1{\tau^2}+\frac1{\tau_{sf}^2}+e^{-t/\tau_{sf}}(\sin\theta\dot{\phi}^2+\dot{\theta}^2)\left( \cos\Omega t+\frac1{\Omega\tau_{sf}}\sin\Omega t \right) \right\}, \notag\end{aligned}$$
where we have defined $\Omega^2=1/\tau^2+(\sin\theta\dot{\phi}^2+\dot{\theta}^2)$ and $1/\tau=1/\tau_{ex}-\cos\theta\dot{\phi}$. Since $\varepsilon_1=\tau_{ex}\sin\theta\dot{\phi}$ and $\varepsilon_2=\tau_{ex}\dot{\theta}$ are small quantities, we have $\Omega\sim\frac1{\tau_{ex}}[1+\mathcal{O}(\varepsilon^2)]$ where the first order terms $\mathcal{O}(\varepsilon)$ all vanish. Regarding this, we neglect second order terms $\mathcal{O}(\varepsilon^2)$ in the above equations, by which Eq. is justified.
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| 2024-07-15T01:26:59.872264 | https://example.com/article/1893 |
import gc
from numba import jit, int32
import unittest
def foo(a, b):
return a + b
def bar(a, b):
return cfoo(a, b) + b
@jit
def inner(x, y):
return x + y
@jit(nopython=True)
def outer(x, y):
return inner(x, y)
class TestInterProc(unittest.TestCase):
def test_bar_call_foo(self):
global cfoo
cfoo = jit((int32, int32), nopython=True)(foo)
cbar = jit((int32, int32), nopython=True)(bar)
self.assertEqual(cbar(1, 2), 1 + 2 + 2)
def test_bar_call_foo_compiled_twice(self):
# When a function is compiled twice, then called from another
# compiled function, check that the right target is called.
# (otherwise, LLVM would assert out or crash)
global cfoo
for i in range(2):
cfoo = jit((int32, int32), nopython=True)(foo)
gc.collect()
cbar = jit((int32, int32), nopython=True)(bar)
self.assertEqual(cbar(1, 2), 1 + 2 + 2)
def test_callsite_compilation(self):
self.assertEqual(outer(1, 2), 1 + 2)
if __name__ == '__main__':
unittest.main()
| 2023-10-11T01:26:59.872264 | https://example.com/article/8008 |
Worldwide PC shipments are expected to drop 12% this year - vaksel
http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2009/03/03/BUT1167QI5.DTL
======
Jem
Already posted: <http://news.ycombinator.com/item?id=501410> :)
| 2024-07-30T01:26:59.872264 | https://example.com/article/5184 |
[Analysis of the N-nitrosamines in products of plant origin].
A spectrofluorometric method of analyzing the carcinogenic N-nitrosoamines in the form of 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole derivatives is proposed. The content of nitroso-amines in a number of products of the vegetative origin was determined. In some samples of beetroots, radish and apples dimethyl-nitroso-amine in concentrations of 0.7--1.5 gamma/kg was detected. A conclusion is drawn on a relatively low content of carcinogenic N-nitroso-amines in the products of the vegetable origin. | 2023-08-11T01:26:59.872264 | https://example.com/article/9126 |
Egyptian authorities have announced that twenty Al-Jazeera journalists, including four foreigners, will stand trial on charges of joining or aiding a terrorist group and endangering national security. The move has stoked fears of a crackdown on the freedom of the press.
The journalists are alleged to have set up a “media center” for the Muslim Brotherhood and to have “manipulated pictures” to give the world the impression that “there is a civil war that threatens to bring down the state.”
Authorities have long viewed Al-Jazeera as biased toward the Brotherhood, which was designated a terrorist organization by the government last month, but the Qatar-based network denies the allegations.
Experts told Associated Press that journalists had previously been detained in Egypt, but never tried in court.
Amnesty International urged Cairo to immediately drop all charges, and U.S. State Department Spokeswoman Jen Psaki said that, “the government’s targeting of journalists and others on spurious claims is wrong and demonstrates an egregious disregard for the protection of basic rights and freedoms.”
The trial date has not yet been set, and the full list of charges and defendants’ names not yet issued, but they are known to include the Canadian-Egyptian acting bureau chief for Al-Jazeera English, Mohammed Fahmy, the award-winning Australian correspondent Peter Greste and Egyptian producer Baher Mohamed. | 2023-10-21T01:26:59.872264 | https://example.com/article/8705 |
<?xml version="1.0" encoding="UTF-8"?>
<!-- SPDX-License-Identifier: Apache-2.0 -->
<!-- Copyright Contributors to the ODPi Egeria project. -->
<project xmlns="http://maven.apache.org/POM/4.0.0"
xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"
xsi:schemaLocation="http://maven.apache.org/POM/4.0.0 http://maven.apache.org/xsd/maven-4.0.0.xsd">
<parent>
<artifactId>open-metadata-collection-store-connectors</artifactId>
<groupId>org.odpi.egeria</groupId>
<version>2.3-SNAPSHOT</version>
</parent>
<modelVersion>4.0.0</modelVersion>
<scm>
<connection>scm:git:git://github.com/odpi/egeria.git</connection>
<developerConnection>scm:git:ssh://github.com/odpi/egeria.git</developerConnection>
<url>http://github.com/odpi/egeria/tree/master</url>
</scm>
<name>OMRS REST API Connector</name>
<description>
Uses the OMRS REST API to call an open metadata compliant repository.
</description>
<artifactId>omrs-rest-repository-connector</artifactId>
<dependencies>
<dependency>
<groupId>org.odpi.egeria</groupId>
<artifactId>open-connector-framework</artifactId>
</dependency>
<dependency>
<groupId>org.odpi.egeria</groupId>
<artifactId>repository-services-client</artifactId>
</dependency>
</dependencies>
</project>
| 2023-12-06T01:26:59.872264 | https://example.com/article/5317 |
UNITED STATES COURT OF APPEALS
FOR THE FIRST CIRCUIT
No. 91-1602
METCALF & EDDY, INC.,
Plaintiff, Appellee,
v.
PUERTO RICO AQUEDUCT AND SEWER AUTHORITY,
Defendant, Appellant.
ON REMAND FROM THE SUPREME COURT
OF THE UNITED STATES
Before
Breyer, Chief Judge,
Aldrich, Senior Circuit Judge,
and Selya, Circuit Judge.
Perry M. Rosen, Paige E. Reffe, Thomas D. Roth, Cutler &
Stanfield, Arturo Trias, Hector Melendez Cano, and Trias, Acevedo
& Otero on supplemental brief for appellant.
Peter W. Sipkins, Dorsey & Whitney, Jay A. Garcia-Gregory,
and Fiddler, Gonzalez & Rodriguez on supplemental brief for
appellee.
May 3, 1993
SELYA, Circuit Judge. Notwithstanding that trial is
SELYA, Circuit Judge.
still some distance away, this diversity case alights on our
doorstep for the second time. The appellate roundelay began when
Metcalf & Eddy, Inc. (M&E) sued the Puerto Rico Aqueduct and
Sewer Authority (PRASA) for damages in Puerto Rico's federal
district court. In the course of pretrial proceedings, the court
denied PRASA the benefit of Eleventh Amendment immunity. The
disappointed defendant essayed an interlocutory appeal.
Following circuit precedent, see Libby v. Marshall, 833 F.2d 402
(1st Cir. 1987), we dismissed the appeal for want of
jurisdiction. M&E v. PRASA, 945 F.2d 10, 14 (1st Cir. 1991).
The Supreme Court granted certiorari and, resolving an existing
split in the circuits, determined that pretrial orders granting
or denying Eleventh Amendment immunity were immediately
appealable. PRASA v. M&E, 113 S. Ct. 684, 689 (1993).
PRASA's appeal returns to us on remand from the Supreme
Court. This time around, we must address the merits of the
ruling below. After reviewing supplemental briefs and
considering PRASA's overall relationship with the central
government of Puerto Rico, we affirm the district court's denial
of Eleventh Amendment immunity.
I.
Setting the Stage
Puerto Rico's legislature created PRASA over forty
years ago in order to provide safe drinking water for inhabitants
and to manage wastewater treatment. See P.R. Laws Ann. tit. 22,
2
141-168 (1987 & Supp. 1989). PRASA's stewardship has not been
without blemish. The incident that sparked this suit occurred in
1985, when the United States Environmental Protection Agency
(EPA) brought an enforcement action pursuant to the Clean Water
Act, 33 U.S.C. 1251-1376 (1988), seeking to provoke a
substantial modernization of PRASA's wastewater treatment
facilities.
In due course, PRASA and EPA signed a consent order
limning the changes necessary to bring PRASA's treatment system
into compliance. Toward that end, PRASA hired M&E, a
Massachusetts-based engineering firm with professed expertise in
wastewater management, to oversee the refurbishment. M&E's
duties included contracting for design and construction services
on PRASA's behalf, procuring necessary equipment, and supervising
work on the project. M&E was to be remunerated on a time-plus-
expense basis, invoiced as accrued. Bills were due and payable
within thirty days of presentment.
Over time, project expenditures mushroomed well beyond
budget. As costs mounted, PRASA grew increasingly inhospitable
to M&E's invoices. The denouement occurred when PRASA, amidst
charges of skulduggery, suspended all payments to M&E and
demanded a complete audit. M&E consented to the audit, but did
not acquiesce in the cessation of payments. The audit dragged on
and PRASA accumulated a huge stockpile of M&E invoices. Its
financial plight ingravescent, M&E sued before the audit had run
its course to force payment of the arrearage (roughly
3
$52,000,000).
Confronted by defendant's motion to dismiss, the
district court determined as a matter of law that PRASA did not
enjoy Eleventh Amendment immunity. In so holding, the court
stressed that PRASA possessed the "ability to raise funds for
payment of its contractual obligations" and, thus, its
obligations "do not affect the Commonwealth's funds." PRASA
appeals this decision as a legal rather than a factual matter.
Although there may sometimes be genuine issues of material fact
sufficient to preclude brevis disposition in Eleventh Amendment
litigation, there are none here. Agreeing with PRASA that the
issue in this case is one of law, we afford plenary review to the
district court's denial of immunity. See Dedham Water Co. v.
Cumberland Farms Dairy, Inc., 972 F.2d 453, 457 (1st Cir. 1992);
New England Legal Found. v. Massachusetts Port Auth., 883 F.2d
157, 167 (1st Cir. 1989).
II.
Analysis
A.
The Eleventh Amendment: An Overview
In Chisholm v. Georgia, 2 U.S. (2 Dall.) 419 (1793),
the Supreme Court held that the federal courts had jurisdiction
to hear a South Carolina citizen's suit against the State of
Georgia. This result, popularly perceived as a threat to state
autonomy in a newly minted federal system, produced an
overwhelmingly negative reaction. See Edelman v. Jordan, 415
4
U.S. 651, 662 (1974). Ratification of the Eleventh Amendment
followed apace.1
On its face, the amendment appeared to introduce a
fairly simple proposition into our constitutional jurisprudence.
Nevertheless, driven by the pressure of pragmatic necessity,
judicial sketching of the amendment's scope and requirements has
displayed a creative bent. Under the gloss supplied by this
abstract impressionistic flair, the federal courts now read the
Eleventh Amendment, notwithstanding its plain language, to
prohibit them from hearing most suits brought against a state by
citizens of that or any other state.2 See De Leon Lopez v.
Corporacion Insular de Seguros, 931 F.2d 116, 121 (1st Cir. 1991)
(collecting cases); see also Edelman, 415 U.S. at 662-63.
Withal, there are apertures in the Eleventh Amendment's
protective swaddling. If a case falls within one of these gaps,
the Eleventh Amendment will not bar maintenance of the suit in a
federal court. See Ramirez v. Puerto Rico Fire Serv., 715 F.2d
694, 697, (1st Cir. 1983) (explaining that the Eleventh Amendment
1The Amendment reads:
The Judicial power of the United States
shall not be construed to extend to any suit
in law or equity, commenced or prosecuted
against one of the United States by Citizens
of another State, or by Citizens or Subjects
of any Foreign State.
U.S. Const. amend. XI.
2There is, of course, an exception for prospective
injunctive relief. See, e.g., Ramirez v. Puerto Rico Fire Serv.,
715 F.2d 694, 697 (1st Cir. 1983).
5
"bars federal court lawsuits by private parties insofar as they
attempt to impose liabilities necessarily payable from public
coffers, unless the state has consented to suit or unless the
protective cloak of the amendment has been doffed by waiver or
stripped away by congressional fiat"). Specifically, the
amendment's raiment unravels if any one of four circumstances
eventuates: a state may randomly consent to suit in a federal
forum, see, e.g., Paul N. Howard Co. v. PRASA, 744 F.2d 880, 886
(1st Cir. 1984), cert. denied, 469 U.S. 1191 (1985); a state may
waive its own immunity by statute or the like, see, e.g.,
Edelman, 415 U.S. at 673; Congress may sometimes abrogate state
immunity (so long as it speaks clearly and acts in furtherance of
particular powers), see, e.g., Fitzpatrick v. Bitzer, 427 U.S.
445, 451-54 (1976); or under certain circumstances other
constitutional imperatives may take precedence over the Eleventh
Amendment's federal-court bar, see Pennhurst State Sch. & Hosp.
v. Halderman, 465 U.S. 89, 99 (1984) (involving Fourteenth
Amendment); Bitzer, 427 U.S. at 456 (same).
Here, M&E does not argue that PRASA consented to be
sued, that Puerto Rico waived PRASA's immunity, that Congress
abrogated PRASA's immunity, or that some other provision of the
federal Constitution has usurped the field. Hence, this suit
skirts the gaps. Rather, it is a "pure" Eleventh Amendment case
in which this court must focus on whether PRASA enters the
6
Eleventh Amendment's sphere at all.3
B.
The Test
The mere imprimatur of state authority is insufficient
to inoculate an agency or institution against federal court
jurisdiction. A "slice of state power," without more, will not
sate the Eleventh Amendment. Lake Country Estates, Inc. v. Tahoe
Regional Planning Agency, 440 U.S. 391, 401 (1979). By the same
token and for much the same reasons political subdivisions of
a state, such as municipalities and counties, do not lie within
the Eleventh Amendment's reach. See, e.g., Owen v. City of
Independence, 445 U.S. 622, 650 (1980); Moor v. County of
Alameda, 411 U.S. 693, 717-721 (1973). Only the state itself and
"arms" of the state receive immunity. See PRASA v. M&E, 113 S.
Ct. at 689; Alabama v. Pugh, 438 U.S. 781, 782 (1978); see
generally De Leon Lopez, 931 F.2d at 121 (discussing coverage of
Eleventh Amendment). Because PRASA is not an organic part of the
central government of Puerto Rico, we must investigate whether it
is sufficiently a part of the central government to be considered
an arm of the state. Framed in this way, the question poses an
3We have consistently treated Puerto Rico as if it were a
state for Eleventh Amendment purposes. See, e.g., De Leon Lopez,
931 F.2d at 121; Fred v. Roque, 916 F.2d 37, 38 (1st Cir. 1990);
Paul N. Howard Co., 744 F.2d at 886; Ramirez, 715 F.2d at 697.
Although M&E invites us to revisit this position, we decline the
invitation. In a multi-panel circuit, newly constituted panels,
generally speaking, are bound by prior panel decisions on point.
See United States v. Gomez-Villamizar, 981 F.2d 621, 623 n.9 (1st
Cir. 1992); Jusino v. Zayas, 875 F.2d 986, 993 (1st Cir. 1989).
So it is here.
7
essentially functional inquiry, not easily amenable to bright-
line answers or mechanical solutions.
The Eleventh Amendment's primary concern is to minimize
federal courts' involvement in disbursal of the state fisc. It
follows that "when the action is in essence one for the recovery
of money from the state, the state is the real, substantial party
in interest and is entitled to invoke its sovereign immunity from
suit . . . ." Ford Motor Co. v. Department of Treasury, 323 U.S.
459, 464 (1945); see also Lake Country Estates, 440 U.S. at 400-
01 (identifying the desire to protect state treasuries as a
driving force behind adoption of the Eleventh Amendment); Dugan
v. Rank, 372 U.S. 609, 620 (1963) (recognizing "that a suit is
against the sovereign `if the judgment sought would expend itself
on the public treasury or domain'") (citation omitted); Ainsworth
Aristocrat Int'l Pty. Ltd. v. Tourism Co., 818 F.2d 1034, 1037
(1st Cir. 1987) (similar). Generally, if a state has a legal
obligation to satisfy judgments against an institution out of
public coffers, the institution is protected from federal
adjudication by the Eleventh Amendment. See Quern v. Jordan, 440
U.S. 332, 337 (1979); Reyes v. Supervisor of DEA, 834 F.2d 1093,
1097-98 (1st Cir. 1987).
Because it is not always limpid whether, or to what
extent, the state treasury must stand behind the judgment debts
of a particular institution, we have identified seven related
areas as prospects for further inquiry. These areas, each of
which can be mined for information that might clarify the
8
institution's structure and function, include: (1) whether the
agency has the funding power to enable it to satisfy judgments
without direct state participation or guarantees; (2) whether the
agency's function is governmental or proprietary; (3) whether the
agency is separately incorporated; (4) whether the state exerts
control over the agency, and if so, to what extent; (5) whether
the agency has the power to sue, be sued, and enter contracts in
its own name and right; (6) whether the agency's property is
subject to state taxation; and (7) whether the state has
immunized itself from responsibility for the agency's acts or
omissions. See Ainsworth Aristocrat, 818 F.2d at 1037
(collecting cases from other circuits recounting the same or
similar factors). The list is not an all-inclusive compendium,
for other areas of inquiry may prove fruitful in particular
circumstances. It is, however, clear that all the pertinent
factors have a common orientation: the more tightly the agency
and the state are entangled, the more probable it becomes that
the agency shares the state's Eleventh Amendment immunity.
C.
Applying the Test
In Paul N. Howard Co., supra, we adjudicated a similar
dispute involving PRASA's renitency to make payments due under a
construction contract. 744 F.2d at 881-84. The plaintiff
prevailed in the district court. On appeal, PRASA advanced for
the first time an added defense premised on Eleventh Amendment
immunity. Although we suggested rather strongly that PRASA might
9
"not qualify for immunity under the Eleventh Amendment," id. at
886, we did not conclusively resolve the issue because PRASA had
purposefully availed itself of the federal forum and had thereby
lost whatever entitlement to Eleventh Amendment immunity it might
have possessed with respect to that particular suit. See id.
The case before us today requires that we return to, and resolve,
the question deferred in Howard.4 Faithful to the explication
of legal principles set out above, see supra Part II(B), we first
examine PRASA's access to the public fisc and thereafter
scrutinize how the associated factors are arrayed in this
particular situation.
1. Access to the Commonwealth's Treasury. On the
1. Access to the Commonwealth's Treasury.
principal issue PRASA's access to the Commonwealth's treasury
the die is quickly cast. Puerto Rico's legislature made it
readily evident that PRASA
shall have no power at any time or in any
manner to pledge the credit or taxing power
of the Commonwealth of Puerto Rico or any of
its other political subdivisions. The bonds
and other obligations issued by the Authority
shall not be a debt of the Commonwealth of
Puerto Rico nor of any of its municipalities
nor of its other political subdivisions and
neither the Commonwealth of Puerto Rico nor
any such municipalities nor its other
political subdivisions shall be liable
thereon, nor shall such bonds or other
obligations be paid out of any funds other
4In this quest, we give no weight to the Howard court's
comments concerning PRASA's immunity, for we recognize that, as
dictum, the comments are not binding. That is not to say,
however, that Eleventh Amendment issues must always be resolved
de novo. Where the agency's activity and its relation to the
state remain essentially the same, prior circuit precedent will
be controlling.
10
than those of the Authority.
P.R. Laws Ann. tit. 22, 144. The statute erects a wall between
the agency's appetite and the public fisc. The existence of this
statutory barrier presages the result we must reach: PRASA is
not an arm of the state for Eleventh Amendment purposes.5
PRASA argues that, notwithstanding the Commonwealth's
disavowal of its liabilities, the Commonwealth's significant
financial support of PRASA's activities constitutes the sort of
access to public funds that triggers Eleventh Amendment
protection. We do not agree. Although the central government
subsidizes the agency to some extent, PRASA relies mostly on user
fees and bonds to support its operations. The government does
not give PRASA a blank check or an indeterminant carte blanche
allowing it to draw on the public treasury as it thinks
necessary. Thus, control of the money flow from tax dollars is
unilateral; if the Commonwealth chooses not to open the faucet,
the agency must go thirsty or else, by resort to its own devices,
procure the funds needed to stay liquid.
We think PRASA's situation is not unlike that of a
typical political subdivision. Such an entity often receives
part of its budget from the state and raises the rest
independently. Despite this dual funding, such entities do not
5The statutory barrier is especially important in this case,
for Puerto Rico's legislature has demonstrated that, when it
wishes to do so, it knows exactly how to pledge the
Commonwealth's resources in security for PRASA's debts. See P.R.
Laws Ann. tit. 22, 168 (explicitly agreeing to reimburse the
Farmers Home Administration if PRASA should default on two
particular loans).
11
automatically (or even usually) come within the zone of
protection demarcated by the Eleventh Amendment. Thus, in Mt.
Healthy City Sch. Dist. Bd. of Educ. v. Doyle, 429 U.S. 274
(1977), the Supreme Court denied Eleventh Amendment sanctuary to
a school board despite the "significant amount of money" it
received from the state. Id. at 280; accord Fitchik v. New
Jersey Transit Rail Operations, Inc., 873 F.2d 655, 660 (3d Cir.)
(denying immunity to a regional rail authority despite state
funding while noting "that an entity derives some of its income
from the state does not mean that it is entitled to partake of
the state's immunity"), cert. denied, 110 S. Ct. 148 (1989); see
also Blake v. Kline, 612 F.2d 718, 723 (3d Cir. 1979)
(recognizing that "the nature of the state's obligation to
contribute may be more important than the size of the
contribution"), cert. denied, 447 U.S. 921 (1980). The case at
bar is cut from much the same cloth.
We hold, therefore, that a state agency cannot claim
Eleventh Amendment immunity solely on the basis that judgments
against it may absorb unrestricted funds donated by the state
and, in that way, redound indirectly to the depletion of the
state's treasury. It follows that PRASA's assertion of Eleventh
Amendment immunity in this case is severely flawed.
2. Other Factors. Although PRASA's inability to draw
2. Other Factors.
on the public fisc cripples its immunity defense, we turn to the
other factors mentioned in the case law in order that our
investigation may be complete. In the circumstances at hand,
12
these factors, taken as an aggregate, corroborate the view that
PRASA does not dwell within the Eleventh Amendment's shelter.
To be sure, the two pans of the scale are not
completely out of balance. PRASA to some extent wields the
state's power; after all, the enabling legislation describes
PRASA's mission to provide water and sewer services as fulfilling
"an essential government function." P.R. Laws Ann. tit. 22,
142. Additionally, neither PRASA nor its revenue bonds are
taxable, see id. 155; PRASA enjoys the power of eminent domain,
see id. 144(e); and the Governor of Puerto Rico appoints five
of PRASA's seven board members, see id. 143.
PRASA places particular emphasis on the fact that its
water and sewage functions are governmental rather than
proprietary and insists that this circumstance renders it an arm
of the state.6 But the nature of PRASA's function is only one
6In arguing this point, PRASA leans heavily on our decision
in Puerto Rico Ports Auth. v. M/V Manhattan Prince, 897 F.2d 1,
12 (1st Cir. 1990). This reliance is mislaid. In Manhattan
Prince, the Ports Authority was acting only as the licensor of
harbor pilots for whom it provided no training and over whom it
exercised no assignment power. The Authority derived no revenue
from the licensing function. Moreover, the legislature had
explicitly made Authority members' misfeasance of the kind
alleged in Manhattan Prince attributable only to the
Commonwealth. See P.R. Laws Ann. tit. 23, 2303(b) (1987).
PRASA's situation is much different; it charges for its services,
controls its total operations, and answers for its own bevues.
Thus, a more apt Ports Authority analogy is found in Royal
Caribbean Corp. v. Puerto Rico Ports Auth., 973 F.2d 8 (1st Cir.
1992). That case involved not licensing, but operation of the
ports. See id. at 9. Because the Ports Authority charged user
fees that supported the costs of its port operations and was
relatively free of central government control, we ruled that it
did not enjoy Eleventh Amendment immunity with respect to its
management of the ports. Id. at 12.
13
part of the equation, and, standing alone, it is insufficient to
bring PRASA behind the Eleventh Amendment's shield. Educational
services, for example, are, like water treatment, a traditional
governmental function. Education, however, has an even longer,
stronger governmental history than water treatment, and as
attendance requirements attest, a more entrenched place in state
government. Yet, despite these more evocative characteristics,
school boards are not immune from suits in federal court. See
Mt. Healthy, 429 U.S. at 280-81 (holding that school board is not
entitled to assert Eleventh Amendment immunity).
On the other side of the scale, a heftier array of
indicators suggests that PRASA is distinct from Puerto Rico's
central government. PRASA has the power to raise funds through
user fees (which, significantly, the Commonwealth, as a water-
and-sewer user, must pay with respect to its own operations).
See P.R. Laws Ann. tit. 22, 158. PRASA also has the right to
raise funds by issuing revenue bonds independently of the central
government. See id. 152. The power and opportunity to
generate a revenue stream and thereby finance an agency's
operations is an important attribute of the agency's separate
identity. Cf. Hernandez-Tirado v. Artau, 874 F.2d 866, 872 (1st
We recognize the seeming anomaly in a single agency
being held to possess Eleventh Amendment immunity for some
functions but not for others. However, the two cases cited above
turned on the nature of the function involved in each instance,
presumably because, in light of the Authority's portfolio of
diverse operations, the question of access to the Commonwealth's
treasury was fuliginous. The case before us is free from this
strain of uncertainty.
14
Cir. 1989) (finding agency to be an arm of the Commonwealth
because the central government had the sole power to raise money
for the agency). Moreover, bondholders must look only to PRASA
for recompense in the event of default. See P.R. Laws Ann. tit.
22, 152(I). Then, too, PRASA is separately incorporated as "an
autonomous government instrumentality." Id. 142. It may sue,
be sued, and enter contracts without the Commonwealth's
particular permission. See id. 144(c), (d). Its funds are
kept entirely separate from the funds of the central government
and are totally controlled by its own board. Last, but surely
not least, the Commonwealth has explicitly insulated itself from
any financial responsibility with respect to PRASA's general debt
and ordinary bonded indebtedness.7 See id. 144.
One more item deserves mention. Whether an agency is
an arm of the state vel non is a matter of federal, not local,
law. See Blake, 612 F.2d at 722. Nevertheless, it is notable
that the district court's view of PRASA as a separate political
subdivision rather than as a part of the central government
comports with that of Puerto Rico's highest tribunal. The Puerto
Rico Supreme Court has consistently concluded that PRASA is not
an alter ego of the central government. The court observed over
7PRASA argues that because its generated revenues (bond
monies and user fees) are "pledged" to current debts and
projects, it will have no money to pay a judgment and any
judgment creditor must, therefore, look to the Commonwealth.
This is specious reasoning. If M&E prevails in this suit, it,
like unsecured judgment creditors from time immemorial, would
bear the risk that it might find few assets available to satisfy
the judgment.
15
forty years ago that the legislature intended PRASA to "be as
amenable to judicial process as any private enterprise would be
under like circumstances . . . ." Arraiza v. Reyes, 70 P.R.R.
583, 587 (1949). More recently, the court reiterated that PRASA
has a "personality separate and apart from that of the
government," and does not have the "sovereign immunity
traditionally enjoyed by the State." Canchani v. C.R.U.V., 105
P.R. Dec. 352, 489 n.2, 490 (1976); see also A.A.A. v. Union
Empleados A.A.A., 105 P.R. Dec. 605, 628 (1976) (stating that
PRASA is "unquestionably framed as a private enterprise or
business and in fact operates as such"). While not dispositive,
consistent decisions of a state's highest court construing an
agency's or institution's relationship with the central
government are important guideposts in a reasoned attempt to
locate the agency's or institution's place within the scheme of
things. See Ainsworth Aristocrat, 818 F.2d at 1037.
3. Assessing the Balance. The upshot is that PRASA
3. Assessing the Balance.
lacks eligibility for Eleventh Amendment immunity on several
levels. First, and most fundamentally, PRASA's inability to tap
the Commonwealth treasury or pledge the Commonwealth's credit
leaves it unable to exercise the power of the purse. On this
basis, PRASA is ill-deserving of Eleventh Amendment protection.
Even putting aside PRASA's fiscal separation from the
central government, we find that the sum total of the secondary
factors preponderates against immunity. While PRASA indisputably
operates with some quantum of state authority, as do many other
16
public utilities, it is readily apparent that Puerto Rico's
legislature chose to structure an arm's-length relationship
between PRASA and the central government. To implement this
relationship, the legislature gave PRASA the power to raise
funds, enter contracts, conceive strategy, and to make its own
operational decisions. As a consequence of the legislative
design, the central government does business with PRASA in the
same manner as with other vendors: it pays for the services it
receives and does not extend any credit or generic funding
guarantees. When all the relevant factors are weighed, the
indicia of separateness countervail the indicia of togetherness.
III.
Conclusion
We need go no further. The profound impact of PRASA's
inability to reach the Commonwealth's treasury, and our
calibrating measurement of the secondary factors, dictate that
PRASA's assertion of immunity must fail. Consequently, we today
confirm the suspicions adumbrated in Howard, 744 F.2d at 886: in
its current incarnation, the Puerto Rico Aqueduct and Sewer
Authority is not safeguarded from federal court jurisdiction by
the Eleventh Amendment. Therefore, the district court's denial
of PRASA's motion to dismiss must be
Affirmed.
17
| 2023-12-17T01:26:59.872264 | https://example.com/article/4519 |
-- BSD shared types
local require, error, assert, tonumber, tostring,
setmetatable, pairs, ipairs, unpack, rawget, rawset,
pcall, type, table, string =
require, error, assert, tonumber, tostring,
setmetatable, pairs, ipairs, unpack, rawget, rawset,
pcall, type, table, string
local function init(c, types)
local abi = require "syscall.abi"
local t, pt, s, ctypes = types.t, types.pt, types.s, types.ctypes
local ffi = require "ffi"
local bit = require "syscall.bit"
local h = require "syscall.helpers"
local addtype, addtype_var, addtype_fn, addraw2 = h.addtype, h.addtype_var, h.addtype_fn, h.addraw2
local ptt, reviter, mktype, istype, lenfn, lenmt, getfd, newfn
= h.ptt, h.reviter, h.mktype, h.istype, h.lenfn, h.lenmt, h.getfd, h.newfn
local ntohl, ntohl, ntohs, htons = h.ntohl, h.ntohl, h.ntohs, h.htons
local mt = {} -- metatables
local addtypes = {
}
local addstructs = {
}
for k, v in pairs(addtypes) do addtype(types, k, v) end
for k, v in pairs(addstructs) do addtype(types, k, v, lenmt) end
mt.sockaddr = {
index = {
len = function(sa) return sa.sa_len end,
family = function(sa) return sa.sa_family end,
},
newindex = {
len = function(sa, v) sa.sa_len = v end,
},
}
addtype(types, "sockaddr", "struct sockaddr", mt.sockaddr)
-- cast socket address to actual type based on family, defined later
local samap_pt = {}
mt.sockaddr_storage = {
index = {
len = function(sa) return sa.ss_len end,
family = function(sa) return sa.ss_family end,
},
newindex = {
len = function(sa, v) sa.ss_len = v end,
family = function(sa, v) sa.ss_family = c.AF[v] end,
},
__index = function(sa, k)
if mt.sockaddr_storage.index[k] then return mt.sockaddr_storage.index[k](sa) end
local st = samap_pt[sa.ss_family]
if st then
local cs = st(sa)
return cs[k]
end
error("invalid index " .. k)
end,
__newindex = function(sa, k, v)
if mt.sockaddr_storage.newindex[k] then
mt.sockaddr_storage.newindex[k](sa, v)
return
end
local st = samap_pt[sa.ss_family]
if st then
local cs = st(sa)
cs[k] = v
return
end
error("invalid index " .. k)
end,
__new = function(tp, init)
local ss = ffi.new(tp)
local family
if init and init.family then family = c.AF[init.family] end
local st
if family then
st = samap_pt[family]
ss.ss_family = family
init.family = nil
end
if st then
local cs = st(ss)
for k, v in pairs(init) do
cs[k] = v
end
end
ss.len = #ss
return ss
end,
-- netbsd likes to see the correct size when it gets a sockaddr; Linux was ok with a longer one
__len = function(sa)
if samap_pt[sa.family] then
local cs = samap_pt[sa.family](sa)
return #cs
else
return s.sockaddr_storage
end
end,
}
-- experiment, see if we can use this as generic type, to avoid allocations.
addtype(types, "sockaddr_storage", "struct sockaddr_storage", mt.sockaddr_storage)
mt.sockaddr_in = {
index = {
len = function(sa) return sa.sin_len end,
family = function(sa) return sa.sin_family end,
port = function(sa) return ntohs(sa.sin_port) end,
addr = function(sa) return sa.sin_addr end,
},
newindex = {
len = function(sa, v) sa.sin_len = v end,
family = function(sa, v) sa.sin_family = v end,
port = function(sa, v) sa.sin_port = htons(v) end,
addr = function(sa, v) sa.sin_addr = mktype(t.in_addr, v) end,
},
__new = function(tp, port, addr)
if type(port) == "table" then
port.len = s.sockaddr_in
return newfn(tp, port)
end
return newfn(tp, {len = s.sockaddr_in, family = c.AF.INET, port = port, addr = addr})
end,
__len = function(tp) return s.sockaddr_in end,
}
addtype(types, "sockaddr_in", "struct sockaddr_in", mt.sockaddr_in)
mt.sockaddr_in6 = {
index = {
len = function(sa) return sa.sin6_len end,
family = function(sa) return sa.sin6_family end,
port = function(sa) return ntohs(sa.sin6_port) end,
addr = function(sa) return sa.sin6_addr end,
},
newindex = {
len = function(sa, v) sa.sin6_len = v end,
family = function(sa, v) sa.sin6_family = v end,
port = function(sa, v) sa.sin6_port = htons(v) end,
addr = function(sa, v) sa.sin6_addr = mktype(t.in6_addr, v) end,
flowinfo = function(sa, v) sa.sin6_flowinfo = v end,
scope_id = function(sa, v) sa.sin6_scope_id = v end,
},
__new = function(tp, port, addr, flowinfo, scope_id) -- reordered initialisers.
if type(port) == "table" then
port.len = s.sockaddr_in6
return newfn(tp, port)
end
return newfn(tp, {len = s.sockaddr_in6, family = c.AF.INET6, port = port, addr = addr, flowinfo = flowinfo, scope_id = scope_id})
end,
__len = function(tp) return s.sockaddr_in6 end,
}
addtype(types, "sockaddr_in6", "struct sockaddr_in6", mt.sockaddr_in6)
mt.sockaddr_un = {
index = {
family = function(sa) return sa.sun_family end,
path = function(sa) return ffi.string(sa.sun_path) end,
},
newindex = {
family = function(sa, v) sa.sun_family = v end,
path = function(sa, v) ffi.copy(sa.sun_path, v) end,
},
__new = function(tp, path) return newfn(tp, {family = c.AF.UNIX, path = path, sun_len = s.sockaddr_un}) end,
__len = function(sa) return 2 + #sa.path end,
}
addtype(types, "sockaddr_un", "struct sockaddr_un", mt.sockaddr_un)
function t.sa(addr, addrlen) return addr end -- non Linux is trivial, Linux has odd unix handling
-- TODO need to check in detail all this as ported from Linux and may differ
mt.termios = {
makeraw = function(termios)
termios.c_iflag = bit.band(termios.iflag, bit.bnot(c.IFLAG["IGNBRK,BRKINT,PARMRK,ISTRIP,INLCR,IGNCR,ICRNL,IXON"]))
termios.c_oflag = bit.band(termios.oflag, bit.bnot(c.OFLAG["OPOST"]))
termios.c_lflag = bit.band(termios.lflag, bit.bnot(c.LFLAG["ECHO,ECHONL,ICANON,ISIG,IEXTEN"]))
termios.c_cflag = bit.bor(bit.band(termios.cflag, bit.bnot(c.CFLAG["CSIZE,PARENB"])), c.CFLAG.CS8)
termios.c_cc[c.CC.VMIN] = 1
termios.c_cc[c.CC.VTIME] = 0
return true
end,
index = {
iflag = function(termios) return tonumber(termios.c_iflag) end,
oflag = function(termios) return tonumber(termios.c_oflag) end,
cflag = function(termios) return tonumber(termios.c_cflag) end,
lflag = function(termios) return tonumber(termios.c_lflag) end,
makeraw = function(termios) return mt.termios.makeraw end,
ispeed = function(termios) return termios.c_ispeed end,
ospeed = function(termios) return termios.c_ospeed end,
},
newindex = {
iflag = function(termios, v) termios.c_iflag = c.IFLAG(v) end,
oflag = function(termios, v) termios.c_oflag = c.OFLAG(v) end,
cflag = function(termios, v) termios.c_cflag = c.CFLAG(v) end,
lflag = function(termios, v) termios.c_lflag = c.LFLAG(v) end,
ispeed = function(termios, v) termios.c_ispeed = v end,
ospeed = function(termios, v) termios.c_ospeed = v end,
speed = function(termios, v)
termios.c_ispeed = v
termios.c_ospeed = v
end,
},
}
for k, i in pairs(c.CC) do
mt.termios.index[k] = function(termios) return termios.c_cc[i] end
mt.termios.newindex[k] = function(termios, v) termios.c_cc[i] = v end
end
addtype(types, "termios", "struct termios", mt.termios)
mt.kevent = {
index = {
size = function(kev) return tonumber(kev.data) end,
fd = function(kev) return tonumber(kev.ident) end,
signal = function(kev) return tonumber(kev.ident) end,
},
newindex = {
fd = function(kev, v) kev.ident = t.uintptr(getfd(v)) end,
signal = function(kev, v) kev.ident = c.SIG[v] end,
-- due to naming, use 'set' names TODO better naming scheme reads oddly as not a function
setflags = function(kev, v) kev.flags = c.EV[v] end,
setfilter = function(kev, v) kev.filter = c.EVFILT[v] end,
},
__new = function(tp, tab)
if type(tab) == "table" then
tab.flags = c.EV[tab.flags]
tab.filter = c.EVFILT[tab.filter] -- TODO this should also support extra ones via ioctl see man page
tab.fflags = c.NOTE[tab.fflags]
end
local obj = ffi.new(tp)
for k, v in pairs(tab or {}) do obj[k] = v end
return obj
end,
}
for k, v in pairs(c.NOTE) do
mt.kevent.index[k] = function(kev) return bit.band(kev.fflags, v) ~= 0 end
end
for _, k in pairs{"FLAG1", "EOF", "ERROR"} do
mt.kevent.index[k] = function(kev) return bit.band(kev.flags, c.EV[k]) ~= 0 end
end
addtype(types, "kevent", "struct kevent", mt.kevent)
mt.kevents = {
__len = function(kk) return kk.count end,
__new = function(tp, ks)
if type(ks) == 'number' then return ffi.new(tp, ks, ks) end
local count = #ks
local kks = ffi.new(tp, count, count)
for n = 1, count do -- TODO ideally we use ipairs on both arrays/tables
local v = mktype(t.kevent, ks[n])
kks.kev[n - 1] = v
end
return kks
end,
__ipairs = function(kk) return reviter, kk.kev, kk.count end
}
addtype_var(types, "kevents", "struct {int count; struct kevent kev[?];}", mt.kevents)
-- this is declared above
samap_pt = {
[c.AF.UNIX] = pt.sockaddr_un,
[c.AF.INET] = pt.sockaddr_in,
[c.AF.INET6] = pt.sockaddr_in6,
}
return types
end
return {init = init}
| 2024-07-20T01:26:59.872264 | https://example.com/article/6000 |
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We accept 30 days exchange or money refund of defective item. Buyer is no need to send back the item to us. please do not leave Negative or Neutral feedback before get our reply. Please contact us if you have trouble. We will help you. | 2024-03-27T01:26:59.872264 | https://example.com/article/2721 |
Lamar Odom Brothel Owner’s House Burns, Says Kardashians Put A Curse On Him
Dennis Hof, owner of the Nevada brothel where Lamar Odom overdosed at this time last year, is blaming his house fire on a curse by the Kardashians. Hof says that because of the one year anniversary of Lamar Odom’s brothel tragedy, Khloe Kardashian has put a hex on him. Hof’s two million dollar mansion has burned to the ground.
One of the prostitutes that spent time with Lamar Odom on his fateful trip to the brothel now writes a blog, and wrote a tell-all about Lamar’s brothel visit last week for the anniversary of his overdose, according to a previous report by the Inquisitr. Monica Monroe wrote that despite taking Viagra, Lamar Odom was not able to have sex with her. Instead, Monroe says that she and Odom talked at length about their relationship struggles, and Lamar spoke at length about Khloe Kardashian.
Dennis Hof’s three story mansion in the woods has burned to the ground, and Hof blames the fire on a curse by the Kardashians, according to the Daily Mail. It’s not clear if Hof is alluding to the Kardashians’ Armenian heritage, or if he is making the suggestion that they are witches, but he believes the fire might have been caused by a hex courtesy of Khloe.
A state started “controlled burn” quickly got out of control, and burned the mostly wooden structure in the Nevada woods to the ground. Hof added that on the next anniversary of the Lamar Odom overdose, he will go far away, just in case, maybe to a remote island.
Dennis Hof’s home in the Washoe Valley of Nevada was over one thousand acres away from the area that the fire was supposed to burn, but according to RGJ, the Nevada Division of Forestry fire got out of control quickly and consumed Hof’s home. Hof shared pictures of the home on social media, and posted sarcastic tweets.
“One of my homes before the controlled burn to help the squirrels. My amazing mountain home after the controlled burn THANKS TO THE STATE OF NEVADA (sic).”
Hof says that he was not home at the time of the fire, but neighbors said that they had to flee as the flames started to lick the sides of their property. The fire consumed nineteen homes in all.
Perhaps Dennis Hof is making these claims because the Kardashians accused him of using Lamar Odom’s overdose for publicity, and they were additionally angered when Hof came after them for Odom’s $75k brothel bill. The New York Daily News says that for a long time, it was unclear if Odom would recover from the strokes and heart attack he suffered as a result of large amounts of alcohol and drugs while at the brothel.
Hof, who is running for local office, says that after all of the business with Lamar, the Kardashian family cursed him. Hof tweeted ahead of his return to what is now just ashes.
Dennis Hof had recently mentioned that he was considering suing the Kardashians for their impact on his high-end business, which was harmed by the publicity following Lamar Odom’s overdose. Celebrities allegedly have stayed away from the brothel, fearing a lack of confidentiality. Hof offered tours of the room where Lamar Odom was staying at the time that he overdosed, and allegedly charged a fee.
Do you believe in curses? Do you think that the Kardashians really cursed the brothel owner? | 2024-06-16T01:26:59.872264 | https://example.com/article/8404 |
Friday, 19 June 2009
Opening of the New Holy Year
The Holy Year announced by the Holy Father in March for Priests begins today. In preparation, St. Conleth's Catholic Heritage Association has distributed copies of a prayer written by Revd. Fr. William Doyle, S.J., M.C.
That prayer runs thus:
O my God, pour out in abundance Thy spirit of sacrifice upon Thy priests. It is both their glory and their duty to become victims, to be burnt up for souls, to live without ordinary joys, to be often the objects of distrust, injustice, and persecution.
The words they say every day at the altar, "This is my Body, this is my Blood," grant them to apply to themselves: "I am no longer myself, I am Jesus, Jesus crucified. I am, like the bread and wine, a substance no longer itself, but by consecration another."
O my God, I burn with desire for the sanctification of Thy priests. I wish all the priestly hands which touch Thee were hands whose touch is gentle and pleasing to Thee, that all the mouths uttering such sublime words at the altar should never descend to speaking trivialities.
Let priests in all their person stay at the level of their lofty functions, let every man find them simple and great, like the Holy Eucharist, accessible to all yet above the rest of men. O my God, grant them to carry with them from the Mass of today, a thirst for the Mass of tomorrow, and grant them, ladened themselves with gifts, to share these abundantly with their fellow men. Amen.
The Life of Fr. Doyle, written by Prof. Alfred O'Rahilly, is available here.
Qui Pro Vobis
Contact our Association
Radio Maria Ireland
Listen to the Catholic Heritage Hour on Radio Maria Ireland on Fridays at 3.15 p.m. http://radiomaria.ie/live-stream/
Venerable Father John Sullivan SJ
Born: 8 May 1861, Received into the Catholic Church: 21 December 1896, Received into the Sodality of Our Lady: 22 December 1896, Entered Society of Jesus: 7 September 1900, Ordained Priest: 28 July 1900, Died 19 February 1933. | 2024-03-02T01:26:59.872264 | https://example.com/article/3001 |
News n’ Stuff:
PGA Tour 2K21 announced +Trailer
XBOX Series X “Gameplay” revealed
Ghost of Tsushima gameplay demoed in State of Play
Epic demonstrates Unreal Engine 5 running on PS5
The Last of Us Part 2 new release date: June 19th, 2020
Played/Watched: | 2023-11-20T01:26:59.872264 | https://example.com/article/4516 |
Q:
Django redirect page does not update the view
I'm using the Django Framework on Google App Engine.
I have multiple forms on the same view, to submit to different URL.
Trouble is after I get a form submitted: even if the called method update the datastore and some data, the previous page (where the forms are put in) is not refreshed, showing the updated data.
I could solve this problem using jQuery or some javascrip framework, appending dinamically content returned by the server but, how to avoid it?
Suggestions?
Am I wrong somewhere?
A part of "secure.html" template
<form action="/addMatch" method="post">
{% csrf_token %}
{{ form.as_p }}
<input type="submit" value="Submit" />
</form>
Matches:
<br />
{% for m in matches%}
{{m.description}} ---> {{m.reward}}
{% endfor%}
the "/addMatch" URL view:
def addMatch(request):
form = MatchForm(request.POST)
if form.is_valid():
user = User.all().filter('facebookId =', int(request.session["pbusr"]))
m = Match(user=user.get(),description =form.cleaned_data["description"],reward=form.cleaned_data["reward"])
m.save()
return HttpResponseRedirect("/secure/")
else:
logging.info("Not valid")
return HttpResponseRedirect("/secure")
The view method whose seems not working:
@auth_check_is_admin
def secure(request):
model={}
user = User.all().filter('facebookId =', int(request.session["pbusr"]))
u = user.get()
if (u.facebookFanPageId is not None and not u.facebookFanPageId == ""):
model["fanPageName"] = u.facebookFanPageName
model["form"] = MatchForm()
model["matches"] = u.matches
else:
....
return render(request,"secure.html",model)
Francesco
A:
Based on what you posted, it seems like you're redirecting properly and are having database consistency issues. One way to test this would be to look at the network tab in the Google Chrome developer tools:
Click on the menu icon in the upper right
Click on "Tools"
Click on "Developer Tools"
Click on "Network" in the thing that opened up at the bottom of the screen.
Now, there will be a new entry in the network tab for every request that your browser sends and every response it receives. If you click on a request, you can see the data that was sent and received. If you need to see requests across different pages, you might want to check the "Preserve log" box.
With the network tab open, go to your page and submit the form. By looking at the network tab, you should be able to tell whether or not your browser issued a new GET request to the same URL. If there is a new request for the same page but that request has the old content, then you have a datastore consistency issue. If there was NOT a new request that yielded a response with the data for the page, then you have a redirect issue.
If it turns out that you have a datastore consistency issue, then what's happening is the data is being stored, but the next request for that data might still get the old data. To make sure that doesn't happen, you need what's called "strong consistency."
In a normal App Engine project, you get strong consistency by putting entities in the same entity-group and using ancestor queries. I'm not certain of what database/datastore you're using for Django and how the different database layers interact with App Engine's consistency, so this could be wrong, but if you can give your users the right key and then fetch them from that key directly (rather than getting all users and filtering them by key), you might get strong consistency.
| 2023-08-17T01:26:59.872264 | https://example.com/article/3270 |
In the new episode “Hibbing 911″, Jody Mills (Kim Rhodes) reluctantly attends a mandatory sheriff’s retreat and is partnered with an overeager sheriff named Donna (Briana Buckmaster) who wants to bond.
Just as Jody thinks things can’t get any worse, a body with just strings of meat and skin hanging off the bones is discovered. While the local sheriffs blame an animal attack, Jody knows better and calls Sam (Jared Padalecki) and Dean (Ackles).
Uh, yeah, I can absolutely resist the smile of a homophobic republican douchebag like him. I’ll be really glad once SPN ends and he fades into oblivion. Just my own opinion, based on my own findings. Doesn’t have to be yours, so you don’t have to agree with me. I’ll live.
Mina
So just because he doesn’t share the same beliefs as most celebrities that means he’s homophobic?! The two are not correlated at all. As for him being a republican, so what! Its almost like its a new trend to be a actor/actress and automatically have to be democratic or liberal. Hate to break it to you, Jensen is not the first and won’t be the last celebrity republican. Also, have you even met the guy to be calling him a douche? Your wasting your time commenting on someone you dislike so much and he’s supposedly the bad person… Sweetheart, If Jensen was a douchebag I’m sure a lot more people would be complaining instead of saying how nice he is and how much he cares about his fans. Don’t dump on a person just because they hold different values than your own, and 90 percent of Hollywood.
Tina
You should not forget that the unsubstantiated accusations – it is slander. defamation should be punished!
givemepie
Presuming that a person who is a Christian (most of America) an a Republican (identified by a stalker who traced his home address, identified when he sold a home and it was reported, and looked up the voter registration for that address – not freaky at all, eh) is also homophobic is a statement about you rather than Jensen Ackles. Nothing he has said or done would support your statement; in fact, people he works with seem to love him and the certainly know him better than you do. Prejudice and bigotry can show up in even the most liberal folks, and your presumptions prove it. Personally, I’m a liberal democrat and I find your bigotry out of line.
Erinn Jacob Wilson
Jensen is one of the best and nicest actor I’ve ever seen in this industry, so I’m not surprise that some people get jealous of him and start to attack him because of some personal grudges. They just can’t make peace with this world. | 2024-07-07T01:26:59.872264 | https://example.com/article/6726 |
“We are happy to move on to football and look forward to playing against the Giants,” Salzano said.
Elliott was not available for comment Tuesday as the team was off. They resume practice Wednesday. The Cowboys did not comment on the matter, but it likely won’t sit well with owner Jerry Jones.
Jones wasn’t happy when Elliott visited a marijuana shop in Seattle last month before a preseason game, and Elliott later acknowledged it wasn’t the best idea.
This text exchange, coupled with the Seattle visit, may be enough to put Elliott in the league’s substance-abuse program. Players do not necessarily have to fail a drug test to enter Stage 1 (intervention) of the program.
An NFL spokesman said the decision in a case such as Elliott’s is based upon the opinion of jointly appointed independent medical advisers by the NFL and NFLPA.
“They make the decision if a player should be put into the program,” the NFL spokesman wrote in an email.
Asked if he was worried about Elliott being put in the program, Salzano said: “I can’t control what they do.”
According to the league’s policy on substances of abuse, which was agreed upon with the NFLPA, players are subject to enter the program based on “behavior.”
The policy states: “Behavior (including but not limited to an arrest or conduct related to an alleged misuse of Substances of Abuse occurring up to two (2) football seasons prior to the Player’s applicable scouting combine) which, in the judgment of the Medical Director, exhibits physical, behavioral, or psychological signs or symptoms of misuse of Substances of Abuse.”
The other two ways to get into the program are by a failed drug test or self-referral. | 2024-04-04T01:26:59.872264 | https://example.com/article/9384 |
1973 American League Championship Series
The 1973 American League Championship Series took place between October 6 and 11, 1973. The Oakland Athletics defeated the Baltimore Orioles, three games to two. Games 1 and 2 were played in Memorial Stadium in Baltimore; Games 3–5 were played at the Oakland Coliseum. It was the second match-up between the two teams in the ALCS.
Summary
Oakland A's vs. Baltimore Orioles
Game summaries
Game 1
In Game 1, Jim Palmer spent 16 minutes retiring the side in the top of the first inning. He walked the first two batters and struck out the next three. The Orioles went to work against lefty Vida Blue and his successor, Horacio Piña in the bottom half. Merv Rettenmund singled and Paul Blair walked before Tommy Davis's RBI double put the Orioles up 1–0. Don Baylor then walked and one out later, Earl Williams's two-run single knocked Pina out of the game. Andy Etchebarren was hit by a pitch to load the bases and Mark Belanger's RBI single made it 4–0 Orioles. They added to their lead on Etchebarren's RBI single in the seventh and Baylor's RBI single in the eighth, both with two on off of Blue Moon Odom. It was more than they needed as Palmer pitched a five-hit shutout, striking out 12 A's along the way.
Game 2
The Orioles' ALCS winning streak was snapped at 10 in Game 2. Bert Campaneris led off the game with a home run off of Dave McNally, but the Orioles tied the game in the bottom of the first when Al Bumbry drew to leadoff walk, moved to third on a single and scored on Tommy Davis's groundout. Back-to-back home runs leading off the sixth by Joe Rudi and Sal Bando off of McNally put the A's up 3–1. In the bottom half, the Orioles got back-to-back leadoff singles before Earl Williams's one-out RBI double cut Oakland's lead to 3–2. Bando's second home run of the game in the eighth off of McNally padded Oakland's lead to 5–2. The Orioles hit two singles in the bottom half off of Catfish Hunter, who was relieved by Rollie Fingers and Brooks Robinson's RBI single made it 5–3 Oakland, but they got that run back in the ninth when Angel Mangual hit a leadoff single off of Bob Reynolds, moved to third on a sacrifice bunt and passed ball, and scored on Campaneris's single. Hunter, who served up so many during the season that he threatened an A.L. record, allowed none as the A's evened the series as the two teams headed to Oakland for Game 3.
Game 3
The third game, postponed a day by the lack of a dome—the postponement trigged a rhubarb between A.L. President Joe Cronin and A's President Charlie Finley—was played at Oakland and produced a brilliant pitching battle between a pair of southpaws, Mike Cuellar of Baltimore and Ken Holtzman. Up to that point, Cuellar had allowed only three hits. he had a one-hit shutout for the first seven innings as he carefully nursed a 1–0 lead given him by Earl Williams' homer in the second inning. But in the eighth, pinch-hitter Jesús Alou singled and pinch-runner Allan Lewis was sacrificed to second by Mike Andrews. The play was controversial in that Cuellar appeared to have a force out at second base, but he ignored catcher Etchebarren's yells and took the safe out at first. This proved costly as, one out later, Joe Rudi singled home Lewis to tie the score. Bert Campaneris, first man up in the 11th, snapped a 1–1 tie by hitting Cuellar's second pitch over the left-field fence for a home run.
Game 4
In Game 4, The A's knocked out Jim Palmer with a three-run outburst in the second inning. After a leadoff double and subsequent single, Ray Fosse's double scored two and Dick Green's double scored another. The A's made it 4–0 in the sixth on Fosse's bases-loaded sacrifice fly off of Bob Reynolds. Vida Blue pitched six shutout innings before falling apart in the seventh. Earl Williams drew a base on balls with one out and Don Baylor followed with a single. Brooks Robinson came through with a run-producing single and Andy Etchebarren hit the next pitch for a home run, making the score 4–4. The next inning, Bobby Grich hit a home run off Rollie Fingers and that, coupled with Grant Jackson's stout relief pitching, gave the game to the Orioles.
Game 5
A surprisingly small crowd of 24,265 showed up for the final game and they saw Catfish Hunter pitch a five-hit shutout, winning 3–0. The A's first run in the game come in the third inning when Ray Fosse reached first on an error by third baseman Brooks Robinson, moved to second on a sacrifice bunt, and scored on a single by Joe Rudi. Right-hander Doyle Alexander lasted only until the fourth inning. In that frame he was the victim of a single by Gene Tenace, who scored on a triple by Vic Davalillo before Jesus Alou added an RBI single. He was relieved by Palmer, who shut out Oakland the rest of the way, but the Orioles were helpless against Hunter's powerful pitching as the A's advanced to the World Series.
Pitching dominated the 5-game set, the victorious A's batting only .200 while the O's hit just .211.
Composite box
1973 ALCS (3–2): Oakland A's over Baltimore Orioles
References
External links
1973 ALCS at Baseball-Reference.com
Category:American League Championship Series
American League Championship Series
Category:Oakland Athletics postseason
Category:Baltimore Orioles postseason
Category:1973 in sports in California
Category:1973 in sports in Maryland
Category:1970s in Baltimore
Category:20th century in Oakland, California
Category:October 1973 sports events in the United States | 2024-06-20T01:26:59.872264 | https://example.com/article/6775 |
Bike Safety and Buses
Posted on July 28, 2016
Recently, Local Motion got an inquiry from a contact at GMT (formerly CCTA) about the four-foot passing law. They said a driver had asked why exactly it was necessary to give a minimum of four feet of clearance when passing someone on a bike. We were so glad they asked! GMT puts a major emphasis on safety, and bike-bus interactions are an area where special conditions apply. Here's what we told them about why four feet is so important:
It is difficult to impossible to ride a bike in a completely straight line. Balancing on a bike requires some degree of wavering, especially while going slowly or uphill. So you can't expect that a bike rider will stay exactly where they are.
Bicycling is necessarily unpredictable. Road shoulders are full of broken glass, potholes, sand, and so on. People on bikes have to swerve sometimes. Ideally, they'll look over their shoulder before swerving. But sometimes they forget, or the hazard is so imminent that they can't. You have to give them enough space to account for this.
Bicyclists are vulnerable. We're talking about a human life here. They are in a completely different category in terms of the possible consequences of a mistake than an inanimate object. You get too close to a garbage truck and you scrape up your bus. You get too close to a bicyclist and you kill someone.
Local Motion is proud to be working with GMT to design and lead a training for bus drivers later this summer on how to drive safely around bicyclists. We'll also be calling on their expertise about buses to bring back useful info to the bike community about how to bike safely around buses. Stay tuned!
Create an account
Feedback needed on a draft curriculum for a planned Local Motion training for GMT (aka CCTA) bus drivers on safe bus-bike interactions! Take a look here and add your comments in the doc: http://bit.ly/2aLavVi
I’m less concerned about bus drivers when riding than I am a 20 year old male driving a Civic Honda with loud pipes. Bikers have a lot to be aware of left, right, front, back and what looms ahead beneath the tires. We can use all the help we can get! | 2023-10-01T01:26:59.872264 | https://example.com/article/6190 |
Fans across Los Angeles have been mourning the official demise of longtime diner staple Swingers this month. The Beverly Boulevard restaurant first opened in 1993 as a bright retro option for late-night, post-bar bites and college-age hangouts, and grew up into a 27-year restaurant legend alongside its many longtime regulars. The final day of service was last week, though rumors of Swingers closure had been swirling on social media both before April 1 and for days after.
Ownership confirmed the closure of Swingers today, saying the restaurant had enjoyed a tremendous run, but would not be reopening even after the coronavirus pandemic. Another location of Swingers, out in Santa Monica, closed back in August.
The Sean MacPherson-led company, Committed, Inc., also confirmed the closure of another one of its properties, the casual British pub the Pikey, which opened in 2012. A rep for the company says that the plan is to reformat the Pikey space into a new restaurant at some point in the future.
Fans on Instagram have been posting their goodbye photos to Swingers and the Pikey in recent days, while over on Facebook ownership directed onetime diners to a fundraising page for staff. So far that page has collected just under $50,000. The Pikey has also created a GoFundMe page for its own employees. | 2024-01-04T01:26:59.872264 | https://example.com/article/5686 |
Q:
How to find all grid squares on a line?
I'm trying to implement a line-of-sight algorithm on a 2-dimensional grid. I know how it needs to work conceptually, but I can't think of how to implement it as an algorithm.
The basic idea is pretty simple. In pseudocode:
function LineOfSight(point1, point2): boolean
squares = GetListOfSquaresOnLine(point1, point2)
for each square in squares
if square.IsOpaque then return false
return true
GetListOfSquaresOnLine would (conceptually) draw a straight line from the center of the grid square at point1 to the center of the grid square at point2, and return a list of all squares that this line passes through. But that's the part I have no idea how to implement. Anyone know how to do this? Delphi or C examples preferred, but not required.
A:
Both of the answers so far point to a Wikipedia article on Bresenhams's algorithm. Here's the illustration the article gives, at full size. Notice that the line passes through grid squares that aren't highlighted, so Bresenham's algorithm only gives a subset of what you want.
Since you mention "line of sight", it sounds like you want an algorithm that enumerates all of the grid squares that the line goes through. This set is sometimes referred to as the super cover (of the line), and one algorithm is described here.
There are also some other approaches, given in the answers to this question.
Update: Here's another reference
A:
Isn't Bresenham's Algorithm what you are looking for ?
A:
Here's an implementation I wrote in C.
| 2023-09-12T01:26:59.872264 | https://example.com/article/3809 |
Saturday, November 28, 2015
2012 presidential support among single women
Since universal suffrage was passed into law, women voters have pushed America toward the extreme far Left. Now we have a biological underpinning that helps explain why. The liberal, social safety net, open borders preferences of women align with the political preferences of effeminate men (like John Scalzi, Alex Pareene, and Ezra Klein). The effeminate men never had much of a political voice until they were able to hitch the behemoth female voting bloc to their cause. And now we have gay marriage, mudsharking on prime time TV, and slut walks featuring half-naked fat chicks.
5 comments:
Of course cat lady sluts marry the State. It doesn't mean the rest of us are bound to them until death do us part as part of the contract. Never mind suicide pact.
Perhaps we shouldn't leave our fate in their hands?
Or if it means our destruction: the hapless electorate?
Sometimes the old ways work best. Democracy is old but the franchise without conscription is new and 20th century. Also quite mad. There are other and even older ways who's outcome leaves no doubt as to the winner.
Expanding suffrage inexorably moves the country left. It is no surprise the left wants to lower the voting age, make voting compulsory, allow criminals to vote, remove any I.D. requirements for voting et cetera.
Your image suggests "Single, Never Married" women were for Obama more than five-to-one, which was about the general Nonwhite margin for Obama. On closer examination, this is mostly because Nonwhite single women were so overwhelmingly pro-Obama (The opinion-shapers rallied them to the Obama colors: They had a double serving of victimization points, victims of both White racism and Male patriarchy, and could indulge in such because they had no families).
Looking at only straight White women only (as some of the White pro-Obama "single women" may be disproportionately lesbians or etc.) (Reuters May 1, 2012 to November 6, 2012 combined polls, total sample size, 33,839):
There is a Marriage Gap here but it doesn't come close to reaching five-to-one. It doesn't even reach 3-to-2 for Obama among single or "living with partner" White women, and some of this may also be an artifact of age, with younger people being obviously less likely to be married. Interestingly, the most pro-Obama subdemographic of White Straight Women is not "Single Never Married," but "Living With Partner" (sample size, 2,249), but the margins of error of the two overlap.
Interesting discrepancy, especially since it comes from the same source.
Drilling down further just to never married single white women, n = 330, we still get 61.0%-22.6% in favor of Obama on election day. It is worth noting that the gap widened considerably over the last couple of weeks before the election. I don't remember the specifics of the "war on women" mantra from 2012, but I have a vague recollection that there was some manufactured controversy about it that October. | 2023-10-04T01:26:59.872264 | https://example.com/article/9369 |
Q:
My website is really slow, how to make it faster
So, my website is done, my website is: http://rocase.win/ But now you go to it, you will see that it is going really slow.
Loading time takes 10-20 seconds. I do an test on pingdom, and they say my loading time is 60 seconds, but almost all the performance is 100%.
Here is the result: https://tools.pingdom.com/#!/bObPdM/http://rocase.win I have tried like deleting all the comments I have, all the blank lines deleting.
But still is the loading time really really long. How can I make this shorter?
Thanks!
A:
You have some missing files which result(s) in long timeout,
You are missing some fonts and more....
A:
Your problem is the external load of JS and CSS( kaspersky ). Comment or remove this lines of your code:
<script type="text/javascript" src="https://gc.kis.v2.scr.kaspersky-labs.com/859509E7-F570-4047-AEC0-CEF2BFA49B1B/main.js" charset="UTF-8"></script>
<link rel="stylesheet" crossorigin="anonymous" href="https://gc.kis.v2.scr.kaspersky-labs.com/B1B94AFB2FEC-0CEA-7404-075F-7E905958/abn/main.css"/>
| 2023-11-08T01:26:59.872264 | https://example.com/article/7771 |
/*
* Math library
*
* Copyright (C) 2016 Intel Corporation. All rights reserved.
*
* Redistribution and use in source and binary forms, with or without
* modification, are permitted provided that the following conditions
* are met:
*
* * Redistributions of source code must retain the above copyright
* notice, this list of conditions and the following disclaimer.
* * Redistributions in binary form must reproduce the above copyright
* notice, this list of conditions and the following disclaimer in
* the documentation and/or other materials provided with the
* distribution.
* * Neither the name of Intel Corporation nor the names of its
* contributors may be used to endorse or promote products derived
* from this software without specific prior written permission.
*
* THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS
* "AS IS" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT
* LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR
* A PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT
* OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL,
* SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT
* LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE,
* DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY
* THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT
* (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE
* OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.
*
*
* Author Name <jingwei.zhang@intel.com>
* History:
* 03-14-2016 Initial version. numerics svn rev. 12864
*/
.file "exp_table.c"
.section .rodata, "a"
.align 8
.align 8
.globl __libm_exp_hi_table_64
__libm_exp_hi_table_64:
.long 0x667f3c00,0x3fe6a09e
.long 0x3c651a40,0x3fe6dfb2
.long 0xe8ec5f80,0x3fe71f75
.long 0x56426800,0x3fe75feb
.long 0x73eb01c0,0x3fe7a114
.long 0x36cf4e80,0x3fe7e2f3
.long 0x994cce20,0x3fe82589
.long 0x9b449300,0x3fe868d9
.long 0x422aa0e0,0x3fe8ace5
.long 0x99157740,0x3fe8f1ae
.long 0xb0cdc600,0x3fe93737
.long 0x9fde4e60,0x3fe97d82
.long 0x82a3f0a0,0x3fe9c491
.long 0x7b5de580,0x3fea0c66
.long 0xb23e2560,0x3fea5503
.long 0x5579fdc0,0x3fea9e6b
.long 0x995ad3c0,0x3feae89f
.long 0xb84f1600,0x3feb33a2
.long 0xf2fb5e60,0x3feb7f76
.long 0x904bc1e0,0x3febcc1e
.long 0xdd8552a0,0x3fec199b
.long 0x2e57d150,0x3fec67f1
.long 0xdcef9070,0x3fecb720
.long 0x4a078980,0x3fed072d
.long 0xdcfba490,0x3fed5818
.long 0x03db3290,0x3feda9e6
.long 0x337b9b60,0x3fedfc97
.long 0xe78b3ff8,0x3fee502e
.long 0xa2a490e0,0x3feea4af
.long 0xee615a28,0x3feefa1b
.long 0x5b6e4544,0x3fef5076
.long 0x819e90da,0x3fefa7c1
.long 0x00000000,0x3ff00000
.long 0x3e778060,0x3ff02c9a
.long 0xd3158574,0x3ff059b0
.long 0x18759bc8,0x3ff08745
.long 0x6cf9890c,0x3ff0b558
.long 0x32d3d1a0,0x3ff0e3ec
.long 0xd0125b50,0x3ff11301
.long 0xaea92dd8,0x3ff1429a
.long 0x3c7d5178,0x3ff172b8
.long 0xeb6fcb70,0x3ff1a35b
.long 0x3168b9a8,0x3ff1d487
.long 0x88628cd0,0x3ff2063b
.long 0x6e756230,0x3ff2387a
.long 0x65e27cd0,0x3ff26b45
.long 0xf51fdee0,0x3ff29e9d
.long 0xa6e40300,0x3ff2d285
.long 0x0a31b710,0x3ff306fe
.long 0xb26416f0,0x3ff33c08
.long 0x373aa9c0,0x3ff371a7
.long 0x34e59ff0,0x3ff3a7db
.long 0x4c123420,0x3ff3dea6
.long 0x21f72e20,0x3ff4160a
.long 0x60618920,0x3ff44e08
.long 0xb5c13cc0,0x3ff486a2
.long 0xd5362a20,0x3ff4bfda
.long 0x769d2ca0,0x3ff4f9b2
.long 0x569d4f80,0x3ff5342b
.long 0x36b527c0,0x3ff56f47
.long 0xdd485420,0x3ff5ab07
.long 0x15ad2140,0x3ff5e76f
.long 0xb03a5580,0x3ff6247e
.long 0x82552220,0x3ff66238
.long 0x667f3bc0,0x3ff6a09e
.type __libm_exp_hi_table_64,@object
.size __libm_exp_hi_table_64,520
.align 8
.globl __libm_exp_mi_table_64
__libm_exp_mi_table_64:
.long 0x33018800,0xbfd2bec3
.long 0x8735cb80,0xbfd2409b
.long 0x2e274100,0xbfd1c114
.long 0x537b3000,0xbfd14029
.long 0x1829fc80,0xbfd0bdd7
.long 0x92616300,0xbfd03a19
.long 0x9accc780,0xbfcf69d9
.long 0x92edb400,0xbfce5c99
.long 0xf7557c80,0xbfcd4c6a
.long 0x9baa2300,0xbfcc3945
.long 0x3cc8e800,0xbfcb2321
.long 0x8086c680,0xbfca09f5
.long 0xf5703d80,0xbfc8edb9
.long 0x12886a00,0xbfc7ce66
.long 0x37076a80,0xbfc6abf1
.long 0xaa180900,0xbfc58652
.long 0x9a94b100,0xbfc45d81
.long 0x1ec3a800,0xbfc33175
.long 0x34128680,0xbfc20224
.long 0xbed0f880,0xbfc0cf85
.long 0x13d56b00,0xbfbf3321
.long 0x8d417580,0xbfbcc076
.long 0x18837c80,0xbfba46f9
.long 0xafc3b400,0xbfb7c695
.long 0x1822db80,0xbfb53f39
.long 0xe1266b80,0xbfb2b0cf
.long 0x64232500,0xbfb01b46
.long 0x874c0080,0xbfaafd11
.long 0xd5b6f200,0xbfa5b505
.long 0x19ea5d80,0xbfa05e41
.long 0x92375780,0xbf95f134
.long 0x985bc980,0xbf860f9f
.long 0x00000000,0x00000000
.long 0x3bc03000,0x3f864d1f
.long 0xc5615d00,0x3f966c34
.long 0x0eb37900,0x3fa0e8a3
.long 0x9f312180,0x3fa6ab0d
.long 0x5a7a3400,0x3fac7d86
.long 0x0125b500,0x3fb1301d
.long 0xea92dd80,0x3fb429aa
.long 0xc7d51780,0x3fb72b83
.long 0xb6fcb700,0x3fba35be
.long 0x168b9a80,0x3fbd4873
.long 0x43146680,0x3fc031dc
.long 0x73ab1180,0x3fc1c3d3
.long 0x2f13e680,0x3fc35a2b
.long 0xa8fef700,0x3fc4f4ef
.long 0x37201800,0x3fc6942d
.long 0x518db880,0x3fc837f0
.long 0x9320b780,0x3fc9e045
.long 0xb9d54e00,0x3fcb8d39
.long 0xa72cff80,0x3fcd3ed9
.long 0x6091a100,0x3fcef532
.long 0x87dcb880,0x3fd05828
.long 0x81862480,0x3fd13821
.long 0xd704f300,0x3fd21a8a
.long 0x54d8a880,0x3fd2ff6b
.long 0xda74b280,0x3fd3e6c9
.long 0x5a753e00,0x3fd4d0ad
.long 0xdad49f00,0x3fd5bd1c
.long 0x75215080,0x3fd6ac1f
.long 0x56b48500,0x3fd79dbc
.long 0xc0e95600,0x3fd891fa
.long 0x09548880,0x3fd988e2
.long 0x99fcef00,0x3fda8279
.type __libm_exp_mi_table_64,@object
.size __libm_exp_mi_table_64,520
.align 8
.globl __libm_exp_lo_table_64
__libm_exp_lo_table_64:
.long 0x682764c9,0xbcf9b7ba
.long 0x1d341e44,0xbce10ddf
.long 0x1e1a21ea,0xbcd845b9
.long 0xb2ae62dc,0xbcfba048
.long 0x77ee0499,0xbcfc9415
.long 0xfd45ea87,0xbcedefa2
.long 0xeea0a997,0xbcdaea60
.long 0xe26f53db,0xbce37f1b
.long 0xea979b4e,0xbcc29160
.long 0xb17471a2,0xbcd3a8cf
.long 0xe3c0dabf,0xbceb0baf
.long 0x6df06e17,0xbce07461
.long 0x729f1c1b,0xbcdfc707
.long 0x25747355,0xbceb4d65
.long 0xdb71a83c,0xbcbba5ed
.long 0x78840167,0xbc97829b
.long 0xcb2e88ce,0xbce2a178
.long 0xbc6109ae,0xbcc42500
.long 0x4f7e54ac,0xbce91558
.long 0xbe174986,0xbcdbb708
.long 0xa76afb72,0xbcbeeef9
.long 0x200b7c35,0xbcc2d77b
.long 0xd0b85ad9,0xbccbabf0
.long 0x743797aa,0xbcc1cbc3
.long 0xf4a29324,0xbcd1b44b
.long 0xfcb49256,0xbcd51ee7
.long 0x53c612d7,0xbca46973
.long 0xcfeac66e,0xbcad8c2e
.long 0x3179c289,0xbcc9e9c2
.long 0xbcada4a8,0xbc911c05
.long 0xda44ebcf,0xbcbcc583
.long 0x818b4d9c,0xbcad16f5
.long 0x00000000,0x00000000
.long 0x95949ef4,0x3cadcdef
.long 0xa475b465,0x3c8d73e2
.long 0x4bb284ff,0x3c6186be
.long 0xc95b8c21,0x3ccb14c5
.long 0x1727c57b,0x3cc0103a
.long 0xe35db263,0x3ca49d77
.long 0x0650ec96,0x3cdecd04
.long 0xe4628759,0x3cc6e6fb
.long 0x63da4b47,0x3cd4f2da
.long 0xc0144c88,0x3cc3c02d
.long 0xac0a5425,0x3cd8ee3b
.long 0xf5b6382c,0x3ce0cd83
.long 0xce6503a7,0x3cea4af4
.long 0x15f5a24b,0x3cb2c25d
.long 0x3aa6da0f,0x3ce68012
.long 0x56918c17,0x3cd4b7a3
.long 0x0c21b2cd,0x3cee9939
.long 0xaa05e8a9,0x3ce54e28
.long 0x24a67828,0x3cdba86f
.long 0x911f09ec,0x3cc1ada0
.long 0x4b71e7b7,0x3ce3f086
.long 0xde813be0,0x3cea0626
.long 0xa3b69063,0x3cf013c1
.long 0x5ebfb10c,0x3cdc750e
.long 0x62da6a82,0x3cdab4cf
.long 0x3c49d86a,0x3cbdf0a8
.long 0xb004764f,0x3cfa66ec
.long 0x602a323d,0x3ce2b192
.long 0xc9840733,0x3ce0dd37
.long 0xe81bf4b7,0x3cd2c7c3
.long 0x678a6e3d,0x3cd2449f
.long 0x5f626cdd,0x3ce92116
.type __libm_exp_lo_table_64,@object
.size __libm_exp_lo_table_64,520
.align 8
.globl __libm_exp_table_128
__libm_exp_table_128:
.long 0x908b2fb1,0x3def3bcc
.long 0x66600000,0x3fe6a09e
.long 0xdaed5330,0x3dd7b57d
.long 0x75000000,0x3fe6c012
.long 0xc8838b30,0x3dc468bb
.long 0x3c600000,0x3fe6dfb2
.long 0xcf87e1b5,0x3de19483
.long 0xf9400000,0x3fe6ff7d
.long 0xba46e1e6,0x3dd8bee7
.long 0xe8e00000,0x3fe71f75
.long 0xf572693a,0x3dc605ce
.long 0x48a00000,0x3fe73f9a
.long 0xfb74d51a,0x3db33e45
.long 0x56400000,0x3fe75feb
.long 0x619ae028,0x3dee5d3f
.long 0x4fc00000,0x3fe78069
.long 0xafaa2048,0x3dd6030d
.long 0x73e00000,0x3fe7a114
.long 0x7c493344,0x3de0c132
.long 0x01200000,0x3fe7c1ed
.long 0x20ba0574,0x3dde9cc4
.long 0x36c00000,0x3fe7e2f3
.long 0xb60de676,0x3dee1a11
.long 0x54200000,0x3fe80427
.long 0x159f115f,0x3dd99c25
.long 0x99400000,0x3fe82589
.long 0x7297b5cc,0x3dbe3d66
.long 0x46200000,0x3fe8471a
.long 0x03907643,0x3dc24bb2
.long 0x9b400000,0x3fe868d9
.long 0xcca6179c,0x3dd4cd32
.long 0xd9800000,0x3fe88ac7
.long 0xb74f8ab4,0x3dd541b6
.long 0x42200000,0x3fe8ace5
.long 0xef2aa1cd,0x3de5448b
.long 0x16a00000,0x3fe8cf32
.long 0x2b982746,0x3de57736
.long 0x99000000,0x3fe8f1ae
.long 0x88a61b47,0x3de1ffc5
.long 0x0b800000,0x3fe9145b
.long 0xe8a0387e,0x3ddb8bc9
.long 0xb0c00000,0x3fe93737
.long 0xd36906d3,0x3dd0a41d
.long 0xcbc00000,0x3fe95a44
.long 0x8b9e9210,0x3dee4e4f
.long 0x9fc00000,0x3fe97d82
.long 0x74621372,0x3dd40f73
.long 0x70c00000,0x3fe9a0f1
.long 0xe3e23584,0x3dbf8480
.long 0x82a00000,0x3fe9c491
.long 0xc12653c7,0x3db91918
.long 0x19e00000,0x3fe9e863
.long 0xb29ada8c,0x3dede564
.long 0x7b400000,0x3fea0c66
.long 0xb182e3ef,0x3dd45a66
.long 0xec400000,0x3fea309b
.long 0x8b424492,0x3dee255c
.long 0xb2200000,0x3fea5503
.long 0x6f2dfb2b,0x3de0b358
.long 0x13200000,0x3fea799e
.long 0x43eb243c,0x3de9fdbf
.long 0x55600000,0x3fea9e6b
.long 0xc0db966a,0x3de3f379
.long 0xbfc00000,0x3feac36b
.long 0x5e8734d1,0x3dead3ad
.long 0x99400000,0x3feae89f
.long 0x2108559c,0x3ddb6ccb
.long 0x29800000,0x3feb0e07
.long 0xed7fa1cf,0x3dde2bf5
.long 0xb8400000,0x3feb33a2
.long 0x38e20444,0x3dc564e6
.long 0x8de00000,0x3feb5972
.long 0xeaa7b082,0x3deb5e46
.long 0xf2e00000,0x3feb7f76
.long 0x40cb3c6b,0x3da06498
.long 0x30a00000,0x3feba5b0
.long 0x48f741e9,0x3dd783a4
.long 0x90400000,0x3febcc1e
.long 0x8408d702,0x3de71e08
.long 0x5bc00000,0x3febf2c2
.long 0x88832c4b,0x3dc54a70
.long 0xdd800000,0x3fec199b
.long 0x6d14df82,0x3defd07a
.long 0x5fe00000,0x3fec40ab
.long 0x4a2137fd,0x3de7d14b
.long 0x2e400000,0x3fec67f1
.long 0x46b2f122,0x3dcb9ed4
.long 0x94000000,0x3fec8f6d
.long 0x2a0797a4,0x3ddf20d2
.long 0xdce00000,0x3fecb720
.long 0xc44f8959,0x3dedc3f9
.long 0x55400000,0x3fecdf0b
.long 0x343c8bc8,0x3dce25ee
.long 0x4a000000,0x3fed072d
.long 0x15bc2473,0x3ddb13e3
.long 0x08000000,0x3fed2f87
.long 0x25da05af,0x3deba487
.long 0xdce00000,0x3fed5818
.long 0x7709f3a1,0x3dd3072f
.long 0x16c00000,0x3fed80e3
.long 0x708c01a6,0x3deb3285
.long 0x03c00000,0x3feda9e6
.long 0xb695de3c,0x3dab4604
.long 0xf3000000,0x3fedd321
.long 0xb968cac4,0x3deb9b5e
.long 0x33600000,0x3fedfc97
.long 0xa12761fa,0x3de5a128
.long 0x14e00000,0x3fee2646
.long 0x4e7a2603,0x3dd67fec
.long 0xe7800000,0x3fee502e
.long 0x2d522ca1,0x3dcd320d
.long 0xfbc00000,0x3fee7a51
.long 0x163dce86,0x3dc24366
.long 0xa2a00000,0x3feea4af
.long 0x1b60625f,0x3ddccfe1
.long 0x2d800000,0x3feecf48
.long 0x71fd21a9,0x3da5a277
.long 0xee600000,0x3feefa1b
.long 0x9d0d2df8,0x3dd7752e
.long 0x37600000,0x3fef252b
.long 0xce9f096f,0x3ddc8a80
.long 0x5b600000,0x3fef5076
.long 0x8913b4c0,0x3decbe13
.long 0xad800000,0x3fef7bfd
.long 0x2e90a7e7,0x3dee90d8
.long 0x81800000,0x3fefa7c1
.long 0x12eb7496,0x3ddee3e2
.long 0x2b800000,0x3fefd3c2
.long 0x00000000,0x00000000
.long 0x00000000,0x3ff00000
.long 0x6d84a66b,0x3dfb3335
.long 0xa9e00000,0x3ff0163d
.long 0xee6f7cad,0x3df78060
.long 0x3e600000,0x3ff02c9a
.long 0x7ae71f34,0x3decff09
.long 0xe8600000,0x3ff04315
.long 0x3ae7c549,0x3df58574
.long 0xd3000000,0x3ff059b0
.long 0xc6dc403b,0x3dfdf6dd
.long 0x29c00000,0x3ff0706b
.long 0x08c35f26,0x3df59bc8
.long 0x18600000,0x3ff08745
.long 0x14878183,0x3ddbce0d
.long 0xcac00000,0x3ff09e3e
.long 0x6298b92b,0x3df9890f
.long 0x6ce00000,0x3ff0b558
.long 0x407b705c,0x3df247f7
.long 0x2b600000,0x3ff0cc92
.long 0x020742e5,0x3df3d1a2
.long 0x32c00000,0x3ff0e3ec
.long 0xf232091e,0x3dfed31a
.long 0xafe00000,0x3ff0fb66
.long 0xa4ebbf1b,0x3df25b50
.long 0xd0000000,0x3ff11301
.long 0xf72575a6,0x3de86397
.long 0xc0600000,0x3ff12abd
.long 0x66820328,0x3de25bbf
.long 0xaea00000,0x3ff1429a
.long 0x920355cf,0x3dd63944
.long 0xc8a00000,0x3ff15a98
.long 0xdcdf7c8c,0x3dfd517a
.long 0x3c600000,0x3ff172b8
.long 0x777ee173,0x3de91bd3
.long 0x38800000,0x3ff18af9
.long 0x796d31ed,0x3def96ea
.long 0xeb600000,0x3ff1a35b
.long 0x6ac79cad,0x3dd1734e
.long 0x84000000,0x3ff1bbe0
.long 0xf00b7005,0x3de17354
.long 0x31600000,0x3ff1d487
.long 0xb8819ff6,0x3dfcd91c
.long 0x22e00000,0x3ff1ed50
.long 0xdc775815,0x3dc466b1
.long 0x88600000,0x3ff2063b
.long 0x2552fd29,0x3dfddc96
.long 0x91600000,0x3ff21f49
.long 0x66c1fadb,0x3df56238
.long 0x6e600000,0x3ff2387a
.long 0x3582ab7e,0x3df2a63f
.long 0x4fa00000,0x3ff251ce
.long 0x2bd33994,0x3dc3e6e9
.long 0x65e00000,0x3ff26b45
.long 0x96cf15cf,0x3df56380
.long 0xe1e00000,0x3ff284df
.long 0x2c25d15f,0x3dffdee1
.long 0xf5000000,0x3ff29e9d
.long 0xfddea465,0x3dfad98f
.long 0xd0c00000,0x3ff2b87f
.long 0x0024754e,0x3dd00c2d
.long 0xa6e00000,0x3ff2d285
.long 0x11ca0f46,0x3dfe2f56
.long 0xa9200000,0x3ff2ecaf
.long 0x2de8d5a4,0x3df1b715
.long 0x0a200000,0x3ff306fe
.long 0x6a739e38,0x3de9b062
.long 0xfc400000,0x3ff32170
.long 0x32721843,0x3dd05bfd
.long 0xb2600000,0x3ff33c08
.long 0xc9462347,0x3df29ff0
.long 0x5f800000,0x3ff356c5
.long 0xa7145503,0x3dfaa9ca
.long 0x37200000,0x3ff371a7
.long 0x16a72c36,0x3dd76196
.long 0x6d000000,0x3ff38cae
.long 0xa86f24a6,0x3dd67fdb
.long 0x34e00000,0x3ff3a7db
.long 0x84001f23,0x3df3a8e4
.long 0xc3000000,0x3ff3c32d
.long 0x35b41224,0x3df23422
.long 0x4c000000,0x3ff3dea6
.long 0x417ee035,0x3de90037
.long 0x04a00000,0x3ff3fa45
.long 0xf84325b9,0x3df72e29
.long 0x21e00000,0x3ff4160a
.long 0xdc704439,0x3df0a896
.long 0xd9400000,0x3ff431f5
.long 0x3136f40a,0x3db892d0
.long 0x60600000,0x3ff44e08
.long 0x72512f46,0x3dfd0057
.long 0xed000000,0x3ff46a41
.long 0x3c1a3b69,0x3db3cd01
.long 0xb5c00000,0x3ff486a2
.long 0x672d8bcf,0x3df7d3de
.long 0xf0c00000,0x3ff4a32a
.long 0x1d4397b0,0x3df62a27
.long 0xd5200000,0x3ff4bfda
.long 0x63b36ef2,0x3dfddd0d
.long 0x99e00000,0x3ff4dcb2
.long 0xad33d8b7,0x3dfd2ca6
.long 0x76800000,0x3ff4f9b2
.long 0x8225ea59,0x3deecc83
.long 0xa2c00000,0x3ff516da
.long 0xdf0a83c5,0x3dfd4f81
.long 0x56800000,0x3ff5342b
.long 0xc52ec620,0x3dfd920e
.long 0xca400000,0x3ff551a4
.long 0x66ecb004,0x3df527da
.long 0x36a00000,0x3ff56f47
.long 0x252bc2b7,0x3df7c7fd
.long 0xd4800000,0x3ff58d12
.long 0xb192602a,0x3de0a852
.long 0xdd400000,0x3ff5ab07
.long 0x01c4b1b8,0x3df946b7
.long 0x8a400000,0x3ff5c926
.long 0xdd37c984,0x3dea4290
.long 0x15a00000,0x3ff5e76f
.long 0xb076f593,0x3df6dc08
.long 0xb9600000,0x3ff605e1
.long 0xb1f0fa07,0x3dfa5584
.long 0xb0200000,0x3ff6247e
.long 0x8edf0e2a,0x3de9863f
.long 0x34c00000,0x3ff64346
.long 0x9127d9e3,0x3df52224
.long 0x82400000,0x3ff66238
.long 0x1038ae45,0x3de952e6
.long 0xd4400000,0x3ff68155
.long 0x908b2fb1,0x3dff3bcc
.long 0x66600000,0x3ff6a09e
.type __libm_exp_table_128,@object
.size __libm_exp_table_128,2064
.data
.section .note.GNU-stack, ""
# End
| 2024-02-01T01:26:59.872264 | https://example.com/article/2645 |
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No, you cannot use Premium Ad Credits purchased for one type of Premium Ad for activating a different type of Premium ad type. For eg: If users buy an ad pack for Top of the Page ad, they will not be able to use ad credits from that ad pack for activating an Urgent ad.
Pack validity means the time frame within which the ad credits have to be used. For eg: If a Premium Ad pack with 100 Ad credits and a validity period of 6 months is purchased on May 1st , 2011 then all the 100 Ad Credits need to be used before Oct 31st, 2011. All the Ad Credits will expire on Nov 1st and you will not be able to use them. Also, after the expiry date, there will be no refund if you have unused ad credits in your account. | 2023-08-13T01:26:59.872264 | https://example.com/article/6907 |
Wednesday, October 3, 2012
Atheists Lose First Amendment Legal Challenge to State‘s ’Year of the Bible’ Declaration
Atheists technically lost their legal battle, challenging
Pennsylvania’s “year of the Bible” declaration. That said, there’s a
light at the end of the non-theistic tunnel, as the judge, despite
ruling against secularists, also chastised state politicians for
pandering to the electorate.
In February, the foundation for the Freedom From Religion Foundation’s (FFRF) legal battle
was set after the Pennsylvania House of Representatives unanimously
passed a resolution (H.R. 535) declaring 2012 the “Year of the Bible.”
Naturally, this riled non-believers, causing them to publicly protest
what they saw as a discriminatory breach of the separation of church and
state.
“This nation faces great challenges that will test it as it has never
been tested before … and renewing our knowledge of and faith in God
through Holy Scripture can strengthen us as a nation and a people,” a
portion of the declaration read.
After months of jockeying back and forth between the two sides, U.S.
District Judge Christopher Conner dismissed the case, siding with House
Republicans who had motioned for the court to do so (the judge said he
was bound by legislative immunity — a protection of lawmakers for actions they take within their respective duties).
While Conner dismissed the FFRF challenge, he also chastised the
lawmakers, calling the resolution a “waste of legislative resources” and
dismissing it as “exclusionary,” Philly.com reports.
“At worst, it is premeditated pandering designed to provide a
reelection sound bite for use by members of the General Assembly,” the judge wrote.
“At a time when the Commonwealth of Pennsylvania faces massive public
policy challenges, these resources would be far better utilized in
meaningful legislative efforts for the benefit all of the citizens of
the Commonwealth, regardless of their religious beliefs.”
EFN Twitter
About Us
JMC Ministries is the founder of Eternal Flame News. We report the hot topics that effect Christians today in their daily walk with Christ. So we can inform them of what is happening in our world today and how we can make a difference to change the path our world is on.
The truth and word of God is like a consuming fire. It consumes all the lies the world tries to feed us and tears us down. With this truth we can destroy those lies and consume them with the Fire of the Holy Spirit. | 2023-10-14T01:26:59.872264 | https://example.com/article/2884 |
Q:
Protractor JS Invalidselectorerror
I'm getting InvalidSelectorError when i tried to find anchor tag with certain href in li in some div :
txt1 = ptor.findElement(protractor.By.xpath("//div[@class='caption'][1]//ul//li[1]//a[contains(@href='http://www.youtube.com/')]"));
expect(txt1.getText()).toEqual('Why?')`
what is wrong with this since if anchor tags statement is not mentioned then it works
A:
You are using a contains condition but also using equals at the same time:
//a[contains(@href='http://www.youtube.com/')]
You are looking for:
//a[contains(@href, 'http://www.youtube.com/')]
| 2023-09-07T01:26:59.872264 | https://example.com/article/8702 |
Computational structure determination of novel metal-organic frameworks.
A structure prediction tool has been developed to guide the discovery of MOF materials. This computational strategy has been trained over a series of existing MOFs and further successfully applied in tandem with an experimental effort to produce novel Zr MOFs based on naturally occurring carboxylic acids. | 2023-12-05T01:26:59.872264 | https://example.com/article/4905 |
Ukrainian Chaos, NATO Expansion, Lockheed, and Bruce Jackson
Regarding the expansion of NATO and the chaos in the Ukraine, my mind went back to the efforts of Lockheed and Bruce Jackson, which was widely reported during the expansion. Here is a nice example:
Hartung, William D. 2003. How Much Are You Making on the War, Daddy?: A Quick and Dirty Guide to War Profiteering in the Bush Administration (NY: Thunder’s Mouth Press).
17: William Hartung described Bruce Jackson is “a one-man military-industrial-complex.” “He has served as director of the U.S. Committee to Expand NATO during the run-up to the 1998 U.S. Senate vote to ratify the inclusion of Poland, Hungary, and the Czech Republic in the alliance. He has also served on the boards of the Project for the New American Century, a neo-con “dream team” that was founded with the backing of such Bush administration luminaries as Donald Rumsfeld, Paul Wolfowitz, Richard Perle, and Elliot Abrams, and of the Center for Security Policy, the pro-missile defense advocacy organization run by the ubiquitous gadfly, Frank Gaffney.” | 2024-02-17T01:26:59.872264 | https://example.com/article/1465 |
Introduction {#sec1_1}
============
Coeliac disease (CD) is a common autoimmune condition affecting the small bowel; it is a gluten-sensitive enteropathy in genetically susceptible individuals \[[@B1]\]. Gluten is a constituent of wheat and gluten-like molecules are present in related foodstuffs including barley, rye and oats \[[@B2]\]. CD has a reported prevalence of up to 1% in western populations \[[@B1]\]. Advances in clinical awareness and serological testing have influenced its prevalence over the last decade \[[@B1], [@B3]\]. It is reported 1.5 times more frequently in women compared with men and is also associated with a range of other autoimmune conditions \[[@B1], [@B3]\]. From a genetic perspective there is a strong association with the HLA-DQ2 and the HLA-DQ8 haplotype, which are expressed in over 90% of patients \[[@B1]\]. The pathogenesis of CD is thought to be related to an increase in intestinal permeability \[[@B4], [@B5]\] and the accumulation of gliadin in the lamina propria, which stimulates both the adaptive and innate immune responses. There is eventually enterocyte destruction and subsequent villous atrophy \[[@B6]\]. This manifests clinically in constitutional and malabsorptive symptoms, including diarrhoea, bloating and weight loss.
The diagnosis of CD relies on clinical presentation, detection of serum IgA autoantibodies and the demonstration of villous atrophy on duodenal biopsy (in accordance with Marsh\'s histological criteria) \[[@B7]\]. Most patients have a rapid recovery to normal health following a gluten-free diet (GFD), with improvement of symptoms seen within weeks to month \[[@B3]\]. In the majority, GFD induces both clinical and histological remission of the disease. The complications of this disease are related to malnutrition and an association with enterocyte-associated T cell lymphoma (EATL).
We present the clinical course of diagnosis and management in a case of refractory coeliac disease (RCD). This report highlights the particular therapeutic challenges faced by this phenomenon and the potential utility for parenteral nutrition in the management of such cases.
Case History {#sec1_2}
============
We present the case of a 68-year-old lady who developed persistent non-bloody diarrhoea and vomiting whilst travelling in India. She had a 10-day stay with her family, spending time in both urban and rural settings and drinking only bottled water and unpasteurised buffalo milk. She was treated for suspected gastroenteritis.
On return to the UK, her symptoms did not resolve and she was referred to the gastroenterology team at Ealing Hospital. Her initial clinical investigations revealed a positive tissue transglutaminase assay (234 U/ml, normal range 0--10 U/ml) and normocytic anaemia (haemoglobin 10.9 g/l, mean corpuscular volume 87.1 fl). She had multiple stool cultures which were negative. Endoscopic biopsies from the second part of the duodenum showed shortened broad-based villi with an increased number of intraepithelial lymphocytes, consistent with a diagnosis of CD. She commenced a strict GFD, with a later addition of steroid therapy (budesonide). This did not control her symptoms, and when seen at follow-up (6 months after her initial presentation), she complained of worsening diarrhoea and steatorrhoea, with bowels opening up to 16 times a day. She also complained of colicky abdominal pain, significant weight loss (from 62 to 49 kg) and was noted to be peripherally oedematous up to her knees.
Given the alarming rate of progression of her symptoms, she was admitted from the clinic to hospital. Clinically, we questioned whether this was progression of her CD or the presentation of a second pathology. Her admission investigations were consistent with severe malnutrition and pancreatic exocrine insufficiency, with an albumin of 12 g/l and reduced faecal elastase of 86 µg/g. She was initially treated with a strict GFD, high-energy high-protein diet, Fresubin^®^ energy drinks and Creon^®^ supplementation, with no significant improvement.
While she was an inpatient, we proceeded to exclude other causes of malnutrition. Indeed, stool cultures were negative for bacteria, ova and cysts; tuberculosis was excluded with a negative QuantiFERON test; she was negative for HIV and was empirically treated for small bowel bacterial overgrowth with cyclical ciprofloxacin and metronidazole, with no effect. Her imaging included a normal computed tomography of the chest, abdomen and pelvis and a magnetic resonance imaging of the small bowel showing only small bowel diverticula. Upper gastrointestinal endoscopy showed chronic gastritis (negative for *Helicobacter pylori*) and colonoscopy was unremarkable, with no evidence of neoplasia in her biopsies. She underwent small bowel enteroscopy at a specialist unit (fig. [1](#F1){ref-type="fig"}) which showed ulcerative jejunitis, consistent with severe CD. Gene array studies of the biopsies obtained from D2 confirmed polyclonal T cell receptor arrangement, further reducing the likelihood of lymphoma. Thus overall, we were unable to find a second pathology explaining her intestinal failure, leaving RCD as her diagnosis of exclusion.
She was then given a short trial (5 days) of total parenteral nutrition (TPN) via a Hickman line. The TPN regimen was Kabiven 14 (day 1: 768 ml at 32 ml/h, day 2: 1,560 ml at 65 ml/h, day 3: 1,920 ml at 80 ml/h, day 4: 1,920 ml at 80 ml/h, day 5: 1,920 ml at 80 ml/h). Table [1](#T1){ref-type="table"} details the constituents of each bag of Kabiven 14. While on TPN, her fluid balance, weight and blood sugar levels were closely monitored. In addition, she had daily monitoring of her haemoglobin, sodium, potassium, calcium, phosphate, magnesium, liver function tests, urea and creatinine. Following this period of TPN, her diarrhoea and steatorrhoea settled, her peripheral oedema improved and her albumin climbed to 34 g/l. She was transferred to a specialist intestinal failure unit, where she received just 2 further days of TPN before being safely discharged back to the community. A short period of TPN thus induced remission, characterised by a complete resolution of symptoms and biochemical improvement, which were sustained at follow-up.
Discussion {#sec1_3}
==========
RCD is characterised by recurrent or persistent symptoms and villous atrophy despite strict adherence to a GFD for at least 6 months when other causes on non-responsive CD and malignancy have been excluded \[[@B3], [@B8], [@B9]\]. This is essentially a diagnosis of exclusion, made only after eliminating other causes of malabsorption, gluten contamination in diet and malignancy. RCD can be categorised into primary (persistent symptoms without initial response to diet) and secondary (relapse following initial response to diet) \[[@B7]\]. A further classification of RCD is recognised, type 1 and type 2. Type 1 RCD displays a predominantly normal intraepithelial lymphocyte population and type 2 RCD shows an aberrant population \[[@B10]\], whereby the intraepithelial lymphocytes demonstrate a loss of surface T cell receptor, CD3 or CD8 expression, and have a greater potential to progress and evolve into an aggressive EATL \[[@B11]\]. This explains the poor prognosis associated with type 2 (5-year survival between 44 and 58%), in contrast to type 1, which generally runs a benign course \[[@B12], [@B13]\]. Immunohistochemistry for our patient showed the presence of CD3 and CD8, consistent with increased phenotypically normal intraepithelial lymphocytes in type 1 RCD (fig. [2](#F2){ref-type="fig"}).
Following the exclusion of other causes of malabsorption such as giardiasis, topical sprue, HIV and Whipple\'s disease, a diagnosis of primary RCD was confirmed in our patient. Currently there are no standardised treatment regimens for RCD due to the rarity of the condition. Clinicians are usually guided by the limited number of cases reported in the literature which have successfully responded to different managements \[[@B7]\]. There are a number of potential therapies already described in the literature, including the use of steroids and steroid-sparing agents such as azathioprine. In the majority of RCD type 1 cases, steroid use is effective in inducing clinical remission and mucosal recovery; however, use in RCD type 2 shows clinical response in 75%, but does not induce mucosal recovery or prevent the progression to EATL.
Although majority of the literature focuses on immunosuppressive therapies for RCD treatment, nutritional support is an essential part of management which should not be overlooked. Hospitalisation is sometimes necessary to ensure dietary adherence and exclude gluten contamination. Symptomatic and histological improvement has been reported following hospitalisation for dietary monitoring \[[@B8]\]. Elemental and liquid diets can be used to ensure total gluten withdrawal \[[@B14]\]; however, malabsorption and protein-losing enteropathy can be so severe in some cases that patients may require intravenous nutritional support. Studies have shown that up to 60% of patients who were hospitalised for RCD required TPN due to severe weight loss, malnutrition, severe electrolyte abnormalities, complex nutritional deficiencies and/or steatorrhoea \[[@B12], [@B13], [@B15]\]. TPN has the ability to provide adequate nutrition and replacement of the necessary proteins whilst allowing time for intestinal mucosal recovery. All RCD patients would benefit from the involvement of an experienced dietician who can provide TPN regimes tailored to each patient\'s requirement. In our case, the patient showed improvement with TPN. Biochemically, her albumin levels increased from 12 to 34 g/l and her haemoglobin improved from 6.7 to 12 g/dl at follow-up 6 months later. Clinically, her diarrhoea slowly subsided within 1 week of starting TPN, and her weight increased from 39 kg on admission to 43 kg at follow-up.
We have described a case of severe RCD where symptoms persisted despite a strict GFD, treatment with steroids, antibiotics for small bowel bacterial overgrowth and pancreatic supplementation for pancreatic insufficiency. There is limited evidence and guidance on the most effective treatment options for RCD patients. Currently, only a strict GFD has been shown to be effective. However, our case illustrates the importance of the consideration of TPN in patients presenting with RCD; a short period of TPN in our patient induced remission of CD, enabling successful recovery, weight gain and total control of symptoms. This was sustained at follow-up.
Disclosure Statement {#sec1_4}
====================
We declare no support from or financial relationships with any organizations that might have an interest in the submitted work. We declare no financial, personal or professional competing interests related to the work. No ethical approval was required. The subject gave informed consent for publication. We maintained patient anonymity throughout the report.
We would like to thank Dr. A. Pal and Dr. S. Shariq for their help in revising the manuscript, Dr. J. Hoare for providing us with the enteroscopy images for inclusion in this case report, and Dr. F. Kubba for providing the immunohistochemistry images.
{#F1}
{#F2}
######
Constituents of Kabiven 14 per bag
-------------------------------- -----------
Nitrogen, g 13.5
Glucose, g/kcal 250/1,000
Lipid, g/kcal 100/1,000
Total non-protein energy, kcal 2,000
Sodium, mmol 80
Potassium, mmol 60
Calcium, mmol 5
Magnesium, mmol 10
Phosphate, mmol 25
Osmolarity, mOsm/l 1,230
-------------------------------- -----------
Each bag contains a total volume of 2,566 ml.
| 2024-06-10T01:26:59.872264 | https://example.com/article/9211 |
Q:
Remove double quote from an array
I am using WhereIn() method in Laravel to fetch various 'id', but the problem is the data am getting is like this ["6,19"] what am i expecting is an array with numbers without double quotes.
The data am getting is from a varchar field so, it comes as varchar and now i need to change that as [6,19] without double quotes. Please guide me to do so.
The whereIn method supports only array with numbers.
public function getusers($id)
{
$users = User::where('member_id', $id)->get();
foreach($users as $user)
{
$s = $user->path;
$s = str_replace('/', ',', $s); //this gives 6,19 and if i wrap that with [] it gives us ["6,19"].
return $usergs = User::whereIn("id", [$s])->get(); //[$s] gives like ["6,19"] -but i need to change that as [6,19] (array not string)
}
}
A:
You can explode on / instead, which makes it an array. You can then pass that array into whereIn() without needing to replace anything.
public function getusers($id)
{
$users = User::where('member_id', $id)->get();
foreach($users as $user) {
$s = explode("/", $user->path);
return $usergs = User::whereIn("id", $s)->get();
}
}
| 2023-11-03T01:26:59.872264 | https://example.com/article/5817 |
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