Vama Veche's reputation certainly precedes it. Situated in the southeast of Romania – right on the Black Sea coast, near the border with Bulgaria – the village has been regarded as a bohemian, non-mainstream tourist destination since communist times.
In more recent years, it has become widely known for the "Save Vama Veche" campaign, set up by locals who fear that their nudist beach and liberal morals are under threat from gentrification.
Yet, after having a look at these photos, I think we can safely say that Vama Veche's liberalism is still holding strong.
See more of Amdraci's photos here.


text: ==Physiography== The distribution of high and low ground ([[Media:P948957.jpg|P948957]]) is related both to the nature of the underlying rocks and to the denudation to which they have been subjected. In general, the Palaeozoic rocks, by reason of their relative hardness, give rise to areas of moderately high relief. In parts of south Gloucestershire and Avon, however, the outcrops of the Cambrian, Silurian, Old Red Sandstone and Carboniferous beds are characterised by low undulating country. This apparent anomaly is due to the removal by erosion of the Mesozoic cover from these older strata, revealing part of an ancient erosion surface which had been reduced to very low relief before it was covered by sediments in Mesozoic times. In the south-west and south of Bristol, Palaeozoic rocks form areas of moderate relief lying between 100 and 200 m above sea level. These comprise the Long Ashton to Clevedon ridge, which is separated by the Flax Bourton valley from the dome-like mass of Broadfield Down, with Dundry Hill, formed of Mesozoic rocks, on the north-east. This mass is limited to the south and east by the valleys of the Yeo and Chew rivers. Apart from the inlier of Cannington Park, near Bridgwater, the most southerly outcrop of Palaeozoic rocks in the district forms the elevated, undulating plateau of the Mendips, which extends from Frome on the east to Brean Down on the west, and continues out to sea in the rocky islands of Flat Holm and Steep Holm. Three hill ridges in the western part of the Mendips reach a height of just over 300 m. In contrast with this, there lies to the south of the Mendips an expanse of alluvial flats ([[Media:P206222.jpg|P206222]]) concealing extensive depressions scoured out of soft Mesozoic sediments. The dead flat of these moors or 'levels' is broken by the low ridge of the Polden Hills, Brent Knoll and the rising ground above Wedmore. Running roughly parallel with the eastern margin of the district, comparatively hard Jurassic limestones form the mass of the Cotswolds, whose indented, wall-like scarp, overlooking the Vale of the Severn, runs from Chipping Campden to Bath. On Cleeve Common, near Cheltenham, the Cotswolds reach their maximum height of 330 m. Southwards to Bath the general height of the range gradually decreases, the hills around Bath attaining an altitude of 180 to 240 m. To the south of Bath, the Mesozoic strata form a tract of ground which, though seldom exceeding 175 m in general height, is very varied in relief, being deeply dissected by the River Avon and its tributaries, notably the River Frome and the Cam and Wellow brooks. This region merges into the eastern part of the Mendips, where the Mesozoic rocks form a thin intermittent covering to the Palaeozoic strata. Between Bath and the Mendips the clay interval between the Jurassic limestones becomes more marked because of the replacement of the Great Oolite by the Frome Clay. Two roughly parallel ridges, separated from one another by low ground, are thus formed. The Inferior Oolite gives rise to the range of hills that runs from Lamyatt Beacon, near Bruton, past Castle Cary and Cadbury Camp, to near Yeovil. A second ridge, formed by the Forest Marble, lies to the east and extends from Wanstrow, past Redlynch, to Bratton. South of this point it comprises the eminences of Charlton Hill and East Hill near Milborne Port and, outside the region, the ridge of Lillington Hill lying to the south-east of Sherborne. Between Yeovil and Crewkerne, the Forest Marble limestone forms the Abbott's Hill and Ashlands Hill ridge, which reaches a height of 182 m. The drainage of the district is comparatively simple. Practically all rivers west of the Cotswold scarp flow into the Severn Estuary, whereas those which follow the dip slope of the Cotswolds join the Thames ([[Media:P948957.jpg|P948957]]). The Bristol Avon is an exception. Rising within the eastern margin of the district at Badminton, it flows eastwards as a consequent stream down the dip slope of the Cotswolds for about ten miles to Malmesbury, as if belonging to the Thames drainage system. At Malmesbury it turns south-west and follows the strike of the Jurassic beds to Bradford-on-Avon, whence it flows west and north to Bath, re-entering the district at Limpley Stoke. In its passage to Bath it runs against the dip of the Jurassic rocks and cuts a wide, deep valley. From Bath to Hanham Mills the river flows mainly over Triassic and Lower Jurassic strata, and then cuts a gorge in Coal Measures sandstone from which it emerges at Bristol. Here it turns as if heading for the Low Flax Bourton Valley and the sea at Clevedon, but instead of following this apparently easy route along the outcrop of the soft Triassic rocks it turns north-west at Clifton and enters the famous gorge carved in the hard Carboniferous Limestone ([[Media:P006701.jpg|P006701]]). Before flowing into the Severn Estuary at Avonmouth it is joined at Sea Mills by the River Trym, which cuts a similar, though smaller gorge through the Carboniferous Limestone ridge near Henbury. The Avon and its tributaries thus appear to represent superimposed drainage, i.e. their present anomalous courses were initiated not on the rocks and land surface at present exposed, but on a comparatively regular covering of Mesozic rocks which was subsequently removed by denudation. The course of the River Wye may have been similarly determined during the initial stages of its development.

redpajama_set_name: RedPajamaCommonCrawl


text:
‹ February 27: Election Day Sermon : Rev. Samuel Payson • February 29: Alta Woods Presbyterian Church [1948-2005] ›
February 28: Van Horn on WSC Q. 65
28 February, 2016 in February 2016 by archivist | No comments
Back-tracking slightly, we present today our previously missing treatment by Rev. Van Horn of Q. 65 of the Westminster Shorter Catechism.
STUDIES IN THE WESTMINSTER SHORTER CATECHISM
Q. 65 What is forbidden in the fifth commandment?
A. The fifth commandment forbiddeth the neglecting of, or doing anything against, the honor and duty which belongeth to everyone in their several places and relations.
Scripture References: Romans 13:7-8.
1. What are the sins of the superiors?
The sins of the superiors include the following: the neglect of those who are under their authority; the seeking of their own glory in the midst of their responsibility; the encouraging of inferiors into things that are wrong; the wrong use of authority toward inferiors, thus provoking them to wrath; the exposing of inferiors to wrong or temptation to wrong; the subjecting of the inferiors to a bad example because of wrong conduct.
2. What are the sins of inferiors?
The sins of the inferiors include the following: the neglect of obeying their superiors; the sin of envy toward their superiors; the act of rebellion toward those who are their superiors; the sin of wrong conduct against those in command; the showing of dishonor toward their superiors and the government they represent.
3. What are the sins of equals.
The sins of equals include the following: the neglect of Christian love toward one another; the despising of those that are good; the sin of envy because an equal has been blest by God with a gift greater than one's own; the lack of rejoicing at the success of an equal; the usurping of pre-eminence over equals when such pre-eminence has not been granted by God.
4. Do these sins relate to all relationships of man?
Yes, these sins are applicable to the relationships of man whether they be parent-child, husband-wife, master-servant, ruler-subject, minister-congregation, older-younger relationships.
5. In what areas of our lives today does this commandment relate?
It is pertinent in the family relationships, in the church relationships, in employment relationships and in the civic relationships. Sin in any of the areas is sin in the sight of God.
RESPECT FOR AUTHORITY.
"As long as you think a law or a rule is wrong it is alright to disobey it."—such is the reasoning being used today by children toward superiors, by the citizen toward the state, by the worker toward the boss, by the congregation toward the man called of God to preach The Word. It is a dangerous philosophy that is becoming very prevalent in our country and has even spread to conservative churches. This seems to be a day when everyone feels he has the perfect right to make his own rules and not be concerned about The Rulebook handed down by God. This fifth commandment speaks very clearly to the person following this false philosophy.
The Almighty, Sovereign God knew that respect for authority was very important in order that a family, a nation, an economy, a church might be able to carry on its duties in the world. Therefore He emphasized proper respect for authority in His Word time and time again. His words, "Obey them that have rule over you" are stated over and over again in different ways by different writers in The Word. he knew that a lawless society becomes a mob and a mob becomes a group of people out of hand.
What has caused the loss of respect for authority? What has caused this new philosophy to make inroads into our way of thinking? There is not space in this short devotion to answer the question for all of life but a suggestion could be offered as to why it is happening in conservative churches. It is simply another indication of a departing from what God hath said, a closing our eyes to certain portions of The Word because we find them too unpopular for the certain portion of society in which we find ourselves. Whenever a Christian or a Christian church breaks a principle of Scripture the result is always disaster. Disaster in this area not only comes to the person or the church but it also comes to the young people committed to the care of the person or the church.
Why are the young people of today showing such a disrespect for authority? Could it not be that they see such inconsistencies in their elders that they have no example to follow? Where is church discipline today? Where is Christian love toward all people today? Where is the unqualified stand against compromise today? Do our children see things in us? Might we read again Titus 2 – 3:3?
Published by The Shield and Sword, Inc.
Vol. 4, No. 59 (November 1965)
Rev. Leonard T. Van Horn, Editor.


text:
Safety And Security On Campus
Covid-19: Planning a Safe Return to Campus
Our Strategic Direction
Vision and Ambition
The Welsh language
How to Request Information
Appeals Procedure
The Freedom of Information Act (2000) came fully into force from 1 January 2005, and provides public access to information held by public authorities. The Act covers any recorded information that is held by a public authority in England, Wales and Northern Ireland, and by UK-wide public authorities based in Scotland. Recorded information includes printed documents, computer files, letters, emails, photographs, and sound or video recordings. Because of their access to public funding, universities are designated as public authorities for the purposes of the Act.
The Act enables any person anywhere in the world to make a Freedom of Information request, in writing, to a public authority, and normally the public authority must respond within 20 working days. "In writing" can be by either hard copy or electronic means. The person making the request does not have to say that they are exercising their rights under the Freedom of Information Act.
According to government guidance, Students' Unions are not considered public authorities for the purposes of the Act.
Implementation of the Freedom of Information Act is overseen nationally by the Information Commissioner's office, which has the same role in relation to Data Protection.
The Act does not give people access to their own personal data (information about themselves) such as their student records. If a member of the public wants to see information that a public authority holds about them, they should make a subject access request under the The General Data Protection Regulation and the Data Protection Act 2018.
FOI Compliance Statistics


text:
// Copyright 2018 The Chromium Authors. All rights reserved.
// Use of this source code is governed by a BSD-style license that can be
// found in the LICENSE file.

package org.chromium.chrome.browser.customtabs;

import androidx.browser.customtabs.CustomTabsCallback;
import androidx.browser.customtabs.CustomTabsSessionToken;

import org.chromium.chrome.browser.browserservices.BrowserServicesIntentDataProvider;
import org.chromium.chrome.browser.dependency_injection.ActivityScope;
import org.chromium.chrome.browser.tab.EmptyTabObserver;
import org.chromium.chrome.browser.tab.Tab;
import org.chromium.chrome.browser.tab.TabHidingType;
import org.chromium.chrome.browser.tab.TabSelectionType;
import org.chromium.components.security_state.SecurityStateModel;

import javax.inject.Inject;

/**
 * An observer for firing navigation events on {@link CustomTabsCallback}.
 */
@ActivityScope
public class CustomTabNavigationEventObserver extends EmptyTabObserver {
    // An operation was aborted (due to user action). Should match the value in net_error_list.h.
    private static final int NET_ERROR_ABORTED = -3;

    private final CustomTabsSessionToken mSessionToken;
    private final CustomTabsConnection mConnection;

    @Inject
    public CustomTabNavigationEventObserver(
            BrowserServicesIntentDataProvider intentDataProvider, CustomTabsConnection connection) {
        mSessionToken = intentDataProvider.getSession();
        mConnection = connection;
    }

    @Override
    public void onPageLoadStarted(Tab tab, String url) {
        mConnection.notifyNavigationEvent(mSessionToken, CustomTabsCallback.NAVIGATION_STARTED);
    }

    @Override
    public void onPageLoadFinished(Tab tab, String url) {
        mConnection.notifyNavigationEvent(mSessionToken, CustomTabsCallback.NAVIGATION_FINISHED);
    }

    @Override
    public void onPageLoadFailed(Tab tab, int errorCode) {
        int navigationEvent = errorCode == NET_ERROR_ABORTED ? CustomTabsCallback.NAVIGATION_ABORTED
                                                             : CustomTabsCallback.NAVIGATION_FAILED;
        mConnection.notifyNavigationEvent(mSessionToken, navigationEvent);
    }

    @Override
    public void onShown(Tab tab, @TabSelectionType int type) {
        mConnection.notifyNavigationEvent(mSessionToken, CustomTabsCallback.TAB_SHOWN);
    }

    @Override
    public void onHidden(Tab tab, @TabHidingType int type) {
        mConnection.notifyNavigationEvent(mSessionToken, CustomTabsCallback.TAB_HIDDEN);
    }

    @Override
    public void onDidAttachInterstitialPage(Tab tab) {
        boolean isContentDangerous = SecurityStateModel.isContentDangerous(tab.getWebContents());
        if (isContentDangerous) {
            return;
        }
        mConnection.notifyNavigationEvent(mSessionToken, CustomTabsCallback.NAVIGATION_FAILED);
    }
}

redpajama_set_name: RedPajamaGithub


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text:
Q: Very large numbers in C++ for competitive programming I would like to know how to use very large numbers (being accurate 10^100 in C++) for competitive programming. I know libraries like GMP exist but they can't be used sites like SPOJ or CodeChef.
I have used strings, however it takes lot of time to implement it. Now I would like to know what efficient methods do  other programmers use and resources to learn those methods. Thanks!

A:
I would like to know what efficient methods other programmers use

Most of the time you can't use any third-party libraries when submitting your solutions to online judge systems like SPOJ or at contests (however some contests need only .out files, so it doesn't matter how you get them).
Since you cannot use anything external, competitive programmers write their BigNum classes on their own. It is not really so hard using dynamic arrays or data structures like std::string in C++.

How to?
Practice is your best friend when you are trying to beat and solve online judge/contest problems.
Paper, pencil, your mind, nothing else is required to find out how to implement your BigNum class.
Consider how you can read/write big numbers as std::string, then go one level further and try to add/remove leading-zeros, count a sum of two big numbers... and then, further things will be easier.

redpajama_set_name: RedPajamaStackExchange


text:
Q: A Question Regarding the Command optimization.step(closure) in PyTorch I, as a PyTorch beginner, have a question regarding the command optimizer.step(closure) . According to PyTorch documentation:
Some optimization algorithms such as Conjugate Gradient and LBFGS need to reevaluate the function multiple times, so you have to pass in a closure that allows them to recompute your model. The closure should clear the gradients, compute the loss, and return it.
Example:
    def closure():
        optimizer.zero_grad()
        output = model(input)
        loss = loss_fn(output, target)
        loss.backward()
        return loss
    optimizer.step(closure)

What I cannot understand is why we need to define closure for some particular optimization algorithms?


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Current Projects Blog: check out the latest news!
Steve Belardo is a hands-on builder, from the initial drawings and design to the groundbreaking to the completion of my handmade house. He and his team made my home, one of the largest projects they've worked on in recent years, rise up from the native rock on this mountain and take its place as part of the landscape. The process was incredible to watch over the year (2013) it took to make my dream a reality. I'll never forget it–a magical time with a magical result!
We asked Steve to build our adobe home on a mountain top in a remote area which was a challenging task. We are very pleased with the construction of our passive solar home completed in 2012.
It is our little gem in the mountains.


LAWRENCE — The former governor of Missouri and a Florida Federal Emergency Management Agency official will be introduced at a public reception Thursday, Feb. 1, as the spring 2007 fellows at the Robert J. Dole Institute of Politics at the University of Kansas.
Bob Holden, a former Missouri governor, and Scott Morris, director of FEMA's Florida Long-Term Recovery, will spend the spring semester at the institute leading weekly not-for-credit study groups beginning in late February. Students, faculty and the public are invited to meet Holden and Morris at a reception in their honor at 5 p.m. Feb. 1 at the institute.
Holden's 25-year career in public service includes his terms as governor from 2000 to 2004, Missouri state treasurer from 1992 to 2000 and state representative from 1983 to 1989. He is chairman of The Holden Group LLC, a business development and international trade strategies firm. He leads the Governor Bob Holden Pubic Policy Forum at Webster University in St. Louis.
Morris has served as director of the Florida Long-Term Recovery operation since its inception in May 2005. He was immediately responsible for FEMA's recovery from the 2004 hurricane that hit Florida. He continues to oversee recovery efforts in the state. He was also the deputy chief of staff for the Department of Homeland Security's Emergency Preparedness and Response directorate. Before joining homeland security, Morris was deputy chief of staff and White House liaison for the Small Business Administration.
Holden's study group will meet at 4 p.m. Thursdays beginning March 1. His group, titled "You Be the Governor: Making Decisions in the Fast Lane — Policy vs. Politics," will examine real-life problems and decisions that governors face.
Morris' study group will meet at 4 p.m. Wednesdays beginning Feb. 28. His group, titled "The Politics of Disasters," will examine the policy process of disastrous events such as Hurricane Katrina. More information is available on the Dole Institute's Web site.
The institute's spring semester faculty liaisons are Mary Banwart from the Department of Communication Studies, Raquel Alexander from the School of Business and Catherine Weaver from the Department of Political Science. They will also be introduced at the reception.


text:
March 8, 2010 — In addition to this week's NewsBreaks article and the monthly NewsLink Spotlight, Information Today, Inc. (ITI) offers Weekly News Digests that feature recent product news and company announcements. Watch for additional coverage to appear in the next print issue of Information Today. For other up-to-the-minute news, check out ITI's Twitter account: @ITINewsBreaks.
Alexander Street Press Jazzes Up Its Collections
Alexander Street Press (http://alexanderstreet.com) announced that its suite of Music Online streaming audio collections will triple in size over the next 9 months, growing from a current total of more than 250,000 recordings to more than 750,000 by the end of the year. In 2011, Alexander Street's plan is for Music Online to hit the milestone of 1 million recordings. The company also promises no price increases.
Individual streaming collections in Alexander Street's Music Online suite that will double or triple in size include Classical Music Library, Jazz Music Library, American Song, and Contemporary World Music. Libraries that subscribe to the entire suite of Music Online listening collections will have access to an additional 140,000 popular music recordings. The publisher also announced that recording stream quality will improve to 320Kbps, and that, soon, listening collections will be accessible via handheld mobile devices. None of these enhancements will result in a price increase. New, lower price points are available for Jazz Music Library, American Song, and Contemporary World Music, and all new subscriptions to these collections will come with unlimited access.
In partnership with the State University of New York-Binghamton's Center for the Historical Study of Women and Gender, Alexander Street also announced that the online resource Women and Social Movements in the United States 1600-2000, Scholar's Edition, will be freely accessible for the month of March so that all librarians, students, instructors, and scholars can explore the site's rich collection of primary materials and teaching tools without passwords or fees (http://wass.alexanderstreet.com).
Alexander Street Press is an electronic publisher of online collections in the humanities, social sciences, performing arts, and music.
Source: Alexander Street Press
1/20/2011 Streaming Video and Music Developments at Alexander Street Press


For the Lord who has an eye in His forehead.
Of the Lord enthroned in the Flower-Temple.
Red-lipped and liana-like --, that hath my mind captivated"?
Not to be attained even by the celestial beings."
Is immense as the seven ocean-streams."
Hied and entered the temple of the God of gods.
Unto the Lord to gift her to him.
That abides at the Ant-Hill.
The swan, dear as my life?"
Of ruddy lips and bright and white teeth.
She is sure the grace of God; whither has she gone."
Which way did she -- my Lord's grace --, wend her way."
Which way did she -- my Father's grace --, go?"
"Where is she, my life?" said he.
The one whose locks were decked with flowers.
My life -- the damsel like the one on the lotus throaned."
Behold this, I can surely pass beyond this sea."
As he plunged into the sea.
Repaired to their nests and were slunk.
Thus came the dreadful evening to grieve the parted.
The great heavens did darken dense.


With the 2019 Budget week having concluded following the formal delivery of the 2019/20 Federal Budget by the Treasurer on 2 April 2019, and the Opposition response on 4 April 2019, it's now "game on" in terms of policy positions as the electorate starts to consider where they will cast their vote in the upcoming election.
For some voters, the decision on where they cast their vote will be influenced by where the future elected Government will focus their spending. In this respect, both sides of politics have made announcements for spending on defence, education, welfare, health, transport and infrastructure. Often, expenditure in these areas will not show an immediate benefit to individuals, but can form the basis for longer term changes. The actual or perceived benefits of expenditure in these areas will differ from person to person, and in this paper there will not be a comparison of the relative benefits from such expenditure.
For many however, reform or changes to areas such as taxation or superannuation have a more immediate impact because of their ability to influence shorter term actions. To help provide you with an overview of the differences (or in some cases consistency) in positions, the following is a comparison of the more significant positions proposed by both sides of politics, drawn from announcements during both Budget week itself, and at other times as both sides have positioned themselves towards the upcoming election.
Both the Coalition and Labor parties are in agreement on the need to provide additional tax relief to low and middle income earners. There is also consistency in the view to lift the level of tax offset available to individuals with more than $48,000 of taxable income and up to $126,000. Both sides are in agreement on a maximum offset of $1,080 being available to those with taxable incomes between $48,000 and $90,000 and a gradual phase out of the benefit up to a taxable income of $126,000, with the changes to have effect for the current financial year (ie from 1 July 2018).
The Coalition has proposed a minimum tax offset of $255 for those with taxable income up to $37,000 and a gradual increase until taxable income reaches $48,000.
Labor have instead proposed a minimum tax offset of $350, again with a gradual increase until income reaches $48,000 at which point the maximum $1,080 offset is available.
More significant differences in approach arise when it comes to the issue of the broader reform of the marginal tax rates and thresholds that apply to individuals.
The Coalition has already legislated (subsequent to the 2018/19 Federal Budget) for changes to take effect to this system through to 2024/25. In this year's Federal Budget, the Coalition announced further changes.
From 1 July 2022, the current taxable income threshold of $37,000 where an individual moves from a 19% marginal tax rate to a 32.5% marginal tax rate will rise to $45,000 – a $4,000 increase in the threshold level announced in the previous Federal Budget. At the same time, the upper threshold for application of the 32.5% tax rate is scheduled to rise from $90,000 to $120,000 of taxable income.
From 1 July 2024, whilst in government the Coalition has already legislated for the existing marginal tax rate of 37.0% that would then have applied to taxable income between $120,001 and $180,000 to be removed, with the same marginal tax rate to then apply to taxable income between $45,000 and $200,000. In this year's Budget, the Coalition have indicated their intent to reduce that applicable marginal tax rate from 32.5% to 30.0% from 1 July 2024. The existing 45.0% marginal tax rate would then apply to taxable income above $200,000.
The Labor party is not supportive of this level of reform to the personal marginal tax rates and thresholds, specifically not to the changes due to take effect from 1 July 2024. If elected, we would expect the Labor party to look to legislate for the proposed 2024 changes not to take effect, although it is not clear to what extent they would seek to make changes to the existing rates and thresholds due to apply from 1 July 2022.
However, what the Labor party has proposed is the re-introduction of the 2% "budget repair levy" for those generating taxable income greater than $180,000. In recent times Labor have confirmed this effective increase in the highest marginal tax rate from 45% to 47% (excluding Medicare) would be a temporary increase until 2023.
In the 2019/20 Federal Budget, the Coalition announced that small businesses would receive an extension of the ability to immediately write off (ie deduct for tax purposes) the value of an eligible asset. This immediate write down will be extended to 30 June 2020, and the write off value lifted to $30,000 (from $20,000) for assets purchased after 7:30pm AEST on 2 April 2019. Additionally, they proposed that the definition of a small business eligible for this will be increased from business valued at up to $10 million to those valued at up to $50 million.
The Labor party has indicated it would support this measure, although it has proposed a broader measure they have termed the "Australian Investment Guarantee" that would allow any Australian business (irrespective of its size) to immediately deduct 20% of the purchase price of any eligible asset purchased that is worth more than $20,000.
The Coalition haven't announced any changes to the taxation rules on negative gearing arrangements and capital gains discounting. As such at this point we have to assume that their position is to maintain the status quo.
From 1 January 2020, negative gearing will only be permitted in respect of a geared investment into newly constructed housing purchased on or after that date. Any deductions for geared investments (whether property, shares, or managed funds) purchased from that date will be limited to the assessable income generated by the investment. Any excess interest costs can be added to the cost base of the asset for determining the level of any future capital gain.
For assets purchased on or after 1 January 2020 that would be entitled to a 50% CGT discount on sale under existing rules, that discount will be reduced to 25%.
Grandfathering arrangements will apply to geared investments and CGT calculations for assets purchased before 1 January 2020. That is, the current rules allowing negative gearing deduction and a 50% CGT discount will continue to apply to those investment assets.
The Labor party remains committed to amending the law such that where an individual or super fund has excess imputation credits remaining after calculation of its tax payable, those excess imputation credits will be forfeited, rather than refunded. This change, which is due to take effect from 1 July 2019, is a return to the position that applied before 1 July 2000.
A "pensioner guarantee" exemption is available to allow for the refund to continue in specific circumstances.
The Coalition's policy positon is to allow the refund of excess imputation credits to continue.
The Labor party has stated that where a distribution is made from a discretionary trust (such as a family trust) to a beneficiary aged at least 18, that distribution will be taxed at a minimum of 30%. If the beneficiary's effective tax rate is less than 30%, they will not receive a refund of the difference. If it is higher, they will need to pay the difference as additional tax. Some trusts (eg testamentary trusts) will be exempt from this change.
The Coalition has not announced any policy position in this area.
Make contributions to super without the need to meet a work test until they turn 67. Currently the work test applies from your 65th birthday.
Receive a spouse contribution until they turn 75. Currently, a spouse contribution can only be received before the receiving spouse turns 70.
The annual contribution limit for non-concessional (after tax) contributions will be lowered from $100,000 to $75,000. It is expected the requirement to have less than $1.6 million in order to qualify to make these contributions will continue to apply.
The level of adjusted taxable income a person can have before an additional 15% tax is applied to concessional contributions made to their super will be lowered to $200,000 (from the current level of $250,000).
The ability to carry forward any unutilised concessional cap space for up to 5 years to allow a greater concessional contribution cap in the future (subject to certain criteria) will be removed.
The changes that took effect from 1 July 2017 to allow all eligible taxpayers to claim a deduction for contributions made to their super fund will be reversed, and the position that applied before that change will be reinstated.
A ban on future borrowings within a superannuation fund.
With an election set for 18 May 2019, the policy positions for both sides largely remain just that - announcements of their stated intent if they were successfully elected.
Even when it becomes known who is able to form Government after the election, the measures will still need to be successfully passed through the parliamentary processes and it is possible that the final version of these measures could be different to that which has currently been stated. It is important therefore not to rush out and take action on what is currently just a potential future outcome in case changes are made.
The best course of action however is to continue to monitor development on both sides of politics through the election and subsequent parliamentary process to ensure informed decisions can be made at the right time.
Stay current. Get access to economic updates, market news and practice insights.
Updates covering the Australian Federal Budget 2019 and how it will affect you and your investments.
The information has been prepared by BT, a part of Westpac Banking Corporation ABN 33 007 457 141 AFSL and Australian Credit Licence 233714 (Westpac), and is current as at 11 April 2019.
Material contained on this website is an overview or summary only and it should not be considered a comprehensive statement on any matter or relied upon as such. This website may contain material provided by third parties derived from sources believed to be accurate at its issue date. While such material is published with necessary permission, no company in the Westpac Group accepts any responsibility for the accuracy or completeness of, or endorses any such material. Except where contrary to law, we intend by this notice to exclude liability for this material. The information on this website regarding legislative changes is intended as a guide only. It is not exhaustive and does not constitute legal advice. It is based on our interpretation of the law currently in force on the date of this notification and does not undertake to provide any updates to the extent that any of the laws or regulations referred to change in the future. Consequently, it should not be relied upon as a complete statement of the relevant laws, the application of which may vary, depending on your particular circumstances.
This information does not take into account your personal objectives, financial situation or needs and so you should consider its appropriateness, having regard to these factors before acting on it.
Any case studies and examples used on this website are purely for illustration only.
The tax position described on this website on the 2019-20 Federal Budget update is a general statement and is for guidance only. It has not been prepared by a registered tax agent. It does not constitute tax advice and is based on current tax laws and our interpretation. Your individual situation may differ and you should seek independent professional tax advice. It is important to note that the policies outlined in this website are yet to be passed as legislation and therefore may be subject to change or further refinement. Superannuation is a means of saving for retirement, which is, in part, compulsory. The government has placed restrictions on when you can access your investments held in superannuation. The Government has set caps on the amount of money that you can add to your superannuation each year and over your lifetime on both a concessional and non-concessional tax basis. There will be tax consequences if you breach these caps. For more detail, speak with a financial adviser or registered tax agent or visit the ATO website.


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Home/Entertainment/Kyle Sandilands reveals if he'd ever return to TV and how much he was offered for I'm A Celebrity
Kyle Sandilands reveals if he'd ever return to TV and how much he was offered for I'm A Celebrity
DUK Editor Team Send an email June 9, 2021
Kyle Sandilands reveals if he'd ever return to TV and the shocking amount of money he was offered to be cast on I'm a Celebrity… Get Me Out of Here!
Published: 04:20 EDT, 9 June 2021 | Updated: 04:20 EDT, 9 June 2021
Kyle Sandilands has focused on cultivating an incredibly successful radio career over the past two decades.
And while he's had several stints on TV shows over the years, the shock jock revealed if he would ever return to the small screen on the latest installment of Samantha Armytage's podcast, Something To Talk About.
Speaking on the eve of his 50th birthday, he explained that he does not get 'a thrill' out of TV as he does with radio.
Never saying never: Kyle Sandilands told Samantha Armytage on her podcast that he 'wouldn't say no to TV' following stints on shows like Australian Idol and X-Factor in the past
'It's live, it happens, once you've said it it's done. No one else can edit it out.'
He explained that TV opportunities – with shows like Australian Idol and X-Factor – were exciting, but pointed out the TV production process frustrated him.
'It was fun, Idol was fun, X-Factor was fun. All those shows, but it takes forever (to film). One hour of Idol, it take four days non-stop filming,' he said.
'And then someone else decides what's funny. That's what I didn't like, that someone editing. I'd watch and I think "oh, I said something that I thought was better that, but someone else has edited it",' he added.
No way! Kyle went on to reveal that he was asked to join Channel Ten's I'm a Celebrity… Get Me Out of Here! but said it was something he would 'never do'. Recalling a call with one of the show's producers, he said: 'They offered me $1.4million to go over to the jungle and I said no'
But if presented with another opportunity to be on TV he said: 'I wouldn't say no to TV.'
He then went on to reveal that he was asked to join Channel Ten's I'm a Celebrity… Get Me Out of Here! but said it was something he would 'never do'.
Recalling a call with one of the show's producers, he said: 'Like "do you want to go and sit in the jungle for three weeks with Casey Donovan and eat worms?" No! I do not want to do this thing.
Reality TV: Fans of Kyle Sandilands will remember one of earliest TV stints was on Celebrity Big Brother in 2002
Idol judge: He was then cast as a judge on Australian Idol in 2005, but was sacked in by Channel 10 in 2009 after a controversial radio stunt
He continued: 'I'll give you one million dollars, I said no,' leaving Samantha shocked at the offer.
'They offered me $1.4million to go over to the jungle and I said no, and then they gave Warnie (Shane Warne) $2million and I was like "oh well, f*** you forever",' he added.
'They offered me a million for three weeks work. But there's no way I'm going to do that. I'd rather not do it,' he said of the offer to join I'm A Celebrity.
The shock jock added that he also chose to decline the offer because he was busy with radio survey and did not want to fly 'all the way' to Africa.
Breakfast judge: In 2010, Kyle was cast as a judge on Australia's Got Talent and The X Factor but left in 2011. He left TV in 2011 to focus on his radio show with Jackie 'O' Henderson
Fans of Kyle Sandilands will remember one of earliest TV stints was on Celebrity Big Brother in 2002.
He was then cast as a judge on Australian Idol in 2005, but was sacked in by Channel 10 in 2009 after a controversial radio stunt.
In 2010, Kyle was cast as a judge on Australia's Got Talent and The X Factor but left in 2011 to focus on his radio show with Jackie 'O' Henderson.
His most recent stint was back in 2018 on Channel 10 with his own show Trial By Kyle in which he passed judgement on a range of real life cases.
TV judge: His most recent stint was back in 2018 on Channel 10 with his own show Trial By Kyle in which he passed judgement on a range of real life cases
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import { fromJS, Repeat, OrderedMap } from 'immutable';
import {
    CHANGE_ACTIVE_LAYOUT,
    RESET_TRADES,
    REMOVE_TRADE,
    REMOVE_PERSONAL_DATA,
    UPDATE_TRADE_ERROR,
    CLEAR_TRADE_ERROR,
} from '../../_constants/ActionTypes';

const defaultError = new OrderedMap({
    durationError: undefined,
    barrierError: undefined,
    stakeError: undefined,
    proposalError: undefined,
    contractForError: undefined,
    purchaseError: undefined,
});

const initialState = fromJS([defaultError]);

export default (state = initialState, action) => {
    switch (action.type) {
        case CHANGE_ACTIVE_LAYOUT: {
            const oldTradesCount = state.size;
            const newTradesCount = action.tradesCount;
            const countDiff = newTradesCount - oldTradesCount;

            if (countDiff > 0) {
                const additionalError = Repeat(fromJS(defaultError), countDiff);   // eslint-disable-line new-cap
                return state.concat(additionalError);
            }

            if (countDiff < 0) {
                return state.take(newTradesCount);
            }

            return state;
        }
        case RESET_TRADES: {
            return initialState;
        }
        case REMOVE_TRADE: {
            if (!state.get(action.index)) {
                return state;
            }
            return state.remove(action.index);
        }
        case REMOVE_PERSONAL_DATA: {
            return initialState;
        }
        case UPDATE_TRADE_ERROR: {
            const { index, errorID, error } = action;
            return state.setIn([index, errorID], error);
        }
        case CLEAR_TRADE_ERROR: {
            const { index } = action;
            return state.set(index, fromJS({}));
        }
        default: return state;
    }
};


text:
Breaking News Featured Sport
More Brilliant Events for Olympic star Georgia
Gary Carter December 31, 2021	No Comments 2021correspodnentdroysldengeorgia taylor brownMBEnew years eveNewsolympianqueens honourssportTameside
TAMESIDE'S Olympic gold medallist Georgia Taylor-Brown has won another major honour – an MBE.
The Droylsden triathlete has been recognised in the New Year's List after her achievements in Tokyo.
Not bad for someone who started their journey by running along the canal bank in her hometown on her way to cycling training.
And her first memory was just wanting to beat the boys in swimming lessons at Audenshaw's Aldwyn Primary School, where her nephew attends.
Georgia Taylor-Brown silver medal Toyko Olympics 2021 @TeamGB David Pearce
Georgia's honour has come after she won gold in the triathlon mixed relay, to add to the silver medal from the women's individual event.
Speaking to The Correspondent after her Tokyo triumphs, which were under threat when she suffered a leg stress fracture only 11 weeks before the Olympics, Georgia will have three more letters to bring home with her.
The 27-year-old, who now lives in Leeds, said: "I used to pop home quite regularly before Covid but haven't been able to since the beginning of last year.
"I enjoy a nice little run along the canal and I really love going to the mountain bike track by the Manchester Velodrome – it's so much more fun than being on the road.
"I don't think the silver medal added any pressure. I was just really excited.
Georgia Taylor-Brown in the Womens Triathlon Tokyo 2020
"I was just happy to be back at the race site and ready to go and we all want to inspire. Hopefully we can do that for the next generation.
"And I definitely remember being better than all of the boys at swimming lessons and very competitive on sports day!"
Georgia's then teacher Caroline Charnock is now Aldwyn's headteacher and she recalled the medals and certificates she won as a child laying the platform.
Caroline said: "What I loved most of all was Georgia's positive attitude when interviewed.
"It demonstrated that she competes with intelligence, determination and above all, the love for her sport and the fun she has with her team-mates.
"The way she was congratulated by her fellow competitors showed us that her achievement was being celebrated not only as an Olympian but as a valued member of Team GB.
"Little did we know when we awarded Georgia numerous certificates and medals rewarding her sporting achievements in assembly that we were recognising the great strides Georgia was taking towards becoming an Olympian.
"We did know, however, that her attitude to learning and friendships would contribute to a successful career."
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text:
Brillion FFA students ready for Indianapolis
By David Nordby The Brillion News
BRILLION – Four Brillion High School students will embark on a trip to Indianapolis next week to compete for national recognition in the 89th National Future Farmers of America (FFA) Convention and Expo.
Ben Kasten, Katarina Meyer, Hannah Roehrig and Tyler Schmidt will participate in the area of poultry evaluation. Poultry evaluation is one of 24 national CDE areas, but to the students involved, FFA is about way more than just chickens.
"It [FFA] relates to everything. Decision making, leadership traits and responsibility. [It] helps make you a better person," Kasten, the lone senior on the team, said.
The poultry team took first at the state competition earlier this year in Madison, which qualified them for Indianapolis.
"It's cool we get to represent our chapter and our school when we get to go down there," Meyer said.
FFA is the largest student organization at Brillion High School, with around 75 members. Nationally, it is in all 50 states with 7,757 chapters and 629,367 students.
The group has plenty of experience including a recent trip to Minnesota where they took third in their region at a poultry event and Kasten finished sixth overall. The other three members finished in the top 50 of the large event too. They also took first at a competition in Platteville and second at Fox Valley Tech.
"It's pretty amazing what these guys have done," Brillion FFA Advisor Stacey Kunde said.
The trip lasts from Tuesday, October 18 through the 22nd with competition on the 20th. Unlike their previous experiences, the group will be paired with other FFA members from around the country, which they all admit to some apprehension about. The groups will judge different categories, identify different parts of chickens, participate in a written exam on chickens and farms and meet with judges to give their reasoning behind their assessments.
All of the uncertainty of the trip has the students admittedly anxious, but not in a bad way. "You don't know what's going to happen," Schmidt said. Roehrig added she's nervous to be in a room alone with the judges.
"It's not anything specific, it's just the fact it's nationals … That's nerve-racking," Kasten said.
Please see the complete story in the October 13, 2016 edition of The Brillion News.


text:
For example: Senior Care
Faith Christian School
What is Faith Christian School? Why do we exist? Is our school a collection of desks, books, computers, and science equipment?
Address 505 S Englewood Dr Rocky Mount, NC 27804-4020
Website www.fcspatriots.com
MISSION AND COMMITMENT
What is Faith Christian School? Why do we exist? Is our school a collection of desks, books, computers, and science equipment? If these were the essence of Faith, words and pictures could capture it well. But, Faith is not just a building or blackboards, crayons or computers, libraries or lesson plans. Faith Christian School is a concept; a vision conceived in the hearts of parents in our community who saw both a tremendous need and an outstanding opportunity. Faith is a commitment; a desire for excellence, for achieving ones personal best in every area of living. Faith is Christian, an unapologetic dedication to the truth of God. All curricula choices, all teachers, all lesson plans, all spending decisions, and all programs are filtered through our conviction that God is in all and over all. We seek to accomplish academic excellence, athletic excellence, social excellence and excellence of character, but none of this is truly possible apart from the foundation of every aspect of Faith Christian in the Word of God.
Faith exists to assist families who are committed to raising godly children. Our mission is to provide teachers and curriculum that will make a life-changing impact on our students lives, so that they, in turn, will impact their school, community and world with the truth of God. We desire to produce students who are trained and prepared to model a life of commitment to God and His principles in all of the circumstances of their lives.
Faith Christian School aspires to glorify God by assisting Christian families in providing a Biblical education that cultivates Godly character and promotes academic excellence.
In accordance with the teachings of the Word of God, this institution is committed to the following fundamental principles: 1) The instruction and education of children in the school as well as the home must conform to the Word of God. 2) The school, as an institution, properly depends on and proceeds from the home, rather than the church or state.
In addition, the administration of the school would urge Christian parents to recognize their Scriptural responsibility (Deut. 6:1-9, Ps. 78:5-6, Pro. 22:6) to provide their children with an education from a Biblical world and life view. Faith Christian School provides families with the expertise and assistance to accomplish this task. The process of Christian education involves the cooperative effort of the home, church and school. Each must support the other for the training to become effective.
School Verse
And whatever you do, whether in word or deed, do it all in the name of the Lord Jesus, giving thanks to God the Father through him. Colossians 3:17
Branches and additional offices:
(252) 443-3700 1333 Faith Christian Dr Rocky Mount, NC 27803-2122
(336) 824-8388 5449 Brookhaven Rd Ramseur, NC 27316-8001
Gaston Christian School Middle High School
The mission of Gaston Christian School is to help students mature spiritually and excel academically by offering a Biblically integrated, college-prep
1625 Lowell Bethesda Rd Gastonia, NC 28056-9496
St Pius X Catholic School
Catholic Elementary and Middle School education emphasizing Catholic values, traditions, heritage and doctorine.
2200 N Elm St Greensboro, NC 27408-5118
Covenant Classical School
While other schools trim subjects like history, language, literature, and logic, Covenant Classical School pursues these traditional subjects
3200 Patrick Henry Dr NW Concord, NC 28027-7890
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Childcareconnections. org offers School Age, Day Care Centers, Professional Development, and Assistance Program.
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text:
Major traumatic brain injury linked to higher dementia risk
Researchers from Finland have found that people who required a hospital stay following a major traumatic brain injury (TBI) were more likely to develop dementia. The new study was published today (Wednesday 11 May) in the journal Neurology.
TBI is one of 12 potentially modifiable or preventable risk factors for dementia. Others include smoking, excessive alcohol consumption and physical inactivity. According to a landmark study published in The Lancet, if it were possible to entirely eliminate these 12 risk factors we could prevent up to 40% of dementia cases worldwide.
In this new study, researchers at the University of Helsinki looked at the hospital records of 31,909 Finnish people spanning a 20-year period. The participants were aged between 25-64, had regular health check-ups every five years between 1992-2012 and were monitored for dementia diagnoses for up to five years after the study.
Nearly 700 of the participants had been hospitalised with TBI between 1970 and 2017. Out of all the participants in the study, 976 were diagnosed with a form of dementia.
This study classified people as having either major or minor TBI based on the length of their stay in hospital and whether doctors found evidence of physical damage to the brain. The results showed that participants who were in hospital for three or more days following major TBI had a higher risk of developing dementia in later life. This was true even when age, sex and other dementia risk factors such as excessive alcohol consumption and physical inactivity were considered.
The researchers found that people who were hospitalised for up to one day following minor TBI did not have a significantly increased risk of developing dementia.
Dr Rosa Sancho, Head of Research at Alzheimer's Research UK, said:
"There are many different risk factors for dementia including genetics, which we cannot change, but also environmental and lifestyle factors which we may be able to influence. Research has highlighted traumatic brain injury as an important risk factor for dementia, but there is huge variation in the severity of these injuries and we don't yet know the point at which they will significantly affect the long-term health of the brain or how they interact with other dementia risk factors.
"This study provides further evidence that major traumatic brain injury increases dementia risk, but the findings suggest that this effect was weakened in people who were physically active and didn't drink too much alcohol. The results highlight the complex nature of dementia risk and the importance of the combined effects of several factors.
"The researchers only considered TBI cases requiring hospital admission in the study and did not look at the effects of smaller, more frequent head impacts common in some sports. Alzheimer's Research UK is currently working to identify the most important questions in how sport and head injuries can affect our brain health. Studies like this are crucial for informing clinicians and policymakers and to implement strategies to reduce dementia risk as much as possible. Our Think Brain Health campaign has more information about dementia risk factors that may be possible to influence."
Read the full paper 'Risk of Dementia After Hospitalization Due to Traumatic Brain Injury: A Longitudinal, Population-Based Study' in Neurology.
Share with your followers!
Major traumatic brain injury linked to higher dementia risk. Read more here: Click To Tweet


text:
package net.dougqh.jak.jvm.operations;

import java.lang.reflect.Type;

import net.dougqh.jak.jvm.JvmOperationProcessor;

public final class lload_3 extends FixedLoadOperation {
	public static final String ID = "lload_3";
	public static final byte CODE = LLOAD_3;

	public static final lload_3 instance() {
		return new lload_3();
	}

	private lload_3() {}

	@Override
	public final String getId() {
		return ID;
	}

	@Override
	public final int getCode() {
		return CODE;
	}

	@Override
	public final int slot() {
		return 3;
	}

	@Override
	public final Type type() {
		return long.class;
	}

	@Override
	public final void process( final JvmOperationProcessor processor ) {
		processor.lload_3();
	}
}


text:
Frontiers in Pharmacology
Neuropharmacology
Biomarker Exploration in Neuropsychiatry: Understanding of the Pathophysiology and Therapeutic Implications View all 10 Articles
Pei Jiang
Jining Medical University, China
Zunnan Huang
Guangdong Medical College, China
Sarah Allegra
Department of Medical Sciences
Front. Pharmacol., 04 July 2019 | https://doi.org/10.3389/fphar.2019.00761
ABCB1 Gene Is Associated With Clinical Response to SNRIs in a Local Chinese Han Population
Xiao-Xiao Shan1,2†, Yan Qiu1,2†, Wei-Wei Xie3, Ren-Rong Wu1,2, Yan Yu4, Hai-Shan Wu1,2* and Le-Hua Li1,2*
1Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, China
2Mental Health Institute of the Second Xiangya Hospital, Central South University, Chinese National Clinical Research Center on Mental Disorders, Chinese National Technology Institute on Mental Disorders, Human Key Laboratory of Psychiatry and Mental Health, Changsha, China
3Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, China
4The People's Hospital of Hunan Province, Changsha, China
Background: The relation between the ATP-binding cassette subfamily B member 1 (ABCB1) gene and major depressive disorder (MDD) has been studied in a local Chinese Han population. MDD is associated with the rs2032582 (G2677T) and rs1128503 (C1236T) single-nucleotide polymorphisms (SNPs) of ABCB1 but not with rs1045642, rs2032583, rs2235040, and rs2235015. This study aims to explore the potential correlations of therapeutic responses with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in a local Chinese Han population.
Methods: The study population included 292 patients with MDD. All patients were assessed at baseline and at first, second, fourth, and sixth weeks according to the 17-item Hamilton Rating Scale for Depression (HAM-D17) to determine their therapeutic responses to SSRIs and SNRIs.
Results: In the SSRI therapy group, the genotype or allele distribution of six SNPs was not significantly different between responders and nonresponders. In the SNRI therapy group, only rs2032583 was associated with a therapeutic response to SNRIs. The C allele of the ABCB1 rs2032583 polymorphism was negatively correlated with therapeutic responses according to logistic regression analysis.
Conclusion: The ABCB1 gene polymorphisms may not be associated with therapeutic responses to SSRIs but not with SNRIs. The TT genotype of rs2032583 could be a predictive factor of improved treatment responses to SNRIs in the Chinese population. These findings should be replicated in future studies with larger patient groups.
The ATP-binding cassette subfamily B member 1 (ABCB1) gene, a multidrug resistance protein 1 (MDR1) gene, is located on the chromosomal region 7q21.1 and encodes p-glycoprotein (P-gp), which plays an important role in drug bioavailability and response to drugs. P-gp is a 1280-amino acid transporter and serves as a genetically polymorphic efflux transporter that removes foreign substances from cells. This protein is expressed in the blood–brain barrier and protects the brain from drugs or neurotoxic substances, such as glucocorticoids and amyloid beta (de Klerk et al., 2013).
After treatment with regular doses of antidepressants, several patients with major depressive disorder (MDD) fail to obtain satisfactory therapeutic effects, and some patients even incur serious side effects. Among patients with MDD treated with a single antidepressant medication, only 50% of patients received adequate clinical response, and 30% of patients achieved recovery. There was a delayed response to symptom relief, ranging from 4 to 8 weeks. During this period, the risk of suicide increased significantly, whereas another 10% of the patients were ineffective for any kind of antidepressant medication (Weizman et al., 2012). ABCB1 gene polymorphisms affect the ability of drugs to pass through the blood–brain barrier into the central nervous system, leading to inadequate drug concentrations in the brain (Uhr et al., 2008). ABCB1 gene polymorphisms can predict the effect of antidepressant drugs that are MDR1 substrates (Mihaljevic Peles et al., 2008; Sarginson et al., 2010).
Some drugs have been identified as substrates of P-gp. These drugs include nortriptyline, imipramine, escitalopram, amitriptyline, paroxetine, venlafaxine, and citalopram; and those with non-ABCB1 substrates include bupropion, mirtazapine, and fluoxetine (Mihaljevic Peles et al., 2008). The ABCB1 gene has single-nucleotide polymorphisms (SNPs) in the encoding regions. Variants such as C3435T (rs1045642), G2677T/A (rs2032582), and rs2032583 are the most commonly studied. Ameyaw et al. (2001) reported that ABCB1 gene knockout mice possessed insufficient P-gp, leading to high drug concentrations in the blood and weak ability to eliminate drugs. The plasma concentrations of drugs in mice without the ABCB1 gene were fivefold higher and seven- to 36-fold higher in the cerebrospinal fluid (Ameyaw et al., 2001).The concentrations of citalopram, venlafaxine, and d-venlafaxine in the brain of mutant mice were 3.0, 1.7, and 4.1 times higher than those in their wild-type littermates (Uhr et al., 2008). In vivo studies indicated that mdr1 ab (−/−) mutant mice possessed higher cerebral concentrations of paroxetine compared with those of mdr1ab (+/+) control mice. This finding suggests that P-gp could prevent paroxetine from entering into the brain (Uhr et al., 2003). Patients with the CC genotype of SNP rs2232583 in the ABCB1 gene exhibited a higher response rate than that of patients with the TT genotype after 4 weeks of antidepressant treatment. However, in the non-P-gp substrate mirtazapine group, no difference in genotype was observed between remission and nonremission groups (Uhr et al., 2007). A similar result was also found by Sarginson et al. (2010). Moreover, Dong et al. reported that ABCB1 gene polymorphisms rs4728697, rs2032583, and rs58898486 were associated with depression therapeutic response, and rs17064 was related to the curative effect of desipramine (Dong et al., 2009). ABCB1 haplotypes and SNPs rs1045642, rs2032582, and rs2032583 affect responses to antidepressant treatment (Menu et al., 2010; Rosenhagen and Uhr, 2011; Lin et al., 2011; Singh et al., 2012; de Klerk et al., 2013).
A total of 292 Chinese patients with MDD and 208 unrelated control individuals from a local Chinese Han population were studied. There are few studies on the relationship between gene polymorphism of ABCB1 and depression in the Chinese Han population; only a team of Taiwan scholars studied the relationship between the efficacy of escitalopram and gene polymorphism of ABCB1 in patients with depression (Lin et al., 2011). The purpose of this study was to further understand the relationship between the two in the Chinese Han population and to provide a theoretical basis for individualized treatment.
A total of 292 patients with MDD and 208 healthy controls were included in this study. All participants were biologically unrelated and of Chinese Han ethnicity. The patients were diagnosed as having MDD as defined in the Axis I of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and obtained scores ≥18 by the 17-item Hamilton Depression (HAM-D17) Rating Scale. A consensus diagnosis by at least two psychiatrists was made for each patient according to the DSM-IV criteria. Patients were not eligible to participate in the study if they have any other mental disorder according to DSM-IV-TR Axis I criteria, had major physical and neurological illnesses and sequelae of serious illness, or serious suicide attempts and behavior. Patients were also excluded if they had used electroconvulsive therapy or antipsychotic drugs with long-lasting effects within the last 6 months or any antipsychotic drugs within the last 4 weeks. The mean ages ± standard deviations of the patients and controls were 30.89 ± 10.92 years and 31.71 ± 8.25 years, respectively. Among the 292 patients with MDD, 71.6% had a single episode and 28.4% had recurrent episodes. The study protocol was approved by the Medical Ethics Committee of Second Xiangya Hospital, Central South University. Written informed consent was obtained from each patient after the study was explained.
Eligible patients were treated with one of the five antidepressants (escitalopram, paroxetine, sertraline, duloxetine, and venlafaxine) for 6 weeks. All patients affirmed a regular dose intake of antidepressant drug per day during the study. The primary efficacy measurement was the change in the HAM-D17 total score from baseline until the end of the study period. Patients were evaluated at screening, baseline, and on the first, second, fourth, and sixth weeks of treatment. Response was defined as changes in the HAM-D17 total score of ≥50%.
Sample Collection and DNA Extraction
Peripheral blood samples were collected from ethylene diamine tetraacetic acid (EDTA)-containing tubes following the standard venipuncture technique. Genomic DNA was extracted from whole blood according to standard procedures. In this study, we selected SNPs by the following three methods: literature reviewing, searching for Tag-SNP, and searching for functional variant sites by FAST SNP. Finally, we investigated the following six SNPs of the ABCB1 gene: SNP1 (rs1045642) in exon 27, SNP2 (rs2032583) in intron 22, SNP3 (rs2032582) in exon 22, SNP4 (rs2235040) in intron boundary exon 21, SNP5 (rs1128503) in exon 13, and SNP6 (rs2235015) in intron 5 of the ABCB1 gene. All genotyping experiments were carried out by Shanghai BioWing Applied Biotechnology Company (http://www.biowing.com.cn). The AxyPrep Blood Genomic DNA Kit was used for extraction, and the ligase detection reaction (LDR) was used to detect the six SNPs. The LDR was performed in 30 cycles at 95°C for 2 min, 94°C for 15 s, and 50°C for 25 s. Target DNA sequences were amplified using a multiplex polymerase chain reaction method. The fluorescent products of the LDR were differentiated using a 3730 ABI sequencer.
Haplotype and Statistical Analysis
Two independent sample t-test and χ2 test were used to examine the clinical and demographic variables between responders and nonresponders. Genotype and allele frequency distributions were compared between the patients and controls and between the responders and nonresponders using the χ2 test for independence. The observed genotype frequencies were compared with the predicted frequencies to investigate the concordance with the Hardy–Weinberg (H-W) equilibrium. Logistic regression analysis was used to estimate the therapeutic effect associated with each genotype; odds ratios with 95% confidence intervals were obtained. A p < 0.05 was considered to be statistically significant. The SHEsis online analysis software was used for linkage disequilibrium and haplotype analysis. Logistic regression analyses were performed using Statistical Package for the Social Sciences version 17.0 for Windows software (SPSS Inc., Chicago, IL). Adjustment for multiple comparisons was performed by Bonferroni correction.
Comparison of General Data Between Control and Case Groups
A total of 208 cases in the control group, 101 males and 107 females, the average age was 31.71 ± 8.25 years. There were 292 patients in the study group, 143 males and 149 females; the average age was 30.89 ± 10.92 years. There was no significant difference in gender and age composition between the control group and the case group (χ2 = 0.008, p = 0.927; t = 0.954, p = 0.341), which was comparable.
Hardy–Weinberg Balance Analysis of ABCB1 Gene Polymorphisms in the Control and Case Groups
Among the 208 control subjects, the theoretical number of genotypes was 81, the number of genotypes of CT was 98, and the number of genotypes of TT was 29. H-W analysis showed that there was no significant difference in the actual genotype distribution of rsl045642 SNP and the theoretical gene type distribution under H-W equilibrium, χ2 = 1.231, p = 0.267. According to this method, the H-W balance test was performed on the polymorphic loci rsl045642, rs2032583, rs2032582, rs2235040, rsl128503, and rs2235015 between the control group and the case group. As shown in Table 1, the six SNPs loci in the control and case groups all met the H-W balance. The population selected in this study is representative of the Han population and suitable for genetic analysis.
Table 1 Equilibrium test of six single-nucleotide polymorphisms (SNPs) between the control group and the case group.
Comparison of Clinical Features Among the Responders and Nonresponders
Among the 292 patients included in this study, 39 patients dropped out because of adverse effects (n = 12), withdrawal of consent (n = 9), contrary to the scheme (n = 2), and lost to follow-up (n = 16); lastly, 253 patients completed the study. Clinical characteristics, use of drugs, and average drug doses between responders and nonresponders are shown in Table 2. No significant differences were found between the two groups according to the above indicators.
Table 2 Clinical features, dosage, and drug among the responders and the nonresponders.
Genotype and Allele Frequencies in the Responders and Nonresponders
Genotype and allele distributions for the examined ABCB1 gene SNPs in nonresponders and responders are shown in Table 3. The genotype and allelic distributions of rs1045642, rs2032582, rs2235040, rs1128503, and rs2235015 SNPs were not significantly different between nonresponders and responders. For rs2032583, genotype and allelic distributions significantly differed between the nonresponders and responders. The distribution of TT genotype and T allele frequency was higher in the responders than that in the nonresponders (p = 0.027, p = 0.033, respectively).
Table 3 Genotype and allele frequencies of six SNPs of the ABCB1 gene in the nonresponders and the responders.
ABCB1 Gene Polymorphism Loci and Clinical Response to Selective Serotonin Reuptake Inhibitors
For SSRIs (sertraline, paroxetine, and escitalopram), no significant difference in genotype and allele frequency distribution was observed between the responders and nonresponders (p > 0.05) (Table 4).
Table 4 Genotype, allelic distribution of all genotyped single nucleotide polymorphisms among the treatment responders and nonresponders for selective serotonin reuptake inhibitor (SSRI) drugs group.
The efficacy of SSRIs was examined for genotypes in the SSRI treatment group according to the HAM-D17 scores, decreased scores, and reducing score rate during the first, second, fourth, and sixth weeks. The HAM-D17 scores, decreased scores, and reducing score rate at the first, second, fourth, and sixth weeks were not significantly different among rs1045642, rs2032583, rs2032582, rs1128503, and rs2235015 (p > 0.05). HAM-D17 decreased scores and reducing score rate did not reveal any significant difference with rs2235040 (Table 5); however, a significant difference was observed for the genotype of rs2235040 in the HAM-D17 scores (F = 4.349, p = 0.039) (Figure 1).
Table 5 Rs2235040 and response to antidepressants.
Figure 1 Hamilton Rating Scale for Depression (HAM-D) scores at the first, second, fourth, and sixth week.
ABCB1 Gene Polymorphism Loci and Clinical Response to Serotonin–Norepinephrine Reuptake Inhibitors
For SNRIs (venlafaxine and duloxetine), no significant difference was observed in the distribution of genotype and allele frequency of the rs1045642, rs2032582, rs2235040, rs1128503, and rs2235015 SNPs between the responders and nonresponders (p > 0.05). For rs2032583, the T allele frequency and TT genotype were significantly increased in the responders compared with those in the nonresponders (p = 0.025 and p = 0.018, respectively) (Table 6).
Table 6 Genotype, allelic distribution of all genotyped SNPs among the treatment responders and nonresponders for serotonin-norepinephrine reuptake inhibitors (SNRIs).
For SNRIs (venlafaxine and duloxetine), no significant difference was observed for the rs1045642, rs2032582, and rs1128503 SNPs in any of the HAM-D17 scores, decreased scores, and reducing score rate during the first, second, fourth, and sixth weeks (p > 0.05). For rs2032583, the HAM-D17 scores of TT genotype are lower than those of the CT genotype, whereas the decreased scores and reducing score rate are higher than those of the CT genotype (Table 7 and Figure 2). The GG genotypes of rs2235040 have lower HAM-D17 scores than AG genotypes and higher decreased score and reducing score rate than AG genotypes (Table 8 and Figure 3). For rs2235015, the GG genotypes have lower HAM-D17 scores than those of the GT genotypes and higher in decreased score and reducing score rate than those of the GT genotypes (Table 9 and Figure 4).
Figure 2 HAM-D scores at the first, second, fourth, and sixth week (Rs2032583).
We investigated the association among the six SNPs of the ABCB1 gene and therapeutic response in the local Chinese Han population. Among the five SNPs, only one SNP (rs2032583) differed in genotype and allele frequencies between the responders and nonresponders. In particular, the TT genotype of this SNP was significantly more common in the responders than that in the nonresponders. This finding suggests that the C allele of rs2032583 may be a risk factor for MDD. In the SSRI therapy group, no correlation was found between the six SNPs of the ABCB1gene and therapeutic response to SSRIs (p > 0.05). However, for the SNRI therapy group, only rs2032583 is associated with a therapeutic response to SNRIs in patients with MDD. The C allele of the ABCB 1 gene SNP rs2032583 was negatively correlated with therapeutic response according to the logistic regression analyses. The genotype of ABCB1 gene SNPs rs2235015 and rs2235040 were associated with decreased score and reducing score rate in the SNRIs therapy group, but because of the small sample size, there was no significant difference in the final effective and ineffective grouping. This finding indicated that ABCB1 gene polymorphisms may not be associated with the treatment response to SSRIs, but with SNRIs. The TT genotype of the ABCB1 gene SNP rs2032583 could be a predictive factor of improved treatment response to SNRIs. To our knowledge, this study is the first to report the genetic association of ABCB1 gene polymorphism with therapeutic responses in a case-control design in Chinese Han people in Mainland China.
P-gp can restrict the entry of various substrates, such as antidepressants, from the bloodstream into the brain. Studies on ABCB1 knockout animals have shown that ABCB1−/− mice possess higher intracerebral concentrations of escitalopram, trimipramine, amitriptyline, doxepin, venlafaxine, and paroxetine compared with those in wild-type mice (Uhr et al., 2000; Uhr et al., 2002; Uhr et al., 2003). Kato et al. (2008) reported a significant association of the nonsynonymous SNP G2677T/A (rs2032582) with treatment response to paroxetine in depressed patients. Moreover, the wild variant haplotype 3435C–2677G–1236T is associated with poor response (Kato et al., 2008). In contrast, Nikisch et al. (2008) found that depressed patients harboring the 2677 GG/GT genotype responded to escitalopram treatment significantly better than patients with the 2677TT genotype and suggested that this polymorphism could be used as genetic markers for predicting treatment response to escitalopram treatment in MDD (n = 15). Uhr et al. (2008) showed that polymorphisms in the ABCB1 gene predict the response to antidepressant treatment in depressed patients (n = 133) receiving drugs that have been identified as substrates of P-gp (amitriptyline, paroxetine, venlafaxine, and escitalopram). However, Mihaljevic et al. (2008) found that MDR1 variants G2677T (rs2032582) and C3435T (rs1045642) are not associated with therapeutic response to paroxetine in patients with MDD (n = 127). Furthermore, Peters et al. (2008) did not find an association between ABCB1C3435T, G2677T, and C1236T polymorphisms and response and tolerance to citalopram in a large study sample (n = 831).
ABCB1 gene polymorphism loci mutation might cause the variation of P-gp, thereby increasing drug concentrations in the brain to improve therapeutic effects. The specific function of rs2032583 (intron 22) is not clear. Clinical research has found the association between rs2032583 and antidepressant effects. The wild-type allele of rs2032583 is T and the mutant allele is C. The study by Sarginson et al. (2010) showed that carriers of the C allele remitted faster than those with the TT genotype in the rs2032583 among paroxetine-treated patients and support the findings of Uhr et al. (2002) who found that rs2032583 genetic variants affected efficacy in patients of various ages treated with paroxetine and other ABCB1 substrates (Uhr et al., 2008; Sarginson et al., 2010). By contrast, the two previous results are inconsistent with our present results. For rs2032583, we found that TT genotype has lower HAM-D17 scores than those of CT genotype and higher in decreased score and reducing score rate than those of CT genotype. This finding suggested that the TT genotype of rs2032583 is likely to be a predictive factor of better treatment response to SNRIs.
Whether the locus mutation manipulates the coding region of P-protein conformation remains to be further basic research. The rs2032583 locus mutation might change the dimensional conformation of P-gp by allowing entry of drugs and toxic substances into the brain simultaneously to exacerbate the symptoms. In addition, the locus mutation changes P-gp conformation and then stops the SNRIs into the brain but does not affect SSRI substrate. Furthermore, locus mutation may not change the conformation of P-gp. The positive results of SNRIs may be attributed to the small sample size, thereby causing false-positive results in the study. Foreign studies may have different results because of various factors such as race, region, environment, and diet.
Several limitations of the present study should be acknowledged. First, we did not distinguish the first and recurrence of depressive patients joining the patients' group. Regression analysis determines the total course of the disease and whether they accepted treatment; however, previous treatment had some influence on the overall response rate. Hence, the present study can only obtain a trend about differences. Second, the present study only selected the drugs that have been identified as substrates of P-gp. Future studies should include no-P-gp substrates such as mirtazapine. Third, genetic effect is slight because of the small sample size. A large sample size is needed to improve the power of the test. Fourth, many receptors are involved to determine the effect of antidepressant drugs; hence, a combination of gene should be considered. Larger and more homogenous samples will be included in our future research to improve the statistical power. Because there may be a delayed response to symptom relief, 6 weeks of treatment may not be sufficient to fully demonstrate the relationship between ABCB1 gene and clinical response, and we consider extending the duration of efficacy observation in future studies.
The study protocol was approved by the Medical Ethics Committee of Second Xiangya Hospital, Central South University. Written informed consent was obtained from each patient after the study was explained.
X-XS and YQ contributed equally to this work, mainly responsible for essay writing and conducting the study. W-WX mainly participated in conducting the study. YY assisted the study. R-RW, H-SW and L-HL contributed to guide of conducting the study and essay writing.
This research was supported by National Natural Science Foundation of China (grant no. 81501163), National Natural Science Foundation of China (grant no. 81270019), National R&D Special Fund for Health Profession (grant no. 201002003), and National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2012ZX09303014-001).
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Keywords: ABCB1 gene, clinical response, SNRIs, major depressive disorder, local Chinese Han population
Citation: Shan X-X, Qiu Y, Xie W-W, Wu R-R, Yu Y, Wu H-S and Li L-H (2019) ABCB1 Gene Is Associated With Clinical Response to SNRIs in a Local Chinese Han Population. Front. Pharmacol. 10:761. doi: 10.3389/fphar.2019.00761
Received: 17 August 2018; Accepted: 12 June 2019;
Pei Jiang, Jining Medical University, China
Zunnan Huang, Guangdong Medical College, China
Sarah Allegra, University of Turin, Italy
Copyright © 2019 Shan, Qiu, Xie, Wu, Yu, Wu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hai-Shan Wu, wuhaishan@csu.edu.cn; Le-Hua Li, lilehua@csu.edu.cn
†These authors have contributed equally to this work.


Fall is in full swing and the leaves have hints of color. In search of the bright leaves, we drove the Adventure Subaru into the Ozarks. We stopped at the serene Lake Fort Smith State Park where you can view the ever-changing trees from a different perspective.
The state park offers lake tours year-round but there's something special about visiting the water in October.
"Our fall magic lake tours are something that's very popular because we are going out during the peak fall season and we get to see a lot of those shoreline colors," stated Heather Hula, a Park Interpreter at Lake Fort Smith State Park.
We joined one of the refreshing lake tours to learn the history of the lake, take in the nature around us, and hopefully see some changing leaves.
"But when you're along the lakeshore you get to see those smaller trees that grow under the shadow of those large hardwood trees, and those are the trees that put on a little bit more of a show. Like our gum trees and our dogwood trees will have the bright red leaves. They'll be a few other smaller shrubs that have the same colors too. Without this lakeside you wouldn't otherwise be able to see that," Hula said.
The brilliant changing colors depend on three things: shorter, days, leaf pigments, and the weather.
More rainfall in the summertime and more moisture in the soil means we'll see a more spectacular and brighter display of colors during the fall season. You can already start to see the golden colors in the leaves behind me along the lakeshore.
After spotting a few changing leaves on the boat, you can test the trails, check out the campgrounds, or grab a kayak.
"It's an oasis here in the Boston Mountains. Lake Fort Smith is tucked away yet close enough to all these metropolitan areas, yet when you're here it's like stepping back in time or stepping into nature and drowning out all the stuff that creates such busy lives," stated Hula.
For Adventure Arkansas, and touring the lake where you live, I'm 5NEWS Meteorologist Sabrina Bates.


text:
Have you felt ill after using tobacco products bought in north Powys?
Powys illegal tobacco warning
By Rory Sheehan
ILLEGAL tobacco is putting the health of Powys residents at risk, the authorities have warned.
Members of the public who have purchased tobacco in north Powys but then suffered immediate health problems are being asked to report it to trading standards, the council has urged.
Powys County Council's Trading Standards Service has received reports that people have fallen ill after purchasing tobacco products.
The service is urging those who have suffered from any illnesses after purchasing tobacco, to seek medical attention straight away.
Clive Jones, the council's professional lead for trading standards, community safety and emergency planning, said: "We have received intelligence that members of the public have experienced immediate health problems after purchasing, what we believe are, illegal tobacco products.
"These illegal products are often counterfeit and do pose a major health risk as they often contain high levels of heavy metals such as cadmium or in matters where illness follows smoking, are contaminated with high levels of mould.
"I would urge anyone who has recently purchased tobacco in the north of the county and immediately suffered illness to seek medical attention or advice
"We also want those members of the public who have suffered after purchasing these products, or family members/acquaintances to report it to our service. These reports will be treated anonymously.
"Combating the supply of counterfeit and illegal tobacco is one of our ongoing priorities of our service as it provides a threat to the economy of Powys as well as increasing the health risk for smokers.
"Please report by email to trading.standards@powys.gov.uk or by phone to 01597 826031."