Earth

In a new study published in EPJ B, Basant Lal Sharma from the Indian Institute of Technology Kanpur provides a detailed analysis of how the flow of heat and electrons is affected at the interface between an 'armchair' shaped carbon nanotube and a zigzagging nanoribbon made up of a single-layer carbon honeycomb sheet of graphene. Applications of this method can help us understand the propagation of electrons and thermal flow in graphene and similar materials for electromagnetic devices. For example, a partially unzipped carbon nanotube could act as a device with varying electrical resistance depending on the strength of an external magnetic field applied to it. By contrast, these junctions can also act as perfect 'valley filters', allowing certain types of electrons through the junction with the maximum possible conductance, while other electrons can't pass through.

In this study, the author relies on a highly simplified view of the physics involved in the problem of electron and heat flow at the junction, one which nevertheless retains the essence of the problem. To study the junction, the author removes a zigzag chain of carbon atoms from the edge of the nanoribbon so as to create a defect in the junction.

Unlike previous studies, this work resolves the complex problem of electron transport using a method that is mathematically elegant. The model describes the interactions between electrons and relies on a matching method to calculate the transmission properties of the electrons through the junction. A similar method was previously used to explain wave propagation in different kinds of materials, but had little connection to the applications of such electron flows, which involve modelling individual particles' flow.

The author was able to obtain results that very nearly matched the numerical results.

About 250 million years ago, a massive volcanic eruption flooded modern-day Siberia with lava, creating the Siberian Traps, giant plateaus made of multiple layers of lava. The eruption also released huge quantities of carbon dioxide into the atmosphere that rapidly altered the climate and triggered the Permian-Triassic mass extinction event that wiped out more than 90% of marine species and 70% of terrestrial species. After the eruption, however, the Siberian Traps began drawing atmospheric carbon dioxide back into the crust through weathering and erosion. The Siberian Traps are the largest of several floods of basalt, called Large Igneous Provinces (LIPs), that have occurred during Earth's history and that likely have played a role in regulating Earth's climate.

In a new paper in Geophysical Research Letters, lead author Louis Johansson, along with Deep Carbon Observatory members Sabin Zahirovic and Dietmar Muller at the University of Sydney's School of Geosciences modelled the eruption of LIPs and their movement as a result of plate tectonics around the globe for the last 400 million years.

The researchers compared the timing of LIP eruption and weathering with estimates of atmospheric carbon dioxide to see if eruptions and weathering had a controlling effect. Through their analysis the researchers were able to pinpoint specific times when LIPs were instrumental in turning up or down Earth's global thermostat.

"These huge eruptions bring up an enormous amount of carbon dioxide and can change the climate and trigger major extinctions," said Zahirovic.

"But Earth has inbuilt mechanisms to scrub out the carbon dioxide from the atmosphere over geological timeframes."

LIPs can absorb large amounts of carbon dioxide because the basalt lavas are full of silicate-rich rocks that are especially vulnerable to weathering. When rain falls through a carbon dioxide-rich atmosphere, it dissolves the gas and forms acid rain. The weak acid reacts with silicate minerals in the LIPs to make long-lived carbonate sediments. Warm, rainy environments speed up the erosion process, and so more erosion occurs when LIPs are in regions near the equator, which have high temperatures and receive the most rainfall.

Scientists have looked at the climate impacts of individual LIPs, but no one had considered the long-term, global impacts of LIPs, as they moved around Earth on shifting continents.

The researchers used GPlates, an open-source software tool that reconstructs the movement of tectonic plates through Earth's history, developed by Müller's EarthByte group at the University of Sydney along with international collaborators. They took into account the timing of LIP eruptions and how many million years each LIP spent near the equator to estimate erosion. Then they compared the emission and absorption of carbon dioxide from LIPs to estimates of atmospheric carbon dioxide using proxy data from a previously published compilation.

To attain an unbiased comparison, the researchers performed a wavelet analysis, which is a statistical test that compares two sets of measurements over time to see if and when they are correlated.

"This analysis eliminates arm waving and also tells us when a particular signal leads another signal, so it gives us an indication, perhaps, of causation," said Zahirovic.

When the researchers compared the estimated level of carbon dioxide in the atmosphere with the eruption and erosion of LIPs, they were able to identify several associated jumps and dips in atmospheric carbon dioxide, showing that these basalt floods have played a role in modulating Earth's temperature for millions of years.

"What surprised me was that 200 million years ago, as Pangaea was breaking apart, and the Atlantic was opening up, the Central Atlantic Magmatic Province produced a huge amount of lava," said Zahirovic.

"You can see that in the carbon dioxide proxy record, there's a huge increase of carbon dioxide [after the eruption], but then because the volcanic province spends a lot of time in the humid near-equatorial belt, it is followed by a rapid decrease in carbon dioxide."

The eruption and weathering of LIPs is only one aspect of Earth's carbon cycle, and there are points when the influence of LIPs likely took a backseat to other geological processes. The researchers also note that their model omitted LIPs that erupted underwater, because these basalts tend to be recycled back into the mantle and thus are more difficult or impossible to reconstruct.

Next, the researchers are looking into other ways that plate tectonics influence the deep carbon cycle. "What we're trying to understand are the longer-term variations of climate and the carbon cycle, over geological time frames," said Zahirovic.

Currently they are compiling a global database of ophiolites, which are chunks of basaltic oceanic crust that get thrust up onto the continents during tectonic collisions. Like LIPs, ophiolites take up carbon dioxide from the atmosphere as they weather, and similarly to LIPs also have a finger on the global thermostat.

Cancer cells in children tend to develop by following four main trajectories - and two of them are linked to relapse of the disease, research led by Lund University in Sweden shows. The four strategies can occur simultaneously in a single tumour, according to the study that is now published in Nature Genetics.

The researchers mapped out the genome of cancer cells from more than 50 tumours in order to identify the four strategies. The genome of cancer cells often evolves, both in order to avoid the body's own defence mechanisms and to survive treatment with chemotherapy or other drugs. When cancer cells multiply, mutations are formed and thus new types of tumour cells, known as clones, can occur.

A challenge when treating patients is that, within a single tumour, there may be several different clones, which individually trigger the development of cancer in varying ways. The clones may also respond to chemotherapy differently. More knowledge about how such clones develop is therefore an important part of improving treatment.

"We wanted to learn more about how some tumours evade treatment and the strategies the cancer cells develop", explains Jenny Karlsson at Lund University, one of the researchers behind the study.

The developmental trajectories of tumours have so far been unknown in childhood cancer. Therefore, the researchers mapped out the genome of cancer cells from more than 50 tumours from patients with Wilms tumour, neuroblastoma and rhabdomyosarcoma. This allowed the researchers to track the types of mutations that caused the emergence of four main survival strategies: tolerance, coexistence, competition and chaos.

"The strategies are key as they give us an indication of the evolutionary capacity a tumour has at the time of discovery. Patients with the first two variants generally have good outcomes, while the latter two strategies are associated with risk of relapse", says Professor David Gisselsson Nord, who led the study.

If two of the strategies - competition or chaos - existed in the tumour at the onset of illness, the risk of relapse was more than 50 per cent.

"The same two strategies were found when we analysed relapse tumours. It seems that some cancer cells are programmed from the outset to single-handedly create a relapse. Relapsed tumours hade genomes that were often radically altered compared to the patient's first tumour. We conclude that the first tumour should not be used as a proxy to predict targeted treatment in case of a relapse. A new biopsy is well warranted. The genome of the tumour usually changes over time", says David Gisselsson Nord.

The next step will be to identify which mechanisms drive the survival strategies adopted by the cancer in the initial phase of the disease.

"If we knew more about how the environment in the patient's tissues triggers cancer cells to develop, we could also influence how they change during treatment and perhaps prevent a relapse. We are now applying for funding to conduct such studies and to evaluate, in a major study, whether the four strategies can really be used in the clinic", concludes David Gisselsson Nord.

THE FOUR STRATEGIES:

Strategy 1: Tolerance.
New clones are allowed to emerge locally in the tumour, but they stay in their place of origin. The researchers did not find that this strategy was associated to relapse.

Strategy 2: Coexistence.
New clones grow together with the original tumour cells, and coexist with them in many parts of the tumour. The researchers did not find that this strategy was associated to relapse.

Strategy 3: Competition.
A new clone outcompetes the original tumour cell, and then builds up parts of the tumour entirely on its own. The researchers found that this strategy was associated with increased risk of relapse.

Strategy 4: Chaos.
New clones mutate intensively so that a variety of cell types emerge in a specific part of the tumour at the same time. This strategy was also associated with increased risk of relapse.

MAYWOOD, IL - A 21-gene test performed on tumors could enable most patients with the most common type of early breast cancer to safely forgo chemotherapy, according to a landmark study published in the New England Journal of Medicine.

Loyola Medicine oncologist Kathy Albain, MD, is among the main co-authors of the study and a member of the clinical trial's steering committee. First author is Joseph Sparano, MD, of Montefiore Medical Center in Bronx, NY. The study was published in conjunction with its Sunday, June 3 presentation at the plenary session of the American Society of Clinical Oncology 2018 meeting in Chicago.

"With results of this groundbreaking study, we now can safely avoid chemotherapy in about 70 percent of patients who are diagnosed with the most common form of breast cancer," Dr. Albain said. "For countless women and their doctors, the days of uncertainty are over."

Dr. Albain, the Huizenga Family Endowed Chair in Oncology Research at Loyola University Chicago Stritch School of Medicine, has conducted research with the 21-gene test and also used it in her practice for years.

The test examines 21 genes from a patient's breast cancer biopsy sample to determine how active they are. The tumor is assigned a "recurrence score" from 0 to 100; the higher the score, the greater the chance the cancer will recur in distant organs and decrease survival. If patients with higher scores receive chemotherapy, this risk of recurrence will be significantly reduced, enabling more patients to be cured.

Previously, the challenge doctors and patients have faced is what to do if a patient has a mid-range score. It was uncertain whether the benefit of chemotherapy was great enough to justify the added risks and toxicity. Previous studies demonstrated that patients with low scores (10 or lower) did not need chemotherapy, while women with high scores (above 25) did require and benefit from chemotherapy.The new study examined the majority of women who fall in the intermediate range of 11 to 25.

The study enrolled 10,273 women who had the most common type of breast cancer (hormone-receptor positive, HER-2 negative) that had not spread to lymph nodes. Researchers examined outcomes of the 69 percent of patients who had intermediate scores on the 21-gene test.

Patients were randomly assigned to receive chemotherapy followed by hormonal therapy or hormone therapy alone. Researchers examined the chemotherapy and non-chemotherapy groups for several outcomes, including being cancer free, having cancer recur locally or to distant sites in the body and overall survival.

For the entire study population with gene test scores between 11 and 25-and especially among women aged 50 to 75-there was no significant difference between the chemotherapy and no chemotherapy groups. Among women younger than 50, outcomes were similar when gene test scores were 15 or lower. Among younger women with scores 16 to 25, outcomes were slightly better in the chemotherapy group.

"The study should have a huge impact on doctors and patients," Dr. Albain said. "Its findings will greatly expand the number of patients who can forgo chemotherapy without compromising their outcomes. We are de-escalating toxic therapy."

New research presented at this year's Euroanaesthesia congress in Copenhagen, Denmark shows that in patients undergoing a coronary artery bypass graft (CABG) surgery, taking aspirin before and after surgery is associated with an 18% to 34% reduced mortality risk after 4 years. The study is by Professor Jianzhong Sun, Director of Clinical Outcomes Research at the Department of Anesthesiology, Thomas Jefferson University and Hospitals, Philadelphia, USA, and colleagues.

CABG surgery is used to restore normal blood flow to an obstructed artery in the heart. Cardiac surgery frequently provokes a state of extreme and complex stress with a greatly elevated risk of blood clots and an increased predisposition to long-term vascular disease and mortality. It is hoped that perioperative aspirin (taken before and after the operation) may reduce these adverse effects.

Preoperative and postoperative uses of aspirin are defined as within 5 days preceding surgery and continuously on discharge respectively. The discharge prescription of aspirin often is indicated for patients with CABG and it should be continued indefinitely, except for patients with contraindications. The reported rates of patient aspirin adherence for cardiovascular protection are high, range from 72% to 92% in the literature.

Most previous studies on aspirin's effects in cardiac surgery were limited by the length of follow-up. And little is known about perioperative aspirin's effect on the long-term survival in patients undergoing CABG surgery. This study from institutions in the US and China studied the effects of perioperative aspirin on long-term mortality in patients undergoing coronary artery bypass graft (CABG).

The team looked at the medical records of 9,584 patients who received cardiac surgery in three hospitals, selecting the 4,132 individuals who underwent CABG. This selection was then further divided into four groups; in which patients had one of preoperative or postoperative aspirin, both, or neither.

Among the studied patients, 76.5% received preoperative aspirin, 23.5% did not, 92.3% received postoperative aspirin, and just 7.7% did not. Patients taking preoperative aspirin were significantly more likely to have other risk factors including smoking, diabetes, peripheral vascular disease, angina, high blood pressure, and previous heart attacks.

For patients taking preoperative aspirin, 4-year mortality was 14.8% versus 18.1% for those not taking preoperative aspirin, a statistically significant mortality reduction of 18%. For postoperative aspirin, there was a larger mortality reduction: those taking aspirin had a 4-year mortality rate of 10.7%, compared with 16.2% in the non-aspirin patients -- a statistically significant mortality reduction of 34%.

Professor Sun says: "Our study showed that aspirin was associated with similar effectiveness to other proven medical treatments in patients with cardiovascular disease, such as statins and ACE inhibitors."

He concludes: "Among patients undergoing CABG, perioperative uses of aspirin were associated with significant reduction in 30-day mortality and improvement in long-term survival, without significant increased postoperative bleeding complications. We believe that all patients undergoing CABG should take aspirin before and after the procedure, except those for whom aspirin is contraindicated."

CHICAGO - Matching targeted therapies to tumor-specific gene mutations across tumor types improved progression-free survival (PFS) and overall survival (OS) in patients with advanced disease relative to those receiving non-matched treatment (NMT), according to research from The University of Texas MD Anderson Cancer Center. The researchers also found that receiving matched targeted therapy (MTT) was an independent factor for predicting longer OS.

Long-term data from IMPACT show that the three-year OS was 15 percent in the MTT group compared to 7 percent in the NMT group. The 10-year OS was 6 percent in the MTT group, compared to 1 percent in the NMT group. Apostolia M. Tsimberidou, M.D., Ph.D., professor, Investigational Cancer Therapeutics, presented the findings on the press program at the 2018 American Society for Clinical Oncology Annual Meeting.

The study is the first and largest precision medicine trial to look at survival and has the longest follow-up of any such trial, explained Tsimberidou, IMPACT's principal investigator.

MD Anderson opened IMPACT in 2007 after her experience with the targeted therapy Gleevec showed how it changed both the treatment and survival rates for chronic myeloid leukemia (CML), once a deadly disease, she said.

"When we opened IMPACT, it was viewed as incredibly novel. Because of the variability, frequency and rarity of alterations in specific solid tumor types, it was thought it would be difficult to use molecular testing for clinical trial selection, without taking into consideration any specific characteristics," Tsimberidou said. "However, gleaning from our Gleevec-CML experience, we hypothesized that genetic and molecular analysis of solid tumors also could enable the selection of optimal therapy for patients with solid tumors."

The umbrella protocol enrolled 3,743 MD Anderson patients from 2007 to 2013. All were referred to MD Anderson's Phase I program with end-stage disease. The patients' median age was 57 years, with a range in age from 16 to 86. The ratio of women to men was 61 to 39 percent, respectively. The most common cancers treated were gastrointestinal, gynecologic, breast, melanoma and lung, with the rest being more rare types.

As expected in this population, patients were heavily pre-treated; the median number of prior therapies received was four, with some being treated with any many as 16 previous therapies, said Tsimberidou.

All 3,743 patients enrolled in IMPACT received molecular testing; 1,307 were found to have at least one molecular alteration, with 711 receiving MTT (with or without chemotherapy) and 596 receiving NMT. The majority of IMPACT participants who received MTT received an investigational drug then being tested in a clinical trial; others received an FDA-approved targeted therapy commercially approved for another indication.

In those who received MTT, the median PFS was 4 months and the median OS was 9.3 months, compared to 2.8 months and 7.3 months, respectively, in those who received NMT.

Given the quantity of patients enrolled and the length of follow-up, the MD Anderson researchers were able to analyze the different pathways that predicted response in the MTT groups.

Given the number of patients in the trial and the length of follow-up, the investigators were able to develop a prognostic score to predict OS. Taking into consideration all baseline characteristics in the 1,307 patients who received molecular testing, the absence of liver metastases, normal LDH levels, normal functional status, albumin levels and platelet counts were all found to be independent factors for longer OS. Most interestingly, said Tsimberidou, receiving MTT was also found to be an independent factor associated with longer OS.

In contrast, shorter survival was associated with liver metastases, elevated LDH levels, poor functional status, low albumin levels, elevated platelet counts, and age 60 years or older. In addition, molecular alterations in the PI3K/AKT/mTOR pathway were an independent factor predicting shorter overall survival compared to other alterations.

When type of therapy was added to the model, NMT was found to be an independent factor predicting shorter survival, said Tsimberidou.

IMPACT's follow-up study, IMPACT2, is a randomized Phase II looking at PFS and is ongoing. Tsimberidou noted that the advances from IMPACT to IMPACT2, like next-generation sequencing technologies, and the use of immune features and new drugs, including immunotherapy, are staggering.

"When IMPACT first opened, we tested for no more than one-to-two genes," she said. "Now patients are being tested for hundreds of actionable genes, amplifications and mutations, as well as for immune markers. Ideally, in the future, patients' tumor testing and cell-free DNA analysis will become the standard of care at the time of diagnosis, in hopes of making a difference for patients upfront, especially in those with hard-to-treat cancers."

The study was supported by philanthropy funds from: Mr. Alberto Barretto, Jamie's Hope, Mr. and Mrs. Zane W. Arrott, and Mr. Steven McKenzie. Tsimberidou will present the study in full in a poster session on June 4, 2018. Tsimberidou serves as a consultant to Roche, Europe.

Walter and Eliza Hall Institute researchers have visualised for the first time how the protein SOCS1 'switches off' cell signalling to dampen immune responses and block cancer growth.

The atomic-level structure of SOCS1 binding to its partner protein JAK could guide the development of drugs that alter disease-causing cell signalling pathways, and may have applications for treating some blood cancers, including leukaemias.

The research, led by Dr Nick Liau, Dr Nadia Kershaw, Associate Professor Jeff Babon and Professor Nick Nicola, was published in the journal Nature Communications.

AT A GLANCE

- The SOCS1 protein binds to JAK proteins to 'switch off' cell signalling, which dampens processes including immune responses and cancer growth.

- Our researchers have used structural biology to visualise how SOCS1 binds to JAK proteins in never-before seen detail.

- The detailed structure may guide the development of new drugs that modify JAK activity, amplifying or dampening cell responses, with potential applications in cancer therapies.

SWITCHING OFF SIGNALLING

Dr Liau said the structure of the protein pair revealed for the first time how SOCS1 binds to JAK proteins to disable signalling.

"Using the Australian Synchrotron and the CSIRO Collaborative Crystallisation Centre, we produced an incredibly detailed view of how SOCS1 interacts with the JAK1 protein," Dr Liau said.

"With this image, we were able to explain for the first time why JAK proteins cannot signal when bound to SOCS1. This information could help to underpin the development of new medicine targeting this important cell signalling pathway."

A BLUEPRINT FOR NEW MEDICINES

Dr Kershaw said both SOCS1 and JAK proteins had been implicated in driving diseases including cancer and inflammatory conditions.

"In particular, overactive JAK signalling is linked to the development of cancer-like conditions called myeloproliferative neoplasms (MPNs) - which include polycythemia vera, essential thrombocythemia and primary myelofibrosis - as well as certain acute childhood leukaemias.

"Medicines that inhibit JAK signalling are in use for treating MPNs, but they are only able to manage the disease, not cure it. New medicines for these conditions are needed, and we envisage that a drug designed to mimic the SOCS1 protein to switch off JAK proteins might be a more effective treatment," Dr Kershaw said.

As well as guiding the development of drugs mimicking SOCS1, the team's research may also underpin the development of a second new class of drugs that inhibit SOCS1, Associate Professor Jeff Babon said. "SOCS1 binding JAK proteins normally applies a 'brake' to immune responses - which in a healthy person is a good thing," he said.

"However, in certain conditions, releasing this brake could be the key to enhanced immune responses. This approach to boosting the immune response could be the key to improving immunotherapies for treating cancer. If we could design a drug that inhibits SOCS1, this might boost anti-cancer immune responses, potentially improving anti-cancer immunotherapies."

Highlights

Among living kidney donors, the post-donation concern that was considered most important was kidney health, followed by the surgical, lifestyle, functional, and psychosocial impacts of donation.

The hypothetical long-term risks associated with kidney removal--including mortality and cardiovascular disease--were of relatively lower importance.
Living kidney donor transplants comprise nearly one-quarter of kidney transplants performed worldwide.

Washington, DC (May 31, 2018) -- In a new study that examined living kidney donors' concerns about their decision to undergo kidney removal, long-term kidney health, aspects of surgery and recovery, and impacts on life satisfaction were among those that donors felt were most important. The findings appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN).

Increasing living kidney donations is critical to address the global shortage of organs. Donor candidates must accept a range of risks and benefits when they decide to have a kidney removed, and it is important to determine which of these they consider most important.

To identify which impacts of kidney donation are deemed important by living kidney donors, Camilla Hanson, BPsych(Hons), PhD (University of Sydney, in Australia) and her colleagues recruited previous donors from 3 transplant units in Australia and Canada to participate in focus groups. Participants had a range of demographic (gender and age), and donation characteristics (time since donation, relationship with the recipient, and complications).

Across 14 focus groups that included 123 donors, the post-donation outcome that was most important to kidney donors was kidney health, followed by the surgical, lifestyle, functional, and psychosocial impacts of donation. The hypothetical long-term risks associated with kidney removal--including mortality and cardiovascular disease--were of relatively lower importance.

Specifically, the 10 highest ranked outcomes were kidney function, time to recovery, surgical complications, impact on family, donor-recipient relationship, life satisfaction, lifestyle restrictions, kidney failure, mortality, and acute pain/discomfort.

Some differences were observed in the importance of outcomes between donors recruited from Australia and Canada. Canadian donors ranked kidney function and failure higher than Australian participants, who ranked time to recovery, physical function, impact on family, donor-recipient relationship, and financial impact higher.

"Our results may help to ensure that the outcomes most relevant to donors are consistently included in research, education, assessment, and follow-up care," said Dr. Hanson.

In an accompanying editorial, Milda Saunders, MD, MPH and Michelle Josephson, MD (University of Chicago) note that the study illustrates that past donors care about both medical and non-medical outcomes. "More than anything, this work demonstrates that we cannot simply assume we know what donors care and worry about. We must talk with them about their priorities and concerns both before and after surgery," they wrote.

An accompanying Patient Voice article reflects the impact that pediatric-onset end- stage renal disease has on patients and their families and the personal perspective of a donor-recipient team.

SYRACUSE, N.Y. - Researchers in the Department of Earth Sciences at Syracuse University have confirmed that rising oceanic and atmospheric oxygen levels co-evolved with marine life hundreds of millions of years ago.

Wanyi Lu, a Ph.D. candidate studying under associate professor Zunli Lu (no relation) in the College of Arts and Sciences, is the lead author of a groundbreaking paper in Science magazine (American Association for the Advancement of Sciences, 2018).

The paper stems from a multi-year, multinational research effort led by Zunli Lu that rethinks the causes and impacts of increased oxygenation on the continental shelves during the current Phanerozoic Eon, which began more than 542 million years ago.

"Most studies of oxygen history focus on the atmosphere and deep oceans, with implications on the evolution of life," Zunli Lu says. "We believe the oceanic oxygen level in the water column above the continental shelves [i.e., the upper ocean] may have been a different beast."

Central to the team's research was a geochemical proxy that Lu pioneered in 2010. Using a novel approach based on iodine geochemistry, he and his colleagues measured the ratio of iodine to calcium in calcium carbonate minerals and fossils.

Timothy Lyons, Distinguished Professor of Biogeochemistry at the University of California, Riverside (UCR), considers iodine geochemistry a "powerful tool" for constraining oxygen conditions in surface-to-near-surface conditions of the ancient ocean. "These are the waters in which the earliest animals first appeared, evolved and advanced toward complex ecologies," he says. "The results from this study reveal previously unimagined environmental dynamics in those early waters, and those conditions must have impacted animals."

Lu takes the praise in stride, but insists the group's findings are novel. "The upper ocean became well-oxygenated much later than originally thought," he says.

The Syracuse geochemist illustrates his point by describing a thick haze of methane that originally enveloped the planet, leaving little to no oxygen in the atmosphere. Photosynthesizing microbes eventually produced enough chemical energy, causing free oxygen to accumulate in the atmosphere. "This set the stage for the Great Oxidation Event about 2.3 billion years ago," he says.

With oxygenation came the rise of multicellular life forms over the next billion years. Among them were eukaryotes, whose genetic information was stored within a membrane-bound nucleus or nuclei.

The question on everyone's mind, notably Wanyi Lu's, was how and when the global ocean became oxygenated enough to accommodate diverse marine life forms, including those alive today.

"Our iodine data is consistent with a major rise in the atmospheric oxygen level that occurred around 400 million years ago," says Lu, whose doctoral studies involve low-temperature geochemistry and global environmental changes. "Nevertheless, upper-ocean oxygen levels did not stabilize at near-modern conditions until 200 million years ago, when larger eukaryotic plankton dominated the world's oceans. The timing makes perfect sense."

To understand such observations in the rock record, one must appreciate large-scale biogeochemical and oceanographic processes, as well as atmospheric chemical composition. "We examined the roles of these two controls in the upper ocean, using a sophisticated Earth System Model [ESM] with an interesting name: GENIE, which is short for 'Grid-ENabled Integrated Earth,'" Zunli Lu says.

Andy Ridgwell, professor of Earth Sciences at UCR, developed GENIE's signature modeling framework, which composes a range of ESM simulations over various timescales. "The innovative way that the Syracuse team combined measurements of ancient rocks with a complex, mathematical model of the global climate system and carbon cycle was impressive," he says.

Ridgwell lauds the main conclusion of the team's final analysis--that a fundamental change in eukaryotes led to greater re-mineralization depth of organic matter and, ultimately, a "resiliently oxygenated" upper ocean. "This fits perfectly with our developing understanding of the key evolutionary steps taken to create the planet we have today," says Ridgwell, who studies biogeochemical modeling and long-term climate change.

Lee Kump, dean of the College of Earth and Mineral Sciences at Penn State, says the group's findings are a potent reminder of how Darwin's theory of evolution may be only half-right. "Changes in the environment affect biological evolution, to be sure, but biological innovation can affect the environment, even at the global scale," says the renowned paleoclimatologist.

That is not the end of the story, however. Ros Rickaby, professor of geochemistry at the University of Oxford (U.K.), says the findings also reinforce the link between oxygenation and marine animal body size. "It is incredible to think that the increasing success of microscopic mineralizing plankton out in the ocean, through the change in oxygen distribution, could have had such far-reaching effects across the Earth system to boost the average body size of animals," she says. "It reminds us of the intricate interconnection between every part of the marine ecosystem."

Adds Zunli Lu: "It is a prime example of the co-evolution of life and the planet."

Fires ignited by lightning have and will likely continue to increase across the Mediterranean and temperate regions in the Southern Hemisphere under a warmer climate, according to a new study co-led by a Portland State University researcher.

The study, published online in May in the journal Geophysical Research Letters, examined the observed and forecasted relationship between lightning-ignited fires, rising temperatures across the Southern Hemisphere and natural climate variability in three leading climate drivers that affect weather worldwide: El Niño-La Niña, the Indian Ocean Dipole and the Southern Annular Mode.

El Niño-La Niña, known as ENSO, is the periodic warming and cooling periods of the equatorial eastern and central Pacific Ocean that affects the world's climate the most. The Indian Ocean Dipole, or IOD, is a similar ocean-atmospheric phenomenon characterized by changes in sea-surface temperatures between the eastern and western part of the Indian Ocean, while the Southern Annular Mode, or SAM, describes the north-south movement of the westerly wind belt that circles Antarctica and carries moisture to the southwest corners of all the Southern Hemisphere continents.

Heat, oxygen, fuel and an ignition source combine to start wildfires, but where and how quickly a fire moves depends on the terrain, the types and condition of vegetation present and the weather, said Andrés Holz, the study's co-lead author and a geography professor in PSU's College of Liberal Arts and Sciences.

The study found that of the three climate drivers, the SAM had the strongest impact on fire activity - both lightning- and human-caused wildfires - due to a combination of lower precipitation and higher temperatures, said Holz, who also serves as a faculty fellow at PSU's Institute for Sustainable Solutions.

During the positive phase of SAM, the westerly winds contract toward Antarctica, leaving large areas in southern South America, South Africa and Australia rain-free. The recent positive trends in SAM are attributed to increasing greenhouse gas levels and the hole in the ozone layer.

"Now the winter is not as rainy and the summer is longer, drier and warmer," Holz said.

Drier winters mean less moisture on the land, and warmer springs and summers are pulling the soil moisture into the air more quickly, allowing the soil and vegetation to dry out and ignite more readily, he said.

The study found that the natural influence of the three climate modes (ENSO, IOD and SAM) on fire activity was stronger during the 21st century than during the last couple of decades of the 20th century as a result of anthropogenic warming. That trend is expected to continue.

Among the study's findings:

Global warming is linked to increased natural (lightning-ignited) fire occurrence

Climate change is amplifying climate-fire teleconnections, or the strength of long-distance relationships between weather patterns and fire
During the onset of the 21st century, lightning-ignited fires were tightly coupled with upward trends in the SAM and rising temperatures across the Southern Hemisphere

"We think that by having warmer oceans and warmer temperatures in general, we're going to see higher evaporation and heat transfer, and thus higher frequency of convective storms that in turn results in more lightning-ignited fires," Holz said. "And with a climate mode such as SAM stuck in its positive, fire-prone phase that seems to amplify climate change, it doesn't look good."

But Holz cautions that it does not mean that there will be an increasing number of fires everywhere. Under warmer conditions, if precipitation stays constant, there will be increased fire activity in areas that already have plenty of fuel to burn but have historically been too humid or wet to burn. On the flip side, areas that are dry year-round will likely see a decline in fire activity with global warming unless there's a strong increase in rainfall.

"These trends are expected worldwide, not just in the Southern Hemisphere," Holz said.

New research from the Center for BrainHealth at The University of Texas at Dallas shows that certain cognitive training exercises can help reduce depression and improve brain health in individuals years after they have suffered a traumatic brain injury (TBI).

The recent study, published in Human Brain Mapping, revealed significant reductions in the severity of depressive symptoms, increased ability to regulate emotions, increases in cortical thickness and recovery from abnormal neural network connectivity after cognitive training.

"To our knowledge, this is the first study to report brain change associated with reduced depression symptoms after cognitive training," said Dr. Kihwan Han, a research scientist at the Center for BrainHealth who works in the lab of Dr. Daniel Krawczyk. Han is the lead author of the study.

"Overall, these findings suggest that cognitive training can reduce depressive symptoms in patients with traumatic brain injury even when the training does not directly target psychiatric symptoms," he said.

A past study involving the same protocol showed cognitive gains as well as similar changes in cortical thickness and neural network connectivity.

This study included 79 individuals with chronic TBI who all were at least six months post-injury. These individuals were randomly assigned into one of two groups: strategy-based training, which used the Strategic Memory Advanced Reasoning Training (SMART) program developed at the center; and information-based training, which used the Brain Health Workshop program. Researchers used the Beck Depressive Inventory to classify 53 of the participants as depressed.

The participants' depressive-symptom severity, psychological functioning scores and data from magnetic resonance imaging brain scans were collected before training, after training and three months post-training. Scans were used to study changes in brain structure and neural network connectivity.

Both training programs consisted of 12 one-and-a half-hour sessions over eight weeks that included quizzes, homework assignments, and projects conducted in small group settings that involved social interactions.

All participants in the depressed group showed significantly reduced depressive symptoms that were associated with improvements in cognitive and daily life functioning. According to Han, the social engagements, cognitive stimulation from new learning opportunities and hope of improvement afforded by both programs may help explain the reductions in depressive symptoms.

Based on the observed brain change patterns, Han suggested that improved emotion regulation also may be related to the reduced depressive symptoms. Over time, the reductions in depression symptom severity correlated with increased cortical thickness within the prefrontal cortex -- an area of the brain responsible for executive functions needed for emotional control -- and reductions in abnormally elevated neural connectivity within this region.

"Identifying what changes are happening in the brain when interventions successfully reduce depressive symptoms could allow us to create more effective, pharmaceutical-free approaches to help alleviate depression in people who experience chronic traumatic brain injury symptoms," said study author Dr. Sandra Bond Chapman, founder and chief director of the Center for BrainHealth, and Dee Wyly Distinguished University Professor.

RIVERSIDE, Calif. -- Drugs available to treat multiple sclerosis, a leading cause of neurological disability affecting roughly 2.3 million people worldwide, alter the body's immune system to reduce disease symptoms and disability.

They do not induce, however, repair of damaged axons, the long threadlike parts of nerve cells that conduct impulses between cells or restore myelin, the protective sheath that surrounds the axons of neurons essential for the proper functioning of the brain and spinal cord.

Researchers at the University of California, Riverside, now report that indazole chloride, a synthetic compound that acts on one form of the body's estrogen receptors previously shown to reduce multiple sclerosis symptoms in mouse models, is able to do both: remyelinate (add new myelin to) damaged axons and alter the immune system.

"While additional translational studies are required, indazole chloride and similar drugs may represent a promising new avenue of treating the underlying loss of myelin in multiple sclerosis," said Seema Tiwari-Woodruff, an associate professor of biomedical sciences in the School of Medicine, who led the mouse study.

Multiple sclerosis is triggered when the immune system attacks and damages the myelin sheath. As myelin is lost, nerve signals slow down or stop, affecting the patient's vision, movement, memory, and more. Oligodendrocytes are the mylenating cells of the central nervous system. Normally, oligodendrocyte precursor cells mature into myelin-producing oligodendrocytes when myelin is damaged.

This process often fails, however, in multiple sclerosis, resulting in permanent damage. The UCR researchers found the change in the immune system provides a protective shield for oligodendrocytes, preventing this damage and possibly even reversing it.

"With remyelination of axons, nerve impulses travel faster than before, thus decreasing multiple sclerosis disability," Tiwari-Woodruff said. "As a potential therapy for the treatment of multiple sclerosis, indazole chloride may represent the first in a novel class of drugs capable of reducing disability burden in patients with multiple sclerosis. We still don't know the mechanism of action of pre-clinical therapies like indazole chloride. Our report aims to understand how drugs like indazole chloride are working so we can make more selective and efficacious drugs."

Study results appear this week in the Proceedings of the National Academy of Sciences.

Indazole chloride, a ligand, stimulates ERβ, an estrogen receptor in the body. Indazole chloride is an attractive drug because it does not produce the negative side-effects of estrogen therapy. Because ERβ are present not just in oligodendrocytes but also in microglia, neurons, and T-cells, indazole chloride may have therapeutic benefits not just for multiple sclerosis, but also other autoimmune diseases.

Tiwari-Woodruff explained that while inflammation causes a lot of damage in autoimmune diseases, not all inflammation is harmful. Beneficial inflammation is required to fight infectious disease and speeds up wound healing by clearing dead cells and tissue. Indazole chloride reduces "bad" inflammation and promotes "good" inflammation, thereby protecting new oligodendrocytes while they remyelinate. Tiwari-Woodruff and her group found that indazole chloride accomplishes this by strengthening the production of a molecule called "CXCL1," which makes oligodendrocytes resistant to "bad" inflammatory signals.

Tiwari-Woodruff's findings provide a stepping stone toward a way to repair the damage to axons and oligodendrocytes caused by multiple sclerosis. In collaboration with John Katzenellenbogen, a research professor of chemistry at the University of Illinois at Urbana-Champaign, Tiwari-Woodruff's group is screening chemically similar analogs of indazole chloride for more efficacious and safe therapy. Provisional patents have been filed for some of these analogs.

"It's quite possible we may find an analog far superior to indazole chloride," Tiwari-Woodruff said.

The concept of survival of the fittest most often applies to the competition that occurs within and between animal species, but evolutionary pressures can be found elsewhere--even in a cancerous tumor.

Cancer researchers have come to understand tumors not as lumps of identical cells, but rather as diverse, dynamic populations unto themselves. And, like individuals within animal populations, cells within tumors compete with one another, some thriving, some failing.

In a new study, researchers from the University of Pennsylvania have crafted a mathematical model to understand the dynamics at play as cancerous tumors grow and spread. Setting their model into action, Jimmy Qian, a rising senior in the Vagelos Scholars Program in the Molecular Life Sciences, and Erol Akçay, an assistant professor of biology in the School of Arts and Sciences, were able to explain a somewhat paradoxical observation, that mutations that lead to metastasis--the spread of cancer to sites distant from the primary tumor--often arise early, rather than late, in a tumor history.

Reporting in the journal PLOS ONE, Qian and Akçay suggest that incorporating evolutionary and ecological theory into cancer biology may help guide more effective treatment plans.

"In the public consciousness it often seems like cancer is this big, unitary disease that we need to beat somehow, like polio, which it isn't," says Akçay. "Each cancerous tumor is a community of essentially different 'species' doing different things."

"Understanding how cancer evolves," adds Qian, "may help us to predict which lineage will come to dominate in a tumor and, possibly, preemptively treat that to minimize the chance for drug resistance. Or, if we can predict what sort of evolutionary mechanisms cause metastasis, we can try to tackle that before metastasis even starts."

Cancer cells don't simply dwell and reproduce amidst normal cells; they actively modify the environment around them to make it more conducive to their own growth. This process may entail enhancing blood-vessel formation or altering the structure and metabolism of nearby cells. Cultivation of the so-called tumor microenvironment, or tumor niche, isn't limited to neighboring tissues, however. Metastasis arises when malignant cells secrete factors through the bloodstream to distant sites in the body as a way of readying new spaces for cancer to grow.

"It's like humans. We prepare our kids by creating college funds and things like that," Qian says. "Cancer is doing the same thing. It's preparing a distant site that its kids will one day migrate to."

To Qian and Akçay, steeped in theoretical evolutionary biology and ecology theory, this feature of cancer's spread presented interesting questions: Assuming that cancer cells must sacrifice some of their own resources to prepare these distant areas of the body, how would such a lineage compete with others that cultivated areas closer to the primary tumor? And what about "cheating" lineages that didn't contribute to constructing the tumor niche, and therefore used fewer resources?

Imagining a primary tumor, the researchers crafted a model tumor composed of four types of cancer cells: producers that help construct the tumor's immediate microenvironment; producers that help construct distant, pre-metastatic sites by secreting various molecules; producers that do both of these tasks (and bear twice the cost in resources); and cheaters, which do not contribute to niche construction (and thus sacrifice fewer resources).

Setting up competitive interactions among these various cancer cell subsets and running simulations, the researchers observed that, when tumors were small, producers that contributed to the formation of pre-metastatic niches were more likely to "win" because there were fewer competitors around to overtake them. But once the tumors grew in size, more mutations arose, and thus the pool of competitors increased.

"The mutants that contribute to pre-metastatic niches are more likely to arise in bigger tumors, but are less likely to establish themselves in those tumors," Akçay says. "That's the tradeoff."

"This would predict that some smaller tumors are actually more likely to lead to metastasis," Qian says, a finding supported by recent observations showing that, indeed, cancer-cell mutations that arise early are more likely to be the source of metastatic disease.

"It happens a lot," Qian notes, "that by the time a lot of patients identify the primary tumor, there are already the seeds of metastasis elsewhere in the body. So even if you successfully treat the primary tumor, the metastases could take more years to grow and well up later." While concerning, the study does suggest that cancer therapies may benefit from considering a tumor as an ecosystem, one with clashing and cooperating populations of cells that could be manipulated to a patient's benefit.

"I think you can bring a lot of ecological and evolutionary theory to bear in designing treatments," Akçay says. "There are people who are looking at optimal treatment schedules for controlling the expansions of cell populations and trying to disrupt the dynamics that would allow cancerous and metastatic tumors to grow.

"We're not there yet--our model is still trying to understand the basic idea--but I think ideas like that can eventually find their way into treatment design."

JUPITER, FL--May 29, 2018--As scientists gain insights into which genes drive diseases, they are pursuing the next logical question: Can gene editing technologies be developed to treat or even cure those diseases? Much of that effort has focused on developing technologies such as CRISPR-Cas9, a protein-based system.

At The Scripps Research Institute campus in Florida, chemist Matthew D. Disney, PhD, has taken a different approach, developing a small-molecule-based tool that acts on RNA to selectively delete certain gene products.

Disney's deletion tool opens the possibility of creating drugs that can be taken conveniently as pills to correct genetic diseases--by destroying toxic gene products, and by chemically controlling the body's defense mechanisms. The paper, "Small molecule targeted recruitment of a nuclease to RNA," was published online by the Journal of the American Chemical Society.

"These studies, like much science, were about a decade in the making. We are very excited to see how this initial application evolves," Disney says. "This research further shows that RNA is indeed a viable target to make medicines."

RNAs represent a diverse group of molecules within cells that act like the cells' laborers, reading, regulating and expressing DNA's genetic instructions. Within our cells, RNAs are constantly in motion. They assemble, they carry out their duties, and then they are broken up for recycling by RNA-degrading enzymes, which are chemical scissors that cut apart other molecules.

While about 2 percent of our genome encodes proteins, 70 to 80 percent of the genome is transcribed into RNA, potentially offering significantly more druggable targets, Disney says. Until recently, however, most researchers considered RNAs undruggable, because of their small size and relative lack of stability.

Disney's innovation tethers a drug-like molecule--one engineered to bind precisely and selectively to a specific RNA--to a common RNA-degrading enzyme. The small-molecule/enzyme complex is designed to latch onto the undesirable gene product and destroy it. Disney named the technology RIBOTAC, short for "ribonuclease-targeting chimeras."

To test the RIBOTAC technology, Disney chose for his RNA-degrading enzyme RNase L, which is a critical part of the human antiviral immune response. Present in small amounts in every cell, production of RNase L typically surges on viral infection to destroy the viral RNA and overcome the illness.

For the other piece of the RIBOTAC complex, its drug-like molecule, Disney chose Targaprimir-96, a molecule engineered by his lab in 2016 to bind with a microRNA oncogene known to boost cancer cell proliferation, especially in difficult-to-treat triple-negative breast cancer, miRNA-96.

Destroying the oncogene led to a reawakening of the cancer cell's innate self-destruct program, via an increase in the FOXO1 gene, which ultimately spurred the death of the malignant cells, says Matthew G. Costales, first author of the paper and a graduate student in the Disney lab.

"Anchoring our previous work with Targaprimir-96 to the targeted recruitment of RNase L, we were able to program the RIBOTACs approach to only degrade cells that highly express the miRNA-96 oncogene, thus allowing FOXO1 to signal the selective destruction of triple negative breast cancer cells," says Costales.

Awakening the body's ability to kill its own cancer by exploiting cells' RNA degradation system offers a novel approach to attacking cancer, Disney says. The RIBOTAC technology has potentially broad applications for cancer and other gene-driven diseases as well, he says.

"I believe this is just the tip of the iceberg of how this approach will ultimately be applied," says Disney.

Disney's lab has spent many years developing a computational method called InfornaTM to match RNAs with adequate stability and structure to small, drug-like molecules capable of binding to them. His technique led to the development of Targaprimir-96 and multiple other disease-modifying compounds, some of which are now moving toward clinical development.

"Since it is now known that RNA is a key driver in nearly every disease, optimization of this approach that turns a cell's natural defenses toward destroying disease-causing RNAs is likely broadly applicable. We will be laser-focused on diseases for which there are no known cure and have a poor prognosis, such as hard-to-treat cancers and incurable human genetic disease," Disney says. "I am excited to see where we and others ultimately take this."

Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.

From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two different forms (isomers) at the molecular level. The difference lies in the relative orientation of the nuclear spins of the two hydrogen atoms. Depending on whether the spins are aligned in the same or opposite direction, one refers to ortho- or para-water.

Experiments with sorted water molecules

The research group headed by Professor Stefan Willitsch from the University of Basel's Department of Chemistry has investigated how the two forms of water differ in terms of their chemical reactivity - their ability to undergo a chemical reaction. Both isomers have almost identical physical properties which makes their separation particularly challenging.

This separation was made possible by a method based on electric fields developed by Professor Jochen Küpper from the Hamburg Center for Free-Electron Laser Science. Using this approach, the researchers were able to initiate controlled reactions between the "pre-sorted" water isomers and ultracold diazenylium ions ("protonated nitrogen") held in a trap. During this process, a diazenylium ion transfers its proton to a water molecule. This reaction is also observed in the chemistry of interstellar space.

Increased reactivity

It was demonstrated that para-water reacts about 25% faster than ortho-water. This effect can be explained in terms of the nuclear spin also influencing the rotation of the water molecules. As a result, different attractive forces act between the reaction partners. Para-water is able to attract its reaction partner more strongly than the ortho-form, which leads to an increased chemical reactivity. Computer simulations confirmed these experimental findings.

In their experiments, the researchers worked with molecules at very low temperatures close to the absolute zero point (about -273°C). These are ideal conditions to precisely prepare individual quantum states and define the energy content of the molecules, and to cause a controlled reaction between them. Willitsch explains the experimental approach: "The better one can control the states of the molecules involved in a chemical reaction, the better the underlying mechanisms and dynamics of a reaction can be investigated and understood."