A long-standing challenge in synthetic biology has been to create gene circuits that behave in predictable and robust ways. Mathematical modeling experts from the University of Houston (UH) collaborated with experimental biologists at Rice University to create a synthetic genetic clock that keeps accurate time across a range of temperatures. The findings were published in a recent issue of the Proceedings of the National Academy of Sciences.

“Synthetic gene circuits are often fragile, and environmental changes frequently alter their behavior,” said Krešimir Josić, professor of mathematics in UH’s College of Natural Sciences and Mathematics. “Our work focused on engineering a gene circuit not affected by temperature change.”

Synthetic biology is a field in which naturally occurring biological systems are redesigned for various purposes, such as producing biofuel. The UH and Rice research targeted the bacterium E. coli.

“In E. coli and other bacteria, if you increase the temperature by about 10 degrees the rate of biochemical reactions will double – and therefore genetic clocks will speed up,” Josić said. “We wanted to create a synthetic gene clock that compensates for this increase in tempo and keeps accurate time, regardless of temperature.”

The UH team, led by Josić and William Ott, an assistant professor of mathematics, collaborated with the lab of Matthew Bennett, assistant professor of biochemistry and cell biology at Rice. Josić, Bennett and Ott have been working together on various research projects for three years. The team also included UH postdoctoral fellow Chinmaya Gupta.

According to Bennett, the ability to keep cellular reactions accurately timed, regardless of temperature, may be valuable to synthetic biologists who wish to reprogram cellular regulatory mechanisms for biotechnology.

The work involved engineering a gene within the clock onto a plasmid, a little piece of DNA that is inserted into E. coli. A mutation in the gene had the effect of slowing down the clock as temperature increased.

UH researchers created a mathematical model to assess the various design features that would be needed in the plasmid to counteract temperature change. Gupta showed that the model captured the mechanisms essential to compensate for the temperature-dependent changes in reaction rates.

The computational modeling confirmed that a single mutation could result in a genetic clock with a stable period across a large range of temperatures – an observation confirmed by experiments in the Bennett lab. Josić’s team then confirmed the predictions of the models using real data.

“Having a mechanistic model that allows you to determine which features are important and which can be ignored for a genetic circuit to behave in a particular way allows you to more efficiently create circuits with desired properties,” Gupta said. “It allows you to concentrate on the most important factors necessary in the design.”

“Throughout this work, we used mathematical models to find out what is important in designing robust synthetic gene circuits,” Josić said. “Computational and mathematical tools are essential in all types of engineering. Why not for biological engineering?”

Josić, Ott and Bennett’s research is funded by the National Institutes of Health through the joint National Science Foundation/National Institute of General Medical Sciences Mathematical Biology Program.

Story written by Kathy Major, College of Natural Sciences and Mathematics.

About the University of Houston

The University of Houston is a Carnegie-designated Tier One public research university recognized by The Princeton Review as one of the nation’s best colleges for undergraduate education. UH serves the globally competitive Houston and Gulf Coast Region by providing world-class faculty, experiential learning and strategic industry partnerships. Located in the nation’s fourth-largest city, UH serves more than 39,500 students in the most ethnically and culturally diverse region in the country. For more information about UH, visit the university’s newsroom at http://www.uh.edu/news-events/.

About the College of Natural Sciences and Mathematics

The UH College of Natural Sciences and Mathematics, with 193 ranked faculty and nearly 6,000 students, offers bachelor’s, master’s and doctoral degrees in the natural sciences, computational sciences and mathematics. Faculty members in the departments of biology and biochemistry, chemistry, computer science, earth and atmospheric sciences, mathematics and physics conduct internationally recognized research in collaboration with industry, Texas Medical Center institutions, NASA and others worldwide.

Highlights from GSA Bulletin articles published online on 20 March through 1 April 2014 include a discussion of a catastrophic rock avalanche in the Atlas Mountains of Morocco 4,500 years ago and that village situated there now; evidence of rain and humidity in ancient soils in the western United States; a contribution to the on-going EarthTime initiative, which is working to refine and calibrate deep time geochronometers; and a call for intensive field studies in volcanic areas.

GSA Bulletin articles published ahead of print are online at http://gsabulletin.gsapubs.org/content/early/recent; abstracts are open-access at http://gsabulletin.gsapubs.org/.

Highlights are provided below.

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Catastrophic rock avalanches in a glaciated valley of the High Atlas, Morocco: 10Be exposure ages reveal a 4.5 ka seismic event
Phillip D. Hughes et al., School of Environment, Education and Development, The University of Manchester, Manchester M13 9PL, UK. Published online 20 Mar. 2014; http://dx.doi.org/10.1130/B30894.1.

A huge, catastrophic rock fall occurred 4,500 years ago in the high Atlas Mountains, Morocco. The timing of this event has been determined using exposure-age dating. The collapse of the northwest face of Mount Aksoual, which reaches a height of nearly 13,000 ft (4000 m), caused large-scale landscape change. the rock fall represents one of the biggest recorded in Africa and sits below a cliff face 6500 ft (2000 m) high, close to an active tectonic fault. Today, a village sits precariously on this huge mass of boulders.

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Early to Middle Ordovician back-arc basin in the southern Appalachian Blue Ridge: Characteristics, extent, and tectonic significance
James Tull et al., Florida State University, Earth Ocean and Atmospheric Science, Tallahassee, Florida 32306-4520, USA. Published online 20 Mar. 2014; http://dx.doi.org/10.1130/B30967.1.

This paper by James Tull and colleagues links the stratigraphy and tectonic history of a large segment of the southern Appalachian Blue Ridge and adjacent areas in Alabama, Georgia, and North and South Carolina to a common tectonic setting: formation within an Ordovician (about 480 to 460 million years ago) proto-North American (Laurentian) back-arc basin. The tectonic setting suggested by this study indicates that the Taconic (early to middle Ordovician time) orogeny in the southernmost Appalachians differs from that in the northern Appalachians, and began as an extensional accretionary orogen along the outer margin of the Laurentian continent, rather than resulting from an exotic (non-Laurentian) arc collisional setting.

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Analogue modeling of positive inversion tectonics along differently oriented pre-thrusting normal faults: An application to the Central-Northern Apennines of Italy
Alessandra Di Domenica et al., Dipartimento di Ingegneria e Geologia, Università degli Studi “G. d’Annunzio” Chieti-Pescara, Campus Universitario Madonna delle Piane, Via dei Vestini, 31-66013 Chieti Scalo (CH), Italy. Published online 20 Mar. 2014; http://dx.doi.org/10.1130/B31001.1.

Alessandra Di Domenica and colleagues created a sandbox experiment to test the influence of preexisting discontinuities on foreland fold-and-thrust systems development. The model provide innovative results concerning the development of a chain, in terms of thrusts geometry and tectonic styles, highlighting the role exerted by coexisting differently oriented inherited faults. The experimental setup design was based on field data and observations collected in the Central-Northern Apennine chain (Italy).

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Multiproxy approach reveals evidence of highly variable paleoprecipitation in the Upper Jurassic Morrison Formation (western United States)
Timothy S. Myers et al., Roy M. Huffington Dept. of Earth Sciences, Southern Methodist University, Dallas, Texas 75275, USA. Published online 20 Mar. 2014; http://dx.doi.org/10.1130/B30941.1.

Geochemical analyses of ancient soils in the western United States provide estimates of rainfall and humidity during deposition of the Morrison Formation in the Late Jurassic, approximately 150 million years ago. Weathering indices, used as proxies for rainfall, indicate that precipitation was highly variable within the Morrison depositional basin, with estimates ranging from 50 to 1200 mm per year and averages around 800 mm per year. These estimates of ancient precipitation indicate that aridity decreased over time, and there was an abrupt transition from relatively dry southern environments to wetter northern environments. Humidity regimes inferred from geochemical proxies range from semiarid to humid, suggesting somewhat wetter conditions than the precipitation estimates. The inferred paleo-precipitation patterns do not match the modern latitudinal distribution of rainfall that arises from zonal atmospheric circulation.

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Integrating 40Ar/39Ar, U-Pb, and astronomical clocks in the Cretaceous Niobrara Formation, Western Interior Basin, USA
Bradley B. Sageman et al., Dept. of Earth and Planetary Sciences, Northwestern University, 1850 Campus Drive, Evanston, Illinois 60208, USA. Published online 20 Mar. 2014; http://dx.doi.org/10.1130/B30929.1.

This study by Brad Sageman and colleagues develops and applies new methods for refinement of the geologic time scale to a key Late Turonian through Early Campanian (Late Cretaceous, about 80 to 90 million years ago) succession in the Western Interior Basin of North America. Integration of new high-precision radioisotope dates using both Ar-Ar and U-Pb systems, and floating astrochronologies developed from spectral analysis of the chalk and marl beds of the Niobrara Formation, produce revised estimates for these age boundaries. Sageman and colleagues introduce a new method of estimating uncertainties due to geologic correlation and combines these with astrochronologic uncertainties and those associated with radioisotopic methods to achieve comprehensive total uncertainty estimates for the Stage boundary ages. The co-occurrence of U-Pb and Ar-Ar data from the same ashes allows confirmation of the recently revised age for the Fish Canyon monitor mineral (28.201 million years old) and thereby makes a contribution to the on-going EarthTime initiative, which is working to refine and calibrate deep time geochronometers.

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Testing the astronomical time scale for oceanic anoxic event 2, and its extension into Cenomanian strata of the Western Interior Basin (USA)
Chao Ma et al., Department of Geoscience, University of Wisconsin–Madison, 1215 W Dayton Street, Madison, Wisconsin 53706, USA. Published online 27 Mar. 2014; http://dx.doi.org/10.1130/B30922.1.

Late Cretaceous strata of the Western Interior Basin, USA, preserve astronomically influenced sedimentation and abundant volcanic ash beds, providing a remarkable opportunity to develop integrated astronomical and radioisotopic time scales. Chao Ma and colleagues used X-ray fluorescence (XRF) core scanning to develop a new elemental data set for cyclostratigraphic investigation of Cenomanian/Turonian strata, including the uppermost Lincoln Limestone Member, the Hartland Shale Member, and the Bridge Creek Limestone Member. 40Ar/39Ar ages from ashes in three biozones, including a new age from the uppermost Lincoln Limestone Member, provide geochronologic constraints for the cyclostratigraphic analysis. Ma and colleagues note that results from the Bridge Creek Limestone Member are consistent with the previously published astrochronology from the USGS #1 Portland core. They note that identification of an astronomical signal in the underlying Hartland Shale Member permits extension of the Western Interior Basin astrochronology into the earlier Cenomanian, prior to Oceanic Anoxic Event 2 (OAE2). High rates of sedimentation in the Angus core during the interval of OAE 2 initiation allow recognition of a strong precessional control on bedding development. As a consequence, the new results provide a rare high-resolution chronometer for the onset of OAE 2, and the timing of proposed hydrothermal trace metal enrichment as observed in the XRF data.

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Landscape modification in response to repeated onset of hyperarid paleoclimate states since 14 Ma, Atacama Desert, Chile
Teresa E. Jordan et al., Department of Earth & Atmospheric Sciences, Cornell University, Ithaca, New York 14853-1504, USA. Published online 1 Apr. 2014; http://dx.doi.org/10.1130/B30978.1.

The Atacama Desert of western South America is an extreme environment that spans from the western flank of the Andes Mountains to the Pacific coast. Where annual rainfall is less than 5 mm, there is no plant life, and water almost never flows either in abandoned stream channels or on hill sides. Given millions of years of time to act, the Atacama Desert processes that shape the landscape and develop soils create a mixture of materials on the desert floor that are unique. By studying the record of landforms and soils in a valley in which sediments are trapped, authors Teresa E. Jordan and colleagues demonstrate that the Atacama Desert has been hyperarid for 12 million years. Yet, like all other places on Earth, the climate changed repeatedly. Whereas the growth of height of the Andes Mountains may have set in place a necessary condition to initiate extreme aridity, it is likely that changes in the temperature of the Pacific Ocean set the pace for the repeated climate shifts of the last six million years.

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Age and eruptive center of the Paeroa Subgroup ignimbrites (Whakamaru Group) within the Taupo Volcanic Zone of New Zealand
D.T. Downs et al., School of Environment, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Published online 1 Apr. 2014; http://dx.doi.org/10.1130/B30891.1.

The Whakamaru Group ignimbrites are the result of the largest rhyolitic eruption within New Zealand and one of the largest eruptions of the past million years. This study by D.T. Downs and colleagues demonstrates that this eruptive episode was more prolonged and complex than previously documented. There were at least two distinct eruptive episodes from geographically separate vents. The distribution and locations of vent derived lithic clasts within the younger part of the Whakamaru Group (termed the Paeroa Subgroup) indicates that these ignimbrites erupted in non-energetic manner, and from a linear vent zone source. This Paeroa linear vent zone coincides with the preset-day Paeroa Fault, and eruptions are speculated to have occurred in a fissure style. No caldera has been identified for such a large eruption, and collapse maybe concealed as fault related movement and/or collapse in adjacent calderas. Downs and colleagues note that the results of this study demonstrate the need for intensive field studies in volcanic areas, and that structural controls may play an as yet unknown role in controlling vent locations and eruptive styles.

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Mid-Miocene rhyolite volcanism in northeastern Nevada: The Jarbidge Rhyolite and its relationship to the Cenozoic evolution of the northern Great Basin (USA)
Matthew E. Brueseke et al., Department of Geology, Kansas State University, 108 Thompson Hall, Manhattan, Kansas 66506, USA. Published online 1 Apr. 2014; http://dx.doi.org/10.1130/B30736.1.

This study of the Jarbidge Rhyolite by Matthew E. Brueseke and colleagues focuses on understanding the occurrence and cause of widespread mid-Miocene felsic volcanism in the northern Great Basin, USA. Physical characteristics, whole rock geochemistry, 40Ar/39Ar geochronology, and oxygen isotope data indicate that at least 500 cubic kilometers of primarily phenocryst-rich rhyolite lavas erupted 15 to 16.1 million years ago in the vicinity of the Jarbidge Mountains (Nevada). Brueseke and colleagues interpret the distribution of the Jarbidge Rhyolite in northeastern Nevada to reflect an intimate association with temporally and spatially coincident extension that resulted from the rapid collapse of the Nevadaplano high plateau approx. 17 to 16 million years ago, rather than the Yellowstone hotspot and its interaction with North America.

Source: www.geosociety.org

A research team led by a cell biologist at the University of California, Riverside has generated a 3D model of the human malaria parasite genome at three different stages in the parasite’s life cycle — the first time such 3D architecture has been generated during the progression of the life cycle of a parasite.

The parasite that causes malaria in humans is Plasmodium falciparum. The female Anopheles mosquito transmits P. falciparum from an infected human to healthy individuals, spreading malaria in the process. According to the World Health Organization, an estimated 207 million people were infected with malaria in 2012, leading to 627,000 deaths.

“Understanding the spatial organization of chromosomes is essential to comprehend the regulation of gene expression in any eukaryotic cell,” saidKarine Le Roch, an associate professor ofcell biology and neuroscience, who led the study.

Her research team also found that those genes that need to be highly expressed in the malaria parasite — for example, genes involved in translation — tend to cluster in the same area of the cell nucleus, while genes that need to be tightly repressed — for example, genes involved in virulence — are found elsewhere in the 3D structure in a “repression center.” The 3D structure for the malaria parasite genome revealed one major repression center.

Virulence genes in the malaria parasite are a large family of genes that are responsible for the parasite’s survival inside humans. Le Roch’s team found that these genes, all organized into one repression center in a distinct area in the nucleus, seem to drive the full genome organization of the parasite.

Video here

Study results appeared online last week in Genome Research, an international, peer-reviewed journal that features outstanding original research providing novel insights into the genome biology of all organisms. The research paper will appear in print in the June issue of the journal.

“We successfully mapped all physical interactions between genetic elements in the parasite nucleus,” Le Roch said. “To do so, we used a ‘chromosome conformation capture method,’ followed by high throughput sequencing technology — a recently developed methodology to analyze the organization of chromosomes in the natural state of the cell. We then used the maps of all physical interactions to generate a 3D model of the genome for each stage of the parasite life cycle analyzed.”

To understand the biology of an organism or any cell type, scientists need to understand not only the information encoded in the genome sequence but also how the sequence is compacted and physically organized in each cell/tissue, and how changes in the 3D genome architecture can play a critical role in regulating gene expression, chromosome morphogenesis and genome stability. In human cells, changes in chromosome organization and compaction can lead to diseases such as cancer.

“If we understand how the malaria parasite genome is organized in the nucleus and which components control this organization, we may be able to disrupt this architecture and disrupt, too, the parasite development,” Le Roch said. “We know that the genome architecture is critical in regulating gene expression and, more important, in regulating genes that are critical for parasite virulence. Now we can more carefully search for components or drugs that can disrupt this organization, helping in the identification of new anti-malaria strategies.”

Le Roch’s lab is now looking at other stages of the malaria life cycle in order to identify components responsible for the 3D genome architecture.

“The importance of the genome architecture was initially thought to be critical for only higher eukaryotes,” she explained. “But we found, to our surprise, that the genome architecture is closely linked to virulence even in the case of the malaria parasite.”

Le Roch was joined in the study by Evelien M. Bunnik (co-first author of the research paper), Sebastian M. Bol, Jacques Prudhomme at UC Riverside; Ferhat Ay (co-first author of the research paper) and William Stafford Noble at the University of Washington; Nelle Varoquaux (co-first author of the research paper) and Jean-Phillippe Vert at Mines ParisTech, France.

The study was supported by grants to Le Roch and Noble from the National Institutes of Health, and other grants to Ay, Bunnik and Vert.

The University of California, Riverside is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California’s diverse culture, UCR’s enrollment has exceeded 21,000 students. The campus opened a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual statewide economic impact of more than $1 billion.

For the first time, researchers have been able to demonstrate that the use of helium ions in radiation therapy could provide accurate treatment to tumours while helping to spare healthy organs. A treatment planning study to be presented at the ESTRO 33 congress today [Sunday] has been able to show that helium may have effects that are superior to radiotherapy using protons, themselves a considerable advance on conventional photon beam radiotherapy.

Mr Hermann Fuchs, a PhD student at the Medical University of Vienna/AKH Vienna, Austria, working with Dr Barbara Knäusl and Professor Dietmar Georg, set out to devise a method of calculating the optimal dose of helium ions for use in radiation treatment. The dose calculation algorithm was then used for treatment plan calculation for ten paediatric patients, five with neuroblastoma (tumours arising in cells of the hormonal and nervous system), and five with Hodgkin’s lymphoma (a cancer of the white blood cells).

“Particle beam therapy involving protons or carbon ions has advantages over conventional radiotherapy. Helium ions may represent another kind of particle that can improve radiotherapy treatment. Due to their increased mass, spreading of the beam is reduced by a factor of two as compared with protons. Moreover helium ions have an increased biological effectiveness at the end of their range,” Mr Fuchs explains.

Heavier ions like carbon have the potential to kill cancer cells more effectively due to their underlying biology. But by modelling these biological processes, large uncertainties are introduced, and these can be reduced by using lighter ions like helium. “Helium ions reside in the low Linear Energy Transfer (LET) area,” says Mr Fuchs. “LET is a physical quantity describing how much energy of a particle is deposited at a given range, and this measure is important when looking at the biological effects of therapy.”

This greater accuracy and sparing of normal tissue is very important in the case of children, the researchers say. When treating them it is particularly important to ensure that as little dose of radiation as possible is deposited outside the area to be treated, since an increased area treated with a low dose can lead to the development of secondary cancers. Given that children have a potentially long lifespan ahead of them, this probability needs to be reduced as much as possible through the use of therapies that are targeted as accurately as possible to the tumour, while sparing the dose to surrounding areas, and especially to healthy organs particularly sensitive to radiation located nearby (the organs at risk).

“After three years of extensive research and validation efforts, we were able to produce a treatment planning algorithm that enabled us to investigate the possibilities for using helium ion therapy in children treated with low dose radiation. We would now like to investigate its potential in patients being treated with higher doses, for example, those with brain tumours. The good results that have been achieved so far warrant the verification of the model in order to investigate the real clinical potential of helium ions,” Mr Fuchs will say. “In the long term, clinical trials of this therapy will be needed to substantiate the effects of our treatment planning model.

“Particle beam therapy has already advanced care and treatment options for cancer patients. We hope that the use of helium ions may help to bring about further improvements,” he will conclude.

President of ESTRO, Professor Vincenzo Valentini, a radiation oncologist at the Policlinico Universitario A. Gemelli, Rome, Italy, commented: “This is an exciting study that holds out hope for improved, more accurate radiation treatment for young cancer patients.”

Source: European Society for Radiotherapy and Oncology (ESTRO)

A study by researchers at the University of Geneva concludes that prevalent ankle fractures should be considered as osteoporotic fractures and taken into account in fracture-risk assessment.

The research was presented at the World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases in Seville, Spain.

After vertebral fractures, ankle fractures are among the most common fractures in adults. The objective of this study was to investigate the association between bone microstructure in women at the age of 65 and prevalent ankle fracture.

The study evaluated 749 women aged 65.0±1.4 (x±SD) years, with or without prevalent ankle or forearm fracture. Researchers determined distal radius cortical and trabecular bone microstructure by HR-pQCT, together with areal BMD (aBMD) by DXA. Dietary protein and calcium intakes, and physical activity were evaluated by questionnaires.

Prevalent ankle and forearm fractures (both having occurred after the age of 20) were found in 8.0% and 7.8% of the women, respectively. As compared with women without prevalent fracture, and after adjustment for height, weight, dietary intakes and physical activity, postmenopausal women with prevalent ankle fractures, had lower aBMD (spine: −7.7 %, femoral neck: −6.4 %, distal third radius: −4.1 %), and lower distal radius total volumetric BMD (−7.9 %), cortical thickness (−7 %) and bone volume (BV/TV) (−10.9 %). There was no statistically significant difference in aBMD between women with prevalent ankle and forearm fracture.

Dr Emmanuel Biver MD, Department of Bone Diseases, University Hospital of Geneva, stated, “These results show lower aBMD and altered bone microstructure in postmenopausal women with prevalent ankle or forearm fracture. This suggests that ankle fractures, like forearm fractures, should be considered in the category of osteoporotic fractures and taken into account in risk assessment for secondary fracture prevention.”

Secondary fracture prevention is a key focus of IOF’s global campaign ‘Capture the Fracture’ which seeks to promote the implementation of coordinator-based fracture liaison services in hospitals and clinics worldwide.

Abstracts from IOF-ESCEO World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases: http://www.wco-iof-esceo.org

About IOF

The International Osteoporosis Foundation (IOF) is the world’s largest nongovernmental organization dedicated to the prevention, diagnosis and treatment of osteoporosis and related musculoskeletal diseases. IOF members, including committees of scientific researchers, leading companies, as well as more than 200 patient, medical and research societies, work together to make bone, joint and muscle health a worldwide heath care priority. http://www.iofbonehealth.org ;
http://www.facebook.com/iofbonehealth ;
http://twitter.com/iofbonehealth#OsteoCongress

About Capture the Fracture

Capture the Fracture is a multi-stakeholder initiative led by the International Osteoporosis Foundation. The initiative hopes to drive change so that secondary fracture prevention becomes a reality around the world. It aims illustrate global best practice for FLS; set benchmarks to which clinics and hospitals can aspire; provide essential resources and documentation; give international recognition to FLS programmes around the world; and establish mentoring and grant programmes to assist development of FLS at the local level. http://www.capturethefracture.org