Culture

Proteins do not function in isolation and their interactions with other proteins define their cellular functions. Therefore, detailed understanding of protein-protein interactions (PPIs) is the key for deciphering regulation of cellular networks and pathways.

These complex networks of stable and transient associations can be studied by affinity purification mass spectrometry (AP-MS) and complementary proximity-based labeling methods such as BioID.

In a study published in the 22th of March issue of Nature Communications, a research team led by Dr. Markku Varjosalo (HiLIFE / Institute of Biotechnology, University of Helsinki) introduce an optimized and integrated approach combining AP-MS and BioID in a single workflow. In addition to just exploiting the advantages of both strategies, the authors show that their approach allows identification and quantification of protein-protein interactions and protein complex stoichiometries; identification of transient or close-proximity interactions with BioID; visualization of the bait protein and the proximal interactors with immunofluorescence microscopy; and defining the molecular context with MS microscopy utilizing the reference dataset obtained by identifying proximal interactors for bona fide subcellular localization markers.

The authors show that using the MS microscopy, it is possible to assign the studied protein to it´s correct cellular or even subcellular location in even higher resolution than with confocal microscopy.

"This study is a continuum of our rigorous efforts in developing new systems biology tools for studying the molecular interactions formed by proteins. We have previously proven that AP-MS is highly reproducible method, which is also suitable for large-scale and inter-laboratory studies", Dr. Varjosalo states. He continues:

"Our newly developed integrated workflow and the reference molecular context proteome map, allows an easy way to probe the molecular localization of (m)any protein(s). The developed MAC-tag and the integrated approach should empower, not only the interaction proteomics community, but also cell, molecular and structural biologists, with an experimentally proven integrated workflow for mapping in detail the physical and functional interactions and the molecular context of proteins in human cells."

Alexandria, VA, USA - At the 47th Annual Meeting of the American Association for Dental Research (AADR), held in conjunction with the 42nd Annual Meeting of the Canadian Association for Dental Research (CADR), Abby Siefker, The Ohio State University, Columbus, presented an oral session titled "The Subgingival Virome in Periodontal Health and Disease." The AADR/CADR Annual Meeting is in Fort Lauderdale, Fla., USA from March 21-24, 2018.

The role of viruses in the etiopathogenesis of periodontitis has been studied for several decades, with equivocal results. This might be attributable to close-ended approaches that used methodologies targeted to single organisms. The purpose of this study was to examine the subgingival virome in periodontal health, chronic periodontitis and aggressive periodontitis, using a whole genome shotgun sequencing approach.

Subgingival plaque samples were collected from deep and shallow sites of 25 subjects with untreated chronic periodontitis (17 which were generalized aggressive and 17 localized aggressive periodontitis) and from 25 periodontally healthy controls. Whole genome sequencing was performed on the Illumina platform, and viral identities were assigned using the Lowest Common Ancestor (LCA) alignment to the M5NR database.

The results show that healthy controls demonstrated lower levels of viruses when compared to diseased subjects. The predominant human viruses were members of the Herpes Simplex family, however bacteriophages were the predominant viral constituents overall.

"Significant differences were observed in the levels of gram-positive and gram-negative phages in health and disease," said Abby Siefker. "While health was dominated by gram-positive phages, especially those belonging to the genera Streptococcus, Enterococcus and Lactobacillus, in disease gram-negative phages predominated. These phages were associated with Prevotella, Burkholderia, Campylobacter, Hemophilus and Aggregatibacter."

Viral load, as well as, specific viral types is higher in disease when compared to health. Similarly, aggressive periodontitis demonstrated higher viral load when compared to chronic, suggesting that studies examining the role of viruses in the etiology of periodontitis are warranted.

INDIANAPOLIS -- The first birth cohort study of its kind has found more than 90 percent of a group of pregnant women in Central Indiana had detectable levels of glyphosate, the active ingredient in Roundup, the most heavily used herbicide worldwide.

Researchers from Indiana University and University of California San Francisco reported that the glyphosate levels correlated significantly with shortened pregnancy lengths.

"There is growing evidence that even a slight reduction in gestational length can lead to lifelong adverse consequences," said Shahid Parvez, the principal investigator of this study and an assistant professor in the Department of Environmental Health Science at the IU Richard M. Fairbanks School of Public Health at IUPUI.

The study is the first to examine glyphosate exposure in pregnant women in the United States using urine specimens as a direct measure of exposure.

Parvez said the main finding of the study was that 93 percent of the 71 women in the study had detectable levels of glyphosate in their urine. "We found higher urine glyphosate levels in women who lived in rural areas, and in those who consumed more caffeinated beverages," he said.

"One thing we cannot deny is that glyphosate exposure in pregnant women is real," Parvez said. "The good news is that the public drinking water supply may not be the primary source of glyphosate exposure, as we initially anticipated. None of the tested drinking water samples showed glyphosate residues. It is likely that glyphosate is eliminated in the water-treatment process. The bad news is that the dietary intake of genetically modified food items and caffeinated beverages is suspected to be the main source of glyphosate intake."

Use of glyphosate is heaviest in the Midwest due to corn and soybean production. Its residues are found in the environment, major crops and food items that humans consume daily.

"Although our study cohort was small and regional and had limited racial or ethnic diversity, it provides direct evidence of maternal glyphosate exposure and a significant correlation with shortened pregnancy," Parvez said.

The magnitude of glyphosate exposure in pregnant women and the correlations with shorter gestation length are concerning and mandate further investigation, he said. "We are planning, contingent upon funding, to conduct a more comprehensive study in a geographically and racially diverse pool of pregnant women to determine if our findings are the same."

March 22, 2018 - As more patients undergo total hip arthroplasty (THA) before age 65, the rate of repeat hip surgery due to complications has risen sharply in this younger age group, reports a study in the March 21, 2018, issue of The Journal of Bone & Joint Surgery. The journal is published in partnership with Wolters Kluwer.

Between 2007 and 2013, the rate of THA revision surgery has increased in adults aged 45 to 64 while decreasing in all other age groups, according to the research by Sean Rajaee, MD, and colleagues from Cedars-Sinai Medical Center, Los Angeles. Other findings, based on analysis of nationwide data, suggest "a trend in the right direction" toward better outcomes over time for patients undergoing THA revision surgery.

"Hip arthroplasty revision is a lot safer and more successful than 20 years ago, but still occurs too frequently," comments senior author Guy Paiement, MD. "We need to continue improving techniques and implants."

Increasing Burden of THA Revisions in Middle-Aged Patients

The researchers analyzed nearly 320,500 THA revision procedures performed between 2007 and 2013, identified from the Agency for Healthcare Research & Quality's Nationwide Inpatient Sample. While THA is a highly successful procedure, failure can occur for various reasons. In these cases, revision surgery may be needed to remove or replace the hip prosthesis or parts of it.

The data showed a 12 percent increase in the overall estimated THA revision rate over six years, after adjustment for population growth. However, that increase was driven exclusively by patients aged 45 to 64: in this group, the THA revision rate increased by more than 30 percent. In all other age groups, the revision rate decreased during the six-year study period.

The reasons for revision surgery also changed between 2007 and 2013, with about a 14 percent decrease in revisions due to THA dislocations. This gain was offset by an increase in revision surgery due to "other mechanical complications." That trend likely reflects complications related to the increased use of "metal-on-metal" hip implants during that period, Dr. Rajaee and colleagues believe.

The data also showed improved outcomes for patients undergoing THA revision surgery. Rates of several serious inpatient complications decreased significantly, including blood clot-related problems, myocardial infarction (heart attack), pneumonia, and urinary tract infections.

The mortality rate also decreased significantly, as did the percentage of patients discharged from the hospital to a skilled nursing facility. There was also a 19 percent decrease in inflation-adjusted cost per THA revision--perhaps reflecting a reduction in length of hospital stays resulting from lower inpatient complication rates.

"Over the last several decades, there have been substantial advancements in both surgical technique and implant design that have improved patient outcomes" after THA, Dr. Rajaee and coauthors write. While THA provides excellent long-term outcomes, high rates and costs of revision surgery continue to be a problem.

Even if they don't experience a revision surgery, most hip arthroplasty patients aged 45 to 64 have a life expectancy of 20 years or longer after their THA. "A large proportion of these patients will outlive their implants" the authors observe. "This presents a challenge to the orthopaedic and scientific communities as the need for longer-lasting implants in these relatively young patients is critical." The researchers note that in the 1990s and 2000s, metal-on-metal hip implants were more widely used in younger patients. More recently, use of these types of implants has decreased due to concern about adverse outcomes.

Meanwhile, for patients who do require THA revision, the procedure is safer today and associated with less complications, even after adjusting for all health problems. Dr. Rajaee and colleagues conclude, "This improving patient safety profile is encouraging and validates the efforts made to improve patient outcomes after THA revision."

MEDFORD/SOMERVILLE, Mass. (March 22, 2018) - Monitoring in real time what happens in and around our bodies can be invaluable in the context of health care or clinical studies, but not so easy to do. That could soon change thanks to new, miniaturized sensors developed by researchers at the Tufts University School of Engineering that, when mounted directly on a tooth and communicating wirelessly with a mobile device, can transmit information on glucose, salt and alcohol intake. In research to be published soon in the journal Advanced Materials, researchers note that future adaptations of these sensors could enable the detection and recording of a wide range of nutrients, chemicals and physiological states.

Previous wearable devices for monitoring dietary intake suffered from limitations such as requiring the use of a mouth guard, bulky wiring, or necessitating frequent replacement as the sensors rapidly degraded. Tufts engineers sought a more adoptable technology and developed a sensor with a mere 2mm x 2mm footprint that can flexibly conform and bond to the irregular surface of a tooth. In a similar fashion to the way a toll is collected on a highway, the sensors transmit their data wirelessly in response to an incoming radiofrequency signal.

The sensors are made up of three sandwiched layers: a central "bioresponsive" layer that absorbs the nutrient or other chemicals to be detected, and outer layers consisting of two square-shaped gold rings. Together, the three layers act like a tiny antenna, collecting and transmitting waves in the radiofrequency spectrum. As an incoming wave hits the sensor, some of it is cancelled out and the rest transmitted back, just like a patch of blue paint absorbs redder wavelengths and reflects the blue back to our eyes.

The sensor, however, can change its "color." For example, if the central layer takes on salt, or ethanol, its electrical properties will shift, causing the sensor to absorb and transmit a different spectrum of radiofrequency waves, with varying intensity. That is how nutrients and other analytes can be detected and measured.

"In theory we can modify the bioresponsive layer in these sensors to target other chemicals - we are really limited only by our creativity," said Fiorenzo Omenetto, Ph.D., corresponding author and the Frank C. Doble Professor of Engineering at Tufts. "We have extended common RFID [radiofrequency ID] technology to a sensor package that can dynamically read and transmit information on its environment, whether it is affixed to a tooth, to skin, or any other surface."

Non-Hodgkin lymphomas are cancers that affect white blood cells of the immune system called B-lymphocytes or B cells. Like cells in all cancers, the B cells begin to grow out of control, creating tumors in the lymph nodes, spleen or other tissues. In 2010 alone, it was estimated that non-Hodgkin lymphomas caused 210,000 deaths worldwide.

One of the driving forces behind non-Hodgkin lymphomas is the over-activation of a receptor on the surface of B cells. This receptor normally stimulates the growth of B-cells only when it is needed, but in non-Hodgkin lymphoma, the growth signal is constantly on, making B-cells grow uncontrollably.

To block this signal, recent clinical studies have focused on inhibiting the activation of the B-cell receptor as a treatment for non-Hodgkin lymphoma patients, but with variable success. For example, a drug called ibrutinib has been tested in clinical trials to treat an aggressive form of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL). Ibrutinib blocks the enzyme BTK (Bruton's tyrosine kinase), which is involved in maturing and activating B cells as part of the B-cell receptor's signaling pathway. Unfortunately, the response to ibrutinib has been limited only to a subgroup of DLBCL patients.

The lab of Elisa Oricchio at EPFL has now carried out a study to identify mechanisms of resistance to ibrutinib. Using tumor cells from DLBCL patients, the scientists discovered that the inactivation of BTK in resistant tumors triggers the over-activation of alternative signals that promote tumor cell survival and proliferation.

To prevent this mechanism of resistance and block the B-cell receptor signaling at its root, Elena Battistello, the PhD student who led this project, targeted the three enzymes (LYN, FYN, and BLK) that initiate the propagation of the signals.

The scientists discovered that blocking these enzymes with a drug called masitinib completely ablated the B-cell receptor pro-tumorigenic signals. In addition, masitinib strongly impaired tumor growth in all of the DLBCL patient-derived tissues that the team tested.

The authors, who are now planning to begin clinical trials based on this study, state that the three enzymes can be promising therapeutic targets for a diverse and broad group of DLBCL patients.

HOUSTON - (March 22, 2018) - It's easy and economical to make shiny pellets of graphite from functionalized graphene, according to scientists at Rice University.

A report in Carbon shows how chemically altered graphene powder can be pressed into a lightweight, semiporous solid that retains many of the strong and conductive qualities of graphite, the form of carbon found in pencils, lubricants and many other products that normally requires high-temperature processing to make.

Mohamad Kabbani, a former graduate student of Rice materials scientist Pulickel Ajayan and lead author of the paper, demonstrated the environmentally friendly, scalable process can be done in minutes by hand by grinding chemically modified graphene into a powder and using a hand-powered press to squeeze the powder into a solid pellet.

Kabbani previously showed how carbon nanotubes could be turned into graphene with a mortar and pestle rather than harsh chemicals. This time, he and his colleagues demonstrated how to make a battery-sized pellet, but the graphene powders with chemical functionalities attached to it can be pressed into any form. Kabbani said the material could be suitable for structural, catalytic, electrochemical and electronic applications.

"This is the first time anyone's made these at room temperature and without very high pressure," he said. "Usually these kind of materials require sintering (a process that uses pressure or heat to form solids without melting them) at temperatures above 1,000 degrees Celsius to produce strong pellets. In this case, mechano-chemistry at the nanoscale saved us a lot of energy and money."

The process began with two sets of functionalized nanotubes, one with carboxylic acid and the other with hydroxyl molecules. Once crushed to combine them either by hand or machine, they are placed in a lab-scale hydraulic press and subjected to 5 tons of pressure. The functional groups cross-linked the graphene sheets to each other, and even though no liquids were involved, they produced a tiny amount of water as a byproduct of the reaction, Kabbani said.

The pellets remained stable when placed in hot water for five hours, even when stirred; this confirmed the interlocking of the graphene sheets within, the researchers reported.

The combination of light weight, high strength and high conductivity is appealing for applications such as conducting cables and electrodes, Kabbani said. "The pellet material is stronger and lighter than commercial graphite electrodes and could be promising for electrical storage applications with high energy and power densities," he said.

Scientists have recently learned how to use light to control specific groups of neurons to better understand the operation of the brain, a development that has transformed areas of neuroscience.

Researchers at Princeton University have now applied a similar method to controlling the metabolism, or basic chemical process, of a living cell. In a series of experiments, they used light to control genetically-modified yeast and increase its output of commercially valuable chemicals. The results offer scientists a powerful new tool to probe and understand the inner working of cells.

"This technique allows us to control the metabolism of cells in an unprecedented way," said co-lead researcher José L. Avalos, an assistant professor of chemical and biological engineering and Princeton's Andlinger Center for Energy and the Environment. "It opens the door to controlling metabolism with light."

Yeast has been used for centuries to make bread, wine and beer. Through fermentation, yeast cells transform sugar into chemicals that make bread rise and turn grape juice into wine. Using their new technique, the Princeton researchers have now used fermentation and genetically-engineered yeast to produce other chemicals including lactic acid, used in food production and bioplastics, and isobutanol, a commodity chemical and an advanced biofuel.

Light played a key role in the experiment because it allowed the researchers to switch on genes that they had added to the yeast cells. These particular genes are sensitive to light, which can trigger or suppress their activity. In one case, turning on and off a blue light caused the special yeast to alternate between producing ethanol, a product of normal fermentation, and isobutanol, a chemical that normally would kill yeast at sufficiently high concentration.

The achievement of producing these chemicals was significant, but the researchers were intrigued by the development of light's broader role in metabolic research.

"It provides a new tool with the ability to do sophisticated experiments to determine how metabolism works and how to engineer it," Avalos said.

In a March 21 paper in the journal Nature, the researchers reported that they used light to increase yeast's production of the chemical isobutanol as much as 5times higher than previously reported levels in peer-reviewed studies The researchers used a genetically modified strain of the yeast Saccharomyces cerevisiae in the experiments.

Isobutanol is an alcohol used in products such as lubricants, gasoline and jet fuel replacements, and plastics. With good compatibility with gasoline infrastructure, isobutanol has properties that could make it a direct substitute for gas as a vehicle fuel. However, most attempts to create isobutanol biofuel have run into difficulties involving cost or scaling production to an industrial level. Although natural yeast fermentation produces isobutanol, it does so in miniscule amounts. Instead, yeast makes high volumes of ethanol (the alcohol in beer and wine) and carbon dioxide (a gas that makes bread rise).

"Yeast don't want to make anything but ethanol; all their systems have evolved to do this," said Evan M. Zhao, a third-year Ph.D. student in Avalos' lab and lead author on the Nature paper. "This has been an age-old problem."

The researchers sought to overcome this barrier. They managed to suppress the yeast's evolutionary self-interest by genetically engineering it to produce large quantities of isobutanol. But they faced a major problem. Isobutanol is toxic to yeast and eventually kills yeast colonies that produce it in any significant quantity. The researchers predicted they could use a combination of genetic engineering and light to fine tune isobutanol production. Using their light-switch technique, the researchers set out to keep the yeast alive while maximizing isobutanol production.

The researchers started by putting a modified gene from a marine bacterium that is controllable by blue light into yeast's DNA. They then used light to turn on a chemical process that activates enzymes that naturally allow yeast to grow and multiply by eating glucose and secreting ethanol. But while those enzymes are active, ones that influence the production of isobutanol can't work. So the team turned to darkness to switch off the ethanol-producing enzymes to make room for the expression of their competitors.

"Normally light turns expression on," said Jared E. Toettcher, assistant professor of molecular biology and co-lead researcher, "but we also had to figure out how to make the absence of light turn another expression on."

The challenge was to find the right balance of light and dark, given that yeast cells die when their natural fermentation process is disturbed, Zhao said: "The yeast get sick. They don't do anything anymore; they just stop."

The researchers allowed the cells to grow by giving them bursts of blue light every few hours. In between they turned the light off to shift their metabolism from powering growth to producing isobutanol. Before the cells completely arrested, the researchers dispersed more bursts of light.

"Just enough light to keep the cells alive," said Toettcher, "but still crank out a whole lot of product that you want, which they produce only in the dark."

Using light to control yeast's chemical production offers several advantages over techniques involving pure genetic engineering or chemical additives. For one, light is much faster and cheaper than most alternatives. It's also adjustable, meaning that turning it on and off can toggle the function of live cells on the spot at any point in the fermentation process (as opposed to chemicals, which generally can't be turned off once they are added.) Also, unlike chemical manipulators that diffuse throughout a cell, light can be applied to specific genes without affecting other parts of the cell.

Optogenetics, as the use of light to control genes is called, is already used in neuroscience and other fields, but this the first application of the technology to control cellular metabolism for chemical production. Gregory Stephanopoulos, an MIT chemical engineering professor who was not involved with Princeton's research, called it a turning point in the field of metabolic engineering.

"It offers a brand new approach to the control of gene expression in microbial cultivation," Prof. Stephanopoulos said.

The work and resulting paper were the culmination of interdisciplinary collaboration between Avalos's and Toettcher's labs.

Both started working at Princeton in the winter of 2015 and immediately saw an opportunity to work together. Zhao worked in both labs.

"Within our first month we wanted to use light to control metabolic engineering," Toettcher said.

Avalos said the researchers are working to improve their results. They have recently tested different colors of light to activate various proteins and cut the time needed for yeast to produce desired chemicals. But he said they would ultimately like to expand the scope of their work.

"We intend to keep pushing," Avalos said. "But metabolic engineering transcends industrial microbiology. It also allows us to study the metabolism of cells for health-related problems. You can control metabolism in any context, for industrial biology or to address medical questions."

NEW YORK (March 22, 2018) -- Logging activities in biodiverse forests can have a huge negative impact on wildlife, particularly large species such as big cats, but a new study proves that the Western Hemisphere's largest cat species--the jaguar (Panthera onca)--can do well in logging concessions that are properly managed, according to conservationists from the San Diego Zoo Global and the Bronx Zoo-based WCS (Wildlife Conservation Society).

The study titled "Do responsibly managed logging concessions adequately protect jaguars and other large and medium-sized mammals? Two case studies from Guatemala and Peru" appears in the online version of the journal Biological Conservation. The authors are: Mathias W. Tobler and Samia E. Carrillo-Percastegui of San Diego Zoo Global; Rony Garcia Anleu, Gabriela Ponce Santizo, John Polisar, and Isaac Goldstein of WCS; and Alfonso Zuñiga Hartley of San Diego Zoo Global and Servicio Nacional Forestal y de Fauna Silvestre, Lima, Peru.

"Our findings indicate that certified logging operations can play an important role in maintaining vital habitat for jaguars and other large wildlife species," said Tobler, a scientist for San Diego Zoo Global and lead author of the study.

Much of the world's tropical forests have disappeared as a result of deforestation, particularly in biodiverse regions such as Central and South America that are home to jaguars, tapirs, peccaries, and many other charismatic species. Reduced impact logging operations, which strive to prevent uncontrolled hunting and other negative environmental impacts, provide conservationists with a sustainable alternative in multiple-use and/or buffer areas near core zones or fully protected areas.

To that end, the study research team initiated large-scale camera trap surveys to gauge the effectiveness of Forest Stewardship Council (FSC)-certified logging concessions in both Guatemala and Peru in maintaining terrestrial mammal communities, with a focus on jaguars. The camera traps in Guatemala's Maya Biosphere Reserve captured a total of 23 individual jaguars, whereas the traps in two concessions in Peru's Madre de Dios region recorded 43 of these big cats. The appearance of the same jaguar in two or more images can be determined from spot patterns that are unique to each individual; such "recaptures" are important for accurately determining jaguar densities.

The spatial capture-recapture models used to calculate jaguar densities in both certified logging concession locations estimated that the Guatemala site contained an average of 1.5 jaguars per 100 square kilometers, whereas the Peru site contained an average of 4.5 jaguars. Further, both sites supported more than 20 large and medium mammal species (with 22 in Guatemala and 27 in Peru).

Additionally, the scientists found that strictly controlled logging roads with limited access in well-managed concessions were used by several species, including carnivores, as movement corridors, a finding contrary to the conventional thinking of the roads being negative disturbances to wildlife. Authors caution that logging roads must still be closed to the public so that traffic levels can be kept low to ensure that impacts to wildlife are minimized.

"Controlling access into an area and hunting of prey are paramount considerations for the objectives of preserving biodiversity and ecological function, both of which are selling points for certified lumber products," said Dr. John Polisar, coordinator for WCS's Jaguar Program and a co-author of the study. "The presence of jaguars in a logging concession is testimony that environmental guidelines are being followed."

Polisar was the lead author in a previously published paper (in the journal Ambio) titled "Using certified timber extraction to benefit jaguar and ecosystem conservation." The study focused exclusively on jaguars (as opposed to jaguars and other large and medium sized species in the aforementioned paper) and explored the factors that contributed to the persistence of these big cats in certified forests in Bolivia, French Guiana, Nicaragua and Guatemala.

Studies assessing the environmental impacts of logging operations are crucial for saving wildlife, say study authors and other conservationists, who add that certified, low-impact timber management by community groups and industrial operators constitutes one of the most effective jaguar conservation strategies available to jaguar-range countries. Properly managed concessions help forests persist in the face of more intensive land uses, generate income for local stakeholders who become lead defenders of the forests, and maintain habitat for jaguars and their prey as they range beyond fully protected areas.

AUGUSTA, Ga. (Mar. 19, 2018) - A newly designed three-part molecule could be the one answer patients with a certain form of breast cancer are looking for, scientists report.

This chimera, created by a team at the Georgia Cancer Center, has the ability to simultaneously decrease the expression of three growth factors that are over-expressed in some cancers.

The growth factors are human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), and epidermal growth factor receptor (EGFR). The new chimera interferes with HER2 and HER3 signaling and ultimately leads to cancer cell death, as shown in the group's recent publication in Molecular Therapy: Nucleic Acids.

"When HER2 is expressed in a cell, you'll usually find high expression of HER3, too," said Dr. Hongyan Liu, bioengineer at the Georgia Cancer Center at Augusta University and the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Augusta University.

Extensive studies have found that 20% to 30% of breast cancers are characterized by over-expression of HER2, which makes the cancer cells grow and divide faster, leading to a cancer that's more aggressive and more likely to be resistant to the standard of care. Patients with this type of breast cancer tend to have a poorer prognosis.

"As a bioengineer, I am developing the materials for cancer-targeted treatment," Liu said. "I have experience building multifunctional chimeras to target different types of genes associated with cancer cells."

Liu and her team created their molecule to target HER family receptors EGFR, HER2, and HER3 all at once, since it is well-known that another HER family member can compensate for one that is blocked by a drug having a single target.

Each component of this tripartite molecule has potent anti-tumor activity. The molecule was designed such that the EGFR-targeting component is sandwiched between the HER2- and HER3-targeting components in what is known as a HER2 aptamer-EGFR siRNA-HER3 aptamer chimera. This construction enables the EGFR component to reach its target within HER2- and HER3-expressing cells. Compared to individual components, the chimera is large enough to avoid renal depletion, resulting in a prolonged circulation time and increased efficiency.

The newly crafted molecule is non-toxic, simple to produce, and cost-effective compared to the production of alternate treatment strategies, such as antibodies and small molecule inhibitors.

Liu's ongoing studies are testing the ability of the three-in-one chimera to treat breast cancers that are resistant to Herceptin, a drug that targets HER2. This work is being done in collaboration with Dr. Hasan Korkaya, assistant professor, Biochemistry and Molecular Biology at the Medical College of Georgia, who has developed drug-resistant cell lines, and with breast cancer clinicians.

"We need to prove that this molecule will work on Herceptin-resistant breast cancer patients," Liu said.

Since other cancers, such as lung and head and neck, proliferate due to HER family over-expression, Liu anticipates that the chimera's utility will not be limited to breast cancers alone.

Engineers at wastewater recycling plants can rest easy knowing that their methods for minimizing the formation of a potent carcinogen are targeting the right chemical compound.

USC Viterbi Assistant Professor Daniel McCurry, undergraduate student Meredith Huang and master's student Shiyang Huang have confirmed the chemical responsible for the formation of the carcinogen N-nitrosodimethyalmine, or NDMA, in recycled wastewater. They began their study after contradictory findings surfaced in the environmental research community, causing hesitation in the adoption of NDMA intervention methods at treatment facilities. Their work was published in Environmental Science and Technology Letters as the March cover study.

"The recent drought in California and subsequent water vulnerability has increased interest in water recycling," said Meredith Huang, the study's first author. "However, disinfection byproducts like NDMA, formed in the process of treating wastewater, are harmful to humans and introduce some issues when the goal is re-consumption."

In the late 90s, high concentrations of NDMA were found in what was otherwise extremely clean recycled wastewater, which in most states is discharged into rivers that are used as sources for drinking water. This discovery set off a years-long research effort by several labs to figure out how the harmful chemical compound was forming.

"The concentration of NDMA that we're worried about is very, very low," said McCurry, who works in the Sonny Astani Department of Civil and Environmental Engineering. "Unlike a lot of organic pollutants in drinking water where the regulatory limit may be in the microgram per liter range, for NDMA, the regulatory guideline in many places ranges from 10 nanograms per liter to 100 nanograms per liter. So, three to four orders of magnitude lower in concentration because it's just a super potent carcinogen."

Most recycled wastewater that will be used as drinking water through a process known as potable reuse, first enters the ground before it goes to a drinking water plant. The soil acts as a filter, removing chemicals and degrading harmful compounds like NDMA. But the high cost of pumping water into and out of the ground has led to an increased interest in direct potable reuse, where recycled wastewater goes directly to a drinking water plant.

"NDMA is one of the major obstacles to direct potable reuse because it is really difficult to get rid of thorough traditional treatment processes," McCurry said. It is instead easier and more affordable to lower NDMA concentrations by eliminating the molecules responsible for its formation.

Originally, researchers found that NDMA is the result of the chlorination step of the recycled wastewater treatment process. Specifically, dichloramine, a minor component of the chlorine mixture, causes the formation of NDMA. These findings led treatment plants to begin manipulating chlorine chemistry in order to lower dichloramine concentrations and, ultimately, reduce NDMA formation.

However, researchers were still uncertain of what dichloramine was reacting with to form NDMA until five years ago when researchers in Toronto found that certain pharmaceuticals, like the antacid Zantac, can form NDMA when chlorinated in wastewater-like conditions. Subsequently, other researchers began looking into the formation mechanism from Zantac-like chemicals.

"They decided that it was monochloramine that was responsible in contrast to several practical studies showing that minimizing dichloramine in real recycled wastewater minimizes NDMA formation," McCurry said. "They came to the wrong conclusion because monochloramine and dichloramine are interconvertible. So, experimentally, it's pretty hard to separate them."

With this in mind, McCurry and his team carefully designed their experiment to avoid conversions between the two molecules by using much lower doses. Then, by systematically applying a range of monochloramine and dichloramine doses to pharmaceutical precursors, they were able to determine which molecule was the root cause of NDMA formation.

The results

To verify their approach, they first used a precursor molecule with a well-known reaction, dimethylamine, and compared their experimental results to those of a computer modeling program before testing the four other precursors. The model, which doesn't include a reaction from monochloramine and dimethylamine to NDMA, matched their experimental results and proved that formation of NDMA from monochloramine either doesn't exist or is unimportant.

"Our paper showed that dichloramine is responsible for the formation of NDMA from these pharmaceutical-derived precursors. And we were able to see that you get more and more NDMA as you increase monochloramine, but that's just because of monochloramine going to dichloramine," McCurry said. "So, our results from fundamental chemistry work support the practical observation that minimizing dichloramine minimizes NDMA formation."

While their study confirms the identity of the compound responsible for NDMA formation and encourages treatment plants to continue implementing intervention methods, their work is far from complete. Shiyang Huang is currently working on a model that will show in detail the complete mechanism of NDMA formation.

"Our results are based on NDMA yield experiments that only consider the final products of the reactions. The exact pathway from precursors to NDMA has not been discovered yet," Shiyang Huang said. "Understanding the complete mechanism would give us more information to explain what factor - pH, temperature, other chemicals - would affect NDMA formation in practice."

About a third of all Swiss exports result from fundamental discoveries in synthetic chemistry. Certain drugs and perfumes, as well as food and agricultural products -- and even Ferrari's famous red colour - are derived from new molecular structures invented by Swiss scientists. Chemists at the University of Geneva (UNIGE), Switzerland, have just discovered that chemical bonds based on antimony -- a forgotten element at the very bottom of the periodic table -- yield powerful new catalysts that can be used to accurately stimulate the transformation of a molecule from within. These bonds complement existing interactions such as conventional hydrogen bonds or the more recent chalcogen bonds with sulfur. This finding, published in the journal Angewandte Chemie, will lead to the creation of innovative materials that will become part of our daily lives. It has triggered a small revolution in the world of synthetic chemistry, which had always believed that there was a limit to the number of possible bonds to build new catalysts.

Basic research in chemistry requires creativity. But the chemist, a true sculptor of molecular structures, needs specific tools. To induce a molecular transformation, the molecule that the scientist wants to alter -- the substrate -- must enter into contact with an element from the periodic table in the catalyst. Under normal conditions, the contact -- or bond -- used is with hydrogen. But the creative possibilities are reduced when restricted to this single element. Finding new ways to initiate contact between molecules would make it possible to transform them differently, thereby enabling chemists to create new materials. "That's why my team is constantly looking for new bonds for catalysis," explains Stefan Matile, a professor in the Department of Organic Chemistry in UNIGE's Faculty of Science. "After discovering the sulfur-based bond for catalysis, called the chalcogen, two years ago, we decided to look at another category in the periodic table, pnictogen elements, which are distinguished by their metallic components." Nitrogen, phosphorus, arsenic, antimony and bismuth all belong to this category.

Elements revealed using empty space

Unearthing new bonds for the catalysis requires innovation. "Research usually focuses on studying the electrons of the elements. We took the opposite approach: we only examined the empty spaces left by the electrons, which are essential for molecular construction, so we could look for possible new interactions", continues professor Matile. And rightly so, since heavy pnictogen elements, like ripe fruits, are more flexible and deformable than, for instance, hydrogen, which is very compact. In this way, the empty spaces become more accessible and intelligible for the chemists.

Seven elements were chosen by the UNIGE scientists. "Theoretical calculations make for a better visualisation of the empty spaces," says Amalia I. Poblador-Bahamonde, a researcher in the Organic Chemistry Department in the Faculty of Science. "That's why we first carried out computer modeling of the seven elements alone so we could visualise where both the electrons and the empty spaces were located. We then did it again with the molecules to be tested in order to measure the strength of the new bond." The more visible the molecule's empty spaces became, the better the bond works, and the element is a better catalyst. At this theoretical stage, antimony turned out to be the best of the seven elements tested. The findings encouraged the chemists to focus on elements at the bottom of the periodic table, an area that is little explored in organic chemistry.

An element that has been ignored since ancient Egypt

Basing their work on the theoretical modeling, the chemists studied the bonds using nuclear magnetic resonance, which makes it possible to visualise the molecules and the transformations in their structure. "Our results were perfectly consistent with the theoretical predictions," points out Sebastian Benz, a PhD student in professor Matile's team. "Antimony proved to be ultra-efficient once more, up to 4,000 times faster than the other elements tested in creating a new structure!"

Antimony turned out to be a surprise for the UNIGE researchers. It was used as eye makeup in ancient Egypt before falling into oblivion. This research puts the element firmly back into the spotlight, all thanks to the exceptional qualities it showed for molecular transformation. "Antimony is not only ultra-fast but also - unlike other catalysts that act on the molecule's surface - it works from within. This impacts on the material's entire environment and enables the chemist to be more precise when undertaking the transformations," continues professor Matile.

The pnictogen bonds with antimony are the third bonds for catalysis discovered by the UNIGE chemists, following anion-π bonds and chalcogen bonds with sulfur. All three introduce new ways of looking at molecular transformations and open up untried prospects. "We don't intend to stop there, of course: we're going to keep on looking for new bonds and ways in which we can make use of them!" says professor Matile. Illustrative examples for these bright perspectives are the first enzymes that work with anion-π bonds, made in the National Centre of Competence in Research (NCCR) Molecular Systems Engineering, and the first fluorescent probes that can visualise mechanical forces in living cells thanks to chalcogen bonds with sulfur, made in the NCCR Chemical Biology at UNIGE.

NEW ORLEANS, March 21, 2018 -- Adults over the age of 45 who consume large amounts of sugary beverages including soft drinks, fruit drinks and fruit juices may have a higher risk of dying from heart disease or other causes, compared to those who drink fewer sugary drinks, according to preliminary research presented at the American Heart Association's Epidemiology and Prevention | Lifestyle and Cardiometabolic Health Scientific Sessions 2018, a premier global exchange of the latest advances in population based cardiovascular science for researchers and clinicians.

The researchers found a graded association between consuming more sugary beverages and an increased risk of death from heart disease or any cause. Study participants in the top 25 percent of consumers, those who tended to drink 24 ounces or more of sugary beverages each day, had twice the risk of death from coronary heart disease compared to those in the lowest 25 percent of people who drank less than 1 ounce. In addition, there was an increased risk of death from all causes, including other cardiovascular conditions. The study, however, found no link between the consumption of sugary foods and increased risk of death, a distinction the researchers said may be related to how sugary drinks and foods are processed by the body.

Several studies have shown an association between added sugar and obesity and various chronic diseases. However, few have been able to look at the association between increased sugar consumption and death. It is important to note that this study does not prove cause and effect, rather it identifies a trend.

"There were two parts of this question we wanted to understand," said Jean Welsh, Ph.D., M.P.H., study author, assistant professor at Emory University and a research director with Children's Healthcare of Atlanta. "Do added sugars increase risk of death from heart disease or other causes, and, if so, is there a difference in risk between sugar-sweetened beverages and sugary foods? We believe this study adds strong data to what already exists highlighting the importance of minimizing sugary beverages in our diet."

This study used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a U.S.-based longitudinal study of 30,183 black and white adults over age 45. The final study population was 17,930 after excluding those with a self-reported history of heart disease, as well as stroke and Type 2 diabetes. This type of study is designed to find an association or trend, not to prove cause and effect.

The researchers estimated sugary food and beverage consumption using a food frequency questionnaire. Sugar-sweetened beverages included those pre-sweetened, such as sodas and fruit drinks. Sugar-sweetened foods included desserts, candy and sweetened breakfast foods as well as foods to which calorie-containing sweeteners such as sugars or syrups had been added.

The participants were followed for an average of about 6 years, and researchers used death records to look at the cause of death, focusing on deaths from heart disease, such as heart attack, heart failure and deaths from all other causes.

The researchers observed this effect when they statistically made the participants equal with respect to income, race, education, smoking history and physical activity. When they controlled for known heart disease risk factors such as total calorie consumption, high blood pressure, abnormalities in blood lipids or body weight, the effect remained. Researchers did not see any increased risk with consumption of sugary foods.

The quantity and frequency of consumption of sugary beverages, coupled with the fact that they contain few, if any other nutrients, results in a flood of sugars that need to be metabolized, Welsh said. When people consume sugars in foods there are often other nutrients such as fats or proteins which slow down metabolism and may explain the different effect seen between the two.

The study's finding should encourage healthcare providers to ask patients about sugary beverage consumption during well visits to open the door to a conversation about a dietary change that could be made to reduce risk, Welsh said.

"We know that if healthcare providers don't ask patients about lifestyle practices linked to obesity and chronic disease, patients tend to think they're not important," Welsh said. "Simply asking patients about their sugary beverage consumption is valuable."

Scientists have found that high carbon dioxide levels cause squid to bungle attacks on their prey.

PhD candidate Blake Spady from the ARC Centre of Excellence for Coral Reef Studies (Coral CoE) at James Cook University (JCU) led the investigation. He said that the oceans absorb more than one-quarter of all the excess carbon dioxide (CO2) released into the atmosphere by humans and this uptake of additional CO2 causes seawater to become more acidic.

"Climate models project that unless there is a serious commitment to reducing emissions, CO2 levels will continue increasing this century to reach levels that will have far-reaching effects on sea life," he said.

Mr Spady said the team chose to study cephalopods (a group that includes squid, cuttlefish and octopuses) because while most previous behavioural studies have focused on fishes, the effects of elevated CO2 on highly active invertebrates is largely unknown.

"Cephalopods also prey on just about anything they can wrap their arms around and are themselves preyed upon by a wide range of predator species, so they occupy an important place within marine food webs."

The scientists tested the effects of elevated CO2 on the hunting behaviours of pygmy squid and bigfin reef squid.

"For pygmy squid, there was a 20% decrease in the proportion of squid that attacked their prey after exposure to elevated CO2 levels. They were also slower to attack, attacked from further away, and often chose more conspicuous body pattern displays at elevated CO2 conditions.

Bigfin reef squid showed no difference in the proportion of individuals that attacked prey, but, like the pygmy squid, they were slower to attack and used different body patterns more often."

Mr Spady said both species showed increased activity at elevated CO2 conditions when they weren't hunting, which suggests that they could also be adversely altering their 'energy budgets'.

"Overall, we found similar behavioural effects of elevated v on two separate cephalopod orders that occupy largely distinct niches. This means a variety of cephalopods may be adversely affected by rising CO2 in the oceans, and that could have significant consequences in marine ecosystems," said co-author Dr Sue-Ann Watson.

"However, because squid have short lifespans, large populations, and a high rate of population increase, they may have the potential to adapt to rapid changes in the physical environment," Mr Spady added.

"The fast lifestyle of squid could mean they are more likely to adapt to future ocean conditions than some other marine species, and this is the next question we intend to investigate."

Alexandria, VA, USA - The 47th Annual Meeting of the American Association for Dental Research (AADR), held in conjunction with the 42nd Annual Meeting of the Canadian Association for Dental Research (CADR), featured a symposium titled "Three-dimensional Printing and Bioprinting for Tissue Engineering." The AADR/CADR Annual Meeting is in Fort Lauderdale, Fla., USA from March 21-24, 2018.

Dental, oral and craniofacial tissues are complex structures requiring simultaneous regeneration of various tissues. This, in turn, causes major limitations in relation to conventional regenerative procedures.

3-D printing technologies have been introduced into both clinical dentistry and dental/craniofacial research with claims to eliminate these limitations. This symposium aims to review current developments and challenges in research related to 3-D printing and bioprinting technologies for regeneration of dental, craniofacial and oral structures.

The symposium featured the topics "Guided Self-assembly and Coding of Three-dimensional Living Architectures" by Utkan Demirci, Stanford University School of Medicine, Palo Alto, Calif., "3D-printing Constructs for Treatment of Critically-Sized Oral and Craniofacial Defects" by Lobat Tayebi, Marquette University School of Dentistry, Milwaukee, Wis., "Geometric Controls of Periodontal Tissue Regeneration Using 3-D Printing Technology" by Chan Ho Park, Seoul National University Dental Research Institute, Republic of Korea and "3-D Printing Technology for Periodontal/Peri-implant Regeneration" by Sophia Pilipchuk, University of Michigan, Ann Arbor, Mich.