Ecumenical Patriarch Bartholomew is shocked by the current invasion of the armed forces of the Russian Federation on the territory of the Republic of Ukraine, he said in a telephone conversation with Metropolitan Epiphanius of Kiev, head of the Autocephalous Church of Ukraine, expressing his deep sorrow and its support for the Ukrainian people defending their native lands.
The statement said:
“His Holiness condemns this unprovoked attack by Russia against Ukraine, which is an independent and sovereign European state, as well as the brutal violence against its neighbors and especially against civilians.
He prays to the God of Love and Peace to enlighten the leadership of the Russian Federation to understand the tragic consequences of its decisions and actions, which could ignite even a world war.
The Ecumenical Patriarch calls on the leaders of all countries of the European institutions and international organizations to work for a peaceful settlement of this critical situation through honest dialogue, which is the only means of resolving every problem and resolving every dispute.
Finally, he called on the local Orthodox Churches, as well as all Christians and every person of good will, to pray incessantly for the Ukrainian people and for the establishment of peace and justice in Ukraine.
While 11 of the Council’s 15 members voted in favour of the text, China India, and the United Arab Emirates abstained.
A ‘no’ vote from any one of the five permanent members of the Council stops action on any measure put before it. The body’s permanent members are: China, France, Russian Federation, the United Kingdom, and the United States.
The Security Council’s latest attempt to end the Ukraine crisis caps a week of activity at the United Nations seeking a diplomatic offramp to Russian military action in the country, including near daily press stakeouts by the Secretary-General, three emergency Council sessions, and one meeting of the 193-member General Assembly, which saw speaker after speaker call for de-escalation.
Speaking to journalists after this evening’s Council meeting, Secretary-General António Guterres, stressed that while the United Nations had today not achieved its primary objective to end war, “we must never give up.”
“We must give peace another chance. Soldiers need to return to their barracks. Leaders need to turn to the path of dialogue and peace,” he said.
And despite growing operational challenges, he assured that the UN is scaling up the delivery of life-saving support on both sides of the line of contact.
Dedicated UN coordinator
Against the backdrop of multiplying humanitarian needs, dying civilians and at least 100,000 Ukrainians reportedly fleeing their homes – with many crossing into neighbouring countries, underlining the regional nature of this growing crisis – Mr. Guterres announced the appointment of Amin Awad as UN Crisis Coordinator for Ukraine.
A close colleague of Mr. Guterres when he was chief of the UN refugee agency, UNHCR, Mr. Awad will lead the coordination of all UN efforts, including its humanitarian response, on both sides of the contact line.
“All concerned in this conflict must respect international humanitarian law and guarantee the safety and freedom of movement of UN staff and other humanitarians. Especially in a moment like this, it is important to remember that the UN…is tens of thousands of women and men around the world,” he said.
Overcoming challenges
The top UN official outlined the work of the Organization, from feeding the hungry, vaccinating children and promoting development to protecting civilians in peacekeeping operations, mediating conflicts and supporting refugees and migrants, all while “standing, delivering, extending a lifeline of hope.’”
He stressed that although the UN Charter has been challenged in the past, it has “stood firm on the side of peace, security, development, justice, international law and human rights”.
“Time after time, when the international community has rallied together in solidarity, those values have prevailed. They will prevail, independently of what happened today,” the UN chief said.
“We must do everything in our power so that they prevail in Ukraine but they prevail for all humanity,” concluded the Secretary-General.
A ‘principled stand’
Introducing the draft resolution, which her country had helped craft, US Ambassador Linda Thomas-Greenfield painted a picture of Russia’s invasion of Ukraine that was “so bold, so brazen,” that it threatens the international system “as we know it.”
“We have a solemn responsibility not to look away,” she said stressing that Russia must be held accountable, and its forces immediately, completely and unconditionally withdrawn.
“Today we are taking a principled stand in this Council,” Ms. Thomas-Greenfield said. “There is no middle ground,” responsible States do not invade their neighbours.
Can’t veto accountability
After the text was defeated, Ms. Thomas-Greenfield took the floor again.
“You can veto this resolution, but you cannot veto our voices; You cannot veto the truth; You cannot veto our principles; You cannot veto the Ukrainian people; cannot veto the UN Charter…and you will not veto accountability,” she underscored.
The US Ambassador said that despite the actions of a “reckless, irresponsible” Member State, the United States will continue to stand with Ukraine against Russia’s aggression.
UN Photo/Mark Garten
Linda Thomas-Greenfield, Permanent Representative of the United States to the United Nations, addresses the Security Council meeting on the situation in Ukraine.
‘Naked aggression’
UK Ambassador Dame Barbara Woodward described how women and children in Kyiv, pensioners in Odessa and people all over Ukraine are “sheltering from Russia’s onslaught.”
She stated that the draft resolution sent “a message to the world that the rules we built together must be defended, because otherwise, who will be next.”
Moreover, President Vladimir Putin’s “massive invasion” of Ukraine to remove the Government is “a naked aggression” that must be condemned, Ms. Woodward added.
After the vote, the UK Ambassador pointed out that Russia was the only Council Member to vote against the draft.
“Make no mistake, Russia is isolated, it has no support for the invasion of Ukraine,” she said, noting that history would record what had happened today, and that the United Kingdom “stands firmly in support” of the Ukrainian people and would hold Russia accountable for its actions.
A veto against international law
After voting in favour of the resolution, France’s Ambassador, Nicolas de Rivière, said that Russia’s “premediated aggression” is killing civilians and destroying infrastructure with goal of rebuilding the Russian empire.
While other members expressed their commitment to international law, Russia vetoed it.
“Russia is alone,” he observed, adding that “within the UN and in all bodies, France will continue to mobilize with its partners to support Ukraine and the Ukrainian people.”
Abstentions
Indian Ambassador T. S. Tirumurti, who abstained, said that “dialogue is the only path forward,” no matter how daunting it might seem, and urged the Council to restore the difficult path forward.
Also abstaining, UAE Ambassador Lana Nusseibeh said that now that the resolution has been vetoed, the United Arab Emirates would continue to seek “inclusive and consultative processes” for a path forward.
Not an outpost
Meanwhile, as the only Permanent Council member to abstain, Chinese Ambassador Zhang Jun warned against actions that might “shut the door” to a negotiated settlement. He reminded that the Ukraine crisis did not occur “overnight” and that the security of one State cannot come at the expense of that of others.
“Ukraine should become a bridge between East and West, not an outpost,” he said, adding that that cold war mentalities must be abandoned to build balanced European mechanisms and all parties should return to diplomacy.
‘Ukrainian chessboard’
Russian Ambassador Vasily Nebenzya said that he would not respond to those who had accused him of abusing his country’s veto power.
He accused the draft’s sponsors of “spinning tales” about the true situation in Ukraine, including Western allies’ attempts to cover up the fact that they had been flooding the Donbas with weapons.
“You have made Ukraine a pawn in your own game… this resolution is nothing other than yet another brutal, inhumane move on this Ukrainian chessboard,” he said.
Speaking to the representatives of France, the UK and US, he said that there was no verifiable confirmation about the death of Ukrainian civilians; that photographs of supposed Russian artillery “is fake”; and that reports of attacks on civilian infrastructure were untrue.
Moreover, with its history of aggressions against other countries, the United States was “in no position to moralize.”
‘A seat in Hell’
Ukraine Ambassador Sergiy Kyslytsya asserted that he would not dignify the “diabolical script” read by the Russian Ambassador, which was in fact “a rather detailed application for… a seat in Hell.”
He recalled that during the Security Council’s discussions on the situation in Ukraine earlier in the week, Russia had begun bombing his country and sending forces across the border, including through Belarus.
Therefore, he was not surprised that Russia voted against the text, he said, denouncing the actions of “the Kremlin regime.”
Mr. Kyslytsya asked the Council to remember how many times the Russian Ambassador said that his country would not invade or bomb Ukraine. But after what had happened in recent days, “how can we trust you? You have no idea what is in the mind of your President,” he declared.
The Ukraine Ambassador also noted that according to the rules of procedure, the Russian Ambassador should not have been presiding over a meeting of which his country was the subject.
Security Council Meets on Current Situation in Ukraine – UN Photo/Evan Schneider
Silent moment for peace
The Ukraine Ambassador asked the Council to dedicate a moment of silence “for peace… and to pray for the souls of those that have already been or may be killed”, inviting the Russian Ambassador to “pray for salvation.”
This was followed by solemn applause throughout the Chamber.
Noting that nothing could justify the bombing of hospitals and kindergartens –considered war crimes under the Rome Statute – he said that Ukraine was collecting evidence to send forward to the International Criminal Court (ICC).
Sever ties
Finally, Mr. Kyslytsya called on nations to break off diplomatic relations with the Russian Federation, and international organizations to sever ties with that country.
“You should stop wiping your feet” on the words of the Secretary-General and the work of the UN, and “show respect for the principles enshrined in the Charter,” he said.
In closing, the Ambassador maintained that while Ukraine remained open to negotiations, it was Russia that had launched an offensive that had sent “thousands of troops” into its territory.
epa09778128 Pope Francis arrives to lead the weekly general audience in the Paul VI Audience Hall, in Vatican City, 23 February 2022. EPA/MAURIZIO BRAMBATTI (MaxPPP TagID: epalivesix023556.jpg) [Photo via MaxPPP]
Pope Francis posted a message on Twitter on Friday 25 February in which he denounced the fact that “any war is a shameful capitulation”. A tweet translated into several languages, including Russian.
“War is always a failure,” writes the pope “Every war leaves the world worse than when it was found. War is always a failure of politics and humanity, a shameful capitulation, a rout before the forces of evil,” wrote the Pope, taking up a passage from his encyclical on peace Fratelli tutti (All brothers) published in 2020.
His tweets, also published in the usual languages of his account (Italian, Portuguese, Polish, French, English, Spanish, German and Arabic), are accompanied by the hashtags #PrionsEnsemble and #Ukraine.
Francis also went Friday morning to the Russian embassy near the Holy See to express “his concern” on the second day of the invasion of Ukraine by Russian troops. A gesture also exceptional for the Argentine pontiff who never goes to foreign representations but receives in the Apostolic Palace the diplomats accredited to the Vatican.
The pontiff, who had called Wednesday to “preserve the world from the madness of war”, stayed “a little more than half an hour on site”, added the same source.
On Thursday, a few hours after the attack of Ukraine by the troops of Moscow, the Vatican had estimated that negotiations were still possible to find a peaceful solution to the Russian-Ukrainian conflict.
The pontiff, who had called Wednesday to “preserve the world from the madness of war”, stayed “a little more than half an hour on site”, added the same source.
On Thursday, a few hours after the attack of Ukraine by the troops of Moscow, the Vatican had estimated that negotiations were still possible to find a peaceful solution to the Russian-Ukrainian conflict.
“I have great pain in my heart at the worsening of the situation in Ukraine. Despite the diplomatic efforts of recent weeks, more and more alarming scenarios are opening up. Like me, many people feel anguish and concern,” he said.
Stratford children’s author Jon-Erik Lappano is getting ready to release his fourth picture book, Martin and the River, on March 1.
Stratford children’s author Jon-Erik Lappano will release his latest picture book, Martin and the River, on March 1. Front cover illustration by Josée Bisaillon
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Just in time for spring, award-winning Stratford children’s author Jon-Erik Lappano is set to release his fourth picture book, which draws on his experiences growing up alongside the Upper Thames River and its wildlife in Mitchell.
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In Martin and the River, Martin loves his river. He watches the great blue herons, he looks for crayfish and otters, and he builds forts and lies in the tall grass near the water. But one day, Martin’s parents tell him they have to move from the country to city.
While exploring his new home, Martin finds the that none of the city’s charms, from the museum to the subway, can compare to his river. However, when his parents bring him to a little stream running through a nearby park, Martin discovers much of that same magic can indeed be found in the city.
“It’s inspired by my childhood growing up in Mitchell, just close to Stratford here, and spending countless hours biking down to the Upper Thames River where I used to look for minnows and spot great blue herons and that sort of stuff,” Lappano said.
“That time in nature was really pivotal for me in my childhood, and I think it really shaped who I am as an adult. I also spent a lot of my time in urban centres and living in the City of Toronto, so the book really explores the notion that we can find connection to nature in any place that we live.”
Through his first three children’s books – the first of which, Tokyo Digs a Garden, won the Governor General’s Literary Award – Lappano’s stories have largely been centred around the natural environment and seeing the natural world through a child’s eyes.
“All of my books taken together certainly have an environmental theme to them, and I don’t know that it’s a conscious thing, but I think it’s the way I sort of interpret the world,” Lappano said. “Since I was young, I always found meaning and connection in natural spaces. I think it’s how I’ve embedded meaning in my life and it’s where I search for meaning. I’ve also got a natural curiosity and wonder for the world around me … and because of that, my stories reflect that theme.”
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Like his previous books, Martin and the River is accompanied by colourful and whimsical illustrations. While Lappano has worked with a few different illustrators in the past, the artwork in this book is by Montreal artist Josée Bisaillon, who has illustrated more than 40 picture books, including The Snow Knows by Jennifer McGrath, which won the Marilyn Baillie Picture Book Award.
“The illustrations in this book are spectacular,” Lappano said. “(It’s) the colour, the light and just everything that she does to bring this story alive. I think one of the things I was most grateful for in working with Josée was her ability to bring this sense of childlike imagination onto the page. So much of the story takes place in Martin’s imagination and just him projecting his imagination onto the world around him, and she capture that so beautifully.”
Martin and the River will be available for purchase on March 1 at Fanfare Books and Fundamentals Books and Toys Inc. in Stratford, as well as through most online book sellers.
LJI researchers shed light on the role of TET enzymes in genomic stability and cancers.
Scientists at the La Jolla Institute for Immunology (LJI) have uncovered how loss of TET enzymes can lead to B cell lymphoma. Their research, published in Nature Immunology, could potentially open opportunities for designing drug treatment strategies to target malignant cells in many cancers.
The new research was led by LJI Professor Anjana Rao, Ph.D., in the LJI Center for Cancer Immunotherapy, and experiments were spearheaded by LJI Instructor Vipul Shukla, Ph.D., (soon to be an Assistant Professor at Northwestern University) and UC San Diego Graduate Student Daniela Samaniego-Castruita.
The new research helps scientists finally link two dangerous phenomena in cancer cells.
In previous studies, scientists spotted mutations that cause TET enzymes to lose their function in many patients with blood cancers and solid cancers. Researchers have also found that genomic instability, such as double-stranded breaks in the DNA code, are a common feature in cancer cells
In this project, scientists explored one potential way in which TET deficiency is connected to genomic instability.
“This study provides insights about an important question in the field,” says Shukla.
By studying a mouse model of lymphoma, the researchers found that deleting TET2 and TET3 enzymes in mature B cells had huge consequences for B-cell homeostasis. “The TET-deficient mice developed lymphoma, and we observed an increase in marks associated with genomic instability, such as double strand breaks,” says Samaniego-Castruita.
The team then performed genomic analysis for clues to what was happening at the molecular level. They saw that without TET2 and TET3, the DNA became riddled with unusual DNA structures called G-quadruplexes and R-loops.
DNA normally has two strands running parallel to each other, like two rails of a ladder. R-loops appear when a third rail, made of RNA, slips in and forces a gap between the two DNA rails. G-quadruplexes act like knots on the DNA rails. Both R-loops and G-quadruplexes make it hard for the original two rails of DNA to “unzip” as the cell tries to read the DNA code and keep the cell working properly.
Diagrammatic representation of a G-quadruplex (G4) with an associated R-loop structure, illustrating the reagents used for detection of G-quadruplexes and R-loops. Credit: Shukla et al
Shulka and Samaniego-Castruita examined these DNA structures in depth thanks to funding from the La Jolla Institute’s Tullie and Rickey Families SPARK Awards for Innovations in Immunology. “These structures represent sites in the DNA that are much more fragile than other regions,” says Shukla. “With this study, we found that TET enzymes are perhaps related to the regulation of these structures, which could in turn explain one mechanism for acquisition of genomic instability in the absence of TET enzymes.”
When it comes to B cell malignancies, G-quadruplexes and R-loops appear to be a missing link between tell-tale TET mutations and dangerous genomic instability.
So if G-quadruplexes and R-loops are causing problems, is there a way to stop them from forming?
Shukla and Samaniego-Castruita observed that DNMT1 was upregulated in TET-deficient B cells. DNMT1 is a key enzyme responsible for maintaining marks on DNA called “DNA methylation.” DNA methylation is an important regulatory mark in the genome, and is normally removed through the activity of TET enzymes.
Without TET enzymes, the normal give-and-take of DNA methylation marks was broken. So in their next experiment, the scientists also deleted the Dnmt1 gene in TET-deficient B cells in mice to test if levels of G quadruplexes and R-loops could be altered upon removal of DNMT1 protein.
Indeed, deleting DNMT1 was associated with a striking delay in the development of aggressive B-cell lymphomas. Deleting DNMT1 was also associated with decreased levels of G-quadruplexes and R-loops, says Samaniego-Castruita.
The researchers emphasize that regulating G-quadruplexes and R-loops may be just one way TET enzymes control genomic stability. There’s also more work to be done to uncover the precise steps that lead TET-deficient cells to accumulate these enigmatic structures in DNA. Someday, the team hopes to devise strategies through which G-quadruplexes and R-loops could be targeted to help cancer patients.
As the Rao Lab continues investigating the effects of TET enzymes, Shukla will be joining the faculty of the Department of Cell and Developmental Biology at Northwestern University this winter. He plans to launch his own laboratory focused on studying alternative structural conformations in DNA.
For more on this research, see Strange Structures in DNA May Drive Cancer Development.
Reference: “TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures” by Vipul Shukla, Daniela Samaniego-Castruita, Zhen Dong, Edahí González-Avalos, Qingqing Yan, Kavitha Sarma and Anjana Rao, 22 December 2021, Nature Immunology. DOI: 10.1038/s41590-021-01087-w
The researchers used resources of the Advanced Light Source, which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231.
Additional study authors include Zhen Dong, Edahi Gonzalez-Avalos, Qingqing Yan, and Kavitha Sarma.
Russia’s military aggression against Ukraine: EU imposes sanctions against President Putin and Foreign Minister Lavrov and adopts wide ranging individual and economic sanctions
The EU today decided to sanction Vladimir Putin, President of the Russian Federation and Sergey Lavrov, Minister of Foreign Affairs of the Russian Federation.
The Council also agreed on a further package of individual and economic measures covering also Belarus to respond to the unprovoked and unjustified military aggression carried out by the Russian Federation against Ukraine.
President Putin and his government started a war against an independent, sovereign neighbouring country. The behaviour of the Russian leadership constitutes a major threat to international peace and security. Today, we are replying with the strongest possible restrictive measures. The European Union is united in its resolve, together with international partners and allies, to defend the peace order, international law and the rules based system.
JOSEP BORRELL, HIGH REPRESENTATIVE FOR FOREIGN AFFAIRS AND SECURITY POLICY
Swiftly implementing the European Council conclusions of 24 February, the package of sanctions adopted today includes:
Individual sanctions
In addition to freezing the assets the Russian President and Minister of Foreign Affairs, the EU will impose restrictive measures on the members of the National Security Council of the Russian Federation who supported Russia’s immediate recognition of the two non-government controlled areas of the Donetsk and Luhansk oblasts of Ukraine as independent entities. Sanctions will also be extended to the remaining members of the Russian State Duma, who ratified the government decision of the Treaty of Friendship, Cooperation and Mutual Assistance between the Russian Federation and the two entities.
Furthermore, the EU will also target those individuals, who facilitated the Russian military aggression from Belarus.
Economic sanctions
Financial sanctions
The package adopted today further expands the existing financial restrictions, thereby cutting Russian access to the most important capital markets. It also prohibits the listing and provision of services in relation to shares of Russian state-owned entities on EU trading venues. In addition, it introduces new measures which significantly limit the financial inflows from Russia to the EU, by prohibiting the acceptance of deposits exceeding certain values from Russian nationals or residents, the holding of accounts of Russian clients by the EU Central Securities Depositories, as well as the selling of euro-denominated securities to Russian clients.
These sanctions will target 70% of the Russian banking market, and key state-owned companies, including in the field of defence. They will increase Russia’s borrowing costs, raise inflation and gradually erode Russia’s industrial base. Additionally measures are taken to prevent the Russian elite’s fortunes from being hidden in safe havens in Europe.
Energy sector
The EU will prohibit the sale, supply, transfer or export to Russia of specific goods and technologies in oil refining, and will introduce restrictions on the provision of related services.
By introducing such export ban, the EU intends to hit the Russian oil sector, and make it impossible for Russia to upgrade its oil refineries.
Russia’s export revenues accounted for EUR 24 billion in 2019.
Transport sector
The EU introduced an export ban covering goods and technology in the aviation and space industry, as well as a prohibition on the provision of insurance and reinsurance and maintenance services related to those goods and technology. The EU will also prohibit the provision of related technical and financial assistance.
This ban on thesale of all aircrafts, spare parts and equipmentto Russian airlines will degrade one of the key sectors of Russia’s economy and the country’s connectivity, as three quarters of Russia’s current commercial air fleet were built in the EU, the US and Canada.
Technology sector
The EU imposed further restrictions on exports of dual-use goods and technology, as well as restrictions on exports of certain goods and technology which might contribute to Russia’s technological enhancement of its defence and security sector.
This will include products such as semiconductors or cutting-edge technologies.
Visa policy
Diplomats, other Russian officials, and business people will no longer be able to benefit from visa facilitation provisions, which allow privileged access to the EU. This decision will not affect ordinary Russian citizens. The decision will enter into force on the day of the adoption.
The European Union condemns in the strongest possible terms the Russian Federation’s unprovoked and unjustified military aggression against Ukraine, as well as the involvement of Belarus in this aggression.
The European Union demands that Russia immediately ceases its military actions, unconditionally withdraws all forces and military equipment from the entire territory of Ukraine and fully respects Ukraine’s territorial integrity, sovereignty and independence within its internationally recognised borders. The European Council calls on Russia and Russia-backed armed formations to respect international humanitarian law and stop their disinformation campaign and cyber-attacks.
The use of force and coercion to change borders has no place in the 21st century. Tensions and conflict should be resolved exclusively through dialogue and diplomacy. The EU will continue cooperating closely with neighbours and reiterates its unwavering support for, and commitment to, the sovereignty and territorial integrity of Georgia and of the Republic of Moldova. It will continue strong coordination with partners and allies, within the UN, OSCE, NATO and the G7.
The relevant legal acts, including the names of the persons concerned by restrictive measures, will be published in the Official Journal.
Background
Individual restrictive measures will apply to a total of 654 individuals and 52 entities, and include an asset freeze and a prohibition from making funds available to the listed individuals and entities. In addition, a travel ban applicable to the listed persons prevents these from entering or transiting through EU territory.
Several FDA-approved drugs — including for type 2 diabetes, hepatitis C and HIV — significantly reduce the ability of the Delta variant of SARS-CoV-2 to replicate in human cells, according to new research led by scientists at Penn State. Specifically, the team found that these drugs inhibit certain viral enzymes, called proteases, that are essential for SARS-CoV-2 replication in infected human cells.
“The SARS-CoV-2 vaccines target the spike protein, but this protein is under strong selection pressure and, as we have seen with Omicron, can undergo significant mutations,” said Joyce Jose, assistant professor of biochemistry and molecular biology, Penn State. “There remains an urgent need for SARS-CoV-2 therapeutic agents that target parts of the virus other than the spike protein that are not as likely to evolve.”
Previous research has demonstrated that two SARS-CoV-2 enzymes — proteases including Mpro and PLpro — are promising targets for antiviral drug development. Pfizer’s COVID-19 therapy Paxlovid, for example, targets Mpro. According to Jose, these enzymes are relatively stable; therefore, they are unlikely to develop drug-resistant mutations rapidly.
Katsuhiko Murakami, professor of biochemistry and molecular biology, Penn State, noted that these virus proteases, because of their capabilities to cleave, or cut, proteins, are essential for SARS-CoV-2 replication in infected cells.
“SARS-CoV-2 produces long proteins, called polyproteins, from its RNA genome that must be cleaved into individual proteins by these proteases in an ordered fashion leading to the formation of functional virus enzymes and proteins to start virus replication once it enters a cell,” Murakami explained. “If you inhibit one of these proteases, further spread of SARS-CoV-2 in the infected person could be stopped.”
The findings were published today (February 25, 2022) in the journal Communications Biology.
The team designed an assay to rapidly identify inhibitors of the Mpro and PLpro proteases in live human cells.
“Although other assays are available, we designed our novel assay so it could be conducted in live cells, which enabled us to simultaneously measure the toxicity of the inhibitors to human cells,” said Jose.
The researchers used their assay to test a library of 64 compounds — including inhibitors of HIV and hepatitis C proteases; cysteine proteases, which occur in certain protozoan parasites; and dipeptidyl peptidase, a human enzyme involved in type 2 diabetes — for their ability to inhibit Mpro or PLpro. From the 64 compounds, the team identified eleven that affected Mpro activity and five that affected PLpro activity based on a cut-off of 50% reduction in protease activity with 90% cell viability.
Anoop Narayanan, associate research professor of biochemistry and molecular biology, monitored the activity of the compounds using live confocal microscopy.
“We designed the experiment so that if the compound was affecting the proteases, you would see fluorescence in certain areas of the cell,” said Narayanan.
Next, the team evaluated the antiviral activity of the 16 PLpro and Mpro inhibitors against SARS-CoV-2 viruses in live human cells in a BSL-3 facility, the Eva J. Pell ABSL-3 Laboratory for Advanced Biological Research at Penn State, and discovered that eight of them had dose-dependent antiviral activities against SARS-CoV-2. Specifically, they found that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl and Nelfinavir mesylate inhibit Mpro. Of these, the team found that MG-101 also hindered the virus’s ability to infect cells by inhibiting protease processing of the spike protein.
“We found that when the cells were pretreated with the selected inhibitors, only MG-101 affected the virus’s entry into cells,” said Narayanan.
In addition, the researchers found that treating cells with a combination of Mpro and PLpro inhibitors had an additive antiviral effect, providing even greater inhibition of SARS-CoV-2 replication.
“In cell culture, we showed that if you combine Mpro and PLpro inhibitors, you have a stronger effect on the virus without increasing toxicity,” said Jose. “This combination inhibition is highly potent.”
To investigate the mechanism by which MG-101 inhibits the activity of Mpro protease, the scientists, including Manju Narwal, postdoctoral scholar in biochemistry and molecular biology, used X-ray crystallography to obtain a high-resolution structure of MG-101 in complex with Mpro.
“We were able to see how MG-101 was interacting with the active site of Mpro,” said Narwal. “This inhibitor mimics the polyprotein and binds in a similar manner to the protease, thereby blocking the protease from binding to and cutting the polyprotein, which is an essential step in the virus’s replication.”
Murakami added, “By understanding how the MG-101 compound binds to the active site, we can design new compounds that may be even more effective.”
Indeed, the team is in the process of designing new compounds based on the structures they determined by X-ray crystallography. They also plan to test the combination drugs that they already demonstrated to be effective in vitro in mice.
Although the scientists studied the Delta variant of SARS-CoV-2, they said the drugs will likely be effective against Omicron and future variants because they target parts of the virus that are unlikely to mutate significantly.
“The development of broad-spectrum antiviral drugs against a wide range of coronaviruses is the ultimate treatment strategy for circulating and emerging coronavirus infections,” said Jose. “Our research shows that repurposing certain FDA-approved drugs that demonstrate effectiveness at inhibiting the activities of Mpro and PLpro may be a useful strategy in the fight against SARS-CoV-2.”
Reference: “Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay” by Anoop Narayanan, Manju Narwal, Sydney A. Majowicz, Carmine Varricchio, Shay A. Toner, Carlo Ballatore, Andrea Brancale, Katsuhiko S. Murakami and Joyce Jose, 25 February 2022, Communications Biology. DOI: 10.1038/s42003-022-03090-9
Other authors on the paper include Sydney A. Majowicz, graduate student, and Shay A. Toner, undergraduate student, Penn State; Carmine Varricchio, postdoctoral research associate, and Andrea Brancale, professor of medicinal chemistry, Cardiff University; and Carlo Ballatore, professor of medicinal chemistry, University of California, San Diego.
The National Institutes of Health, Welsh Government Office for Science and Huck Institutes of the Life Sciences at Penn State (COVID-19 Seed Grant for Jose Laboratory) supported this research.
Churches of all denominations across Europe have joined in firmly condemning Russian invasion of Ukraine, while praying for peace to prevail and expressing heartfelt solidarity with the Ukrainian people.
“We must act together and with determination to immediately put an end to the Russian aggression and do everything possible to protect innocent women, men and children: in the name of God stop now!”, wrote the president of the Council of European Episcopal Conferences (CCEE), Archbishop Gintaras Grušas of Vilnius in a message issued on Thursday, while attending the ongoing meeting of Bishops and Mayors of major cities of the Mediterranean in Floremce.
The prelate expressed the Council’s closeness to the victims and to all those suffering in the conflict, while confirming that the European bishops will join the global day of fasting and prayer Pope Francis has called for on Ash Wednesday, March 2.
COMECE
For his part, Cardinal Jean-Claude Hollerich, President of the Commission of the Bishops’ Conferences of the European Union (COMECE), urged the international community, including the EU, not to stop seeking a peaceful solution to the crisis through diplomatic dialogue, reminding that “war is a serious affront to human dignity and has no place” in Europe.
Cardinal Hollerich also appealed on European governments to “welcome refugees fleeing Ukraine and seeking international protection: “It is our vocation, our responsibility and our duty to welcome and protect them as brothers and sisters”, he said.
CEC, Lutherans, Methodists and Reformed
Other Christian Churches in Europe have also condemned the assault and are supporting the global day of prayer for Ukraine on March 2. The Lutheran World Federation (LWF), the World Communion of Reformed Churches (WCRC), the Conference of European Churches (CEC), and the World Methodist Council (WMC) have issued a joint invitation to an online prayer service at 17.00 CET that day. In the call to prayer for the people of Ukraine and the region, the four Christian communions note the military assault threatens the lives of Ukrainians, as well as peace throughout Europe and beyond. “The crisis is urgent and requires the attention and solidarity of the global Christian community”, they say.
The Anglican Church
The Church of England too has condemned the Russian attack on Ukraine and is calling on the faithful to join in prayer. In a joint statement Archbishop of Canterbury Justin Welby and Archbishop of York Stephen Cottrell said “the horrific and unprovoked attack” is “an act of great evil” and urged Christians to make this Sunday a special day of prayer for Ukraine, Russia and for peace, while supporting the global day of prayer and fasting for peace on Ash Wednesday.
Shots reverberated throughout the Ukrainian capital as Russian forces entered Kyiv on Friday. Civilians tried to hide from Russian airstrikes in underground railway stations and other areas.
After taking a key airport, Moscow now says it is determined to topple the democratically elected government, which Russia’s foreign minister Sergey Lavrov said was steered by what he called “neo-Nazis” and the West.
The United States and the European Union have announced sanctions against Russia. They range from freezing assets of Russian President Vladimir Putin and allies to even halting a critical Russian natural gas pipeline to Europe.
Yet, unshaven and emotional, Ukrainian President Volodymyr Zelensky said the world had abandoned his nation. “This morning, we are defending our state alone as we did yesterday. Yet, the world’s most powerful forces are watching from afar. Did yesterday’s sanctions convince Russia? We hear in our sky and see on our earth that this is not enough,” the president said in a video message.
Massive protest
His sentiments are shared across the border in Hungary. Thousands of Hungarians protested near the Russian embassy in Budapest against the invasion.
One protestor said Hungary still remembers how Russian forces crushed its 1956 Revolution against Soviet domination. “As a nation that was affected by very similar things, it is almost our moral duty to show support [for Ukraine] in our own ways as much as we can, really. And I hate seeing people having to flee their country, having to flee their homes, getting killed, getting bombed. It is horrifying, so this is the least I can do,” she added about the protest.
Hundreds of people are believed to have died on both sides. But there were no signs yet Friday that Europe’s most significant armed conflict since World War Two would end soon.
Hungary and other nearby nations are expecting thousands of refugees.
The Ministry of External Affairs (MEA) on Wednesday celebrated the ‘Azadi ka Amrit Mahotsav’ by inaugurating projects reflecting Buddhist linkages with the ASEAN and East Asian countries.
Bharat ki Azadi Ka Amrit Mahotsav is an initiative of the Government of India to commemorate 75 glorious years of progressive India and its rich history, diverse population, magnificent culture and great achievements.
This Mahotsav is dedicated to the people of India who have not only been instrumental in bringing India thus far in its evolutionary journey but also hold within them the power and potential to enable Prime Minister Narendra Modi’s vision of activating India 2.0, fuelled by the spirit of Aatmanirbhar Bharat.
The official journey of Azadi Ka Amrit Mahotsav commenced on 12th March 2021 which started a 75-week countdown to our 75th anniversary of independence and will end post a year on 15th August 2023.
As part of the celebration, books of Buddhist ‘Jataka’ tales translated into Thai, Korean, Vietnamese and Chinese languages were unveiled, the MEA said.
The Jataka tales are a voluminous body of literature native to India concerning the previous births of Gautama Buddha in both human and animal form. The future Buddha may appear as a king, an outcast, a god, an elephant—but, in whatever form, he exhibits some virtue that the tale thereby inculcates. Often, Jātaka tales include an extensive cast of characters who interact and get into various kinds of trouble – whereupon the Buddha character intervenes to resolve all the problems and bring about a happy ending.
A comprehensive video of e-ITEC courses offered by the MEA on Buddhist teachings was shown during the event.
The Indian Technical and Economic Cooperation Programme (ITEC) is a prestigious programme conducted by the MEA.
Minister of State for External Affairs Rajkumar Ranjan Singh inaugurated an interactive coffee table e-book on Buddhist linkages with the ASEAN (Association of Southeast Asian Nations) and East Asian countries.
The digital exhibition titled “Bodhicitta: Interweaving Buddhist Art Traditions from India Across Asia” curated by National Museum was displayed, the MEA said in a statement.
“The ministry presented an Interactive Template for use by Missions for orientation visits by school/college students to cultural centres/missions for better understanding of India’s Buddhist linkages,” it said.
A series of commemorative events and activities will be organised by the MEA across the country as part of the ‘Azadi Ka Amrit Mahotsav week’ from February 21 to 27.
