Muniswamy Madesh, Ph.D., Professor in the Center for Translational Medicine and the Department of Medical Genetics and Molecular Biochemistry at the Lewis Katz School of Medicine at Temple University. Credit: Lewis Katz School of Medicine at Temple University Inside almost every cell in the human body, tiny mitochondria are continuously generating energy to power countless cellular activities. That process of energy generation also happens to be closely tied to intracellular calcium regulation by a membrane gateway inside mitochondria known as the mitochondrial Ca2+ uniporter (MCU), which has critical roles in both bioenergetics and cell death. How MCU regulates calcium uptake has been unclear, but the recent structural discovery of a key MCU domain by scientists at the Lewis Katz School of Medicine at Temple University points toward the involvement of not one, but two ions - calcium and magnesium - opening new paths to the development of MCU-modulating agents for the treatment of diseases involving mitochondrial dysfunction. "Calcium is a key regulator of energy production in mitochondria, but too much of it can trigger cell death," explained senior investigator on the study, Muniswamy Madesh, PhD, Professor in the Center for Translational Medicine and the Department of Medical Genetics and Molecular Biochemistry at the Lewis Katz School of Medicine (LKSOM) at Temple University. Dr. Madesh and colleagues are the first to solve the crystal structure of the MCU N-terminal domain, which they detail in an article published online August 25, by the journal Cell Chemical Biology. Mitochondrial calcium regulation can set in motion signaling pathways that control cytosolic calcium levels, as well as pathways that influence cell death and energy production and expenditure. Hence, MCU activity is vital to calcium homeostasis and cell survival. "But if the pore fails to close," Dr. Madesh explained, "mitochondria retain the energy they synthesize in the form of ATP. The resulting accumulation of oxidants and calcium overload lead to mitochondrial swelling and cell stress." Such abnormalities in mitochondrial function occur in a variety of diseases, including cardiovascular diseases, such as stroke and heart attack, and certain neurological conditions such as Parkinson's and Alzheimer's diseases. As a result, insight into MCU structure could help researchers find ways to modulate the gateway's activity and potentially restore its function in disease states. In the new study, Dr. Madesh and colleagues describe the atomic structure of the MCU N-terminal domain and report the discovery of a "grasp" region of the domain dedicated specifically to the binding of calcium and magnesium ions. They found that interaction of the ions with the region destabilizes the MCU channel, causing the gateway to close. In experiments in human cells, mutations introduced into the grasp region disrupted MCU assembly and greatly attenuated mitochondrial calcium uptake through the channel. The researchers further discovered that MCU activity could be blocked both by bathing mitochondria in magnesium and by preventing mitochondrial calcium displacement. The discovery supports previous studies, suggesting that MCU is autoregulated via a mechanism involving either calcium-dependent inactivation or magnesium-induced inhibition. According to Dr. Madesh, the new structural and mechanistic insights from his team's study help fill in gaps in scientists' understanding of the role of MCU in controlling mitochondrial calcium uptake. The new findings also have important implications for the understanding of diseases involving mitochondrial dysfunction. "In identifying a region of MCU that directly controls its activity, we have created a framework for modulating MCU function through the development of a small molecule," Dr. Madesh said. Explore further: Researchers identifie gatekeeper protein, new details on cell's power source
Burgazli K.M.,Tal Medical
European review for medical and pharmacological sciences | Year: 2013
Coronary artery aneurysms are rare entities with a prevalence of 0.15%-4.9%. Giant coronary artery aneurysms are known as more than 2 to 5 cm in size. We present a case of 74 year-old female who was admitted to our clinic with chest pain and dyspnea. Coronary angiography demonstrated a giant right coronary artery (RCA) aneurysm with a significant left-to-right shunt. The patient underwent an open heart surgery. During the exploration, an aneurysm of 40 mm in diameter of the RCA was seen. The aneurysmatic RCA was excluded and continuously closed with the support of intra-aortic balloon pump (IABP). The patient was discharged on the 13th postoperative day without any complication.
News Article | May 26, 2015
To Back Startups, PureTech Heads Across the Pond For $160M London IPO PureTech got the financial support of a big U.K. investment manager last year. Now the Boston firm wants the backing of a whole other group of London investors too. PureTech, the creator of a slew of local startups at the nexus of healthcare and technology, this morning filed papers to go public in England. It’s aiming to hold an IPO on the London Stock Exchange, selling at least 25 percent of its outstanding shares in a bid to push forward its various nascent companies—startups like Tal Medical (developing an anti-depression device) and Akili Interactive (therapeutic/diagnostic video games). PureTech expects to raise $160 million in the IPO, and complete the offering in June. PureTech declined to comment on its rationale this morning, citing regulatory restrictions that bar the firm from talking to U.S. reporters. But co-founder and CEO Daphne Zohar (pictured above) said in a few international reports that PureTech chose London over the U.S. stock exchanges because “investors understand [PureTech’s] model,” and because the U.K. “leads the world in the listed technology-transfer space.” Zohar is referring to PureTech’s place in a gray area of startup creation. Though PureTech was originally called PureTech Ventures and births new companies, it isn’t a venture firm, and doesn’t raise the massive funds that VCs generally raise. Instead, it’s structured as a large healthcare operating company with the budget to support itself and the startups it seeds, which function as subsidiaries. It also doesn’t have to think about quickly flipping those companies to get a return, which is why, outside of a recent attempt by weight loss startup Gelesis in the U.S., it doesn’t tend to take its startups public. These ventures are designed to be long-term, revenue-generating holdings that appreciate in value. (None of PureTech’s companies sell products as of yet, though it has generated revenue via partnerships and deals secured by companies like Mersana Therapeutics and Vedanta Biosciences.) PureTech said as much in its London IPO filing; it noted that its goal is to advance its companies to the point that they sell their own products, though it expects “key milestones” might enable those startups to look at some other approaches, like licensing deals or potentially even public offerings of their own. “PureTech is particularly focused on pursuing development paths that enable those companies to partner directly with industry leaders at the right stage and minimize dilutive sources of capital while retaining control over the strategic direction of the business,” the company said in its filing. According to the London filing, PureTech has raised about $250 million in financing since its inception. Late last year, it brought in Invesco Perpetual, a firm with $120 billion under management, as a new investor in a $55 million round. Zohar said in the filing that the cash would bring PureTech’s “most advanced product candidates to revenues.” “With the acceleration of scientific discovery and the convergence of new and disruptive technologies being applied to life sciences, we believe the healthcare industry is on the cusp of a major transformation,” she wrote. “This is an opportune time to leverage PureTech’s expertise in translating science into impactful solutions, to change how we address healthcare problems.” As I wrote last year, PureTech’s strategy has evolved over the years, from building more traditional life sciences companies to launching inter-disciplinary startups that combine various elements of science and technology. Most recently, for instance, PureTech created The Sync Project, a company exploring music-as-therapy techniques. PureTech currently has a portfolio of 12 such companies, of which it owns an average of some 76 percent. The firm has 10 other “concept phase” initiatives that could become future startups as well, filings show. The firm has several big names in its ranks, among them: former Sanofi CEO Chris Viehbacher (an independent non-executive director); MIT professor and Nobel laureate Robert Horvitz (a board observer and the chair of its scientific advisory board); MIT media labs director Joi Ito (chairman); former Pfizer executive John LaMattina (independent non-executive director); and MIT professor and startup creator Bob Langer (also a non-executive director).
News Article | June 24, 2015
Co-founded by entrepreneur Daphne Zohar and MIT professor Robert S. Langer, it may be one of the most difficult businesses to describe in Greater Boston’s booming life sciences cluster. Now it’s raising eyebrows worldwide with a trans-Atlantic IPO. Part venture capital firm, part biomedical incubator, PureTech calls itself a “science-driven health care company.” It has spawned and bankrolled about a dozen startups — among them microbiomics pioneer Vedanta Biosciences and depression-fighting Tal Medical — many of them small research operations based at the PureTech’s offices in Boston’s Back Bay. Fourteen-year-old PureTech, which raised $50 million in a venture round last year, just pulled off another coup by raising $171 million in an initial public offering and going public on the London Stock Exchange. Zohar declined to say why PureTech opted for a London listing, citing a regulator-imposed quiet period. The newly public company has a star-studded board, including ex-Sanofi chief executive Christopher A. Viehbacher, tech entrepreneur and MIT media lab director Joi Ito, and Marjorie Scardino, the former chief executive of publisher Pearson. Puretech Health plc went public at 160 pounds a share, and ended trading Monday at 180.50 pounds — a gain of 13 percent. Rob Weisman covers life sciences and healthcare for the Boston Globe. Email him at firstname.lastname@example.org. Follow Robert on Twitter
News Article | April 24, 2015
After an off-the-charts year in investment for 2014, the Minnesota bioscience industry has seen a more typical 1st quarter, according to a report from medtech lobby LifeScience Alley. Officials with the Minneapolis-based trade association said yesterday that the 1st quarter of 2015 saw $41 million in total investments in the North Star state. Most of that investment went to the medical device field, always a strong industry in the state. In Q1, 57% of the companies raising money were from the medical device field, and 87% of the total funding came in that area. Read more Tal Medical said today that it landed a $14 million Series B round it plans to use in backing clinical trials for its low-field magnetic stimulation technology as a non-invasive neurostimulation treatment for depression and bipolar disorder. CSA’s main product is its truFreeze spry cryotherapy, which is designed to use super-cold liquid nitrogen delivered via catheter, to ablate unwanted tissue inside the body. Read more Maryland’s CSA Medical said last week that it’s close to reaching a $4 million funding goal with a new debt offering. CSA’s main product is its truFreeze spry cryotherapy, which is designed to use super-cold liquid nitrogen delivered via catheter, to ablate unwanted tissue inside the body. Read more Spirox said this week that it nailed down an $18.5 million Series B round to back development and commercialization of its device to treat patients with nasal obstructions. Venrock and Aisling Capital led the round for Menlo Park, Calif.-based Spirox, with existing investors Aperture Venture Partners, Correlation Ventures and Western Technology Investment also participating. Read more