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Martinez-Ruiz A.,Hospital Universitario Of La Princesa | Araujo I.M.,Regenerative Medicine Program | Araujo I.M.,IBB Institute for Biotechnology And Bioengineering | Izquierdo-Alvarez A.,Hospital Universitario Of La Princesa | And 2 more authors.
Antioxidants and Redox Signaling | Year: 2013

Significance: Nitric oxide (NO) classical and less classical signaling mechanisms (through interaction with soluble guanylate cyclase and cytochrome c oxidase, respectively) operate through direct binding of NO to protein metal centers, and rely on diffusibility of the NO molecule. S-Nitrosylation, a covalent post-translational modification of protein cysteines, has emerged as a paradigm of nonclassical NO signaling. Recent Advances: Several nonenzymatic mechanisms for S-nitrosylation formation and destruction have been described. Enzymatic mechanisms for transnitrosylation and denitrosylation have been also studied as regulators of the modification of specific subsets of proteins. The advancement of modification-specific proteomic methodologies has allowed progress in the study of diverse S-nitrosoproteomes, raising clues and questions about the parameters for determining the protein specificity of the modification. Critical Issues: We propose that S-nitrosylation is mainly a short-range mechanism of NO signaling, exerted in a relatively limited range of action around the NO sources, and tightly related to the very controlled regulation of subcellular localization of nitric oxide synthases. We review the nonenzymatic and enzymatic mechanisms that support this concept, as well as physiological examples of mammalian systems that illustrate well the precise compartmentalization of S-nitrosylation. Future Directions: Individual and proteomic studies of protein S-nitrosylation-based signaling should take into account the subcellular localization in order to gain further insight into the functional role of this modification in (patho)physiological settings. Antioxid. Redox Signal. 19, 1220-1235. © Mary Ann Liebert, Inc. Source

News Article | April 7, 2016
Site: http://motherboard.vice.com/

Canada’s Liberal government rode to power with a loud-and-clear message that it would support this country’s scientists, who felt neglected and even outright antagonized under the previous government of Stephen Harper. But, six months later, many of Canada’s young scientists say they might have to shut down their labs, abandon their research, and even leave the country for greener pastures, because of what they see as a crisis within the government’s own funding arm—a crisis that predates the Liberals, but has continued under them. According to these young researchers, a major overhaul undertaken in the past few years at the Canadian Institutes of Health Research, or CIHR, which funds health and biomedical research, has shut them out of the funding that’s critical to keep labs running. These changes, they believe, have stacked the deck against them in favour of older, more established researchers, who are perhaps seen as a safer bet after years of chronic underfunding at CIHR. “It’s potentially a career-killer,” said Michael Hendricks, a biologist at McGill University in Montreal, who studies the nervous system of roundworms. He warns that his generation of scientists is “falling to the wayside.” In March, Hendricks wrote an open letter calling the situation a “crisis” for early career investigators like himself, typically assistant professors at research universities and hospitals who’ve been in their jobs five years or less. Hendricks’ letter has over 100 signatures, which is remarkable given that many young scientists are still reluctant to speak out publicly, worrying it could jeopardize their chance at funding, and therefore their careers. The next round of applications for CIHR funding is now underway. Thousands have applied for grants, and will learn if they succeeded on July 15. With funding up in the air, some were concerned that speaking to Motherboard could hurt their chances for funding or "anger" the community, so they spoke off the record, or indicated they just didn’t feel comfortable talking at all right now. Even so, Motherboard heard from several who did want to speak about their experiences. A handful of Canada’s leading scientists, who are among the most well-established in the country—and could actually benefit from changes at CIHR—are also speaking out. “I’ve never seen this before. Such alienation across an entire community,” stem cell researcher Michael Rudnicki, director of the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Health Research Institute, told me. “People are angry. They’re fearful. And they have lost trust in CIHR in a way that is unprecedented.” In the Liberal budget, released on March 22, CIHR got some good news: an extra $30 million per year. (Its forecast spending for the 2015-16 fiscal year is about $1 billion.) But the boost wasn’t enough to make up for a budget that’s flatlined for a long time. “A lot of the scientific community has been asking for a $150 million increase,” Hendricks said. “That would just correct for inflation since 2009.” Over the past few years, CIHR started to overhaul the way it funds research. Starting in 2015, the agency moved about 45 percent of of its grant money into something called the Foundation Scheme, which is aimed at supporting prestigious, long-running projects. The rest went to the Project Scheme, which is designed to support work on “ideas” from scientists at all levels. (About half of CIHR's total budget is allocated to the Project and Foundation grant programs, according to the agency.) Underfunding was the backdrop against which these changes were made, but, according to Peggy Borbey, director-general of investigator initiated research at CIHR, it was not the reason for them. They sprang from “concerns from the community,” she told Motherboard. The intention was to streamline the process, and make it more “efficient.” To make sure that early career investigators weren’t at a disadvantage, a quota was put in place: they were supposed to get 15 percent of all Foundation grants. But they got just five percent of the money. According to CIHR, that’s partly because early career investigators qualify for five-year grants, whereas more established ones can get funded for seven years. “CIHR decided, let’s put money in the most senior and experienced researchers. That does make sense,” Hendricks said. “Canada has fantastic senior-level scientists. But the reason is that [early in their careers], they had access to stable funding.” Given the current uncertainties faced by up-and-comers, “you won’t have that in the future.” What happened next wasn’t surprising. Because so many people couldn’t get Foundation Scheme grants, and because two other competitions were cancelled to accommodate its launch, there was a stampede towards Project Scheme, which just launched this year. About 3,800 applied in the current round, according to CIHR. According to Jim Woodgett, director of research at the Lunenfeld-Tanenbaum Research Institute at Toronto’s Mount Sinai Hospital, the average prior to these reforms was about 2,400 applications per competition. Nobody's sure how many will get funded, because it will depend on how much money’s requested by each successful application. But even if early career investigators do decently well in the competition, Hendricks predicts that CIHR’s overall support for this group will drop from $90 million per year, to $60 million. With so many applying, “it’s like playing the lottery,” Marlene Oeffinger, who is based at the Institut de recherches cliniques de Montréal, told Motherboard. “I have three grants in the competition, because it increases my odds.” “Because funding is so uncertain at this point, there’s no way we can plan ahead,” agreed Daniel Zenklusen at the Université de Montréal, who is Oeffinger’s husband. The couple, who are originally from Austria and Switzerland, left New York to set up in Montreal in 2009, thinking that Canada would be a good place to establish their careers. Now Oeffinger faces the prospect of closing her lab, and Zenklusen will have to let go of members of his staff, losing the expertise they’ve built as a team. At times, the couple wonders if they made a mistake setting up here. They aren’t alone. In March, an informal survey of early career investigators across the country found that 47 per cent of respondents were considering leaving Canada. In the survey, which asked open-ended questions to collect personal accounts from people who might not want to talk in the open, one anonymous respondent wrote: “If I am not able to obtain funding by Sept. 2016, I will be forced to give up my dream of doing independent research...I will close my lab, fire my students, sell my house and return to the US to look for a job wherever I can find one.” Motherboard reached out to both Kirsty Duncan, the Minister of Science, and Jane Philpott, the Minister of Health. While neither minister was available for an interview, their spokespeople did email statements. “With the change of government, there has also been a change of focus, and a new emphasis on science and scientists,” Philpott said, acknowledging that CIHR has suffered from “significant funding gaps.” “We will be looking at how we can increase the impact of our support,” she wrote. Duncan’s office pointed out that the current government has invested an additional $95 million per year to the granting councils, which include CIHR, “the highest amount of new annual funding for discovery research in more than a decade.” Calls for change are getting louder. The heads of Canada’s 15 largest research universities recently sent a letter to CIHR, calling for a moratorium on any more changes until an independent review is held, according to Postmedia, which obtained the letter. (None of the university presidents contacted by Motherboard, nor the group that represents them and issued the letter, would speak on the record.) “We understand these changes have been extremely challenging,” Borbey acknowledged. She expressed sympathy for researchers who are stressed about funding, “particularly early career investigators trying to establish careers. The old system existed for a very long time.” Maybe so. But Canada’s young scientists don’t have time to deal with a funding agency’s inner turmoil or growing pains. The first five years of a career are critical, and there’s no option for a do-over. That’s when a scientist starts up her lab, builds momentum in her research, and might be evaluated for tenure. It’s also a time when a scientist is likely to be most creative, and to make the breakthroughs that will go on to define her career. “Science is difficult to adjudicate, because it’s about promises to the future,” Woodgett told me. One of Canada's star scientists, Woodgett received a lucrative, multi-year Foundation award from CIHR, but he’s still been very vocal about this. “The most important [role] of a funding agency is to ensure it’s paying for the very best science,” Woodgett continued. “We’ve gotten to a stage where we can’t say we are funding the best science.” CORRECTION: An earlier version of this piece reported that support for early career investigators would drop from $90 million, to $30 million. In fact, it drops to $60 million, and the piece has been corrected to reflect this. In addition, CIHR spends roughly $500 million on the Foundation and Project Schemes, a fact that has been added to the piece. Marlene Oeffinger's affiliation was initially listed as McGill University. While she does indeed have a lab there, her primary affiliation is with Institut de recherches cliniques de Montréal, and the piece has been updated to reflect this. UPDATE: On April 14, CIHR announced it was taking action on this issue. Read our update here.

Ferreira B.I.,Regenerative Medicine Program | Hill R.,Regenerative Medicine Program | Hill R.,University of Algarve | Hill R.,University of Portsmouth | And 2 more authors.
Cancer Journal (United States) | Year: 2015

All drugs have molecular targets; however, this does not mean that they are targeted therapeutics. Only by the interaction with a disease-specific molecule can the drug be classified as a targeted therapeutic. This is often not clearly defined and might refer to several different therapeutic modalities such as genomically targeted therapy, immune checkpoint therapy, or pharmacokinetic targeting. To develop a precise concept of targeted therapy, it is crucial to understand how drugs were discovered and how our rapidly expanding knowledge concerning disease mechanism is driving a fundamental conceptual change in modern drug discovery and development. In combination with the increasingly detailed analysis of disease at an individual patient level, we believe that it is very timely to consider the past and current approaches involved in the development of new medicines and to discuss the paradigm shift in and basic concepts associated with targeted therapies and personalized medicine. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

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