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Cellular traffic congestion in chronic diseases suggests new therapeutic targets November 27, 2024 Whitehead Institute for Biomedical Research Chronic diseases such as diabetes are on the rise and are costly and challenging to treat. Scientists have discovered a common denominator driving these diverse diseases, which may prove to be a promising therapeutic target: proteolethargy, or reduced protein mobility, in the presence of oxidative stress. Facebook Twitter Pinterest LinkedIN Email Chronic diseases like type 2 diabetes and inflammatory disorders have a huge impact on humanity. They are a leading cause of disease burden and deaths around the globe, are physically and economically taxing, and the number of people with such diseases is growing. Treating chronic disease has proven difficult because there is not one simple cause, like a single gene mutation, that a treatment could target. At least, that's how it has appeared to scientists. However, research from Whitehead Institute Member Richard Young and colleagues, published in the journal Cell on November 27, reveals that many chronic diseases have a common denominator that could be driving their dysfunction: reduced protein mobility. What this means is that around half of all proteins active in cells slow their movement when cells are in a chronic disease state, reducing the proteins' functions. The researchers' findings suggest that protein mobility may be a linchpin for decreased cellular function in chronic disease, making it a promising therapeutic target. In this paper, Young and colleagues in his lab, including postdoc Alessandra Dall'Agnese, graduate students Shannon Moreno and Ming Zheng, and research scientist Tong Ihn Lee, describe their discovery of this common mobility defect, which they call proteolethargy; explain what causes the defect and how it leads to dysfunction in cells; and propose a new therapeutic hypothesis for treating chronic diseases. "I'm excited about what this work could mean for patients," says Dall'Agnese. "My hope is that this will lead to a new class of drugs that restore protein mobility, which could help people with many different diseases that all have this mechanism as a common denominator." "This work was a collaborative, interdisciplinary effort that brought together biologists, physicists, chemists, computer scientists and physician-scientists," Lee says. "Combining that expertise is a strength of the Young lab. Studying the problem from different viewpoints really helped us think about how this mechanism might work and how it could change our understanding of the pathology of chronic disease." Commuter delays cause work stoppages in the cell How do proteins moving more slowly through a cell lead to widespread and significant cellular dysfunction? Dall'Agnese explains that every cell is like a tiny city, with proteins as the workers who keep everything running. Proteins have to commute in dense traffic in the cell, traveling from where they are created to where they work. The faster their commute, the more work they get done. Now, imagine a city that starts experiencing traffic jams along all the roads. Stores don't open on time, groceries are stuck in transit, meetings are postponed. Essentially all operations in the city are slowed. The slow down of operations in cells experiencing reduced protein mobility follows a similar progression. Normally, most proteins zip around the cell bumping into other molecules until they locate the molecule they work with or act on. The slower a protein moves, the fewer other molecules it will reach, and so the less likely it will be able to do its job. Young and colleagues found that such protein slow-downs lead to measurable reductions in the functional output of the proteins. When many proteins fail to get their jobs done in time, cells begin to experience a variety of problems -- as they are known to do in chronic diseases. Discovering the protein mobility problem Young and colleagues first suspected that cells affected in chronic disease might have a protein mobility problem after observing changes in the behavior of the insulin receptor, a signaling protein that reacts to the presence of insulin and causes cells to take in sugar from blood. In people with diabetes, cells become less responsive to insulin -- a state called insulin resistance -- causing too much sugar to remain in the blood. In researchpublished on insulin receptors in Nature Communications in 2022, Young and colleagues reported that insulin receptor mobility might be relevant to diabetes. Knowing that many cellular functions are altered in diabetes, the researchers considered the possibility that altered protein mobility might somehow affect many proteins in cells. To test this hypothesis, they studied proteins involved in a broad range of cellular functions, including MED1, a protein involved in gene expression; HP1α, a protein involved in gene silencing; FIB1, a protein involved in production of ribosomes; and SRSF2, a protein involved in splicing of messenger RNA. They used single-molecule tracking and other methods to measure how each of those proteins moves in healthy cells and in cells in disease states. All but one of the proteins showed reduced mobility (about 20-35%) in the disease cells. "I'm excited that we were able to transfer physics-based insight and methodology, which are commonly used to understand the single-molecule processes like gene transcription in normal cells, to a disease context and show that they can be used to uncover unexpected mechanisms of disease," Zheng says. "This work shows how the random walk of proteins in cells is linked to disease pathology." Moreno concurs: "In school, we're taught to consider changes in protein structure or DNA sequences when looking for causes of disease, but we've demonstrated that those are not the only contributing factors. If you only consider a static picture of a protein or a cell, you miss out on discovering these changes that only appear when molecules are in motion." Can't commute across the cell, I'm all tied up right now Next, the researchers needed to determine what was causing the proteins to slow down. They suspected that the defect had to do with an increase in cells of the level of reactive oxygen species (ROS), molecules that are highly prone to interfering with other molecules and their chemical reactions. Many types of chronic-disease-associated triggers, such as higher sugar or fat levels, certain toxins, and inflammatory signals, lead to an increase in ROS, also known as an increase in oxidative stress. The researchers measured the mobility of the proteins again, in cells that had high levels of ROS and were not otherwise in a disease state, and saw comparable mobility defects, suggesting that oxidative stress was to blame for the protein mobility defect. The final part of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only one of the proteins that was unaffected in the experiments, and it had one clear difference from the others: its surface did not contain any cysteines, an amino acid building block of many proteins. Cysteines are especially susceptible to interference from ROS because it will cause them to bond to other cysteines. When this bonding occurs between two protein molecules, it slows them down because the two proteins cannot move through the cell as quickly as either protein alone. About half of the proteins in our cells contain surface cysteines, so this single protein mobility defect can impact many different cellular pathways. This makes sense when one considers the diversity of dysfunctions that appear in cells of people with chronic diseases: dysfunctions in cell signaling, metabolic processes, gene expression and gene silencing, and more. All of these processes rely on the efficient functioning of proteins -- including the diverse proteins studied by the researchers. Young and colleagues performed several experiments to confirm that decreased protein mobility does in fact decrease a protein's function. For example, they found that when an insulin receptor experiences decreased mobility, it acts less efficiently on IRS1, a molecule to which it usually adds a phosphate group. From understanding a mechanism to treating a disease Discovering that decreased protein mobility in the presence of oxidative stress could be driving many of the symptoms of chronic disease provides opportunities to develop therapies to rescue protein mobility. In the course of their experiments, the researchers treated cells with an antioxidant drug -- something that reduces ROS -- called N-acetyl cysteine and saw that this partially restored protein mobility. The researchers are pursuing a variety of follow ups to this work, including the search for drugs that safely and efficiently reduce ROS and restore protein mobility. They developed an assay that can be used to screen drugs to see if they restore protein mobility by comparing each drug's effect on a simple biomarker with surface cysteines to one without. They are also looking into other diseases that may involve protein mobility, and are exploring the role of reduced protein mobility in aging. "The complex biology of chronic diseases has made it challenging to come up with effective therapeutic hypotheses," says Young, who is also a professor of biology at the Massachusetts Institute of Technology. "The discovery that diverse disease-associated stimuli all induce a common feature, proteolethargy, and that this feature could contribute to much of the dysregulation that we see in chronic disease, is something that I hope will be a real game changer for developing drugs that work across the spectrum of chronic diseases." Story Source: Materials provided by Whitehead Institute for Biomedical Research . Original written by Greta Friar. Note: Content may be edited for style and length. Journal Reference : Cite This Page :Capstone Infrastructure Corporation Releases Inaugural ESG Report Since Transition to Dedicated Independent Power Producer

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WASHINGTON — The House shut down Democrats' efforts Thursday to release the long-awaited ethics report into former Rep. Matt Gaetz, pushing the fate of any resolution to the yearslong investigation of sexual misconduct allegations into further uncertainty. Matt Gaetz talks before President-elect Donald Trump speaks during an America First Policy Institute gala at his Mar-a-Lago estate Nov. 14 in Palm Beach, Fla. The nearly party-line votes came after Democrats had been pressing for the findings to be published even though the Florida Republican left Congress and withdrew as President-elect Donald Trump’s nominee for attorney general. Rep. Tom McClintock, R-Calif., was the sole Republican to support the effort. Most Republicans have argued that any congressional probe into Gaetz ended when he resigned from the House. Speaker Mike Johnson also requested that the committee not publish its report, saying it would be a terrible precedent to set. While ethics reports have previously been released after a member’s resignation, it is extremely rare. Shortly before the votes took place, Rep. Sean Casten, D-Ill., who introduced one of the bills to force the release, said that if Republicans reject the release, they will have “succeeded in sweeping credible allegations of sexual misconduct under the rug.” Gaetz has repeatedly denied the claims. Earlier Thursday, the Ethics panel met to discuss the Gaetz report but made no decision, saying in a short statement that the matter is still being discussed. It's unclear now whether the document will ever see the light of day as lawmakers have only a few weeks left before a new session of Congress begins. It's the culmination of weeks of pressure on the Ethics committee's five Republicans and five Democrats who mostly work in secret as they investigate allegations of misconduct against lawmakers. The status of the Gaetz investigation became an open question last month when he abruptly resigned from Congress after Trump's announcement that he wanted his ally in the Cabinet. It is standard practice for the committee to end investigations when members of Congress depart, but the circumstances surrounding Gaetz were unusual, given his potential role in the new administration. Rep. Michael Guest, R-Miss., the committee chairman, said Wednesday that there is no longer the same urgency to release the report given that Gaetz has left Congress and stepped aside as Trump's choice to head the Justice Department. “I’ve been steadfast about that. He’s no longer a member. He is no longer going to be confirmed by the Senate because he withdrew his nomination to be the attorney general,” Guest said. The Gaetz report has also caused tensions between lawmakers on the bipartisan committee. Pennsylvania Rep. Susan Wild, the top Democrat on the panel, publicly admonished Guest last month for mischaracterizing a previous meeting to the press. Gaetz has denied any wrongdoing and said last year that the Justice Department’s separate investigation against him into sex trafficking allegations involving underage girls ended without federal charges. His onetime political ally Joel Greenberg, a fellow Republican who served as the tax collector in Florida’s Seminole County, admitted as part of a plea deal with prosecutors in 2021 that he paid women and an underage girl to have sex with him and other men. The men were not identified in court documents when he pleaded guilty. Greenberg was sentenced in late 2022 to 11 years in prison. Among President-elect Donald Trump's picks are Susie Wiles for chief of staff, Florida Sen. Marco Rubio for secretary of state, former Democratic House member Tulsi Gabbard for director of national intelligence and Florida Rep. Matt Gaetz for attorney general. Susie Wiles, 67, was a senior adviser to Trump's 2024 presidential campaign and its de facto manager. Trump named Florida Sen. Marco Rubio to be secretary of state, making a former sharp critic his choice to be the new administration's top diplomat. Rubio, 53, is a noted hawk on China, Cuba and Iran, and was a finalist to be Trump's running mate on the Republican ticket last summer. Rubio is the vice chairman of the Senate Intelligence Committee and a member of the Senate Foreign Relations Committee. “He will be a strong Advocate for our Nation, a true friend to our Allies, and a fearless Warrior who will never back down to our adversaries,” Trump said of Rubio in a statement. The announcement punctuates the hard pivot Rubio has made with Trump, whom the senator called a “con man" during his unsuccessful campaign for the 2016 GOP presidential nomination. Their relationship improved dramatically while Trump was in the White House. And as Trump campaigned for the presidency a third time, Rubio cheered his proposals. For instance, Rubio, who more than a decade ago helped craft immigration legislation that included a path to citizenship for people in the U.S. illegally, now supports Trump's plan to use the U.S. military for mass deportations. Pete Hegseth, 44, is a co-host of Fox News Channel’s “Fox & Friends Weekend” and has been a contributor with the network since 2014, where he developed a friendship with Trump, who made regular appearances on the show. Hegseth lacks senior military or national security experience. If confirmed by the Senate, he would inherit the top job during a series of global crises — ranging from Russia’s war in Ukraine and the ongoing attacks in the Middle East by Iranian proxies to the push for a cease-fire between Israel, Hamas and Hezbollah and escalating worries about the growing alliance between Russia and North Korea. Hegseth is also the author of “The War on Warriors: Behind the Betrayal of the Men Who Keep Us Free,” published earlier this year. Trump tapped Pam Bondi, 59, to be attorney general after U.S. Rep. Matt Gaetz withdrew his name from consideration. She was Florida's first female attorney general, serving between 2011 and 2019. She also was on Trump’s legal team during his first impeachment trial in 2020. Considered a loyalist, she served as part of a Trump-allied outside group that helped lay the groundwork for his future administration called the America First Policy Institute. Bondi was among a group of Republicans who showed up to support Trump at his hush money criminal trial in New York that ended in May with a conviction on 34 felony counts. A fierce defender of Trump, she also frequently appears on Fox News and has been a critic of the criminal cases against him. Trump picked South Dakota Gov. Kristi Noem, a well-known conservative who faced sharp criticism for telling a story in her memoir about shooting a rambunctious dog, to lead an agency crucial to the president-elect’s hardline immigration agenda. Noem used her two terms leading a tiny state to vault to a prominent position in Republican politics. South Dakota is usually a political afterthought. But during the COVID-19 pandemic, Noem did not order restrictions that other states had issued and instead declared her state “open for business.” Trump held a fireworks rally at Mount Rushmore in July 2020 in one of the first large gatherings of the pandemic. She takes over a department with a sprawling mission. In addition to key immigration agencies, the Department of Homeland Security oversees natural disaster response, the U.S. Secret Service, and Transportation Security Administration agents who work at airports. The governor of North Dakota, who was once little-known outside his state, Burgum is a former Republican presidential primary contender who endorsed Trump, and spent months traveling to drum up support for him, after dropping out of the race. Burgum was a serious contender to be Trump’s vice presidential choice this summer. The two-term governor was seen as a possible pick because of his executive experience and business savvy. Burgum also has close ties to deep-pocketed energy industry CEOs. Trump made the announcement about Burgum joining his incoming administration while addressing a gala at his Mar-a-Lago club, and said a formal statement would be coming the following day. In comments to reporters before Trump took the stage, Burgum said that, in recent years, the power grid is deteriorating in many parts of the country, which he said could raise national security concerns but also drive up prices enough to increase inflation. “There's just a sense of urgency, and a sense of understanding in the Trump administration,” Burgum said. Robert F. Kennedy Jr. ran for president as a Democrat, than as an independent, and then endorsed Trump . He's the son of Democratic icon Robert Kennedy, who was assassinated during his own presidential campaign. The nomination of Kennedy to lead the Department of Health and Human Services alarmed people who are concerned about his record of spreading unfounded fears about vaccines . For example, he has long advanced the debunked idea that vaccines cause autism. Scott Bessent, 62, is a former George Soros money manager and an advocate for deficit reduction. He's the founder of hedge fund Key Square Capital Management, after having worked on-and-off for Soros Fund Management since 1991. If confirmed by the Senate, he would be the nation’s first openly gay treasury secretary. He told Bloomberg in August that he decided to join Trump’s campaign in part to attack the mounting U.S. national debt. That would include slashing government programs and other spending. “This election cycle is the last chance for the U.S. to grow our way out of this mountain of debt without becoming a sort of European-style socialist democracy,” he said then. Oregon Republican U.S. Rep. Lori Chavez-DeRemer narrowly lost her reelection bid this month, but received strong backing from union members in her district. As a potential labor secretary, she would oversee the Labor Department’s workforce, its budget and put forth priorities that impact workers’ wages, health and safety, ability to unionize, and employer’s rights to fire employers, among other responsibilities. Chavez-DeRemer is one of few House Republicans to endorse the “Protecting the Right to Organize” or PRO Act would allow more workers to conduct organizing campaigns and would add penalties for companies that violate workers’ rights. The act would also weaken “right-to-work” laws that allow employees in more than half the states to avoid participating in or paying dues to unions that represent workers at their places of employment. Scott Turner is a former NFL player and White House aide. He ran the White House Opportunity and Revitalization Council during Trump’s first term in office. Trump, in a statement, credited Turner, the highest-ranking Black person he’s yet selected for his administration, with “helping to lead an Unprecedented Effort that Transformed our Country’s most distressed communities.” Sean Duffy is a former House member from Wisconsin who was one of Trump's most visible defenders on cable news. Duffy served in the House for nearly nine years, sitting on the Financial Services Committee and chairing the subcommittee on insurance and housing. He left Congress in 2019 for a TV career and has been the host of “The Bottom Line” on Fox Business. Before entering politics, Duffy was a reality TV star on MTV, where he met his wife, “Fox and Friends Weekend” co-host Rachel Campos-Duffy. They have nine children. A campaign donor and CEO of Denver-based Liberty Energy, Write is a vocal advocate of oil and gas development, including fracking — a key pillar of Trump’s quest to achieve U.S. “energy dominance” in the global market. Wright also has been one of the industry’s loudest voices against efforts to fight climate change. He said the climate movement around the world is “collapsing under its own weight.” The Energy Department is responsible for advancing energy, environmental and nuclear security of the United States. Wright also won support from influential conservatives, including oil and gas tycoon Harold Hamm. Hamm, executive chairman of Oklahoma-based Continental Resources, a major shale oil company, is a longtime Trump supporter and adviser who played a key role on energy issues in Trump’s first term. President-elect Donald Trump tapped billionaire professional wrestling mogul Linda McMahon to be secretary of the Education Department, tasked with overseeing an agency Trump promised to dismantle. McMahon led the Small Business Administration during Trump’s initial term from 2017 to 2019 and twice ran unsuccessfully as a Republican for the U.S. Senate in Connecticut. She’s seen as a relative unknown in education circles, though she expressed support for charter schools and school choice. She served on the Connecticut Board of Education for a year starting in 2009 and has spent years on the board of trustees for Sacred Heart University in Connecticut. Brooke Rollins, who graduated from Texas A&M University with a degree in agricultural development, is a longtime Trump associate who served as White House domestic policy chief during his first presidency. The 52-year-old is president and CEO of the America First Policy Institute, a group helping to lay the groundwork for a second Trump administration. She previously served as an aide to former Texas Gov. Rick Perry and ran a think tank, the Texas Public Policy Foundation. Trump chose Howard Lutnick, head of brokerage and investment bank Cantor Fitzgerald and a cryptocurrency enthusiast, as his nominee for commerce secretary, a position in which he'd have a key role in carrying out Trump's plans to raise and enforce tariffs. Trump made the announcement Tuesday on his social media platform, Truth Social. Lutnick is a co-chair of Trump’s transition team, along with Linda McMahon, the former wrestling executive who previously led Trump’s Small Business Administration. Both are tasked with putting forward candidates for key roles in the next administration. The nomination would put Lutnick in charge of a sprawling Cabinet agency that is involved in funding new computer chip factories, imposing trade restrictions, releasing economic data and monitoring the weather. It is also a position in which connections to CEOs and the wider business community are crucial. Doug Collins is a former Republican congressman from Georgia who gained recognition for defending Trump during his first impeachment trial, which centered on U.S. assistance for Ukraine. Trump was impeached for urging Ukraine to investigate Joe Biden in 2019 during the Democratic presidential nomination, but he was acquitted by the Senate. Collins has also served in the armed forces himself and is currently a chaplain in the United States Air Force Reserve Command. "We must take care of our brave men and women in uniform, and Doug will be a great advocate for our Active Duty Servicemembers, Veterans, and Military Families to ensure they have the support they need," Trump said in a statement about nominating Collins to lead the Department of Veterans Affairs. Karoline Leavitt, 27, was Trump's campaign press secretary and currently a spokesperson for his transition. She would be the youngest White House press secretary in history. The White House press secretary typically serves as the public face of the administration and historically has held daily briefings for the press corps. Leavitt, a New Hampshire native, was a spokesperson for MAGA Inc., a super PAC supporting Trump, before joining his 2024 campaign. In 2022, she ran for Congress in New Hampshire, winning a 10-way Republican primary before losing to Democratic Rep. Chris Pappas. Leavitt worked in the White House press office during Trump's first term before she became communications director for New York Republican Rep. Elise Stefanik, Trump's choice for U.S. ambassador to the United Nations. Former Hawaii Rep. Tulsi Gabbard has been tapped by Trump to be director of national intelligence, keeping with the trend to stock his Cabinet with loyal personalities rather than veteran professionals in their requisite fields. Gabbard, 43, was a Democratic House member who unsuccessfully sought the party's 2020 presidential nomination before leaving the party in 2022. She endorsed Trump in August and campaigned often with him this fall. “I know Tulsi will bring the fearless spirit that has defined her illustrious career to our Intelligence Community,” Trump said in a statement. Gabbard, who has served in the Army National Guard for more than two decades, deploying to Iraq and Kuwait, would come to the role as somewhat of an outsider compared to her predecessor. The current director, Avril Haines, was confirmed by the Senate in 2021 following several years in a number of top national security and intelligence positions. Trump has picked John Ratcliffe, a former Texas congressman who served as director of national intelligence during his first administration, to be director of the Central Intelligence Agency in his next. Ratcliffe was director of national intelligence during the final year and a half of Trump's first term, leading the U.S. government's spy agencies during the coronavirus pandemic. “I look forward to John being the first person ever to serve in both of our Nation's highest Intelligence positions,” Trump said in a statement, calling him a “fearless fighter for the Constitutional Rights of all Americans” who would ensure “the Highest Levels of National Security, and PEACE THROUGH STRENGTH.” Kash Patel spent several years as a Justice Department prosecutor before catching the Trump administration’s attention as a staffer on Capitol Hill who helped investigate the Russia probe. Patel called for dramatically reducing the agency’s footprint, a perspective that sets him apart from earlier directors who sought additional resources for the bureau. Though the Justice Department in 2021 halted the practice of secretly seizing reporters’ phone records during leak investigations, Patel said he intends to aggressively hunt down government officials who leak information to reporters. Trump has chosen former New York Rep. Lee Zeldin to serve as his pick to lead the Environmental Protection Agency . Zeldin does not appear to have any experience in environmental issues, but is a longtime supporter of the former president. The 44-year-old former U.S. House member from New York wrote on X , “We will restore US energy dominance, revitalize our auto industry to bring back American jobs, and make the US the global leader of AI.” “We will do so while protecting access to clean air and water,” he added. During his campaign, Trump often attacked the Biden administration's promotion of electric vehicles, and incorrectly referring to a tax credit for EV purchases as a government mandate. Trump also often told his audiences during the campaign his administration would “Drill, baby, drill,” referring to his support for expanded petroleum exploration. In a statement, Trump said Zeldin “will ensure fair and swift deregulatory decisions that will be enacted in a way to unleash the power of American businesses, while at the same time maintaining the highest environmental standards, including the cleanest air and water on the planet.” Trump has named Brendan Carr, the senior Republican on the Federal Communications Commission, as the new chairman of the agency tasked with regulating broadcasting, telecommunications and broadband. Carr is a longtime member of the commission and served previously as the FCC’s general counsel. He has been unanimously confirmed by the Senate three times and was nominated by both Trump and President Joe Biden to the commission. Carr made past appearances on “Fox News Channel," including when he decried Democratic Vice President Kamala Harris' pre-Election Day appearance on “Saturday Night Live.” He wrote an op-ed last month defending a satellite company owned by Trump supporter Elon Musk. Trump said Atkins, the CEO of Patomak Partners and a former SEC commissioner, was a “proven leader for common sense regulations.” In the years since leaving the SEC, Atkins has made the case against too much market regulation. “He believes in the promise of robust, innovative capital markets that are responsive to the needs of Investors, & that provide capital to make our Economy the best in the World. He also recognizes that digital assets & other innovations are crucial to Making America Greater than Ever Before,” Trump wrote on Truth Social. The commission oversees U.S. securities markets and investments and is currently led by Gary Gensler, who has been leading the U.S. government’s crackdown on the crypto industry. Gensler, who was nominated by President Joe Biden, announced last month that he would be stepping down from his post on the day that Trump is inaugurated — Jan. 20, 2025. Atkins began his career as a lawyer and has a long history working in the financial markets sector, both in government and private practice. In the 1990s, he worked on the staffs of two former SEC chairmen, Richard C. Breeden and Arthur Levitt. Jared Isaacman, 41, is a tech billionaire who bought a series of spaceflights from Elon Musk’s SpaceX and conducted the first private spacewalk . He is the founder and CEO of a card-processing company and has collaborated closely with Musk ever since buying his first chartered SpaceX flight. He took contest winners on that 2021 trip and followed it in September with a mission where he briefly popped out the hatch to test SpaceX’s new spacewalking suits. Rep. Elise Stefanik is a representative from New York and one of Trump's staunchest defenders going back to his first impeachment. Elected to the House in 2014, Stefanik was selected by her GOP House colleagues as House Republican Conference chair in 2021, when former Wyoming Rep. Liz Cheney was removed from the post after publicly criticizing Trump for falsely claiming he won the 2020 election. Stefanik, 40, has served in that role ever since as the third-ranking member of House leadership. Stefanik’s questioning of university presidents over antisemitism on their campuses helped lead to two of those presidents resigning, further raising her national profile. If confirmed, she would represent American interests at the U.N. as Trump vows to end the war waged by Russia against Ukraine begun in 2022. He has also called for peace as Israel continues its offensive against Hamas in Gaza and its invasion of Lebanon to target Hezbollah. President-elect Donald Trump says he's chosen former acting Attorney General Matt Whitaker to serve as U.S. ambassador to NATO. Trump has expressed skepticism about the Western military alliance for years. Trump said in a statement Wednesday that Whitaker is “a strong warrior and loyal Patriot” who “will ensure the United States’ interests are advanced and defended” and “strengthen relationships with our NATO Allies, and stand firm in the face of threats to Peace and Stability.” The choice of Whitaker as the nation’s representative to the North Atlantic Treaty Organization is an unusual one, given his background is as a lawyer and not in foreign policy. Trump will nominate former Arkansas Gov. Mike Huckabee to be ambassador to Israel. Huckabee is a staunch defender of Israel and his intended nomination comes as Trump has promised to align U.S. foreign policy more closely with Israel's interests as it wages wars against the Iran-backed Hamas and Hezbollah. “He loves Israel, and likewise the people of Israel love him,” Trump said in a statement. “Mike will work tirelessly to bring about peace in the Middle East.” Huckabee, who ran unsuccessfully for the Republican presidential nomination in 2008 and 2016, has been a popular figure among evangelical Christian conservatives, many of whom support Israel due to Old Testament writings that Jews are God’s chosen people and that Israel is their rightful homeland. Trump has been praised by some in this important Republican voting bloc for moving the U.S. embassy in Israel from Tel Aviv to Jerusalem. Trump on Tuesday named real estate investor Steven Witkoff to be special envoy to the Middle East. The 67-year-old Witkoff is the president-elect's golf partner and was golfing with him at Trump's club in West Palm Beach, Florida, on Sept. 15, when the former president was the target of a second attempted assassination. Witkoff “is a Highly Respected Leader in Business and Philanthropy,” Trump said of Witkoff in a statement. “Steve will be an unrelenting Voice for PEACE, and make us all proud." Trump also named Witkoff co-chair, with former Georgia Sen. Kelly Loeffler, of his inaugural committee. Trump said Wednesday that he will nominate Gen. Keith Kellogg to serve as assistant to the president and special envoy for Ukraine and Russia. Kellogg, a retired Army lieutenant general who has long been Trump’s top adviser on defense issues, served as National Security Advisor to Trump's former Vice President Mike Pence. For the America First Policy Institute, one of several groups formed after Trump left office to help lay the groundwork for the next Republican administration, Kellogg in April wrote that “bringing the Russia-Ukraine war to a close will require strong, America First leadership to deliver a peace deal and immediately end the hostilities between the two warring parties.” (AP Photo/Mariam Zuhaib) Trump asked Rep. Michael Waltz, R-Fla., a retired Army National Guard officer and war veteran, to be his national security adviser, Trump announced in a statement Tuesday. The move puts Waltz in the middle of national security crises, ranging from efforts to provide weapons to Ukraine and worries about the growing alliance between Russia and North Korea to the persistent attacks in the Middle East by Iran proxies and the push for a cease-fire between Israel and Hamas and Hezbollah. “Mike has been a strong champion of my America First Foreign Policy agenda,” Trump's statement said, "and will be a tremendous champion of our pursuit of Peace through Strength!” Waltz is a three-term GOP congressman from east-central Florida. He served multiple tours in Afghanistan and also worked in the Pentagon as a policy adviser when Donald Rumsfeld and Robert Gates were defense chiefs. He is considered hawkish on China, and called for a U.S. boycott of the 2022 Winter Olympics in Beijing due to its involvement in the origin of COVID-19 and its mistreatment of the minority Muslim Uighur population. Stephen Miller, an immigration hardliner , was a vocal spokesperson during the presidential campaign for Trump's priority of mass deportations. The 39-year-old was a senior adviser during Trump's first administration. Miller has been a central figure in some of Trump's policy decisions, notably his move to separate thousands of immigrant families. Trump argued throughout the campaign that the nation's economic, national security and social priorities could be met by deporting people who are in the United States illegally. Since Trump left office in 2021, Miller has served as the president of America First Legal, an organization made up of former Trump advisers aimed at challenging the Biden administration, media companies, universities and others over issues such as free speech and national security. Thomas Homan, 62, has been tasked with Trump’s top priority of carrying out the largest deportation operation in the nation’s history. Homan, who served under Trump in his first administration leading U.S. Immigration and Customs Enforcement, was widely expected to be offered a position related to the border, an issue Trump made central to his campaign. Though Homan has insisted such a massive undertaking would be humane, he has long been a loyal supporter of Trump's policy proposals, suggesting at a July conference in Washington that he would be willing to "run the biggest deportation operation this country’s ever seen.” Democrats have criticized Homan for his defending Trump's “zero tolerance” policy on border crossings during his first administration, which led to the separation of thousands of parents and children seeking asylum at the border. Former Rep. Billy Long represented Missouri in the U.S. House from 2011 to 2023. Since leaving Congress, Trump said, Long “has worked as a Business and Tax advisor, helping Small Businesses navigate the complexities of complying with the IRS Rules and Regulations.” Former Georgia Sen. Kelly Loeffler was appointed in January 2020 by Georgia Gov. Brian Kemp and then lost a runoff election a year later. She started a conservative voter registration organization and dived into GOP fundraising, becoming one of the top individual donors and bundlers to Trump’s 2024 comeback campaign. Even before nominating her for agriculture secretary, the president-elect already had tapped Loeffler as co-chair of his inaugural committee. Dr. Mehmet Oz, 64, is a former heart surgeon who hosted “The Dr. Oz Show,” a long-running daytime television talk show. He ran unsuccessfully for the U.S. Senate as the Republican nominee in 2022 and is an outspoken supporter of Trump, who endorsed Oz's bid for elected office. Elon Musk, left, and Vivek Ramaswamy speak before Republican presidential nominee former President Donald Trump at an Oct. 27 campaign rally at Madison Square Garden in New York. Trump on Tuesday said Musk and former Republican presidential candidate Ramaswamy will lead a new “Department of Government Efficiency" — which is not, despite the name, a government agency. The acronym “DOGE” is a nod to Musk's favorite cryptocurrency, dogecoin. Trump said Musk and Ramaswamy will work from outside the government to offer the White House “advice and guidance” and will partner with the Office of Management and Budget to “drive large scale structural reform, and create an entrepreneurial approach to Government never seen before.” He added the move would shock government systems. It's not clear how the organization will operate. Musk, owner of X and CEO of Tesla and SpaceX, has been a constant presence at Mar-a-Lago since Trump won the presidential election. Ramaswamy suspended his campaign in January and threw his support behind Trump. Trump said the two will “pave the way for my Administration to dismantle Government Bureaucracy, slash excess regulations, cut wasteful expenditures, and restructure Federal Agencies.” Russell Vought held the position during Trump’s first presidency. After Trump’s initial term ended, Vought founded the Center for Renewing America, a think tank that describes its mission as “renew a consensus of America as a nation under God.” Vought was closely involved with Project 2025, a conservative blueprint for Trump’s second term that he tried to distance himself from during the campaign. Vought has also previously worked as the executive and budget director for the Republican Study Committee, a caucus for conservative House Republicans. He also worked at Heritage Action, the political group tied to The Heritage Foundation, a conservative think tank. Dan Scavino, deputy chief of staff Scavino, whom Trump's transition referred to in a statement as one of “Trump's longest serving and most trusted aides,” was a senior adviser to Trump's 2024 campaign, as well as his 2016 and 2020 campaigns. He will be deputy chief of staff and assistant to the president. Scavino had run Trump's social media profile in the White House during his first administration. He was also held in contempt of Congress in 2022 after a month-long refusal to comply with a subpoena from the House committee’s investigation into the Jan. 6, 2021, attack on the U.S. Capitol. James Blair, deputy chief of staff Blair was political director for Trump's 2024 campaign and for the Republican National Committee. He will be deputy chief of staff for legislative, political and public affairs and assistant to the president. Blair was key to Trump's economic messaging during his winning White House comeback campaign this year, a driving force behind the candidate's “Trump can fix it” slogan and his query to audiences this fall if they were better off than four years ago. Taylor Budowich, deputy chief of staff Budowich is a veteran Trump campaign aide who launched and directed Make America Great Again, Inc., a super PAC that supported Trump's 2024 campaign. He will be deputy chief of staff for communications and personnel and assistant to the president. Budowich also had served as a spokesman for Trump after his presidency. Jay Bhattacharya, National Institutes of Health Trump has chosen Dr. Jay Bhattacharya to lead the National Institutes of Health. Bhattacharya is a physician and professor at Stanford University School of Medicine, and is a critic of pandemic lockdowns and vaccine mandates. He promoted the idea of herd immunity during the pandemic, arguing that people at low risk should live normally while building up immunity to COVID-19 through infection. The National Institutes of Health funds medical research through competitive grants to researchers at institutions throughout the nation. NIH also conducts its own research with thousands of scientists working at its labs in Bethesda, Maryland. Dr. Marty Makary, Food and Drug Administration Makary is a Johns Hopkins surgeon and author who argued against pandemic lockdowns. He routinely appeared on Fox News during the COVID-19 pandemic and wrote opinion articles questioning masks for children. He cast doubt on vaccine mandates but supported vaccines generally. Makary also cast doubt on whether booster shots worked, which was against federal recommendations on the vaccine. Dr. Janette Nesheiwat, Surgeon General Nesheiwat is a general practitioner who serves as medical director for CityMD, a network of urgent care centers in New York and New Jersey. She has been a contributor to Fox News. Dr. Dave Weldon, U.S. Centers for Disease Control and Prevention Weldon is a former Florida congressman who recently ran for a Florida state legislative seat and lost; Trump backed Weldon’s opponent. In Congress, Weldon weighed in on one of the nation’s most heated debates of the 1990s over quality of life and a right-to-die and whether Terri Schiavo, who was in a persistent vegetative state after cardiac arrest, should have been allowed to have her feeding tube removed. He sided with the parents who did not want it removed. Jamieson Greer, U.S. trade representative Kevin Hassett, Director of the White House National Economic Council Trump is turning to two officials with experience navigating not only Washington but the key issues of income taxes and tariffs as he fills out his economic team. He announced he has chosen international trade attorney Jamieson Greer to be his U.S. trade representative and Kevin Hassett as director of the White House National Economic Council. While Trump has in several cases nominated outsiders to key posts, these picks reflect a recognition that his reputation will likely hinge on restoring the public’s confidence in the economy. Trump said in a statement that Greer was instrumental in his first term in imposing tariffs on China and others and replacing the trade agreement with Canada and Mexico, “therefore making it much better for American Workers.” Hassett, 62, served in the first Trump term as chairman of the Council of Economic Advisers. He has a doctorate from the University of Pennsylvania and worked at the right-leaning American Enterprise Institute before joining the Trump White House in 2017. Stay up-to-date on the latest in local and national government and political topics with our newsletter.Cellular traffic congestion in chronic diseases suggests new therapeutic targets November 27, 2024 Whitehead Institute for Biomedical Research Chronic diseases such as diabetes are on the rise and are costly and challenging to treat. Scientists have discovered a common denominator driving these diverse diseases, which may prove to be a promising therapeutic target: proteolethargy, or reduced protein mobility, in the presence of oxidative stress. Facebook Twitter Pinterest LinkedIN Email Chronic diseases like type 2 diabetes and inflammatory disorders have a huge impact on humanity. They are a leading cause of disease burden and deaths around the globe, are physically and economically taxing, and the number of people with such diseases is growing. Treating chronic disease has proven difficult because there is not one simple cause, like a single gene mutation, that a treatment could target. At least, that's how it has appeared to scientists. However, research from Whitehead Institute Member Richard Young and colleagues, published in the journal Cell on November 27, reveals that many chronic diseases have a common denominator that could be driving their dysfunction: reduced protein mobility. What this means is that around half of all proteins active in cells slow their movement when cells are in a chronic disease state, reducing the proteins' functions. The researchers' findings suggest that protein mobility may be a linchpin for decreased cellular function in chronic disease, making it a promising therapeutic target. In this paper, Young and colleagues in his lab, including postdoc Alessandra Dall'Agnese, graduate students Shannon Moreno and Ming Zheng, and research scientist Tong Ihn Lee, describe their discovery of this common mobility defect, which they call proteolethargy; explain what causes the defect and how it leads to dysfunction in cells; and propose a new therapeutic hypothesis for treating chronic diseases. "I'm excited about what this work could mean for patients," says Dall'Agnese. "My hope is that this will lead to a new class of drugs that restore protein mobility, which could help people with many different diseases that all have this mechanism as a common denominator." "This work was a collaborative, interdisciplinary effort that brought together biologists, physicists, chemists, computer scientists and physician-scientists," Lee says. "Combining that expertise is a strength of the Young lab. Studying the problem from different viewpoints really helped us think about how this mechanism might work and how it could change our understanding of the pathology of chronic disease." Commuter delays cause work stoppages in the cell How do proteins moving more slowly through a cell lead to widespread and significant cellular dysfunction? Dall'Agnese explains that every cell is like a tiny city, with proteins as the workers who keep everything running. Proteins have to commute in dense traffic in the cell, traveling from where they are created to where they work. The faster their commute, the more work they get done. Now, imagine a city that starts experiencing traffic jams along all the roads. Stores don't open on time, groceries are stuck in transit, meetings are postponed. Essentially all operations in the city are slowed. The slow down of operations in cells experiencing reduced protein mobility follows a similar progression. Normally, most proteins zip around the cell bumping into other molecules until they locate the molecule they work with or act on. The slower a protein moves, the fewer other molecules it will reach, and so the less likely it will be able to do its job. Young and colleagues found that such protein slow-downs lead to measurable reductions in the functional output of the proteins. When many proteins fail to get their jobs done in time, cells begin to experience a variety of problems -- as they are known to do in chronic diseases. Discovering the protein mobility problem Young and colleagues first suspected that cells affected in chronic disease might have a protein mobility problem after observing changes in the behavior of the insulin receptor, a signaling protein that reacts to the presence of insulin and causes cells to take in sugar from blood. In people with diabetes, cells become less responsive to insulin -- a state called insulin resistance -- causing too much sugar to remain in the blood. In researchpublished on insulin receptors in Nature Communications in 2022, Young and colleagues reported that insulin receptor mobility might be relevant to diabetes. Knowing that many cellular functions are altered in diabetes, the researchers considered the possibility that altered protein mobility might somehow affect many proteins in cells. To test this hypothesis, they studied proteins involved in a broad range of cellular functions, including MED1, a protein involved in gene expression; HP1α, a protein involved in gene silencing; FIB1, a protein involved in production of ribosomes; and SRSF2, a protein involved in splicing of messenger RNA. They used single-molecule tracking and other methods to measure how each of those proteins moves in healthy cells and in cells in disease states. All but one of the proteins showed reduced mobility (about 20-35%) in the disease cells. "I'm excited that we were able to transfer physics-based insight and methodology, which are commonly used to understand the single-molecule processes like gene transcription in normal cells, to a disease context and show that they can be used to uncover unexpected mechanisms of disease," Zheng says. "This work shows how the random walk of proteins in cells is linked to disease pathology." Moreno concurs: "In school, we're taught to consider changes in protein structure or DNA sequences when looking for causes of disease, but we've demonstrated that those are not the only contributing factors. If you only consider a static picture of a protein or a cell, you miss out on discovering these changes that only appear when molecules are in motion." Can't commute across the cell, I'm all tied up right now Next, the researchers needed to determine what was causing the proteins to slow down. They suspected that the defect had to do with an increase in cells of the level of reactive oxygen species (ROS), molecules that are highly prone to interfering with other molecules and their chemical reactions. Many types of chronic-disease-associated triggers, such as higher sugar or fat levels, certain toxins, and inflammatory signals, lead to an increase in ROS, also known as an increase in oxidative stress. The researchers measured the mobility of the proteins again, in cells that had high levels of ROS and were not otherwise in a disease state, and saw comparable mobility defects, suggesting that oxidative stress was to blame for the protein mobility defect. The final part of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only one of the proteins that was unaffected in the experiments, and it had one clear difference from the others: its surface did not contain any cysteines, an amino acid building block of many proteins. Cysteines are especially susceptible to interference from ROS because it will cause them to bond to other cysteines. When this bonding occurs between two protein molecules, it slows them down because the two proteins cannot move through the cell as quickly as either protein alone. About half of the proteins in our cells contain surface cysteines, so this single protein mobility defect can impact many different cellular pathways. This makes sense when one considers the diversity of dysfunctions that appear in cells of people with chronic diseases: dysfunctions in cell signaling, metabolic processes, gene expression and gene silencing, and more. All of these processes rely on the efficient functioning of proteins -- including the diverse proteins studied by the researchers. Young and colleagues performed several experiments to confirm that decreased protein mobility does in fact decrease a protein's function. For example, they found that when an insulin receptor experiences decreased mobility, it acts less efficiently on IRS1, a molecule to which it usually adds a phosphate group. From understanding a mechanism to treating a disease Discovering that decreased protein mobility in the presence of oxidative stress could be driving many of the symptoms of chronic disease provides opportunities to develop therapies to rescue protein mobility. In the course of their experiments, the researchers treated cells with an antioxidant drug -- something that reduces ROS -- called N-acetyl cysteine and saw that this partially restored protein mobility. The researchers are pursuing a variety of follow ups to this work, including the search for drugs that safely and efficiently reduce ROS and restore protein mobility. They developed an assay that can be used to screen drugs to see if they restore protein mobility by comparing each drug's effect on a simple biomarker with surface cysteines to one without. They are also looking into other diseases that may involve protein mobility, and are exploring the role of reduced protein mobility in aging. "The complex biology of chronic diseases has made it challenging to come up with effective therapeutic hypotheses," says Young, who is also a professor of biology at the Massachusetts Institute of Technology. "The discovery that diverse disease-associated stimuli all induce a common feature, proteolethargy, and that this feature could contribute to much of the dysregulation that we see in chronic disease, is something that I hope will be a real game changer for developing drugs that work across the spectrum of chronic diseases." Story Source: Materials provided by Whitehead Institute for Biomedical Research . Original written by Greta Friar. Note: Content may be edited for style and length. Journal Reference : Cite This Page :

BOCA RATON, Fla. (AP) — Deshawn Purdie threw a 47-yard touchdown pass to O'Mega Blake for the go-ahead score and Charlotte defeated Florida Atlantic 39-27 on Saturday in a game that matched two new interim coaches. Charlotte (4-7, 3-4 American Athletic Conference) fired Biff Poggi on Monday and Tim Brewster took over. FAU (2-9, 0-7) fired Tom Ferman, also on Monday, with Chad Lunsford taking charge. After Blake's third touchdown catch of the game that came with 5:25 left, the 49ers extended their lead when Tyriq Starks was strip-sacked by Ja'Qurious Conley and 335-pound Katron Kevans carried it 22 yards into the end zone. Blake made five catches for a career-high 205 yards, including a 75-yard touchdown. Purdie was 16 of 30 for a career-best 396 yards passing with the three scores plus an interception. The 49ers only rushed for 46 yards. Stephen Rusnak kicked four field goals. Starks was 12-of-23 passing for 179 yards including a 65-yard score to Omari Hayes in the final minute of the third quarter to get FAU within six of the 49ers. CJ Campbell rushed 58 yards to score early in the fourth quarter and the Owls had a 27-26 lead. Campbell finished with 150 yards on 21 carries. AP college football: https://apnews.com/hub/ap-top-25-college-football-poll and https://apnews.com/hub/college-football . Sign up for the AP’s college football newsletter: https://apnews.com/cfbtop25

Morgan Rogers looked to have given Unai Emery’s side another famous win when he slammed a loose ball home at the death, but referee Jesus Gil Manzano ruled Diego Carlos to have fouled Juve goalkeeper Michele Di Gregorio and the goal was chalked off. It was a disappointment for Villa, who remain unbeaten at home in their debut Champions League campaign and are still in contention to qualify automatically for the last 16. A very controversial finish at Villa Park 😲 Morgan Rogers' late goal is ruled out for a foul on Juventus goalkeeper Michele Di Gregorio and the match ends 0-0 ❌ 📺 @tntsports & @discoveryplusUK pic.twitter.com/MyYL5Vdy3r — Football on TNT Sports (@footballontnt) November 27, 2024 Emiliano Martinez had earlier displayed why he was named the best goalkeeper in the world as his wonder save kept his side level in the second half. The Argentina international paraded his two Yashin Trophies on the pitch before kick-off at Villa Park and then showed why he won back-to-back FIFA awards when he denied Francisco Conceicao. Before Rogers’ moment of drama in the fourth minute of added time, the closest Villa came to scoring was in the first half when Lucas Digne’s free-kick hit the crossbar. But a draw was a fair result which leaves Villa out of the top eight on goal difference and Juventus down in 19th. Before the game Emery called Juventus one of the “best teams in the world, historically and now”, but this was an Italian side down to the bare bones. Only 14 outfield players made the trip from Turin, with striker Dusan Vlahovic among those who stayed behind. The opening 30 minutes were forgettable before the game opened up. Ollie Watkins, still chasing his first Champions League goal, had Villa’s first presentable chance as he lashed an effort straight at Di Gregorio. Matty Cash then had a vicious effort from the resulting corner which was blocked by Federico Gatti and started a counter-attack which ended in Juventus striker Timothy Weah. Villa came closest to breaking the deadlock at the end of the first half when Digne’s 20-yard free-kick clipped the top of the crossbar and went over. Martinez then produced his brilliant save just after the hour. A corner made its way through to the far post where Conceicao was primed to head in at the far post, but Martinez sprawled himself across goal to scoop the ball away. How has he kept that one out?! 🤯 Emi Martinez with an INCREDIBLE save to keep it goalless at Villa Park ⛔️ 📺 @tntsports & @discoveryplusUK pic.twitter.com/OkcWHB7YIk — Football on TNT Sports (@footballontnt) November 27, 2024 Replays showed most of the ball went over the line, but the Argentinian got there with millimetres to spare. At the other end another fine goal-line block denied John McGinn as Manuel Locatelli got his foot in the way with Di Gregorio beaten. The game looked to be petering out until a last-gasp free-kick saw Rogers slam home, but whistle-happy official Gil Manzano halted the celebrations by ruling the goal out.

BOLINGBROOK, Ill.--(BUSINESS WIRE)--Nov 21, 2024-- Ulta Beauty, Inc. (NASDAQ: ULTA) today announced that its financial results for the third quarter of fiscal 2024 will be released Thursday, December 5, 2024, after the market closes. The Company will host a conference call at 4:30 p.m. ET / 3:30 p.m. CT to discuss the financial results. Investors and analysts who are interested in participating in the call are invited to dial (877) 704-4453. Participants may also listen to a real-time audio webcast of the conference call by visiting the Investor Relations section of the Company’s website located at https://www.ulta.com/investor . A replay will be made available online approximately two hours following the live call for a period of 30 days. About Ulta Beauty At Ulta Beauty (NASDAQ: ULTA), the possibilities are beautiful. Ulta Beauty is the largest U.S. beauty retailer and the premier beauty destination for cosmetics, fragrance, skin care products, hair care products and salon services. In 1990, the Company reinvented the beauty retail experience by offering a new way to shop for beauty – bringing together All Things Beauty, All in One Place®. Today, Ulta Beauty operates more than 1,400 retail stores across 50 states and also distributes its products through its website, which includes a collection of tips, tutorials, and social content. For more information, visit https://www.ulta.com . View source version on businesswire.com : https://www.businesswire.com/news/home/20241121549355/en/ CONTACT: Ulta Beauty Contacts: Kiley Rawlins, CFA Vice President, Investor Relations krawlins@ulta.comCrystal Carroll Senior Director, Public Relations Ccarroll@ulta.com KEYWORD: UNITED STATES NORTH AMERICA ILLINOIS INDUSTRY KEYWORD: LUXURY WOMEN DEPARTMENT STORES SPECIALTY LIFESTYLE COSMETICS CONSUMER RETAIL ONLINE RETAIL SOURCE: Ulta Beauty, Inc. Copyright Business Wire 2024. PUB: 11/21/2024 04:05 PM/DISC: 11/21/2024 04:06 PM http://www.businesswire.com/news/home/20241121549355/enIncredible satellite images show Greenland’s massive ice sheet melting

Wingstop Announces Additional $500 Million Share Repurchase Authorization

Thought Technology Ltd Celebrates 50 Years of Innovation and ExcellenceAston Villa had a stoppage-time goal disallowed as they drew 0-0 with Juventus in the Champions League. Morgan Rogers looked to have given Unai Emery’s side another famous win when he slammed a loose ball home at the death, but referee Jesus Gil Manzano ruled Diego Carlos to have fouled Juve goalkeeper Michele Di Gregorio and the goal was chalked off. It was a disappointment for Villa, who remain unbeaten at home in their debut Champions League campaign and are still in contention to qualify automatically for the last 16. A very controversial finish at Villa Park 😲 Morgan Rogers' late goal is ruled out for a foul on Juventus goalkeeper Michele Di Gregorio and the match ends 0-0 ❌ 📺 @tntsports & @discoveryplusUK pic.twitter.com/MyYL5Vdy3r — Football on TNT Sports (@footballontnt) November 27, 2024 Emiliano Martinez had earlier displayed why he was named the best goalkeeper in the world as his wonder save kept his side level in the second half. The Argentina international paraded his two Yashin Trophies on the pitch before kick-off at Villa Park and then showed why he won back-to-back FIFA awards when he denied Francisco Conceicao. Before Rogers’ moment of drama in the fourth minute of added time, the closest Villa came to scoring was in the first half when Lucas Digne’s free-kick hit the crossbar. But a draw was a fair result which leaves Villa out of the top eight on goal difference and Juventus down in 19th. Before the game Emery called Juventus one of the “best teams in the world, historically and now”, but this was an Italian side down to the bare bones. Only 14 outfield players made the trip from Turin, with striker Dusan Vlahovic among those who stayed behind. The opening 30 minutes were forgettable before the game opened up. Ollie Watkins, still chasing his first Champions League goal, had Villa’s first presentable chance as he lashed an effort straight at Di Gregorio. Matty Cash then had a vicious effort from the resulting corner which was blocked by Federico Gatti and started a counter-attack which ended in Juventus striker Timothy Weah. Villa came closest to breaking the deadlock at the end of the first half when Digne’s 20-yard free-kick clipped the top of the crossbar and went over. Martinez then produced his brilliant save just after the hour. A corner made its way through to the far post where Conceicao was primed to head in at the far post, but Martinez sprawled himself across goal to scoop the ball away. How has he kept that one out?! 🤯 Emi Martinez with an INCREDIBLE save to keep it goalless at Villa Park ⛔️ 📺 @tntsports & @discoveryplusUK pic.twitter.com/OkcWHB7YIk — Football on TNT Sports (@footballontnt) November 27, 2024 Replays showed most of the ball went over the line, but the Argentinian got there with millimetres to spare. At the other end another fine goal-line block denied John McGinn as Manuel Locatelli got his foot in the way with Di Gregorio beaten. The game looked to be petering out until a last-gasp free-kick saw Rogers slam home, but whistle-happy official Gil Manzano halted the celebrations by ruling the goal out.

Taoiseach and Fine Gael leader Simon Harris (Brian LAwless/PA) Taoiseach Simon Harris has said he is taking a “project truth” approach to calling out Sinn Fein’s spending pledges as fears over future economic threats took centre stage in the Irish General Election campaign. Election results on the other side of the Atlantic Ocean have set the background for the final stretch of campaigning for Irish parties ahead of polling day on Friday. Donald Trump’s presidential election victory in the US has brought heightened concern that his administration’s proposals around corporation tax and tariffs would significantly impact Ireland’s economic model. Mr Harris, leader of Fine Gael, has argued Ireland and other EU countries need to prepare for the possibility of trade shocks as he criticised the scale of Sinn Fein’s spending pledges as well as their saving plans. He said: “I think that is irresponsible, I think it is dangerous and I think it is reckless.” He accused Sinn Fein leader Mary Lou McDonald of not being able to say what her party was prepared to do in the event of an economic crash, adding that Fine Gael would borrow and stop putting money towards a rainy-day fund. Asked if the party was engaging in “project fear” to dissuade voters against Sinn Fein, Mr Harris said: “I call it ‘project truth’. It’s telling people what’s being discussed right across European capitals.” Ms McDonald told an RTE interview on Wednesday morning that a Sinn Fein government would also be prepared to start borrowing in the event of an economic downturn. Both Mr Harris and Fianna Fail leader Micheal Martin, who were partners in the last coalition government in Ireland, have made clear they will not countenance Sinn Fein as a potential partner in the next administration in Dublin. One day after the only three-way debate featuring the leaders of the main parties, Mr Martin accused Sinn Fein of being “dishonest” about how they will fund their manifesto plans. Speaking in Dublin on Wednesday, he said he is anxious to get clarity on the issue. “I think Sinn Fein have been very dishonest, frankly, in terms of the funds, because if you go through their figures, and this is a matter of fact, not opinion, they’re predicting a surplus of a billion in 2026, a billion in 2027. “Even in 2025, they’re talking about a mini budget, which would mean reducing the surplus that we’re anticipating in 2025. “There’s a legislative obligation now on any new government to put 0.8% of GDP to one side, and into the funds. There’s no way you can do that with a surplus of a billion in 2026 or 2027, and we would argue they would not have enough funds next year either to put into the funds.” He added: “It means they have no room to manoeuvre if things go wrong, if there’s headwinds come externally, or there are shocks internationally, Sinn Fein is not allowing any headroom at all in terms of room to respond or to move it.” Ms McDonald accused the other two parties of conspiring to keep Sinn Fein out of government and prevent change in Ireland. Mary Lou McDonald, Micheal Martin and Simon Harris took part in a three-way leaders debate on RTE television (Niall Carson/PA) She said the two men were now “indistinguishable” from each other as she claimed they were suffering “acute amnesia” in regard to their records in government. On a visit to Naas fire station in Co Kildare, she said: “To listen to them, you’d imagine they had just arrived on the scene and that they were going to come up with all of these solutions. “They have had ample chances, ample opportunity, to make things better, and they have failed, and in between the two of them I make the case that now we ask for our chance, with our plans, with our team, to demonstrate how change can happen, how your community, your family, yourself, can be supported when the government is actually on your side.” Mr Martin’s and Mr Harris’ coalition partner Roderic O’Gorman, the leader of the Greens, issued a warning to the public over a future government without his party. On Wednesday, he said it is looking likely that Fianna Fail and Fine Gael will be returned to government – but cautioned they may not want the Greens to continue “fighting hard” on policies. He told reporters: “My sense is certainly the mood music from Fianna Fail and Fine Gael is that they’d like an easier life in the next government – and my concern is they use these small populist parties and right-wing independents.” Mr O’Gorman argued that the Greens could continue to provide stability to government at a time when economic shocks may be around the corner. Tanaiste and Fianna Fail leader Micheal Martin during a press event (Brian Lawless/PA) As the Green leader suggested that relying on independents would be unstable, Mr Martin has also argued that “too much fragmentation would lead to incoherence in government”. Reflecting on Tuesday night’s debate, the Fianna Fail leader said the race remained “too close to call” while Mr Harris said it is “all to play for”. The leaders of Ireland’s three main political parties clashed on housing, healthcare and financial management in the last televised debate before Friday’s General Election. The tetchy debate, which was marked by several interruptions, saw the parties set out their stalls in a broadcast that commentators said did little to move the dial before polling day. The latest opinion poll on Monday put the parties in a tight grouping, with Fianna Fail slightly ahead of Sinn Fein, and Fine Gael in a close third after a significant slide in a campaign marked with several hiccups for Mr Harris’s party. After the 2020 general election delivered an inconclusive result, Fine Gael and Fianna Fail, two parties forged from opposing sides of Ireland’s Civil War of the 1920s, agreed to set aside almost a century of animosity and share power – with the Greens as a junior partner. From 2016 to 2020, Fianna Fail had supported Fine Gael in power through a confidence-and-supply arrangement from the Opposition benches in the Dail parliament. Sinn Fein won the popular vote in 2020 but a failure to run enough candidates meant it did not secure sufficient seats in the Dail to give it a realistic chance of forming a government.Aston Villa had a stoppage-time goal disallowed as they drew 0-0 with Juventus in the Champions League. Morgan Rogers looked to have given Unai Emery’s side another famous win when he slammed a loose ball home at the death, but referee Jesus Gil Manzano ruled Diego Carlos to have fouled Juve goalkeeper Michele Di Gregorio and the goal was chalked off. It was a disappointment for Villa, who remain unbeaten at home in their debut Champions League campaign and are still in contention to qualify automatically for the last 16. A very controversial finish at Villa Park 😲 Morgan Rogers' late goal is ruled out for a foul on Juventus goalkeeper Michele Di Gregorio and the match ends 0-0 ❌ 📺 @tntsports & @discoveryplusUK pic.twitter.com/MyYL5Vdy3r — Football on TNT Sports (@footballontnt) November 27, 2024 Emiliano Martinez had earlier displayed why he was named the best goalkeeper in the world as his wonder save kept his side level in the second half. The Argentina international paraded his two Yashin Trophies on the pitch before kick-off at Villa Park and then showed why he won back-to-back FIFA awards when he denied Francisco Conceicao. Before Rogers’ moment of drama in the fourth minute of added time, the closest Villa came to scoring was in the first half when Lucas Digne’s free-kick hit the crossbar. But a draw was a fair result which leaves Villa out of the top eight on goal difference and Juventus down in 19th. Before the game Emery called Juventus one of the “best teams in the world, historically and now”, but this was an Italian side down to the bare bones. Only 14 outfield players made the trip from Turin, with striker Dusan Vlahovic among those who stayed behind. The opening 30 minutes were forgettable before the game opened up. Ollie Watkins, still chasing his first Champions League goal, had Villa’s first presentable chance as he lashed an effort straight at Di Gregorio. Matty Cash then had a vicious effort from the resulting corner which was blocked by Federico Gatti and started a counter-attack which ended in Juventus striker Timothy Weah. Villa came closest to breaking the deadlock at the end of the first half when Digne’s 20-yard free-kick clipped the top of the crossbar and went over. Martinez then produced his brilliant save just after the hour. A corner made its way through to the far post where Conceicao was primed to head in at the far post, but Martinez sprawled himself across goal to scoop the ball away. How has he kept that one out?! 🤯 Emi Martinez with an INCREDIBLE save to keep it goalless at Villa Park ⛔️ 📺 @tntsports & @discoveryplusUK pic.twitter.com/OkcWHB7YIk — Football on TNT Sports (@footballontnt) November 27, 2024 Replays showed most of the ball went over the line, but the Argentinian got there with millimetres to spare. At the other end another fine goal-line block denied John McGinn as Manuel Locatelli got his foot in the way with Di Gregorio beaten. The game looked to be petering out until a last-gasp free-kick saw Rogers slam home, but whistle-happy official Gil Manzano halted the celebrations by ruling the goal out.New $16 240W omnidirectional USB cable orients to your device not vise versa

NASA on Thursday announced another delay to its first crewed lunar mission since Apollo, with astronauts now set to fly around the moon in 2026 and land in 2027. The delay means the Artemis II — the next flight in NASA’s Artemis moon program that looks to return humans to the lunar surface for the first time in more than 50 years — will launch roughly 17 months after it was initially scheduled.

Menendez brothers’ fate hinges on the incoming Los Angeles district attorneyNiagara College’s research and innovation team has earned a consecutive No. 1 ranking for research funding among Canadian colleges. In a report released earlier this month, Research Infosource Inc. announced Canada’s top 50 research colleges based on total research funding numbers for 2023, with Niagara coming out with the top spot. It is the third time in five years Niagara College has been ranked No. 1 and the 10th year in a row it has been in the top 10. “It’s incredibly exciting and we’re very, very proud,” said president Sean Kennedy. “One of the things that is so important for us is always to ensure that we’re supporting the growth and development of local industry and at the same time supporting the growth and learning of all students — and No. 1 in Canada in applied research ranking really speaks to both of those.” In a media release, the college said it earned its ranking by attracting more than $40 million in research support to conduct innovative projects with industry partners in advanced manufacturing, business and commercializing, food and beverage, health, horticulture and the environment. Niagara finished second in the category of completed research projects at a mid-size college with a total of 178. The college also reached the top spot for industry research income, with more At a time when Ontario’s colleges are adjusting to financial challenges tied to government policy on international student enrolment and work-study permits, Kennedy said the top ranking plays a “substantial role” in creating opportunities for the college. “We have a very well-established brand and reputation that really showcases that students can come to Niagara College (and) have the opportunity to work with amazing faculty in amazing facilities,” he said. “They have the chance to be involved in applied research projects, so it really is a differentiator for us in terms of our brand and boosts our student recruitment efforts, and it’s one of the things that we’ll continue to build on. We have amazing momentum at Niagara College, and we want to continue to build on that in the years to come.” In the release, research infosource chief executive officer Ron Freedman said placing in the top spot for a second year in a row is an “impressive feat” and a “testament to the quality of work from their staff, students, faculty and researchers.” Lambton College secured the second spot in the national top 10 list, followed by Northern Alberta Institute of Technology, Southern Alberta Institute of Technology and Humber Polytechnic. Rounding out the list are Cégep de Trois-Rivières, Mohawk College, College of the North Atlantic, Cégep de La Pocatière and Lethbridge Polytechnic.

Photo booths have been around for almost a century, and yet these photo-capturing machines have been so slow in innovation that we still get cringy and unflattering pictures nowadays. However, one company has been trying to change that by offering photo booths with proprietary software designed to enhance not only the user experience, but also the quality of digital and print photos. MirMir — pronounced like "mirror, mirror" — is an on-demand professional photography company that offers rentable photo booths with image-enhancing software. The brand isn't exactly new, since it was founded by former fashion photographer Ryan Glenn and his friend Sean Spencer in 2013, but it's been getting a lot of attention lately due to its growing celebrity following. Before the newfangled business got famous, however, its co-founders decided to take a chance at winning an investor by appearing on "Shark Tank" Season 9 because they were struggling to grow the company. Interestingly, though Glenn and Spencer initially got what they wanted from their appearance on the show, it was not the promised investment that made MirMir what it is today. During their appearance on Season 9, Glenn and Spencer revealed that they only had nine machines, and each set them back $22,000. They had already invested as much as $250,000 in MirMir's operations, but it was not enough to help diversify its clientele and expand the business beyond New York and Los Angeles. Hence, they asked for $350,000 in exchange for a 10% stake in their company, according to Shark Tank Recap . Even though Glenn revealed that their revenue for the first three years crossed the $4 million mark, most of the Sharks were not sold on the idea. Mark Cuban and Daymond John passed on the deal because they believed it wouldn't last long in the industry, considering the rapid technological advancements in photography. Lori Greiner, on the other hand, thought it would be better for MirMir to stick to its premium market. Kevin O'Leary showed interest, but wanted to tweak the terms presented by the pair; offering the $350,000 as a loan and asking for an 18% interest in return, plus a 5% stake. Robert Herjavec — who recognized the brand since he had used the photo booth for his 2016 wedding to wife Kym Johnson — right away said he wanted 50% ownership. Glenn and Spencer responded that they could only cut a deal of 20% equity, prompting Herjavec to change his offer to $700,000 for a 20% stake. The pair took Herjavec's offer in the end. Sadly, the hugs and handshakes between the MirMir co-founders and Herjavec did not lead anywhere, since the deal fell through after taping the episode. There are no details on why this happened, but it's not uncommon for deals to collapse after filming. A Forbes survey even found that about 43% of business owners who appeared on the show did not see their deals materialize for several reasons, such as the Sharks asking for more changes to their terms after the show. Despite the setback, MirMir's owners did not seem to have any difficulty moving forward with their plans due to their brand's increased visibility and demand after its "Shark Tank" appearance. Aside from receiving endorsements from Hollywood's elite stars like the Kardashians, Taylor Swift, and Gigi Hadid, Glenn and Spencer found a partner in Eric Cusin — another businessman who pitched the Reviver on "Shark Tank" Season 6 . After its TV exposure, MirMir increased its number of machines and expanded its operations beyond the Big Apple and the City of Angels. The company branched out to Austin, Dallas, and San Francisco, and it also reached Canada — specifically in Toronto and Montreal — and other parts of the world, including London, Bangkok, and Tokyo. Such big development has thrust MirMir into a bigger spotlight in the photography market. It has been seven years since MirMir appeared on "Shark Tank," but it is not showing signs of slowing down in the booming photo booth rental industry. Per an IBISWorld analysis, the U.S. market for photo booth services alone is projected to generate approximately $101.4 million in total revenue in 2024. MirMir does not publicly disclose its financial performance, but some sources estimate its annual revenue at $24 million as of February 2023. Meanwhile, data analytics company Zoominfo places it at $16.2 million. MirMir has become a staple at high-profile events because Glenn and Spencer did not just tweak an existing model in the event photography market. They redefined it to cater to modern consumers, particularly Millennials and Gen Z. MirMir's proprietary software instantly retouches images to deliver flawless, high-quality snaps that can be printed on-site or shared directly to social media. The booth's professional-grade lighting, which utilizes strobe lights instead of LEDs, also helps achieve that picture-perfect look, explained Fortune . Compared to other typical photo booth companies, MirMir provides a human technician at every event to help users figure out the best positions they can pose to generate satisfying results. So no matter what package clients book — Classic, Wide, GIF, and Portrait — a service professional will be on-site to provide human assistance. It can be presumed that the human aspect of MirMir's photo booth is one of the reasons why clients keep returning. From here on out, MirMir is likely to achieve much more than what it did in the past seven years since its TV show appearance. It has already won the favor of technology giants like Microsoft, Amazon, and even Google, which reportedly bought some of its branded machines for office use. It has also become the go-to choice for photo booths at Coachella, the Academy Awards, the Emmys, and many more high-profile events. All of these the company achieved with very little marketing; word of mouth from its celebrity clients did all the work, according to Racked . Nevertheless, MirMir's success is not rooted solely in the influence of its popular customers. The company's products and services have been exceptional in quality from the get-go. Glenn and Spencer hired skilled software developers to create and improve the company's photo-editing software. Developments made through the years include post-capture effects, such as face-smoothing and blemish removal, among others. Sadly, Spencer will no longer be able to witness MirMir's progress from within the company since he appeared to have quietly left the firm in December 2018, according to his LinkedIn profile . He then ventured into working for AI-focused companies between 2019 and 2023 before landing a top position as chief marketing officer at his present employer, World Plus Inc. Glenn, however, has presumably remained with the company he co-founded, even though the reserved businessman has not updated his profile in years.WASHINGTON, D.C., Dec. 20, 2024 (GLOBE NEWSWIRE) -- Today, the Minority Business Development Agency (MBDA) released its Ways in Which Minority Business Enterprises (MBEs) Can Meet Gaps in the U.S. Supply Chain report. This report presents several avenues for MBEs to meet gaps in the U.S. supply chain and discusses opportunities to conduct, commission, and collaborate on new studies with other federal, state, and private institutions on this topic. This report offers a data-driven snapshot of the MBE supplier landscape, analyzing representation of MBE firms in both manufacturing industries and the service industries that support manufacturing. The data shows there is room to grow representation of MBEs, particularly in manufacturing. MBE firms comprise about 22 percent of the service sector firms support manufacturing but represent only about 10 percent of manufacturing firms. As a comparison, MBEs comprise about 20 percent of all employer firms. The report identifies barriers present in supply chains for MBE participation; and the ways in which policy makers, technical assistance providers, and large corporations can utilize MBEs to advance the U.S. supply chain. “MBDA has embarked on a new chapter of our long and proud history to serve and support MBEs,” said Deputy Under Secretary of Minority Business Development Eric Morrissette . “The Minority Business Development Act of 2021 empowered our agency to work toward equity among U.S. firms and strengthen our national economy, and we are forever committed to that mission. Together with public and private sector partners, we will continue to address capital access disparities and highlight sources of alternative financing while closing gaps in the U.S. supply chain.” The report highlights many public and private initiatives directed toward promoting the success of MBEs in supply chain industries and breaking down barriers. Increasing MBE participation in advanced technologies and manufacturing relies on a range of initiatives to ensure MBEs can develop the capacities and skills needed to compete in rapidly changing markets. The report recommends four potential opportunities through which MBEs can help close supply chain gaps through policy and business plan changes: Leverage the Large Number of MBEs in High-Tech Manufacturing Support Services: Assist MBEs to Access Opportunities as Part of the Growth Spurred by Federal Investments, Including the CHIPS Act. Fostering Inclusive Entrepreneurship In Manufacturing: Promote Talent Pools of Entrepreneurship; and Support Training Programs and Expand Innovation Incentives. Expand Corporate Supply Chain Diversity: Expand and Strengthen Procurement Programs,; Build Corporate-MBE Supplier Relationships; and Ensure Stable Cashflow for MBEs. Provide Support to MBEs in Manufacturing: Leverage Business Centers and Networks; Develop Initiatives Helping MBEs Grow in Scale and Size; Foster Networks and Partnerships; and Encourage Community Engagement. Other suggestions made in the report include addressing unique challenges by MBE demographic groups and expanding qualitative data gathering to learn about the needs of MBEs in manufacturing. This report was mandated under the Minority Business Development Act of 2021. The Act codified MBDA and many of its existing programs. The report, and details of its findings, can be reviewed at www.mbda.gov . About the Minority Business Development Agency (MBDA): The U.S. Department of Commerce, Minority Business Development Agency is the only Federal agency dedicated to the growth and global competitiveness of U.S. minority business enterprises (MBEs). For more than 50 years, MBDA’s programs and services have better equipped MBEs to create jobs, build scale and capacity, increase revenues, and expand regionally, nationally, and internationally. ### Attachment 2024 MBDA Supply Chain Report Press Release