Now that the human genome is sequenced, University of Notre Dame researchers are focusing on the study of the proteome, which is the protein content of an organism, tissue or cell. Bioanalytical chemist and molecular biologist have successfully tracked the changing patterns of protein expression during early development of Xenopus laevis, or African clawed frog, embryos. They have developed the largest data set on developmental proteomics for any organism, and have included the single-cell zygote.

Their research has uncovered an unexpected amount of discordance between the levels of messenger RNA (mRNA) and its corresponding protein. Their findings are published in Scientific Reports in an article titled, “.”

The Notre Dame team based in the in the has identified and measured the levels of about 4,000 proteins, which exhibited patterns of expression that reflect key events during early Xenopus development. For example, the appearance of organ- and tissue-specific proteins, such as those found exclusively in cardiac muscle cells, accurately reflects imminent anatomical changes taking place in the embryo. The research could lead to insight into congenital birth defects that result from the misregulation of gene expression.

The research also contradicted a widely held assumption that the levels of mRNA, which encodes proteins, would be directly related to protein levels. While that was true in most cases, there were a surprisingly high number of exceptions, demonstrating that the amounts of a particular protein can be controlled by multiple mechanisms.

Because development takes place in well-defined stages outside the mother, Xenopus is a favored model. Embryogenesis can be easily monitored in real time; fate maps for organ development have been determined and major regulators of these processes have been identified and characterized, providing an abundance of tissue- and organ-specific markers to track embryo formation. Additionally, embryos develop rapidly, achieving a nearly fully developed nervous system within four days. “It’s easy to manipulate the embryos to mimic certain disease states, making Xenopus extremely valuable to biologists,” Huber said.

“The collaborative, ground-breaking work of Norm Dovichi, Paul Huber and their team is crucial to helping us understand the complexity of life. We are proud of this important milestone,” said , dean of the College of Science at the University of Notre Dame.

Dovichi and Huber co-authored the article with Liangliang Sun, Michelle Bertke, Matthew Champion and Guijie Zhu.

Contact: Norm Dovichi, 574-631-2778, ndovichi@nd.edu

A team of University of Notre Dame researchers led by and have discovered a new class of antibiotics to fight bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant bacteria that threaten public health. Their research is published in the Journal of the American Chemical Society in an article titled “.”

The new class, called oxadiazoles, was discovered in silico (by computer) screening and has shown promise in the treatment of MRSA in mouse models of infection. Researchers who screened 1.2 million compounds found that the oxadiazole inhibits a penicillin-binding protein, PBP2a, and the biosynthesis of the cell wall that enables MRSA to resist other drugs. The oxadiazoles are also effective when taken orally. This is an important feature as there is only one marketed antibiotic for MRSA that can be taken orally.

MRSA has become a global public-health problem since the 1960s because of its resistance to antibiotics. In the United States alone, 278,000 people are hospitalized and 19,000 die each year from infections caused by MRSA. Only three drugs currently are effective treatments, and resistance to each of those drugs already exists.

The researchers have been seeking a solution to MRSA for years. “Professor Mobashery has been working on the mechanisms of resistance in MRSA for a very long time,” Chang said. “As we understand what the mechanisms are, we can devise strategies to develop compounds against MRSA.”

“Mayland Chang and Shahriar Mobashery’s discovery of a class of compounds that combat drug resistant bacteria such as MRSA could save thousands of lives around the world. We are grateful for their leadership and persistence in fighting drug resistance,” said , dean of the at the University of Notre Dame.

Co-authors of the study include Peter O’Daniel, Zhihong Peng, Hualiang Pi, Sebastian Testero, Derong Ding, Edward Spink, Erika Leemans, Marc Boudreau, Takao Yamaguchi, Valerie Schroeder, William Wolter, Leticia Llarrull, Wei Song, Elena Lastochkin, Malika Kumarasiri, Nuno Antunes, Mana Espahbodi, Katerina Lichtenwalter, Mark Suckow, Sergei Vakulenko, Mobashery and Chang, from the , the and the , all at the University of Notre Dame.

Contact: Mayland Chang, 574-631-2965, mchang@nd.edu

A paper published in a special edition of the journal Science proposes a novel understanding of brain architecture using a network representation of connections within the primate cortex. , professor of physics at the University of Notre Dame and co-director of the Interdisciplinary Center for Network Science and Applications, is a co-author of the paper “.”

Using brain-wide and consistent tracer data, the researchers describe the cortex as a network of connections with a “bow tie” structure characterized by a high-efficiency, dense core connecting with “wings” of feed-forward and feedback pathways to the rest of the cortex (periphery). The local circuits, reaching to within 2.5 millimeters and taking up more than 70 percent of all the connections in the macaque cortex, are integrated across areas with different functional modalities (somatosensory, motor, cognitive) with medium- to long-range projections.

The authors also report on a simple network model that incorporates the physical principle of entropic cost to long wiring and the spatial positioning of the functional areas in the cortex. They show that this model reproduces the properties of the connectivity data in the experiments, including the structure of the bow tie. The wings of the bow tie emerge from the counterstream organization of the feed-forward and feedback nature of the pathways. They also demonstrate that, contrary to previous beliefs, such high-density cortical graphs can achieve simultaneously strong connectivity (almost direct between any two areas), communication efficiency, and economy of connections (shown via optimizing total wire cost) via weight-distance correlations that are also consequences of this simple network model.

This bow tie arrangement is a typical feature of self-organizing information processing systems. The paper notes that the cortex has some analogies with information-processing networks such as the World Wide Web, as well as metabolism, the immune system and cell signaling. The core-periphery bow tie structure, they say, is “an evolutionarily favored structure for a wide variety of complex networks” because “these systems are not in thermodynamic equilibrium and are required to maintain energy and matter flow through the system.” The brain, however, also shows important differences from such systems. For example, destination addresses are encoded in information packets sent along the Internet, apparently unlike in the brain, and location and timing of activity are critical factors of information processing in the brain, unlike in the Internet.

“Biological data is extremely complex and diverse,” Toroczkai said. “However, as a physicist, I am interested in what is common or invariant in the data, because it may reveal a fundamental organizational principle behind a complex system. A minimal theory that incorporates such principle should reproduce the observations, if not in great detail, but in extent. I believe that with additional consistent data, as those obtained by the Kennedy team, the fundamental principles of massive information processing in brain neuronal networks are within reach.”

The data was generated by collaborator Henry Kennedy, director of the Stem-cell and Brain Research Institute in Lyon, France, and his research group. Other co-authors of the paper include Kennedy as well as Nikola T. Markov and Kenneth Knoblauch, also of the institute; Mária Ercsey-Ravasz of Babeş-Bolyai University in Romania; and David C. Van Essen of Washington University 91��Ƶ of Medicine in St. Louis.

Contact: Zoltán Toroczkai, 574-631-2618, toro@nd.edu

Researchers for the first time have identified Earth-sized planets within the habitable zone of a Sun-like star. Images of the star taken by University of Notre Dame astrophysicist rule out alternative explanations of the data, confirming that five planets orbit Kepler-62, with two located in the habitable zone. The results were published in today.

“A five-planet system with planets of 1.41 and 1.61 Earth-radii in the habitable zone of a K2V star has been detected with the Kepler spacecraft and validated with high statistical confidence,” the paper reports. Those two, named Kepler-62 e and f, are the outermost of the five observed planets and receive a solar flux from the star similar to that received from the Sun by Venus and Mars. Their size suggests that they are either rocky, like Earth, or composed mostly of solid water. A planet discovered more than a year ago in the habitable zone of another Sun-like star, Kepler-22, has a radius 2.4 times the radius of Earth, leaving researchers less sure of its composition.

“From what we can tell, from their radius and orbital period, these are the most similar objects to Earth that we have found yet,” said Crepp, the Freimann Assistant Professor of Physics. Data from the Kepler mission, launched in 2009 to identify extrasolar planets, have so far resulted in several dozen of some 3,000 “Kepler Objects of Interest” having been studied in detail.

Researchers use fluctuations in the brightness of a star to identify the presence of a potential planet whose transit periodically dims the light of the star. Crepp uses large ground-based telescopes to image the host star and analyzes the system to make sure other astronomical phenomena, such as nearby eclipsing binary stars, are not causing the fluctuation, a common “false positive” encountered in the research. Crepp noticed a faint dot near Kepler-62 a year ago, leading to months of detailed study to confirm the planet interpretation.

“What really helped is that this star has five planets,” he said. “You can mimic one planet with another event, but when you have five of them and they’re all periodic, that helps to put the nail in the coffin. It’s hard to make that kind of signature with anything else that you can dream up.”

Contact: Justin Crepp, 574-631-4092, jcrepp@nd.edu

, professor of physics at the University of Notre Dame, and Brian Hayden, a physics graduate student, are members of the CANDELS+CLASH Supernova Project that recently discovered a supernova that exploded more than 10 billion years ago. The Type Ia supernova, part of a class used for measuring the expansion of space, is the farthest yet found by NASA’s Hubble Space Telescope. Garnavich and Hayden are co-authors of a paper announcing the , which has been accepted for publication in The Astrophysical Journal.

Since 2010, Hubble’s Wide Field Camera 3 has surveyed faraway Type Ia supernovae to determine whether they have changed over the 13.8 billion years since the Big Bang. The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) and the Cluster Lensing and Supernova Survey with Hubble (CLASH) have studied thousands of galaxies.

“We realized that in building up the deep images, we could take data every few months, and by staggering the visits we could search for fresh exploding stars,” Garnavich said, adding that Hayden’s dissertation is on the study of Type Ia supernovae. “Brian and I have great fun searching for supernovae in the Hubble data, and we have personally found a few. We have also contributed to the ground-based follow-up studies including observations with the Large Binocular Telescope (LBT).” The LBT, which is partly funded by Notre Dame, is one of the largest telescopes in the world.

“These supernovae are important tools for studying the dark energy that is speeding up the expansion of space,” said census leader Adam Riess of the Space Telescope Science Institute in Baltimore and Johns Hopkins University. “This study gives us a chance to ‘stress test’ the supernovae themselves to test how well we understand them.” Reiss, who won the Nobel Prize for his discovery of the accelerating universe, and Garnavich were member of the High-Z team, one of two teams that discovered the acceleration using Type Ia supernovae.

The supernova is named SN Wilson after President Woodrow Wilson. The CANDELS+CLASH collaboration has found more than 100 supernovae, including SN Wilson, 350 million years older than the previous record, and seven other Type Ia supernovae that exploded more than 9 billion years ago.

Among other things, the study has provided evidence that supernovae result from the merger of two white dwarfs, rather than the explosion of one white dwarf that was feeding from another. Understanding supernovae explosions can also provide insight into the nature of dark energy and the production of iron and other heavy elements in the universe.

“The addition of the new infrared camera on Hubble has made this supernova search and study of early galaxy formation possible,” Garnavich said. “But NASA’s Shuttle program has ended, so that was the last visit by astronauts to improve the Hubble. We will need new telescopes in space if we want to continue to understand the early universe.”

Contact: Peter Garnavich, 574-631-7262, pgarnavi@nd.edu

University of Notre Dame alumnus Norbert Wiech founded to manage the clinical development needed to bring to market a promising new treatment for people with (NPC) disease. FDA support is being sought for early clinical exploration of an approved drug to fight this rare disease that has no cure or treatment.

Lysomics is based on the work of Notre Dame professors of chemistry and biochemistry and , and Frederick Maxfield at Cornell University’s Weill Medical College, to find treatments for NPC. NPC disease is a rare, fatal neurodegenerative disease that primarily strikes children before and during adolescence.

With support from the , researchers from Notre Dame and Cornell University have demonstrated the effectiveness of small molecule histone deacetylase inhibitors (HDACi) in correcting the NPC phenotype in human patient cells by increasing expression of the NPC1 protein.

The group is focusing on vorinostat, an FDA-approved anti-cancer treatment. Lysomics, which is seeking FDA approval to repurpose vorinostat to treat NPC, will soon submit an Investigational New Drug application. The existing FDA approval of this drug has previously established its safety in humans and means that several expensive steps are not required. Initial clinical trials could start next year. Lysomics is considering clinical collaborations with the National Institutes of Health and other clinical centers for the Phase 1 trials.

NPC, a genetic disease, affects fewer than 100 people in the United States, and an estimated 20-40 who are in the early stage of the disease could benefit from the treatment. Most patients die by the age of 16, and few survive beyond 25. The disorder prevents their bodies from processing cholesterol, which accumulates in the brain. Vorinostat is most effective in the early stages of NPC, although it could improve quality of life for older patients.

The effort will benefit from the 30-year-old Orphan Drug Act, which helps development of treatments for conditions that affect fewer than 200,000 people in the United States. The federal law grants exclusive marketing for seven years after FDA approval, tax credits of 40 percent for clinical research expenses, grants for studies up to $200,000 per year for three years and a waiver of a high filing fee.

“Lysomics from the onset was a not-for-profit operation,” said Wiech, the company’s CEO. “You can’t get a drug approval unless you’re a company. A company has to be structured, so it can handle the data and do all the piles of paperwork that are required to go through this.” After approval, the drug will need no marketing because parents of children with NPC will be eager for access to the treatment, he said.

Contact: Norb Wiech, 410-667-1091, nlwiech@lysomics.com

, Freimann Assistant Professor of at the University of Notre Dame, provided the high-contrast imaging observations that confirmed the first extrasolar planet discovered in a quadruple star system. He is a co-author on a paper about the discovery, “,” recently posted to the open-access arXiv.org, and submitted for publication to The Astrophysical Journal.

Crepp’s images revealed that the system involved two sets of binary stars. The planet was first noticed by volunteer citizen scientists studying publicly available Kepler data as part of the Planet Hunters citizen science project. Crepp says human observers sometimes are more likely than computer algorithms to recognize planets orbiting binary stars because the complex systems do not produce periodic fluctuations like planets orbiting a single star.

“We can’t see the planet directly, but Kepler can see unambiguous indications that it exists,” he says. One of the stars in the binary system is slightly more massive than the sun, one slightly less. They orbit each other once every 20 days, and the planet orbits them once every 137 days. Crepp’s high-contrast image, taken with a telescope in Hawaii, showed a second binary star nearby.

Crepp’s research focuses on imaging extrasolar planets, with the ultimate goal of finding an Earth-like planet in the habitable zone around a star. Such planets are 10 billion times fainter than stars, while Jupiter-like planets are one million times fainter. Crepp also works on creating improved instruments for such research, including one in process for the Large Binocular Telescope (LBT) in Arizona. Crepp’s work would provide precision infrared Doppler shift measurements to the LBT, an international consortium in which Notre Dame is a partner.

Contact: Justin Crepp, 574-631-4092, jcrepp@nd.edu