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Zdrężno lub Zdręsno – jezioro w Polsce w województwie warmińsko-mazurskim, w powiecie ełckim, w gminie Ełk.

Położenie
Jezioro leży na Pojezierzu Mazurskim, w mezoregionie Pojezierza Ełckiego, w dorzeczu Płociczanka–Ełk–Biebrza–Narew–Wisła. Znajduje się około 8 km w kierunku północnym od Ełku. Nad północnym brzegiem położona jest wieś Przytuły, a nad południowym Płociczno. Przez jezioro przepływa ciek wodny o nazwie Dopływ z jez. Przytulskiego, który łączy zbiornik wodny z Jeziorem Przytulskim oraz z jeziorem Płociczno. W najbliższym otoczeniu znajdują się pastwiska, łąki i nieużytki.

Linia brzegowa akwenu jest słabo rozwinięta, brzegi miejscami są strome.

Zgodnie z typologią abiotyczną zbiornik wodny został sklasyfikowany jako jezioro o wysokiej zawartości wapnia, o dużym wypływie zlewni, stratyfikowane, leżące na obszarze Nizin Wschodniobałtycko-Białoruskich (6a).

Jezioro leży na terenie obwodu rybackiego jeziora Zdręsno w zlewni rzeki Ełk – nr 27.

Morfometria
Według danych Instytutu Rybactwa Śródlądowego powierzchnia zwierciadła wody jeziora wynosi 75,4 ha. Średnia głębokość zbiornika wodnego to 7,8 m, a maksymalna – 17,7 m. Lustro wody znajduje się na wysokości 127,3 m n.p.m. Objętość jeziora wynosi 5 872,9 tys. m³. Zgodnie z badaniem z 1998 roku przyznano akwenowi II klasę czystości. Maksymalna długość jeziora to 2500 m a szerokość 475 m. Długość linii brzegowej wynosi 6 300 m.

Inne dane uzyskano natomiast poprzez planimetrię jeziora na mapach w skali 1:50 000 według Państwowego Układu Współrzędnych 1965, zgodnie z poziomem odniesienia Kronsztadt. Otrzymana w ten sposób powierzchnia zbiornika wodnego to 77,5 ha, a wysokość bezwzględna lustra wody – 126,9 m n.p.m.

Przyroda
Jezioro określane jako sielawowe. Spotkać tu można także liny, okonie szczupaki i leszcze. Wśród roślinności zanurzonej – ramienice, rogatek, jaskier krążkolistny i rdestnice. Wokół brzegów roślinność skąpa z uwagi na strome stoki ławicy. Dominuje trzcina, pałka wąskolistna i skrzypy.

Przypisy

Jeziora w powiecie ełckim
Ełk (gmina wiejska)
Jeziora na Pojezierzu Ełckim


Ice Breaker: How has your spiritual journey impacted your relationship to your finances?
READ Philippians 4:10-23 and imagine how these verses would have been received by Paul's friends and spiritual children back in Philippi. How does this function as a fitting conclusion to this letter?
Paul's first focus (v.10) is to Express Gratitude.
How are you at identifying blessings in your life and expressing gratitude a) to God and b) to others?
Who could you encourage this week with special words or actions of gratitude?
Paul moves from gratitude to Contentment In Christ (v.11-13).
List 3 or more truths about contentment that you see in these verses.
Which of those truths do you most need to ask God to sow into your heart and mind? Why?
How do you define Christian contentment? From where does it derive?
4:13 is one of the more famous verses from this epistle. Have you heard this misused or misquoted before? What does this verse mean in its context?
How do we draw strength "through Christ"?
How were they his true partners in contrast to other churches he mentions?
How can a small church, like RSBC, live in true partnership to care for one another and beyond ourselves? How would you evaluate this characteristic in our body currently?
What was Paul more excited about than the material gifts in v.17? Why do you think so?
In what ways is giving any part of ourselves to others an act of worshipping God?
Pause and Pray. Ask the Holy Spirit to reveal any aspects of generosity that He desires you to grow or participate in further.
Paul finishes this passage (v.19-20) worshiping God as a Faithful Father Forever.
Verse 19 has been called "the greatest promise in the entire Bible" by some preachers. Why?
What do you think the promise applies to? Is anything excluded?
Which of these words about our God comforts or encourages you most today: Faithful. Father. Forever. Why?
Close and Pray based on the word you selected in the final question. Spend time praising and petitioning the Lord based on that characteristic.


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Pluduno (; ; Gallo: Ploedunoe) is a commune in the Côtes-d'Armor department of Brittany in northwestern France.

The Arguenon river flows through the commune.

Population

People from Pluduno are called pludunonéens in French.

See also
Communes of the Côtes-d'Armor department

References

External links

Communes of Côtes-d'Armor

redpajama_set_name: RedPajamaWikipedia


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Chapter 2191 The End Of The Big Test (Part One)
The test that took place within the Consulting God Hall of Heavenly Han House usually lasted a total of seven days.
To proving godly warriors, the Heavenly Han House's test wasn't just an exam to verify their abilities, but even more so, an opportunity for cultivation.
There were a few of the proving godly warriors who usually listened to the teachings of True Gods outside the Heavenly Han House. Now that they were inside the Consulting God Hall, they were capable of using what they had learned in order to comprehend the internal momentum inscribed on the Godly Way Tablets.
Despite the fact that these Godly Way Tablets were only mere imitations, being here was still a rare opportunity for such proving godly warriors to cultivate.
Throughout the seven days, more and more proving godly warriors were recognized by the Godly Way Tablets. For these proving godly warriors, they entered the most crucial stage in their entire lives after the recognition. It was then that their fate would be completely changed forever.
This was because the chances of one mastering Godly Ways in the Heavenly Han House were rather high. Becoming a True God in the future was equivalent to obtaining the chance of living forever, as well as other limitless possibilities.
As for Zen, things were a little different on his behalf.
Over the past few days, all of the proving godly warriors present had been used to watching miracles he had created.
Zen tirelessly traversed through the Godly Way Tablets, continuously absorbing their internal momentum and he was equally constantly acknowledged by the Godly Way Tablets.
Other than the Grand Purple Aura Technique, there were certain other Godly Ways that required special conditions and physiques for cultivation. However, despite the fact that Zen had ignored these requirements, h
Clan came to select warriors was also the year when the Heavenly Han House held a bigger test. These proving godly warriors hoped that they would be lucky enough to be chosen by the Han Clan and enter the Floating Island, thus becoming a member of the divine land's core power and rising to prominence.
That said though, the Han Clan sub-branches equally had special rights when it came to recommending warriors. If they were to meet an extremely outstanding warrior, they wouldn't have to wait the aforementioned 16 years. The only requirement was to send someone to apply to the main Han Clan, but the precondition was that the warrior really had outstanding abilities.
The few proving godly warriors who had successfully passed through the Heavenly Han House's test were arranged to stay in a courtyard, while the rest were dismissed. Those who failed could only wait until next year to take the test once again.
The courtyard where the select sixty-seven stayed was very elegantly constructed, with a few bridges built on top of a beautiful pond. Within the pond, a group of little fish with golden scales could be seen swimming around happily. Pink lotus flowers adorned the water and here, they would never wilt.

redpajama_set_name: RedPajamaCommonCrawl


Since our foundation in 1999, we have been dedicated to the transport profession worldwide for the benefit of the community through contributing to safe, environment-friendly and efficient traffic operations.
Under the SIDRA SOLUTIONS brand, our innovative and forward thinking company has created powerful traffic engineering software used by transport professionals in all corners of the globe. These tools have been created to help achieve better solutions to challenges in the areas of road traffic operations, traffic engineering, management and control.
SIDRA INTERSECTION is our company's flagship product; an advanced micro-analytical evaluation tool that employs lane-based traffic and vehicle drive cycle models. It is a highly renowned package used for intersection and network capacity, level of service and performance analysis by traffic design, operations and planning professionals. The software is licenced in 85 countries including the USA & Canada, Australasia, South Africa, the Asian Region, Middle East and Europe.
SIDRA TRIP is a single trip microsimulation software package for assessing travel level of service, performance (delay, speed, travel time), operating cost, user cost, vehicle fuel consumption, emissions, and noise. It has been developed to help traffic engineers perform real-life traffic and travel assessment tasks with ease and minimum cost.
We support our products with an online support site and ticketing system, video tutorials and global training workshops and presentations.
The success of SIDRA SOLUTIONS products has been built on reputation and career-long achievements of Dr Rahmi Akçelik, who is the company director and author of SIDRA INTERSECTION and SIDRA TRIP. As a result of Dr Akçelik's lifelong contribution to his field, motorists around the world have benefited from the practical application of his research. He has gone the extra mile in training and advising thousands of Australian and international traffic systems professionals.


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The Joint Admissions and Matriculation Board (JAMB) has disclosed it has made an interim remittance of N3.5 billion to the Federal Government consolidated revenue account. This was contained in a statement by Dr Fabian Benjamin, JAMB's Head of Media in Abuja.
JAMB logo
According to him, this is in line with Prof. Ishaq Oloyede's commitment to remit wholly, any excess funds generated from its operations to the Federal Government.
It was gathered that earlier, payment of over N3.5 billion had already been made to candidates by way of reduction of N1,500 from the cost of each ePIN sold to each candidate as directed by President Muhammadu Buhari. This brings the total remittances this year to over N7 billion.
The board also said it will remit more as soon as its operations are concluded and proper audit of its books is completed.


Tatum Pri is located in Tatum, Texas. The school belongs to Tatum ISD District, and its zip code is 75691-0808. The contact phone number of Tatum Pri is (903) 947-6482.
Tatum Pri is located at P O Box 808, Tatum, TX, 75691-0808.


Livestock farming for meat production has been an established industry in England, Northern Ireland, Scotland and Wales for many years. Over the years farming techniques have been altered and modernised. Animal health and welfare, and sustainability remain high priorities for farmers. Animals have been bred to produce leaner meat which has a positive impact on our diet and health.
This module contains an overview of information on how cattle, pigs and sheep are farmed.
Cattle, pigs and sheep have been farmed for many years in England and Wales.
Livestock are bred to produce lean meat which benefits consumers as part of a health balanced diet.
The different animals have different lifecycles, however the health and welfare of all animals is a top priority for livestock farmers.
Livestock may graze outdoors in summer, however many animals are housed in sheds during the winter to protect them from bad weather.
Livestock housing must meet certain criteria, have good ventilation and allow the animals to move and be sociable.
Farmers also ensure that maintaining the environment is a priority.
The Red Tractor scheme sets out strict guidelines for farming and reassures consumers about standards of production, welfare and origin.
Use the presentation to assist the students in completing the two worksheets.
Set students the task of creating a diary of a farmer's day on the farm. Alternatively, set students the task of creating a diary of a cattle, pig or sheep's day on the farm.
Arrange the class to visit a farm, or alternatively, a farmer to visit the class.
Challenge students to create flow diagrams of the different life cycles of cattle, pigs and sheep.
A presentation about livestock farming in the UK.


In all ramifications,early childhood education,I mean formal education system,where kids are send to schools before they are 2 years has never been the best choice of any parents, neither has it been a welcome idea. This is because,by sending babies and kids to schools even before some of them begin to craw and walk,or before they learn to speak their mother tongue children would have been deprived a lot of some natural heritage. Yes,why then is there early childhood education since we have seen that it does,can we say some harm to childhood re-cognitive development? Let's find out!
Unlike the time of the past especially in African countries,where parents and households live solely on agricultural produce,parents now have to work so hard in white collar jobs to cater for their families. Today, the basic needs such as housing, education and food are very expensive,and many times,jobs are not forth coming. The times when families rely only on the heads of their families,fathers are gone. Today,women now contribute in providing for the needs of the family. This means that if a woman has a baby and secures employment,she either leaves the baby at home with a care taker,and admits him in school to be taken care of. This is why there is early childhood education.
There are women who are just lazy that they can not take care of their babies. Thus,they admit these babies to school for teachers to do the job for them. This again is a reason why there is early childhood education.
There are again some baby women who have not understood that motherhood is all about responsibility that is keeping the home clean,cooking for her family,and even doing some laundering work. These types of women claim that they can not handle all of these chores along with the responsibility of caring for the babies. Therefore,admitting their babies in school becomes a solution to their problem giving reasons why there is early childhood education.


The International Air Transport Association (IATA) is forecasting global profits for the airline industry of approximately $30 billion in 2017,* down from a peak of roughly $36 billion in 2016 given an uptick in expected fuel costs. With this backdrop, L.E.K. sees the next five years as critical for airlines to continue their transition from subsistence to sustainability via investments in both product and customer-facing services.
While the capacity picture has behaved relatively well in regions like the U.S., airlines must resist the temptation to upset the more profitable balance the industry has achieved. In particular, capacity growth in markets such as China and Trans-Atlantic present significant potential risks.
What are the biggest challenges and opportunities facing the airline industry this year?
1. Recalibrating revenue management. Globally, carriers are increasingly adopting new fare structures, which are not just based on the traditional advanced purchase timelines but also include or exclude different features (such as checked bags or upgrades). As these products expand, airlines will need to adjust revenue management techniques to reoptimize inventory allocation and pricing. For example, carrier models must accommodate the surge in value fares, forcing a rethink of how demand has traditionally been forecasted. Moreover, the growing importance of ancillary revenue requires that revenue management teams increasingly incorporate a "full customer value" lens.
2. Securing the right partners. As the skies open and antitrust immunity (ATI) becomes more prevalent, airlines are revisiting the traditional alliance architecture and contemplating game-changing joint ventures (JVs). This remapping of alliances risks leaving some carriers in compromised positions as new lines are drawn around them. We see continued activity as various protagonists seek partners that can fill network gaps, provide enhanced customer offerings, and effectively achieve the virtual scale that all network businesses desire.
3. Transforming customer experience. Modern travelers are looking for greater control over their journeys and respond favorably when airlines assist them in this effort. Carriers that can get this right stand to gain on high-margin upsell opportunities as well as stronger customer satisfaction (and retention). Successful execution will involve substantial focus and resources, and requires, essentially, an evolution from an operations-based culture to a customer-centric one.
Traditional ways of thinking about mobility are increasingly being challenged. Mobility is now a complex web of decision-making for consumers.


It takes some courage to run into the cold waters of Lake Ontario, you can see the determination on peoples faces.
Then you experience the frigid waters and realize how cold it will be.
See more Polar Swim pictures after the jump.
I stayed in the water, thigh deep, taking pictures during each wave of swimmers. I was very cold when I came in after the dippers were done.


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The Road News 2012
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Phil wins Ivor Novello Award
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A self-deprecating speech from Phil Collins and another top award for Amy Winehouse were the highlights of the Ivor Novello awards held in central London today.
Hosted by the British Academy of Composers and Songwriters, the Ivors celebrate excellence in songwriting. Collins, the much-maligned Another Day in Paradise singer, received the international achievement award, while the much-garlanded Winehouse won the category 'best song musically and lyrically', for Love is a Losing Game.
Receiving his award from Led Zeppelin frontman Robert Plant, with whom he collaborated in the 1970s, Collins thanked the academy and the gorilla whose appearance as a drummer in a Cadbury's Dairy Milk advert helped send Collins's In the Air Tonight to number one for a third time.
"I know now what I want to do and what I don't want to do," he told the audience at London's Grosvenor hotel. "I have two sons back in Switzerland and my life is now focused around them, but I do know that I will continue to write songs. As for the gorilla, I might put him forward as the next drummer of Genesis."
Winehouse attended the ceremony, but arrived too late to collect her award. Instead, her father Mitch received it and made a speech on her behalf. "She's sorry she can't be here but she sends her love," Winehouse senior said. "She is getting better and she'd like to send her love to everyone at the Ivors who first recognised her talent."
Other winners included Mika, who was named songwriter of the year, Soul II Soul's Jazzie B, who claimed the new Ivors inspiration award, Radiohead, who won best album for In Rainbows, and Pink Floyd's David Gilmour, who claimed the lifetime achievement award.
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HomePoliticsBrexit: Talks enter last day before crunch EU summit
Brexit: Talks enter last day before crunch EU summit
October 16, 2019 Admin Politics 0
EU and UK officials have resumed Brexit talks in the hope of reaching a deal that can be agreed by leaders at a key summit on Thursday.
Prime Minister Boris Johnson is expected to update the cabinet on the progress of the negotiations, which continued into the early hours.
On Tuesday, there were unconfirmed reports that an agreement was imminent.
But government sources have now told the BBC that the chances of it happening this week are "shrinking".
The EU's chief negotiator, Michel Barnier, will update the bloc on the state of the negotiations later when he briefs EU commissioners and ambassadors.
Mr Johnson is facing a race against the clock to reach a new Brexit deal before the two-day gathering of EU leaders.
Any deal will need to be published – along with a legal text – if the EU27 are to consider ratifying the withdrawal agreement at their summit.
That meeting is crucial because under legislation passed last month – the Benn Act – Mr Johnson is compelled to ask the bloc for a delay to Brexit if he does not get a new deal approved by MPs by Saturday.
DUP leader Arlene Foster met the PM for 90 minutes on Tuesday night
The UK is due to leave the EU at 23:00 GMT on 31 October and the prime minister has repeatedly insisted he will not request a delay.
But in addition to the challenges of reaching an agreement with the EU this week, Mr Johnson also requires support from Conservative Brexiteers and Democratic Unionists if he is likely to get his deal through Parliament.
Such support rests on the UK's proposed alternative to the Irish backstop – the measure aimed at preventing a hard border on the island of Ireland.
What is happening today?
10:00 BST – Brexit Secretary Stephen Barclay will appear before the Commons Exiting the European Union committee
13:00 – Michel Barnier due to brief EU ambassadors
16:00 – The PM meets the cabinet
17:15 – Angela Merkel and Emmanuel Macron hold joint press conference
19:30 – The PM meets 1922 Committee of Tory backbenchers
On Tuesday evening, meetings were held at Downing Street with backbench MPs and leaders of the DUP.
After a 90-minute meeting with the prime minister, the DUP said "it would be fair to indicate gaps remain and further work is required".
Earlier in the day, the party's leader, Arlene Foster, said she could not accept reported plans of a customs border in the Irish Sea – meaning Northern Ireland would be treated differently from the rest of the UK.
'Key tests'
Former Brexit Secretary David Davis said the support of Tory eurosceptics could not be taken for granted and MPs would subject any agreement to "two or three key tests" – including whether it compromised the future of the United Kingdom.
"Quite a lot of Tory MPs will take their line from what the DUP say," he told BBC Radio 4's Today. "If the DUP say this is intolerable, that will be quite important."
Former Northern Ireland secretary Owen Paterson has already expressed unease about reports of what could be in the agreement, telling the Sun that a customs border down the Irish Sea would be "unacceptable".
But Iain Duncan Smith, another Brexiteer and former Conservative party leader, said there was a "genuine strong sense of goodwill" towards the prime minister's efforts.
Media captionConfused by Brexit jargon? Reality Check unpacks the basics
Most of his party – "bar a small core" – wanted to get a deal and he suspected they would want to back it, he told BBC Breakfast.
He denied reports in the Sun newspaper that he "exploded" at Downing Street officials during Tuesday's meeting, saying he was in fact rushing to get on the London Underground to get back to his constituency.
DBP. Let's have a new one, a new acronym of course, because Brexit has been nothing if not a journey through collections of syllables that once might have seemed unfamiliar to even political aficionados, but now trip off the tongue.
DUP? Easy one, the Tories' Northern Irish allies.
ERG, obvious too, the European Research Group – the Brexiteers' club.
Then there is NCP, what was once upon a time Theresa May's plan for customs, the IP, the implementation period, the departure lounge after Brexit, and so on, and so on, and so on, until we all lose the will to live.
If you are still with me then let's introduce "DBP", because on a very odd day in Westminster, it's the phrase I have heard almost more than any other – difficult but possible.
Read Laura's full blog here.
An emergency sitting of Parliament on Saturday is anticipated – the first in 37 years.
MPs will be able to back or reject any deal presented to them and there will be discussions on what to do next.
However, ministers have yet to confirm the sitting would happen, saying it would depend on events in Brussels.
Media captionBrexit: What can the UK learn from Norway's EU border?
Meanwhile, the Liberal Democrats have tabled an amendment to the Queen's Speech, calling for any deal to be put to voters in a referendum.
If selected by the Commons Speaker, MPs could vote on the amendment for a so-called people's vote next week.
Lib Dem leader Jo Swinson told BBC Breakfast the economic hit of Mr Johnson's deal could be worse than the financial crash of 2008, and therefore it "should be up to the public to have their say".
Timeline: What's happening ahead of Brexit deadline?
Thursday 17 October – Crucial two-day summit of EU leaders begins in Brussels. This is the last such meeting currently scheduled before the Brexit deadline.
Saturday 19 October – Special sitting of Parliament expected – and the date by which the PM must ask the EU for another delay to Brexit under the Benn Act, if no Brexit deal has been approved by MPs and they have not agreed to the UK leaving with no-deal.
Thursday 31 October – Date by which the UK is currently due to leave the EU.
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1, 3-Thiazolidine-4-Ones: Copper Nickel Oxide Bimetallic Nanoparticle Catalyzed Synthesis, Anticancer Potential and Molecular Modeling Studies
Ramesh L. Sawant, Manisha R. Sawant, Jyoti B. Wadekar, Rushikesh D. Ukirde, and 2 more
Background: Cancer is a leading cause of death worldwide. Inhibiting mitosis is the most effective clinical technique for cancer treatment. The most critical field of medicinal chemistry and drug development research is the discovery of innovative anticancer drugs. Thiazolidine is a multifunctional nucleus with anticancer, anti-inflammatory, antioxidant, antibacterial, antifungal, antidiabetic, antihyperlipidemic, and antiarthritic properties.
Methods: In this investigation, copper-nickel oxide nanoparticles synthesized by electrochemical synthesis yielded a significant yield. The capping was done with cetyltrimethyl ammonium bromide (CTAB), and the characterization was done with UV, FTIR, XRD, SEM-EDS, and TEM SAED. The biologically significant 2-(2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12) have been synthesized using copper-nickel oxide nanoparticles as a catalyst and by applying a microwave-assisted tool. It was characterized by melting point, IR, 1H NMR, 13C NMR and LC-HRMS/MS spectroscopy. Using Sulforhodamine B (SRB) test, all newly synthesized compounds were evaluated in vitro for anti-cancer, anti-inflammatory, antioxidant, and angiogenesis activities.
Results: The compounds GB-6 (GI50: 30 μM), GB-8 (GI50: 10 μM) and GB-10 (GI50: 30 μM) exhibited significant cell growth inhibitory activity. The compounds GB-6, GB-8, GB-10 exhibited significant in vitro anti-inflammatory activity in the range of IC50:179.65-194.59 μg/ml as compared with aceclofenac (IC50:191.19μg/ml) and the antioxidant activity by DPPH radical scavenging assay the compounds GB-6 (IC50:11.96 µg/ml), GB-8 (IC50:10.67 µg/ml) and GB-10 (IC50: 9.08 µg/ml) exhibited excellent radical scavenging activities compared to ascorbic acid (IC50:13.04 µg/ml) and by the KMnO4 radical scavenging assay the compounds GB-2 (IC50:15.33 µg/ml), GB-4 (IC50:23.60 µg/ml), GB-8 (IC50:24.93 µg/ml), GB-10 (IC50:24.96 µg/ml) exhibited good radical scavenging activities compared to ascorbic acid (IC50: 26.55 µg/ml). The compounds GB-4, GB-8 and GB-10 at 10 nM test drug concentration and the GB-6 compounds at 100 nM test drug concentration show the maximum capillary growth inhibitory activity compared with thalidomide as a standard drug.
Conclusion: Further development of anticancer drugs may be enabled by the discovery of related compounds to the anticancer agent, such as compound (GB-6), compound (GB-8), and compound (GB-10) as polo-like kinase 1 inhibitors.
Nanocatalytic synthesis
Copper nickel oxide nanoparticles
Thiazolidine-4-ones
Anticancer activity
Angiogenesis activity
Cancer causes uncontrolled growth of cell divisions in which normal body cells transmute into cancerous cells out of control. As per the World Health Organization (WHO) report on cancer 2021, the global cancer burden is significant and increasing and causes the second most fatality worldwide. In 2020, breast cancer will account for around 2.26 million new cases and 6,855,000 deaths [1]. Polo-like kinase 1 (PLK1) is a preserved mitotic serine-threonine protein kinase [2]. PLK1 is the most scientifically studied member of the PLK family that interprets a significant role in cell cycle progression. This is required to regulate the various steps involved in the cell cycle progression [3]. PLK1 overexpression may result in carcinogenesis and is a specific target for inhibiting numerous stages involved in tumor cell proliferation, including mitosis, centrosome maturation, spindle formation, mitotic entry, mitotic exit, chromatin segregation, and cytokinesis [4]. At the moment, over 51 kinase inhibitors have been licensed to treat various forms of cancer [5]. In the current situation, some PLK1 inhibitors are undergoing preclinical and clinical trials in phase 1 and phase 2.
The literature survey reveals that native ligand 1, 3-thiazolidine-4-ones shows a diversity of biological responses like anticancer [6], anti-inflammatory [7], antioxidant [8], antibacterial [9], antifungal [10], antidiabetic [11] and antihyperlipidemic [12] activity. The native ligand 1, 3-thiazolidine-4-ones is used to inhibit polo-like kinase 1 enzyme for the uncontrolled growth of cell division into cancer [13]. Metallic nanocatalysts have played a vital role in the chemical industry; optimizing their catalytic activity enables significant cost reduction [14]. Due to the extraordinary features of nanoparticles, such as optical, catalytic, and electric capabilities that may be adjusted depending on the particle's size, size distribution, and morphology [15], nanoparticles have been extensively explored. Nanoparticles (NPs) are typically spherical particles with a 1–100 nm and NPs have a larger surface-to-volume ratio than non-nano scale particles of the same material, making them more reactive [16]. Cu-NiO, mixed metal oxide nanoparticles, can operate as a catalyst in a variety of organic reactions, including methanol production and non-enzymatic glucose sensing [17]. Numerous methods for preparing copper-nickel oxide nanoparticles have been reported in the literature, including spray pyrolysis, electro-deposition via the sol-gel process, pulsed laser deposition, pulsed plasma deposition, co-evaporation, DC magnetron sputtering, and RF magnetron sputtering [18]. The present study proposes the electrochemical synthesis of copper-nickel oxide nanoparticles and their analysis and the synthesis, structural elucidation, and molecular docking of 1, 3 thiazolidine-4-ones, followed by screening for anticancer activities against the breast cancer cell line MCF-7 using the Sulforhodamine B (SRB) assay.
Copper-nickel oxide nanoparticles were analyzed using a UV-visible spectrophotometer (UV 1800 Shimadzu), a Fourier transform infrared spectrophotometer (FTIR Affinity 1 Shimadzu), a thermogravimetric analyzer (TGA 50 Thermoanalyzer Shimadzu), a high-end X-ray diffractometer, scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), and transmission electron microscopy elected area electron diffraction (TEM-SAED) techniques. Flash chromatography was used to purify the titled compounds. Melting points (m.p.) were obtained in uncorrected open capillary tubes using a Gallenkamp electric melting point device. Thin-layer chromatography (TLC, Silica gel 60 F254, Merck) was used to monitor the reaction's course and determine the purity of the chemicals identified via UV light and iodine vapor absorption. IR, 1H NMR, and 13C NMR spectroscopy were used to characterize all compounds, where as LC-HRMS/MS (small molecules) spectroscopy was used to characterize two compounds. On a Jasco IR Affinity-1 spectrophotometer, IR spectra (KBr discs) were recorded. Bruker 500 MHz 1H NMR spectra were acquired in chloroform (CDCl3) and dimethyl sulfoxide (DMSO-d6) solvents, with tetramethylsilane (TMS) serving as an internal standard. Chemical shifts are expressed in terms of values (ppm). Signals are denoted by the letters s (singlet), d (doublet), t (triplet), q (quintet), and m (multiplet) (multiplet). Bruker 500 MHz 13C NMR spectra were acquired in chloroform (CDCl3) and dimethyl sulfoxide (DMSO-d6) solvents, with tetramethylsilane (TMS) used as an internal standard. Chemical shifts are expressed in terms of values (ppm). The LC-HRMS/MS data were acquired using an Impact II UHR-TOF Mass Spectrometer System and a Dionex UHPLC Ultimate 3000 System spectrometer. The molecular ion for the majority of the substances was identified as (M+1) +. Commercially available compounds were obtained from Sigma Aldrich, S. D. Fine Chemicals, Loba, and Spectrochem.
Electrochemical synthesis:
To prepare copper-nickel oxide nanoparticles, cetyltrimethyl ammonium bromide (CTAB) was dissolved in water to obtain 0.01 N solutions. A 50 mL electrolysis cell vessel was filled with the solution mentioned above as one of the electrodes, a 1 cm x 1 cm sheet of copper and nickel was used. Another 1 cm x 1 cm platinum sheet serves as an inert electrode. Two electrode sheets were immersed in a 0.01 N solution of CTAB. CTAB works as a supporting electrolyte and stabilizing agent during this synthesis process, preventing the generated nanoparticles from growing further. The copper and nickel technique metals are oxidized and transformed to copper and nickel ions during this electrochemical process to create nanoparticles. Copper ions generated in this way migrate towards the cathode. They produce nanoscale oxides of copper-nickel in the electrolyte solution and at the contact between the cathode's surface and the electrolyte solution. Electrolysis was carried out at various current densities. The applied current densities in mA/cm2 were 5, 10, 15, and 20, and the electrolysis was carried out for 2 hours. The color of the solution varies during this electrolysis process. The colorless solution first changed to a bright blue hue, a dirty green hue, and eventually a dark brown residue. After a two-hour interval, the electrolysis process was ended. The brown precipitate-containing solution was then collected in a bottle. Permitted the solid particles to settle and decantation was used to separate the solid obtained in this manner. Three to four times with water washed the separated solid to achieve complete elimination of excess capping agent.
General procedure for the synthesis of 2-(2-substituted-4-oxo-thiazolidin-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12)
In a round bottom flask, guanine (0.01 mol), substituted aldehydes (0.01 mol), thioglycolic acid (0.01 mol), and sodium hydroxide (0.01 mol) were combined in ethanol (10 ml). The mixture was vigorously agitated and then refluxed for 30 minutes at 40W using a microwave synthesizer system (CEM, USA). Once the reaction mixture was reduced to ambient temperature, it was placed in crushed ice and stirred for 5 minutes. The resulting compounds were filtered. Purification of the crude product was accomplished using flash chromatography. The completeness of the reaction was monitored using thin-layer chromatography.
2-(4-Oxo-2-phenyl-thiazolidin-3-yl)-1, 9-dihydro-purin-6-one (GB-1)
White solid; Yield: 64.07%; mp: 160–1620C; FT-IR (KBr) Vmax: 3323, 2927, 2561, 1714, 1659, 1356 cm-1; 1H NMR (DMSO-d6, 500 MHz): δ 4.28 (s, 2H), 7.06–7.14 (m, 5H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (DMSO-d6, 500 MHz) δ 171.216, 167.290, 159.544, 139.544, 129.135, 128.677, 127.943, 120.172, 114.629, 53.173, 40.263, 39.929, 39.763, 34.466; LC-HRMS/MS (ESI): m/z, calcd (M +) 314.06, found 314.0071.
2-[2-(4-Chloro-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-2)
Yellow solid; Yield: 59.22%; mp: 144–1460C; FT-IR (KBr) Vmax: 3323, 2927, 2615, 1714, 1651, 1348, 757 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H, NH), 7.00–7.15 (m, 4H), 7.97(s, 1H), 5.92(s, 1H, CH), 3.33(s, 2H); 13C NMR (CDCl3 500 MHz) δ 130.035, 129.156, 128.081, 127.834, 127.262, 127.118, 126.505, 77.269, 77.016, 76.742, 43.599, 39.788, 33.179, 24.345; LC-HRMS/MS (ESI): m/z, calcd (M +) 348.02, found 348.019.
2-[2-(3-Methoxy-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-3)
Black solid; Yield: 47.36%; mp: 139–1410C; FT-IR (KBr) Vmax: 3329, 2920, 2619, 1718, 1656, 1340, 1240 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 6.50–7.03 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H), 3.73(s, 3H); 13C NMR (CDCl3, 500 MHz) δ 191.199, 154.532, 149.557, 148.954, 133.724, 130.757, 129.846, 126.964, 126.447, 119.311, 111.850, 110.199, 77.483, 66.464, 64.883; LC-HRMS/MS (ESI): m/z, calcd (M +) 344.07, found 344.01.
2-[2-(4-Nitro-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-4)
Black solid; Yield: 68.03%; mp: 167–1690C; FT-IR (KBr) Vmax: 3306, 2928, 2735, 1725, 1656, 1533, 1340 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 7.32–8.07 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (CDCl3, 500 MHz) δ 153.894, 131.695, 131.322, 131.082, 130.683, 130.497, 129.892, 124.357, 124.252, 116.492, 113.092, 112.600, 40.124, 39.791; LC-HRMS/MS (ESI): m/z, calcd (M +) 359.05, found 359.024.
2-[2-(4-Dimethylamino-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-5)
Yellow solid; Yield: 52.29%; mp: 128–1300C; FT-IR (KBr) Vmax: 3329, 2928, 2619, 1725, 1656, 1340 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 6.47–6.88 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H), 2.85(m, 6H); 13C NMR (CDCl3, 500 MHz) δ 190.290, 176.992, 154.336, 131.960, 131.960, 125.123, 124.870, 111.198, 110.976, 110.715, 77.327, 77.073, 76.819, 45.299, 40.052, 34.582; LC-HRMS/MS (ESI): m/z, calcd (M +) 357.11, found 357.27.
2-[2-(3, 4-Dimethoxy-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-6)
Black solid; Yield: 42.02%; mp: 155–1570C; FT-IR (KBr) Vmax: 3346, 2935, 2615, 1729, 1656, 1348, 1240 cm-1. 1H NMR (500 MHz, CDCl3): δ 4.28 (s, 2H), 6.46–6.54 (m, 3H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H), 3.73(s, 6H); 13C NMR (CDCl3, 500 MHz) δ 190.355, 177.324, 169.748, 154.357, 144.642, 141.120, 131.999, 125.172, 110.998, 77.283, 77.029, 76.776, 45.712, 43.243, 40.087, 8.560; LC-HRMS/MS (ESI): m/z, calcd (M +) 374.08, found 374.019.
2-(2-Methyl-4-oxo-thiazolidin-3-yl)-1, 9-dihydro-purin-6-one (GB-7)
Brown solid; Yield: 58.44%; mp: 121–1230C; FT-IR (KBr) Vmax: 3346, 2927, 2615, 1714, 1651, 1348 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 7.97(s, 1H), 4.81(s, 1H), 3.33(s, 2H), 1.54(s, 3H); 13C NMR (CDCl3, 500 MHz) δ 144.854, 144.015, 129.835, 123.618, 114.477, 112.788, 112.560, 63.676, 40.292; LC-HRMS/MS (ESI): m/z, calcd (M +) 252.05, found 252.045.
Yellow solid; Yield: 38.51%; mp: 173–1750C; FT-IR (KBr) Vmax: 3346, 2927, 2615, 1714, 1651, 1533, 1341 cm-1. 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 7.32–8.07 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (CDCl3, 500 MHz) δ 163.244, 155.310, 149.314, 139.148, 121.698, 121.181, 111.198, 110.976, 110.715, 77.282, 77.028, 76.774, 28.317; LC-HRMS/MS (ESI): m/z, calcd (M +) 359.05, found 359.014.
Yellow solid; Yield: 56.11%; mp: 166–1680C; FT-IR (KBr) Vmax: 3351, 3095, 2735, 1718, 1625, 1348, 824 cm-1. 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 7.00–7.15 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (CDCl3, 500 MHz) δ 198.834, 161.638, 141.351, 140.202, 133.832, 131.060, 129.785, 128.098, 127.275, 126.617, 125.512, 77.296, 45.303, 37.250; LC-HRMS/MS (ESI): m/z, calcd (M +) 348.02, found 348.28.
2-[2-(3-Chloro-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-10)
Yellow solid; Yield: 61.35%; mp: 141–1430C; FT-IR (KBr) Vmax: 3346, 2919, 2615, 1722, 1628, 1341, 718 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 6.94–7.08 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (CDCl3, 500 MHz) δ 198.545, 161.367, 145.244, 134.582, 130.179, 129.602, 128.099, 127.397, 126.994, 125.412, 77.296, 77.043, 76.789, 40.434; LC-HRMS/MS (ESI): m/z, calcd (M +) 348.02, found 348.087.
2-[2-(3-Bromo-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-11)
Yellow solid; Yield: 71.09%; mp: 183–1850C; FT-IR (KBr) Vmax: 3385, 3082, 2732, 1722, 1620, 1333, 672 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 7.00–7.24 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (CDCl3, 500 MHz) δ 198.471, 161.293, 145.541, 131.197, 130.446, 130.135, 129.935, 126.614, 125.880, 123.021, 122.841, 77.297, 77.043, 40.320; LC-HRMS/MS (ESI): m/z, calcd (M +) 391.45, found 391.97.
2-[2-(3-Nitro-phenyl)-4-oxo-thiazolidin-3-yl]-1, 9-dihydro-purin-6-one (GB-12)
Black solid; Yield: 67.19%; mp: 153–1550C; FT-IR (KBr) Vmax: 3354, 2926, 2618, 1725, 1623, 1536, 1339; 1H NMR (CDCl3, 500 MHz): δ 4.28 (s, 2H), 7.40–8.00 (m, 4H), 7.97(s, 1H), 5.92(s, 1H), 3.33(s, 2H); 13C NMR (CDCl3, 500 MHz) δ 190.297, 151.153, 140.060, 130.901, 130.499, 129.495, 124.328, 124.009, 121.861, 77.289, 77.035, 76.781, 45.736, 8.547; LC-HRMS/MS (ESI): m/z, calcd (M +) 359.26, found 359.48.
Anticancer activity (Sulforhodamine B assay)
RPMI 1640 medium supplemented with 10% fetal bovine serum and 2 mM L-glutamine was used to culture the cells. For the current screening experiment, cells were injected into 96 well microtiter plates in 90 L at a density of 5000 cells per well. Before adding experimental drugs, the microtiter plates were incubated for 24 hours at 37°C, 5% CO2, 95% air, and 100% relative humidity. The experimental drugs were dissolved in a suitable solvent to form a stock solution with a concentration of 10-2. Four 10-fold serial dilutions of full media were conducted during the experiment. Aliquots of 10 µl of each of these various drug dilutions were added to the appropriate microtiter wells that had been previously filled with 90 µl of a medium, yielding in the required final drug concentrations. Plates were incubated under usual conditions for 48 hours after drug addition, and the test was stopped by adding cold TCA. Cells were gently fixed in situ for 60 minutes at 4°C using 50 µl of cool 30% (w/v) TCA (final concentration, 10% TCA). After discarding the supernatant, the plates were rinsed and dried five times with tap water. Sulforhodamine B (SRB) solution (50 µl) was added to each well at a concentration of 0.4 percent (w/v) in 1% acetic acid, and plates were incubated at room temperature for 20 minutes. Following staining, the unbound dye was recovered, and the remaining dye was removed using a five-step wash with 1% acetic acid. The plates were dried in the air. After eluting the bound dye with 10 mM trizma base, the absorbance was measured using an Elisa plate reader at a wavelength of 540 nm with a reference wavelength of 690 nm.
On a plate-by-plate basis, percent rise was assessed for test wells relative to control wells. Percent Growth was computed as the average absorbance of the test well to the average absorbance of the control well multiplied by 100. The percentage growth rate at each of the four drug concentration levels was calculated using the six absorbance measurements [time zero (Tz), control growth (C), and test growth in the presence of the four-drug concentration levels (Ti)]. For each test article, dosage response parameters were computed. The 50% growth inhibition (GI50) was calculated as [(Ti-Tz)/(C-Tz)] x 100 = 50, which is the drug concentration that results in a 50% reduction in the net protein increase (as shown by SRB staining) in control cells during drug incubation. The medication concentration required to suppress total growth (TGI) was determined using Ti = Tz. The LC50 value (drug concentration that results in a 50% drop in the measured protein at the end of treatment compared to the beginning) indicates a net loss of cells following treatment when [(Ti-Tz)/Tz] x 100 = -50. If the desired level of activity was not achieved or was surpassed, values for each of these three parameters were stated as higher or less than the maximum or minimum concentration tested [19,20].
In vitro Anti-inflammatory activity
The anti-inflammatory efficacy of the synthesized compounds was determined employing the inhibition of the albumin denaturation procedure. Aceclofenac was used as the standard drug. The standard and test substances were dissolved in a small amount of dimethylformamide (DMF) and diluted with phosphate buffer (0.2 M, pH 7.4). In all solutions, the final concentration of DMF was less than 2.5 percent. A test solution (1 ml) containing various drug doses was mixed with 1 ml of a 1% mM albumin solution in phosphate buffer and incubated for 15 minutes at 27 ± 10 0C in a BOD incubator. Denaturation was induced by maintaining the reaction mixture on a water bath at 60 ± 10 0C for 10 minutes. After cooling, the turbidity was determined using a double beam UV-visible spectrophotometer at 660 nm. The percentage inhibition of denaturation was determined by comparing it to a control condition in which no medication was added. Each experiment was repeated twice, and an average was calculated. The percent inhibition can be computed as follows: percent inhibition = 100 ((Vc / Vt) - 1), where Vt represents the absorbance value of the test group and Vc represents the absorbance value of the control group. The 50% Inhibitory Concentration (IC50) was derived using the percentage inhibition [21].
Angiogenesis activity by chorioallantoic membrane (CAM) of chick embryos assay
The chicken chorioallantoic membrane (CAM) experiment was performed using fertilized chicken eggs that were eight days old. Each egg's shell was drilled with a 1-cm diameter hole, and the dermic sheet's surface was removed to expose the CAM. A filter paper with a diameter of 0.5 cm was placed on top of the CAM, and a volume of 1 nM, 10 nM, or 100 nM drug (control, Thalidomide) was deposited in the center. The shell's windows were then sealed with sterile bandages. For 48 hours, the eggs were incubated at 370C and 90% relative humidity. Following 15 minutes of fixation with stationary solution (a 1:1 combination of methanol and acetone), the CAM was removed and photographed using a digital camera. The morphology of chicken blood arteries was determined following various treatments [22].
DPPH radical scavenging assay
The standard solution was made by dissolving 100 mg ascorbic acid in methanol to get 10, 20, 30, 40, and 50 μg/mL concentrations. The tests solutions were prepared by dissolving 10 mg of compounds (GB-1 to GB-12) in 10 mL of methanol to give 100 μg/mL of stock solution of each compound. The 10, 20, 30, 40 and 50 μg/mL concentrations were prepared using this stock solution. To each dilution, 150 μL of DPPH was added and kept in the dark for 30 min. The 150 μL DPPH solution was added to 10 mL methanol, and the absorbance at 517 nm was measured immediately as a control. 10 mL of different test sample concentrations (10, 20, 30, 40, 50 μL) prepared with methanol were taken, and 150 μL DPPH solution was added to each test tube. After 15 minutes, absorbance at 517 nm was determined using methanol as a blank in a UV visible spectrophotometer (Jasco, UV-630). The following equation was used to compute the free radical scavenging activity (FRSA) (% inhibition). The % inhibition for different log concentrations was plotted to obtain a concentration vs. % inhibition graph from which IC50 value was calculated [23].
KMnO4 radical scavenging assay
The experiment was conducted using a Jasco 630 UV-Spectrophotometer. A fresh stock solution of potassium permanganate (0.05N) was produced and stored in a dark place until use. The sulphuric acid stock solution (2N) was prepared for Mn2+ ion separation. L-ascorbic acid (70 mg/100 ml) was produced in distilled water as a positive control, and successive dilutions [10, 20, 30, 40, 50 μg/ml] were made. The compounds were dissolved in methanol (10 mg/10 ml) and serially diluted. At room temperature and in a dark environment, test solutions were allowed to react with KMnO4 solution, and absorbance values at 528 nm were determined compared to a blank. The radical scavenging activity (percent inhibition) was computed and expressed as a percentage of KMnO4 radical elimination [24].
Molecular docking studies
The docking approach is used to determine the proper binding poses and interactions inside the protein's binding site. The docking of molecules is carried out using the VLife MDS 4.4 program. Polo-like kinase 1 crystal structure (PDB code 1q4k) was obtained from the protein data bank database (http://www.rcsb.org/pdb). The initial crystal structure contained the bound ligand; this was removed, and missing loops were inserted using the same software's homology modeling package. The two-dimensional structures were drawn and translated to three-dimensional structures. The three-dimensional structure was optimized using MMFF up to an rms gradient of 0.01. The structure of the protein was optimized. Cavity number one is chosen for the docking procedure. All atoms within a 5A0 radius were defined as the active site of a protein. Batch docking was used to determine the docking score and interactions between the ligand and target protein.
Copper-nickel oxide nanoparticles were synthesized significantly by an electrochemical reduction process with the capping agent cetyltrimethyl ammonium bromide. The capping compounds are organic surface-active agents employed to bind selectively to a particular plane of a nonmaterial crystal. Cetyltrimethyl ammonium bromide is a surfactant that plays a critical function in preventing particle aggregation and flocculation. Due to the capping of the surface of nanoparticles, surface-active substances limit growth pace, affecting the morphological features of nanoparticles and orienting them during crystal formation. The rate of surface-active agent adhesion and diffusion on the surface determines the growth rate of nanoparticles. UV-visible spectral investigations were used to determine the size of nanoparticles after 15 minutes of electrolysis.
Analysis of copper nickel oxide nanoparticles
UV-visible studies:
Copper-nickel oxide nanoparticles were scanned in a twin beam spectrophotometer for UV-visible spectroscopic investigation in the range of 200-1100 nm. The scanning revealed that all samples had wavelength maxima in the UV area. The UV-visible spectra of copper-nickel oxide nanoparticles produced in water using cetyltrimethyl ammonium bromide as a capping agent are shown in Figure 1 at current densities of 5 and 10 mA/ cm2, respectively. According to the analysis, the wavelength maxima are smaller at a current density of 10 mA/ cm2 than 5 mA/ cm2. It confirmed that as current density increases, particle size falls, and a blue shift occurs. After 15 minutes of electrolysis, the absorbance of the sample was found to be greater than after 2 hours of electrolysis. These observations demonstrate that the particle size at a lower electrolysis time is less than at a larger electrolysis time. The particle size increased as the electrolysis time increased.
FT-IR Studies:
FTIR spectroscopy was used to determine the capping effectiveness of copper-nickel oxide nanoparticles electrochemically produced using cetyltrimethyl ammonium bromide. The FTIR spectrum of prepared copper-nickel oxide nanoparticles with cetyltrimethyl ammonium bromide (Figure 2) reveals peaks at 2970, 2864, 2832, 3462, and 3111 cm-1, corresponding to C-H stretching vibrations, 642 cm-1 Br-C stretching vibrations, and 1342-1266 cm-1 N-C stretching vibrations. It demonstrated the presence of cetyltrimethyl ammonium bromide on the surface of nanoparticles. The peaks at 3640 and 3483 cm-1 showed the existence of water due to the ligand's hygroscopic nature. The FTIR spectrum of calcinated copper-nickel oxide a nanoparticle (Figure 3) at 500 0C in a muffle furnace demonstrates that peaks related to the ligand have vanished or have become weak, indicating that the ligand has been removed during the calcination process. At 550 cm-1, the broadband suggests the presence of a CuNi-O bond.
Thermal studies:
As shown in Figure 4, the weight of copper-nickel oxide nanoparticles above 200 °C was constant; indicating that the capping agent cetyltrimethyl ammonium bromide was utilized to create the nanoparticles was not present.
XRD studies:
After two hours of calcination at 500 oC, the XRD pattern of produced copper-nickel oxide nanoparticles was obtained (Figure 5). The measured diffraction peaks indicate that copper-nickel oxide nanoparticles have a biclinic structure. The ten distinctive peaks with lattice parameters a = 4.679, b = 3.431, and c = 5.136 at β = 99.262 with 2θ = 32.889, 35.990, 39.177, 49.182, 54.113, 58.795, 62.094, 68.627, 72.968, and 75.731 were detected, which correspond to miller indices of (101), (031), (130), (141), (042), (132), were observed which accurately coincide with the JCPDS no. 80-0076 of copper-nickel oxide. The average particle size was determined using Debye-equation, Scherrer's, which specifies that D = kλ/βcos θ. In this equation, k denotes the shape constant, λ denotes wavelength, and θ denotes the diffraction angle, where as β denotes the whole width half maximum. Copper-nickel oxide nanoparticles with an average size of 7.79 nm were estimated using XRD data and are given in Table 1.
SEM-EDS studies:
Copper-nickel oxide nanoparticles were studied using scanning electron microscopy at various resolutions in this work. The scanning electron microscope image (Figure 6) illustrates the morphological characteristics of copper-nickel oxide nanoparticles. The SEM image demonstrates the presence of uniform, regular, and irregularly shaped particles. Additionally, it established the creation of nanoscale crystalline particles as well as randomly oriented aggregates. Calcination leads to an increase in the crystal size of particles. As shown in Figure 7, the copper-nickel oxide nanoparticles were examined qualitatively and quantitatively using EDS. The EDS spectra confirmed copper, nickel, and oxygen in the composition, as shown in Table 2.
TEM-SAED analysis:
The various colors are the result of the varying densities revealed by TEM images (Figure 8). The TEM image shows particles with diameters of 27.84, 25.70, 24.47, 31.00, 45.62, 38.23, and 27.18 nm, with an average of 31.43 nm and maximum particles with diameters of 20-30 nm, which is consistent with the XRD study. The image demonstrates the randomly distributed metal nanoparticle aggregates. The electron diffraction pattern of a selected section of the nanoparticle, as shown in Figures 9 and 10 and 11 confirms its crystalline character due to the absence of dispersed holes often associated with amorphous phases.
Synthesis of 2-(2-substituted-4-oxo-thiazolidin-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12)
The title compounds have been synthesized as per the reaction shown in Figure 12 (Scheme 1). Thin layer chromatography is used to monitor reaction progress. The physical and chemical properties of the title compounds have been recorded as shown in Table 3. The calcinated copper nickel oxide nanoparticles were used sucessfully as a catalyst to synthesis of 2-(2-substituted-4-oxo-thiazolidin-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12) using starting material guanine, substituted aldehydes, thioglycolic acid, and sodium hydroxide were combined in ethanol in microwave synthesis system (CEM, USA).
In this study, a novel series of 2-(2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones were designed and synthesized. All synthesized compounds were screened by sulforhodamine (SRB) assay against breast cancer MCF-7 cell line, compared to adriamycin as a reference drug. The results are reported in Table 7, expressed as GI50 μM (growth inhibitory concentration at 50%). Anticancer screening found that compounds GB-6 (GI50: 30 M) and GB-10 (GI50: 30 M) displayed considerable cytotoxic activity against the MCF-7 breast cancer shown in Figure 13 and 14. The most promising compound, GB-8 (GI50: 10 μM), showed excellent activity against MCF-7 cell lines.
In-vitro anti-inflammatory activity
We have devised a novel methodology for synthesizing (2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12) in this work. All synthesized compounds were compared to standard aceclofenac for in vitro anti-inflammatory efficacy utilizing the inhibition of the albumin denaturation technique. Derivatives GB-4, GB-6, GB-8, and GB-9, GB-10 showed significant in vitro anti-inflammatory activity in the range of IC50:179.65-194.59 μg/ml as compared with aceclofenac (IC50:191.19μg/ml). The satisfactory results for anti-inflammatory activity have been correctly reported in Table 4. The anticancer activity study shows similar results to some extent.
Chorioallantoic membrane (CAM) of chick embryos assay
The CAM assay results of 2-(2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12) gives a significant blood vessel growth inhibitory activity of in chick embryo eggs. The 10 nM drug concentration of GB-4, GB-8 and GB-10 compounds shows an excellent capillary growth inhibitory activity. The 100 nM drug concentration of GB-6 compound shows a good capillary growth inhibitory activity shown in Figure 15.
Antioxidant activity was determined appropriately in vitro utilizing the DPPH and KMnO4 radical scavenging assays. The effective concentration (IC50) of each chemical was determined using linear regression. The satisfactory results were expressed as an IC50 value, accurately depicting the concentration at which the investigated chemicals diminish half of the substrate.
The antioxidant activity of the title compounds 2-(2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12) and the parent compound ascorbic acid were evaluated using DPPH free radical scavenging assay. Antioxidant chemicals react with the DPPH radical via the hydrogen atom donation mechanism, resulting in a change in the color of DPPH from violet to yellow as determined by a UV-visible spectrophotometer. The satisfactory result of the antioxidant activity at different test concentrations and IC50 value in μg/ml of the synthesized compounds (GB-1 to GB-12) are demonstrated in Table 5. The data shows that among all the synthesized compounds in IC50 value in (µg/ml) GB-6: 11.96, GB-8: 10.67, GB-10: 9.08, GB-11: 10.30, GB-12: 10.63 exhibited excellent radical scavenging activities compared to ascorbic acid: 13.04µg/ml. The reason for the higher antioxidant activity of compound GB-10, GB-11, and GB-12 may be due to the chloro, bromo and pyridine substituents on the phenyl ring attached with thiazolidine moiety; whereas compounds GB-2, GB-6 and GB-8 exhibited moderate antioxidant potential, and anticancer activity study shows similar results in some extent. Therefore, these molecules could be developed for antioxidant agents and can be potential polo-like kinase 1 inhibitors and promising anticancer agents.
The scavenging activity of synthesized compounds 2-(2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones (GB-1 to GB-12) at different concentrations 10, 20, 30, 40 and 50 µg/ml. were evaluated. The high scavenging activity levels imply a strong antiradical action. The results are summarized in Table 6 as IC50 values (µg/ml). Low IC50 values indicate a greater ability to scavenge. The nitro group substituted at phenyl ring para GB-4: 23.60 µg/ml and ortho GB-8: 24.93 µg/ml positions exhibited good antioxidant activity. The phenyl ring containing para GB-2: 15.33 µg/ml and meta GB-10: 24.96 µg/ml chlorophenyl-containing groups exhibited the highest antioxidant potential compared to ascorbic acid: 26.55 µg/ml as a standard. The phenyl ring containing meta methoxy phenyl GB-3: 20.21 µg/ml containing groups exhibited good radical scavenging activity. These desired outcome results reveal that the compounds GB-8 and GB-10 display good free radical scavenging activity, same as anticancer activity.
Molecular docking studies:
The docking analysis was performed to determine the mechanisms of binding of our compounds to the PLK1 enzyme. The previous results prompted us to investigate the molecular docking among the most bioactive compound, GB-6, GB-8, and GB-10, using PLK1, which is overexpressed in a variety of cancer cell lines, including prostate (PC-3), breast (MCF-7), hepatocellular carcinoma (HepG2), and human cervical (HeLa) cancer cell lines. Figure 13 illustrates the docked compounds GB-1 to GB-12 with (1q4k) into the putative active site of PLK1. The molecular modeling results for the compounds GB-6, GB-8, and GB-10 indicated that the molecule was approximately oriented into the predicted binding location of the receptor pocket, with some extra hydrophobic and hydrogen bonding interactions with adjacent amino acids. These docking results demonstrate that compounds with a phenyl ring containing meta-nitro groups exhibit a favorable binding interaction and elucidate the good docking score (-5.22).
In contrast, compounds with a phenyl ring containing meta and para-dimethoxy (-4.70) groups exhibit a more favorable docking score than compounds with a phenyl ring containing meta-methoxy groups. The phenyl ring containing a meta-chlorophenyl group elucidates more favorable protein-ligand interactions and a higher docking score (-4.78) than the phenyl ring containing ortho (-4.20) or para chlorophenyl groups (-4.20). Table 7 summarises the docking scores (kcal/moles) of all compounds. The nitrogen atom of the guanine ring creates hydrophobic bonds with the LEU511B and LEU523B amino acid residues. The nitro group substituted at the meta position of the phenyl ring produces hydrophobic bonds with amino acid residues LEU511B, LEU523B, LEU543B, ILE542B, and LEU541B, as well as hydrogen bonds with amino acid residues LEU525B, VAL411B, HIS524B, and VAL530B.
The dimethoxy group (electron-donating) substituted on the phenyl ring at meta and para positions developed hydrophobic bonds with amino acid residues LEU541B, ILE542B, LEU543B, LEU523B and LEU511B, as well as hydrogen bonds with amino acid residues ALA549B, VAL411B and LEU525B. The electron-withdrawing group (chlorine) substituted on phenyl ring at meta position forms as hydrophobic bonding with amino acid residues MET377B, LEU543B, ILE542B, LEU41B, LEU523B and LEU511B as well as hydrogen bonding with amino acid residues VAL411B, LEU525B, HIS524B and VAL530B. The molecular docking study also reveals that the compound GB-6, GB-8 and GB-10 shows a good binding interaction and significant anticancer activity shown in Figure 16.
Structure activity relationship (SAR)
Including a nitro group to the para, ortho, or meta position of the phenyl ring (GB-4, GB-8, GB-12) enhances anticancer activity against the breast cancer MCF-7 cell line. Meta-chlorophenyl compounds (GB-10) are more active against cancer cell lines than ortho- and para-chlorophenyl compounds (GB-2 & GB-9). The 3, 4-dimethoxy groups on the meta and para positions of the phenyl ring (GB-6) enhance anticancer and anti-inflammatory action. The antitumor activity of meta-chlorophenyl (GB-10) and 3, 4-dimethoxy phenyl compounds (GB-6) was comparable. The bromo group is substituted in the meta position of the phenyl ring (GB-11), resulting in a more potent anticancer agent than the para and ortho chlorophenyl analogs (GB-2 & GB-9). Unsubstituted phenyl compounds (GB-1) were less effective against a cancer cell line.
In the present work, we synthesized some novel 2-(2-substituted-4-oxo-thiazolidine-3-yl)-1, 9-dihydro-purin-6-ones supported by a newly synthesized copper nickel-oxide nanocatalyst. The newly synthesized compounds were adequately evaluated for their anti-cancer, anti-inflammatory, antioxidant activity and anti-angiogenetic activity. The experimental and docking data were found to be well correlated, indicating that compounds GB-6, GB-8, and GB-10 exhibited significant anti-cancer action against the breast cancer cell line MCF-7, as well as anti-inflammatory, antioxidant, and anti-angiogenic activities. Additionally, docking studies indicate that the drugs' effect may be attributable to their inhibition of polo-like kinase 1. These findings suggest that compounds GB-6, GB-8, and GB-10, similar polo-like kinase 1 inhibitors could serve as lead compounds for future anti-cancer drug development.
We are thankful to the Indian Council of Medical Research (ICMR), a constituent of the Ministry of Health and Family Welfare, New Delhi, autonomous for Medical Research in India for financial support of this work.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This work was supported by the Indian Council of Medical Research, New Delhi (Grant number: BIC/12(12), 2015).
1. World Health Organization, Global Cancer Deaths Report for the https://www.who.int/news-room/fact-sheets/detail/cancer/ 2020. Accessed 3 March 2021.
2. Shakeel I, Basheer N, Hasan GM, Afzal M, Hassan MI. Polo-like Kinase 1 as an Emerging Drug Target: Structure, Function and Therapeutic Implications. J Drug Target 2021; 29 (2):168-184. doi:org/10.1080/1061186X.2020.1818760.
3. Jeyapal P, Krishnasamy G, Suzuki R, Venkatesh C, Chandrasekar M. In-Silico Design and Synthesis of N9-Substituted β-Carbolines as PLK-1 Inhibitors and Their In-Vitro/In-Vivo Tumor Suppressing Evaluation. Bioorg Chem 2019; 88: 1-8. doi:org/10.1016/j.bioorg.2019.04.007.
4. Weiß L, Efferth T. Polo-Like Kinase 1 as Target for Cancer Therapy. Exp Hematol 2012; 1(1):38:1-6. doi:org/10.1186/2162-3619-1-38.
5. Frost A, Mross K, Steinbild S, Hedbom S, Unger C, Kaiser R, Munzert G. Phase I Study of the PLK1 Inhibitor BI2536 Administered Intravenously on Three Consecutive Days in Advanced Solid Tumours. Curr Oncol. 2012;19(1):e28-35. doi:org/10.3747/co.19.866.
6. Horishny V, Chaban T, Matiychuk V. Synthesis and Primary Antitumor Screening of 5-ylidene Derivatives of 3-(Morpholin-4-yl)-2-Sulfanylidene-1,3-Thiazolidin-4-One. Russ J Org Chem. 2020;56: 454–457. doi:org/10.1134/S1070428020030148.
7. Horishny V, Mandzyuk L, Lytvyn R, Bodnarchuk O, Matiychuk V, Obushak M. Synthesis and Biological Activity of Pyrazolo [1, 5-c][1,3]Benzoxazines Containing a Thiazolidin-4-One Fragment. Russ J Org Chem. 2020; 56(4):588–595. doi:org/10.1134/S1070428020040053.
8. Isloor A, Sunil D, Shetty P, Malladi S, Pai K, Maliyakkl N. Synthesis, Characterization, Anticancer, and Antioxidant Activity of Some New Thiazolidin-4-Ones in MCF-7 Cells. Med Chem Res. 2012;22(2):758–767. doi:org/10.1007/s00044-012-0071-5.
9. Ahani Z, Nikbin M, Maghsoodlou MT, Farhadi-Ghalati F, Valizadeh J, Beyzaei H, Moghaddam-Manesh M. Semi-Synthesis, Antibacterial and Antifungal Activities of Three Novel Thiazolidin-4-Ones by Essential Oil of Anethum Graveolens Seed as Starting Material. J Iran Chem Soc. 2018;15: 2423-2430. doi:org/10.1007/s13738-018-1431-y.
10. Panzariu A, Apotrosoaei M, Vasincu IM, Dragan M, Constantin S, Buron F, Tuchilus C. Synthesis and Biological Evaluation of New 1,3-Thiazolidine-4-One Derivatives of Nitro-l-Arginine Methyl Ester. Chem Cent J. 2016; 10(1):1-14. doi:org/10.1186/s13065-016-0151-6.
11. Ottana R, Maccari R, Giglio M, Corso AD, Cappiello M, Mura U, Settimo FD. Identification of 5-Arylidene-4-Thiazolidinone Derivatives Endowed with Dual Activity as Aldose Reductase Inhibitors and Antioxidant Agents for the Treatment of Diabetic Complications. Eur J Med Chem. 2011;46(7): 2797-2806. doi:org/10.1016/j.ejmech.2011.03.068.
12. Raza S, Srivastava S, Srivastava D, Srivastava A, Haq W, Katti S. Thiazolidin-4-One and Thiazinan-4-One Derivatives Analogous to Rosiglitazone as Potential Antihyperglycemic and Antidyslipidemic Agents. Eur J Med Chem. 2013;63: 611–620. doi:org/10.1016/j.ejmech.2013.01.054.
13. Sawant R, Wadekar J, Ukirde R, Barkade G. Synthesis, Molecular Docking and Anticancer Activity of Novel 1,3-Thiazolidin-4-Ones. Pharm Sci. 2020;27(3): 339-346. doi:org/ 10.34172/PS.2020.95.
14. Shao J, Liu M, Wang Z, Li K, Bao B, Zhao S, Zhou S. Controllable Synthesis of Surface Pt-Rich Bimetallic AuPt Nanocatalysts for Selective Hydrogenation Reactions. ACS. Omega. 2019;4: 15621-15627. doi:org/10.1021/acsomega.9b02117.
15. Roldan MV, Pellegri N, Sanctis OD. Electrochemical Method for Ag-PEG Nanoparticles Synthesis. J Nanoparticl. 2013:1-7. doi:org/10.1155/2013/524150.
16. Ozin GA, Arsenault AC, Cademartiri L. Nanochemistry: A Chemical Approach to Nanomaterials. Royal Society Chemistry, United Kingdom: 2009.
17. Meloni D, Monaci R, Solinas V, Auroux A, and Dumitriu E. Characterization of the Active Sites in Mixed Oxides Derived from LDH Precursors by Physicochemical and Catalytic Techniques. Appl Catal. 2008; 350(1):86-95. doi:org/10.1016/j.apcata.2008.08.005.
18. Ravindra K, Reddy HM, Uthanna S. Studies on the Structural, Electrical and Optical Properties of Thermally Oxidized Copper Nickel Oxide Thin Films. Front Nanosci. 2017; 3(2):1-7. doi:org/10.15761/FNN.1000154.
19. Vichai V, Kirtikara K. Sulforhodamine B Colorimetric Assay for Cytotoxicity Screening. Nat Protoc. 2006;1: 1112–1116. doi:org/10.1038/nprot.2006.179.
20. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New Colorimetric Cytotoxicity assay for Anticancer Drug Screening. J Natl Cancer Inst. 1990; 82(13):1107-1112. doi:org/10.1093/jnci/82.13.1107.
21. Banerjee AG, Das N. Design, Synthesis, Evaluation and Molecular Modelling Studies of Some Novel 5,6-Diphenyl-1,2,4-Triazin-3(2H)-Ones Bearing Five Member Heterocyclic Moieties as Potential COX-2 Inhibitors: A Hybrid Pharmacophore Approach. Bioorg Chem. 2016;69: 102-120. doi:org/10.1016/j.bioorg.2016.10.003.
22. Kacan T, Nayir E, Altun A, Kilickap S, Babacan NA. Antitumor Activity of Sorafenib on Colorectal Cancer. J Oncol Sci. 2016:1-5. doi:org/10.1016/j.jons.2016.07.008.
23. Ukirde RD, Patil RB, Sawant SD. Design, Synthesis and Evaluation of Antioxidant Activity of Some Coumarin Derivatives. Asian j org med chem. 2019; 4(3):138-143. doi:org/10.14233/ajomc.2019.
24. Rani PS, Vunguturi S. In-Vitro Study of Antioxidant Activities of Medicinal Plant Extracts using KMnO4 and DPPH-a Comparison. Int j innov sci eng technol. 2015;2(6):116-119.
Table 1: Average size of copper nickel oxide nanoparticles
h k l 2Theta d (A) FWHM Size (nm)
1 0 1 36.537 2.45732 0.8740 9.65
Average particle size 7.79 nm
Table 2: EDS data of copper nickel oxide nanoparticles
Weight percentage
Atomic percentage
Ni k
Cu k
Table 3: Chemical structures and physicochemical characteristics of title compounds (GB-1 to GB-12)
point (0C)
Rf value
GB-1
C14H10ClN5O2S
-CH3
C9H9N5O2S
GB-10
C14H10BrN5O2S
Table 4: In-vitro anti-inflammatory activity and IC50 value (µg/ml)
Anti-inflammatory Activity
IC50 (μg/ml)
Table 5: DPPH radical scavenging assay
Comp. ID
% inhibition
(µg/ml)
Concentration in µg/ml
Table 6: KMnO4 radical scavenging assay
Table 7: Binding free energy and key interactions at the binding site of PLK1 and GI50 value (μM) on MCF-7 human breast cancer cell line
BINDING FREE ENERGY AND KEY INTERACTIONS AT THE BINDING SITE
(µM)
MCF-7 cell lines
Docking score
Hydrophobic bonding
Hydrogen bonding
ILE542B, LEU543B, LEU523B, LEU511B
TYR425B, VAL411B, ILE532B, VAL530B, HIS524B
˃80
GB -2
VAL550B, LEU541B, ILE542B, LEU543B, LEU523B, LEU511B
ILE532B, VAL530B, HIS524B, LEU525B, VAL411B, TYR425B, THR551B
LEU511B, LEU523B, LEU543B, ILE542B, LEU541B
VAL530B, LEU525B, VAL411B, HIS524B
LEU543B, LEU541B, ILE542B, LEU523B, LEU511B
VAL411B, LEU525B, HIS524B, VAL530B
LEU541B, ILE542B, LEU543B, LEU523B, LEU511B
ALA549B, VAL411B, LEU525B,
LEU523B, LEU511B, VAL411B,
LEU541B, HIS524B, VAL530B, ILE525B, VAL411B
LEU525B, VAL411B, HIS524B, VAL530B
LEU525B, VAL411B, VAL530B, SER529B, HIS524B
GB -10
MET377B, LEU543B, ILE542B, LEU41B, LEU523B, LEU511B
MET377B, LEU543B, ILE542B, LEU541B, LEU523B, LEU511B
HIS524B, SER529B, VAL530B, LEU525B, VAL411B
ADR: Adriamycin, Adriamycin was used as standard anticancer drug.
Supplementary Files
SupplementaryFiles.docx


text:
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Information on traditions and folk songs Romanian and Apuseni
From the dawn of its existence, the Romanian people were born in the Christian faith, and this is also observed in the authentic Christian sentiment expressed in an extremely wide popular form. Romanian folklore is an eminently Christian one, and the carol can be considered a representative species of Romanian spirituality, seen as a kind of "popular Bible". The Romanian peasant has always tried to humanize the image of God, of the Holy Child and of His Mother, whom He presents to Him, along with a blessing of the blessings on the whole creation. The verses of the Romanian carols discover a theological message of an intense spiritual experience, whether it is explicitly stated or not, the whole culture being full of symbols of Christian morality, transmitted from generation to generation.
According to the words of Mircea Eliade, the carols are traditional Romanian songs, with pre-Christian origins, which are sung around Christmas and New Year. These songs contain good wishes, positive words that bring glory to the birth of the Son of God on earth and prepare for a new year, from which better things are expected: better and more fruit, prosperity in the community, health, family harmony, love and plenty at home. The carols have their origins since the time of the Daco-Romans in the ancient (pre-Christian) winter holidays, in the pre-Christian, in the Saturnalia, in the holidays dedicated to Sol invictus (The Unbeared Sun) to the Romans and in the January Calendars, by which they are evil spirits were chased away and a reunion with those who were in eternity took place.
It is said that December does not only mean the end of a certain time interval and the beginning of another interval, but the cancellation of the past and of individual or collective sin through a ritual purification, and on holidays, from Christmas to Bobotea, the heavens are open.
We cannot say exactly which of the Romanian provinces gave more carols, but only that they are as beautiful and rich in content. When we speak of the popular origin of carols, we refer to the fact that they are the anonymous creation of the Romanian people, although those who gave them life belong to all social categories: clergy and myriads, teachers and ten or simple peasants with deep Christian faith.
In the Middle Ages, under the influence of the Church and through the overthrow of the Christian religion, which overlapped with the old pagan customs and rituals, the carols were loaded with the Christian spirit of the feast and joy of the Birth of the Savior. The ceremonies, parties and good wishes, occasioned by the end of autumn and the transition to a new year - in a special astral moment, when the heavens are said to open - the traditional carols become songs with strong spiritual significance, with a special emotional load, which leads to kindness, to a state of gratitude and generosity, to the openness of the heart, to the embracing and the care of others. The carols have a unifying ritual function in the community, connecting its members to a sacred, higher reality, which is lived on a social level with the open heart, cleansed by the purifying catharsis of the tunes, not by each individual, but together with the family members. , neighbors or members.
If we are to refer to the environment in which the carol and the tradition of carol appeared and developed, it should be emphasized that the Romanian village represented from the beginning the frame or hearth of its formation. Thousands of carols and songs of the star, the latter being of more recent origin, were collected by Romanian folk and musicians from the 19th-20th centuries. They, listening to them sung by the Romanian peasants from the villages, noted them on their notebooks, thus inscribing them in the treasure of culture and spirituality of the Romanian Orthodox faith.
The first collection of carols and star songs was published by Anton Pann in 1830, containing only the texts. The other four editions will also include carols, but recorded on psaltery. According to him, Teodor Burada, Tiberiu Brediceanu, Bela Bartok, Sabin Drăgoi, George Breazul, Gh. Cucu, Constantin Brăiloiu, Nicolae Ursu and others have made rich collections of carols that we sing today, either in their monodic form or in their choral version, as a result of the compositional mastery of some Romanian composers.
"Carol", "carol" means to walk, to go from place to place, close to the meaning of the word pilgrimage. The caroling, like the pilgrimage, does not happen without a purpose and without a target. In the case of carols, the target is the houses of the people, and the purpose is holy: the announcement of a great event - the Birth of the Lord.
In the religious text of the carols, Jesus is often represented as a son of the Romanian family, born and raised in the Romanian mioritic area, being dressed in the traditional Romanian port: Mititel, wrapped, in a cotton diaper ... On the baby Jesus, no wind you warn him, the snowy snow does not touch him, in the sense that, though he is born of the Mother of the Lord without a father, on earth, however, God being, all the works and works of the cosmos are subjected to him and he confirms him as Creator and Pronator, All-seeing and Omnipotent. He is the Upper East who replaced the old vanishing faith in the cult of Mithra, the deity of Iranian origin. He is the true Sun of justice. The origin and popular value of carols are also expressed by the simple lyrics with a catalytic structure, such as: We walk and corundum, Dalbe flowers, We walk and corundum / Yes colac we do not get, Dalbe flowers, Yes we do not get ... and acatalectic : In the city of Viflaim-u, Come all to see us, the Lord and our Lord / That today we were born, the Emperor of long ago, the Lord and our Lord ..., so peculiar to the verse and to the Romanian folk melos. The emergence of the Lerui ler chorus with its multiple linguistic transformations encountered in different areas of our country, such as lero, oleros, leonda, lerumi, oileranda, oler, oleranda and others, is a direct testimony of the rural origin of our carols.
In the village communities, all the houses were carved, regardless of the financial power of the hosts, as everyone had to enjoy on this holy day the message of carolers. Those who dared not receive the carolers, they were breaking fences or carving the walls of houses and were popular throughout the village. Unfortunately, the consumer society has largely perverted the true meaning and message of the carol.
Some people divide the carols into "Orthodox" and "Catholic", but it is a mistake. Thus, the Gregorian invoice song "Puer natus est" or "Troparul of the Birth of the Lord", of Byzantine origin, is part of the sacred music sphere dedicated to the largest Christian holiday. But they are not carols. Through the seventeenth and eighteenth centuries, as a reply to the "pagan" carols, the so-called "star songs" appear in Muntenia and Moldova, practiced by children who carried in their hands and a star made of various materials. Melos and texts, structurally different from carols, belonged either to people of the church - priests or teachers - or to teachers from the villages. This is the case of the songs "Three screams from the East", Nine today has dawned "," At Bethleem ". About the well-known "Oh, what a wonderful news", Sabin Drăgoi, who mentions it in his 1925 collection, clearly says that it is a star song that, according to its melody and rhythm, belongs to the Transylvanian Saxons. To those who support the idea of "Orthodox" and "Catholic" carols, I would ask the question: "Are the Pluguşorul, Capra, Bears, Căiuţii, Catholic or Orthodox customs?". The answer is only one: they are part of the Romanian folk treasure!
The carol, as a poetic-musical genre, is spread to all Balkan peoples and beyond. We find carols with Christian content also in the Anglo-Saxon, German and Slavic peoples, but the Romanian carols repertoire is much richer than these peoples.
In Romania, as well as in other countries of Eastern Christian rite, where the worship of mages is celebrated at Christmas time, walking with the star takes place on Christmas night, while in countries with western rites, where the worship of mages is celebrated by Boboteaza, they walk star on the eve of this holiday.
The oldest Christian Christmas song is "Jesus repfulsit omnium", composed by St. Ilarie de Poitiers, in the fourth century. Also, the carols "O come today, Emanuel", written in the 12th century and "Song of Mary", sung mainly in the Catholic churches and conceived in the Middle Ages with lyrics extracted directly from the Gospel of Luke, are two of the most old christmas songs.
In the early 1990s, it was a true invasion of international carols. The world wanted them, listened to them and sang with tears in their eyes. Many, especially young people in the urban area, heard them for the first time. Unfortunately, with this huge wave of sympathy on which the carols were "restored", a general confusion of what is meant by "carol" was gradually introduced. Thus appeared the subliminal message of the obsessive and transcontinental "Jingle bells", considered, by the ignorant, as an "international" carol. Many did not think it was an "equivalent" of the Romanian "Sanie cu zurgălăi", but not a carol, and, even more, "international", but just a simple winter song. Carols also have neighboring Slavic peoples: Bulgarians, Ukrainians, Belarusians, Poles, Slovaks, Serbs. In the south, they meet throughout the entire Thracian territory. It can not be "import carols" or "international"! The confusion is maintained by ignorance of numerous media channels, but also of half-persons with high social positions.
Source: ziarullumina.ro, doxologia.ro, tvr.ro, adevarul.ro, Wikipedia
Keywords: Romanian traditions | Christmas traditions | winter traditions | Romanian Christmas carols | traditional Romanian songs | traditional Christmas songs | Christmas | winter holidays | winter songs


text:
Don't Get Caught Out by The Computer Misuse Act
HR & People Original Content
Chris McColgan , 17th May 2018
Specialist IT lawyer and Head of Technology at national law firm, Clarke Willmott LLP, Susan Hall, warns that the idea of 'hacking' can cover a number of offences and online pranksters should be aware that what they're doing probably won't be considered harmless fun.
Online pranks can carry serious consequences. When a journalist asked Kemi Badenoch M.P., "What's the naughtiest thing you've ever done?" they probably were not expecting her to confess to a crime. However, when she admitted that "about ten years ago" she hacked into a Labour MP's website and "changed all the stuff in there to say nice things about the Tories" that was exactly what she did.
Unauthorised access to computer systems can cover hacking, as in this case, or accessing a system to which you have legitimate access for an unauthorised purpose. It's important to have strong passwords, keep them secure and change them regularly, but someone who opportunistically takes advantage of a slip up when it comes to security is still breaching the law, and could go to jail for it. All office computer policies need to make this clear, especially where people are handling valuable data which is a magnet for hackers.
Hacking was criminalised in 1990 by the Computer Misuse Act (the Act). This creates three distinct offences:
a) unauthorised access to a computer
b) unauthorised access to a computer with intent to commit further offences
c) unauthorised access with the intent to impair the operation of a computer or to erase, block or corrupt data or programs.
The conduct Badenoch admitted to appears at first sight to come within the first and the third offences: unauthorised access to a website and changing its contents. Both offences can be now tried either in the Crown Court or the Magistrates Court and the current maximum penalties are currently two and ten years' imprisonment respectively.
Hackers convicted under the Act have frequently been sent to prison or given suspended sentences, even when there has been no financial motive behind the hacking. A police constable who accessed police intelligence systems to snoop on his ex-girlfriends received a nine months suspended sentence, and a hacker who shut Sports Direct's website down for half an hour received a ten months suspended sentence. Other penalties have included community service orders, curfews and prohibitions on using internet-enabled devices.
The arguments put forward by Badenoch to excuse her actions – that it was "a prank", that it stemmed from "youthful exuberance" and that it involved "guessing a password" rather than "real hacking" – have not found favour in earlier cases under the Act.
The Act only requires that access to the computer in question must be unauthorised, and that the person gaining access must know it to be unauthorised. Guessing a password falls precisely within this wording. Furthermore, many of the "phone hacking" cases, brought under a different Act, also involved the perpetrators exploiting lax password security on voicemails.
"Youthful exuberance" also looks a little hollow when applied to the 28-year-old Badenoch. Cal Leeming, the youngest hacker convicted under the Act, was a mere twelve years old at the date of his first conviction, and was still a teenager, serving a fifteen month sentence, at the time when Badenoch claims to have carried out her own hacking.
Furthermore, the Act owes its very existence to a prank which the authorities at the time took very seriously indeed. In 1984 the 27-year-old Stephen Gold and the 21-year-old Robert Schifreen hacked into BT's Prestel online mailbox system, using logon details they had seen a BT engineer enter at a trade show: user ID 2222222222 and password 1234.
The users whose emails they accessed included Prince Philip. BT, understandably, were under some pressure to prosecute, and brought proceedings under a 1981 anti-forgery act. Although the prosecution succeeded before the magistrates, the House of Lords eventually held Gold and Schifreen not guilty, partly because of their lack of intention to profit financially, but also because they held that one could not "deceive" a computer.
Seeing this as a gap in the law, Emma Nicholson, MP for Taw and Torridge, pushed for the adoption of an anti-hacking bill. This became the Act. Like Kemi Badenoch, Emma Nicholson had worked as a software engineer and systems analyst before entering Parliament as a Conservative MP.
Although Badenoch refused to say which Labour M.P. she had hacked, on-line sleuths linked her admission to an April 2008 hacking of Labour Deputy Leader Harriet Harman's blog, in which posts purportedly by Harman announced her resignation from the Labour party and urged her supporters to back Boris Johnson's bid for London Mayor in the upcoming mayoral election. Harman has tweeted to say she has received an apology from Badenoch.
As in the earlier Prestel case, the hack was facilitated by lax security on Harman's part: her logon ID had been "harriet" and her password "harman".
It seems unlikely proceedings will be brought against Kemi Badenoch, but the incident could hardly have come at a worse time. Fake news and cyber security concerns are issues which go to the root of our democracy. With the GDPR, coming into effect next month, everyone is sensitive to risks of security breaches, which give rise to an obligation to notify the Information Commissioner and to the risk of fines. Treating hacking flippantly undermines a lot of hard work done by civil servants and politicians of all parties in getting cyber issues onto the table and properly addressed.
Susan Hall is a Partner in the Intellectual Property team specialising in Intellectual Property and Information and Communications Technology.
Susan's expertise includes working with a wide range of clients ranging from Government Departments and universities to multi-nationals, owner-managed businesses and start-ups.
Clarke Willmott LLP is a national law firm with seven offices across the country, including Birmingham, Bristol, Cardiff, London, Manchester, Southampton and Taunton.
For more information visit www.clarkewillmott.com
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Moving from Swansea to Cardiff over 3 years ago, Chris has taken his passion for publishing and now utilises his skills at the Business News Wales HQ.
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Man dies after huge blast that 'shook houses' in estate
A man has died after an "almighty" explosion on a housing estate.
Police and fire crews rushed to the Pontypool estate in Monmouthshire in South Wales at 11.10am this morning.
Despite arriving five minutes after they were called out the emergency services were unable to save the man, who was pronounced dead at the scene, Wales Online reported.
A spokeswoman for Gwent Police said: "We can now confirm that one man, was sadly pronounced deceased at the scene.
"Formal identification has yet to take place, and the owners of the property will be supported by specialist officers.
"The cause of death has yet to be established and this will be determined following a post mortem.
"At this moment in time it is too early to confirm whether the death is suspicious."
Significant damage has been done to the property.
A cordon is still in place.
One local resident said: "I was stood in my house and there was this almighty bang. The whole house shook and we saw this massive plume of smoke and somebody screaming.
"People came out to see what was happening and the emergency services were here in about five minutes."
At 3.30pm a dozen fire and police officers were still coming and going into the property.
Retired fire officer Paul Taylor, who lives nearby, said: "There was a loud explosion and it sounded like the roof was coming off.
"I drove around and it looked like the garage door had blown off."
He explained that the "popping sounds" he and several other residents heard are common in these sort of incidents and could be anything from aerosol cans to tons of paint.
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Никита Павлович Кириченко (16 декабря (29) 1914 года — 13 ноября 1983 года) — советский учёный-, кандидат исторических наук, академик АПН СССР (1967).

Состоял в Отделении дидактики и частных методик.

Сфера научных интересов: развитие педагогического образования, преподавание истории в высшей школе.

Ссылки


text:
Вонджон () — храмове ім'я корейських правителів. Відомі носії:
 Вонджон — ван Корьо
 Вонджон — титулярний ван Чосону


Before travelling to France I held the misconception that France just didn't cater well for school groups when it came to their accommodation offering. I couldn't have been more wrong! We visited accommodation centres in all three of our new resorts and found them to be absolutely perfect for school groups.
We visited the Lorraine Savoie in Courchevel Village, AEC Les Becchi in Samoëns and Chalet L'Escalade in Morzine. All of these properties had a great standard of accommodation, amazing group spaces and the hospitality afforded to groups staying there at the same time as us, was second to none. The food set-up varied dependent on the size of the accommodation, but all properties really understood what school pupils wanted whilst making sure they still got their greens!
The pedigree of skiing available at Courchevel, Grand Massif and Morzine-Avoriaz needs no introduction and offers ample opportunity for the improving and advanced skiers, but beginners aren't left behind in any of these resorts either.
All three resorts offer dedicated beginner slopes, allowing newbies the space and time to become more confident on the snow. Having ski schools that really understand the requirements of schools is integral and the quality of the ESF ski schools in all of our resorts was clear. One of my colleagues sampled the teaching in her own private lesson and was adamant it was the best ski lesson she'd ever had.
Once the skiing is done we recognise that schools like to keep their pupils busy, so good après ski options are essential to a successful school ski experience. France doesn't disappoint on this front!
All of our resorts offer the après ski options you would expect on any trip, and more. Courchevel adds in a 2km sledging run and indoor surfing, get ready to face-off in Morzine with live ice-hockey, and you don't even need to leave the comfort of AEC Les Becchi in Samoëns with ample in-house activities scheduled throughout the season.
I've only just started to scratch the surface of what France has to offer school groups and there are so many more reasons why it should be on your list of potential ski destinations. We'll be launching all of these resorts for the 2020, so keep your eyes peeled for updates on rayburntours.com!


2/01/2019 · This Guy Saved Pennies For 45 Years. Then He Cashed Them In – And Their Total Is Astounding - Duration: 7:22. watchJojo 8,654,141 views how to find a great front end web developer 27/08/2018 · Hello frnds, In this video, you can know how to find draft folder in facebook App. Watch till end for more information. I hope you like this video.
Drafts will now pop up and you can tap on the draft you'd like to finish or try to re-send. That's all there is to it. Drafts in Twitter for iOS functions in the same way as how you access drafts in the native Mail app so if you've done this before, it's the same concept.
Find Missing or Lost Drafts Folder in Outlook - Remo Software Remosoftware.com Microsoft Outlook makes use of PST file to store email messages, drafts folder, tasks, notes, calendar, and other important data attributes.