Exercise, fasting help cells shed defective proteins

first_imgIt is already well known that exercise has many salutary effects, but the researchers said the new findings hint at the possibility that exercise and fasting could also help reduce the risk of developing conditions associated with the accumulation of misfolded proteins, such as Alzheimer’s and Parkinson’s. That possibility, however, remains to be explored, the team noted.In their experiments, the researchers analyzed the effects of exercise on cells obtained from the thigh muscles of four human volunteers before and after vigorous biking. Following exercise, the proteasomes of these cells showed dramatically more molecular marks of enhanced protein degradation, including greater levels of cAMP. The same changes were observed in the muscles of anesthetized rats whose hind legs were stimulated to contract repeatedly.Fasting — even for brief periods — produced a similar effect on the cells’ protein-breakdown machinery. Fasting increased proteasome activity in the muscle and liver cells of mice deprived of food for 12 hours, the equivalent of an overnight fast.In another round of experiments, the researchers exposed the liver cells of mice to glucago, the hormone that stimulates production of glucose as fuel for cells and tissues during periods of food deprivation or whenever blood sugar levels drop. The researchers observed that glucagon exposure stimulated proteasome activity and enhanced the cells’ capacity to destroy misfolded proteins.Exposure to the fight-or-flight hormone epinephrine produced a similar effect. Epinephrine, also known as adrenaline, is responsible for stimulating the liver and muscle to mobilize energy reserves to boost heart rate and muscle strength during periods of physiologic stress. Liver cells treated with epinephrine showed marked increases in cAMP, as well as enhanced 26S proteasome activity and protein degradation. Epinephrine exposure also boosted proteasome activity — a marker of protein degradation — in the hearts of living rats. Similarly, when researchers exposed mouse kidney cells to vasopressin — the antidiuretic hormone that helps the body retain water and prevents dehydration — they observed higher levels of protein degradation as well.Taken together, these findings demonstrate that the rate of protein degradation can rise and fall swiftly in a variety of tissues in response to shifting conditions, and that such changes are mediated by fluctuations in hormone levels. This response was surprisingly rapid and short-lived, the scientists noted. For example, exposure to the antidiuretic hormone triggered protein breakdown in kidney cells within five minutes and subsided to pre-exposure levels within an hour, the experiments showed. The findings show that the diverse set of hormones that stimulate cAMP appear to share a common mechanism that alters the composition of cells. These have long been known to modify gene expression, but this latest research reveals they also play a critical role in cellular housecleaning by disposing of proteins that are no longer needed.A new twist on a classic conceptThe new findings build on observations about the physiologic effects of hormones first made by HMS physician Walter Cannon nearly a century ago and elegantly captured in his book “The Wisdom of the Body” (1932). Some of Cannon’s most notable work includes defining the mechanism of action of epinephrine and its role in the fight-or-flight response. Epinephrine is one of the hormones whose action on the protein-disposal machinery is now illuminated by Goldberg’s latest work. In a symbolic coincidence, Goldberg’s lab occupies the very space where Cannon made his observations on the same hormone a hundred years ago.“We think ours is truly a neoclassical discovery that builds on findings and observations made right here, in this very building, nearly a century ago,” Goldberg said.Study co-investigators included Jinghui Zhao and Sudarsanareddy Lokireddy, who is no longer at Harvard.The research was made possible through tissue samples provided by colleagues in Houston, Copenhagen, and Sydney.The work was supported by grants from the National Institutes of Health’s National Institute of General Medical Sciences under grants R01 GM051923-20 and F32 GM128322, the Cure Alzheimer’s Fund, the Muscular Dystrophy Association (MDA-419143), Genentech, and Project ALS. The body’s ability to adapt to changing conditions and shifting physiologic demands is essential to its survival. To ensure cellular performance and the health of the entire organism, each cell must be able to dispose of damaged or unnecessary proteins.Now, a study from the Blavatnik Institute at Harvard Medical School (HMS) shows that intense exercise, fasting, and an array of hormones can activate cells’ built-in protein-disposal systems and enhance their ability to purge defective, toxic, or unneeded proteins.The findings, published Feb. 19 in PNAS, reveal a previously unknown mechanism that is triggered by fluctuations in hormone levels, which signal changes in physiologic conditions.“Our findings show that the body has a built-in mechanism for cranking up the molecular machinery responsible for waste-protein removal that is so critical for the cells’ ability to adapt to new conditions,” said Alfred Goldberg, senior author on the study and professor of cell biology at the Blavatnik Institute.Cellular housecleaning in disease and healthMalfunctions in the cells’ protein-disposal machinery can lead to the accumulation of misfolded proteins, which clog up the cell, interfere with its functions, and, over time, precipitate the development of diseases, including neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer’s.The best-studied biochemical system used by cells to remove junk proteins is the ubiquitin-proteasome pathway. It involves tagging defective or unneeded proteins with ubiquitin molecules — a process known as the “kiss of death” — marking them for destruction by the cell’s protein-disposal unit, known as 26S proteasome. Finding our genomic clockwork Harvard researchers discover a biomarker that can determine both chronological and biological age In pursuit of healthy aging The Daily Gazette Sign up for daily emails to get the latest Harvard news. Harvard study shows how intermittent fasting and manipulating mitochondrial networks may increase lifespan Past research by Goldberg’s lab has shown that this machinery can be activated by pharmacological agents that boost the levels of a molecule known as cAMP, the chemical trigger that initiates the cascade leading to protein degradation inside cells, which in turn switches on the enzyme protein kinase A. The lab’s previous research found that cAMP-stimulating drugs enhanced the destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative conditions.The new findings, however, reveal that shifts in physiological states and corresponding changes in hormones can regulate this quality-control process independent of drugs. Goldberg’s lab previously focused on reining in overactive protein breakdown — excessive protein removal that can cause muscle wasting in cancer patients or give rise to several types of muscle atrophy. In fact, a proteasome inhibitor drug Goldberg and his team developed to tamp down protein-disposal activity has been widely used to treat multiple myeloma, a common blood cancer marked by abnormal protein accumulation and overworked proteasomes.The team’s latest work, by contrast, is focused on developing therapies that do just the opposite — invigorate the cell’s protein-disposal machinery when it is too sluggish. These newest findings open the door, at least conceptually, to precisely such treatments.“We believe our findings set the stage for the development of therapies that harness the cells’ natural ability to dispose of proteins and thus enhance the removal of toxic proteins that cause disease,” said study’s lead investigator, Jordan VerPlank, a postdoctoral research fellow in cell biology at the Blavatnik Institute. Such treatments may not necessarily involve the design of new molecules, but instead stimulate the cell’s built-in capacity for quality control.“This is truly a new way of looking at whether we can turn up the cellular vacuum cleaner,” Goldberg said. “We thought this would require the development of new types of molecules, but we hadn’t truly appreciated that our cells continually activate this process.“The beauty and the surprise of it is that such new treatments may involve churning a natural endogenous pathway and harnessing the body’s pre-existing capacity to perform quality control,” he said. Relatedlast_img read more

Crash on 421 ends in one fatality

first_imgVersailles, IN—Friday afternoon, at approximately 3:30 pm an Indiana State Police responded to a report on an injury crash involving two vehicles on US 421 south of County Road 1050 South in Ripley County.Troopers arrived to find a 2016 Kia Soul and a 2019 Mitsubishi Mirage in the east ditch of US 421.  The preliminary investigation shows that the Kia Soul, driven by Shannon Hubbard, was traveling southbound and was attempting to pass another vehicle.   The Mitsubishi Mirage, driven by Henry Finney of Madison, was traveling northbound and could not avoid a collision with the Kia Soul, which was in the northbound lane.Finney was transported by ambulance, to King’s Daughters’ Hospital in Madison where he passed away from his injuries.  Hubbard was also transported by ambulance, to King’s Daughters’ Hospital and then transported by lifeline helicopter, to The University of Cincinnati Hospital.  Ms. Hubbard was in serious but stable condition.It is believed that both drivers were wearing their seatbelts.  Drugs and or alcohol are not believed to be a contributing factor to the crash.  Improper passing and traveling at a high rate of speed are believed to be contributing factors to the crash.last_img read more

Wisconsin endeavors to build off strong 2005 finish

first_imgDEREK MONTGOMERY/Herald photoAfter a cold winter, spring is usually the season of new beginnings, a time to shake off those winter blues and wipe the slate clean. The women’s soccer team on the other hand isn’t looking toward a new beginning.After struggling during the Big Ten regular season in 2005, the women’s soccer team dominated the competition during the last month of the season, in which they won seven consecutive games and won their first Big Ten tournament title since 1994. Although some key personnel are missing from last year’s team, the lady Badgers are poised to make a run deep into the postseason in the upcoming fall.The key thing for Wisconsin in the 2006 season is replacing the four seniors that were instrumental to their success last season. Forwards Marisa Brown, Katy Lindenmuth and Amy Vermeulen comprised 66 of Wisconsin’s 137 points last season. Additionally, Wisconsin lost first team Academic All-American Jessica Ring, who anchored a Badger defense that gave up only 31 goals last season.With most of the scoring gone from last season, Wisconsin is looking toward senior captain Kara Kabellis. Named to the All-Big Ten first team, Kabellis hopes to surpass the numbers she put up last season, scoring seven goals and six assists in Wisconsin’s 24 games. Looking to help take some of the scoring load off Kabellis will be sophomores Taylor Walsh and Elise Weber. Both Walsh and Weber highlighted an outstanding freshmen recruiting class for the Badgers, with both of them playing in every game for the Badgers last season and combining for eight goals.Wisconsin head coach Dean Duerst maintains that the Badgers will be just as potent on offense this season, with the addition of nine red-shirt freshmen competing for playing time.”We’re going to have no problem scoring goals this year,” Duerst said. “We have Weber, Walsh, Kabellis and players like Lindsay Walker and Shannon Terry, who didn’t play a lot of minutes last year but still are dangerous players. We have the personnel to score goals.”In addition to the red-shirt freshman competing for playing time, Wisconsin ushers in a balanced 2006 recruiting class that includes three midfielders, one forward and one goaltender. Out of the five recruits, Ashley Hedges shows the most potential of seeing a lot of time on the field. Hailing from Carmel, Calif., Hedges led Carmel High School to three state championships, in addition to being named twice to the all-state and all-district teams in California. With all this firepower coming in next season, there figures to be a real battle for playing time at the start of the season.”Everybody asks if you see anybody in your recruiting class being able to come right in and play and I think every year is that you just don’t know,” Duerst said. “I think the recruits are really going to help challenge a lot of players … The last [few] recruiting classes have played very good together, where you had multiple players at different positions and that’s what we have with this latest class.”The most interesting battle to watch going into the season will be which goalie Wisconsin decides to use. Junior Lynn Murray saw the majority of action in 2005, playing in 22 games for the Badgers, winning 13, and allowing only 1.11 goals per game. Murray also registered five shutouts and was named the Big Ten’s defensive player of the week in October.On the other hand, senior captain Stefani Szczechowski has proven that she is a capable goalie over her three seasons at Wisconsin. After getting the majority of playing time in her first season, Szczechowski time in goal has varied. She saw action in only seven games last season, but showed a strong defensive presence in the net, allowing only seven goals while notching 10 saves during her time in the net. Although it is feasible to have the two goalies play on a rotational basis, the Wisconsin coaching staff looks to try and avoid that a pick a number one goalie.”As Lynn and Steph are here together, they have always been battling and competing for time and it’s been that way since Lynn has come on board,” Duerst said. “Steph knows what is in front of her. They both have experience and they both will continue to have experience with our backs. You want to keep things competitive but ultimately, coaches and the team want to stick with a number one goalie who has risen to be that number one.”Through three games this spring so far, Wisconsin appears equally as powerful offensively and defensively as they did last season. In their recent match against UWM, Wisconsin got goals from Kabellis and assistant captain Allison Preiss, while the youthful defense didn’t allow a score in the Badgers’ victory.That said, Duerst looks to use this time to try different things on both sides of the ball to give Wisconsin that extra kick it was sometimes missing in games last season.”In essence, spring season is the molding for your year and the beginnings of that mold and what we need in order to play,” Duerst said. “I think what we are really looking at, and the players understand that, is an extension of last year’s play and try to get everything more connected. As coaches, we really have to teach more in the spring because we have more time and that has been a real value so far.”last_img read more

SNAI ups digital marketing & acquisition capabilities with Betgenius

first_imgShare Betgenius: Spare change… how will the increase to five subs affect football trading? June 4, 2020 Share StumbleUpon Related Articles Fabio SchiavolinItalian gambling operator Gruppo SNAI (SNAI) will push its 2017 digital marketing campaigns utilising Betgenius data and player engagement services as the firm looks to increase player acquisition capabilities of its online sportsbook Snai.it.Following an industry review, Betgenius has been selected as SNAI online sportsbook partner to help accelerate player acquisition and growth through a multi-faceted digital marketing campaign.Jack Davison, Managing Director at Betgenius, said: “We are extremely proud to have been chosen by Snai to drive the growth of its online sportsbook. Our proven track record in harnessing unique, data-driven solutions will enable us to attract new customers while maximising their turnover.”The partnership will see Betgenius integrate its unique Betslip Retargeting technology, enabling Snai to track their customers’ unconfirmed betslips and serve up relevant offers, even when they have left the bookmaker’s site.Use of Betgenius’ ‘Popular Bets’ tool is also included in the agreement, while dynamic in-play and video banners will serve up relevant content to customers.Fabio Schiavolin, CEO of SNAI, commented on the marketing partnership: “Our partnership with Betgenius continues to be very important to the growth of our sportsbook, enabling us to deploy a test and learn approach on new creative and acquisition strategies. We truly believe this will lead to consistent and successful campaigns and look forward to even more success with Betgenius in the future.” Betgenius expands virtual sports range with Kiron August 20, 2020 Betgenius: The sound of silence… What impact does an empty stadium have on trading? May 26, 2020 Submitlast_img read more

Take a Look at Thousands of B&H Fans occupied the Main Square (gallery)

first_img(Source: nap.ba) [wzslider autoplay=”true”]Between 15,000 and 20,000 B&H fans cheered for the Dragons last night at the “King Baudouin” stadium in Brussels.Large number of fans of our national team arrived in Brussels. Flags and B&H songs were everywhere. Belgians looked around, confused by happy fans who were preparing for last night’s match between Belgium and B&H, which was played within the qualifiers for the European Championship in France.Fans gathered at the main square in Brussels at 2 p.m., from where they went to the “King Baudouin” stadium at 5 p.m.Atmosphere in the dressing room of Dragons was good as well. Head coach of our national football team, Mehmed Baždarević, stated at the press conference that was held couple of days ago in in Brussels, that Belgium has very quality team, but B&H also has a chance to get a good result in the match.Back then, the coach of the Dragons stated that Džeko and the team will not calculate and go for one point, but they will be brave and play for victory.last_img read more