From Pig to Fuel - Anaerobic digester generates energy, reduces odors

 Teng Lim is operating a small-scale anaerobic digester at the MU swine farm in Columbia. The system generates energy and can mitigate hog odor. Courtesy Jon Lamb.

The University of Missouri has unveiled a prototype small-scale anaerobic digestion system that produces biogas from pig manure. The biogas can be used to heat a farm and create electricity. The device also reduces odor from swine operations.

“What we want to do is improve and fully utilize all the biogas for energy production,” said Teng Lim, Extension Ag Systems Management associate professor.

Funded by the MU College of Agriculture, Food and Natural Resources, the anaerobic digester consists of three tanks. Manure from the hog barn pit is pumped into one tank where the manure is stored and mixed. The anaerobic digestion takes place in the other two tanks, where bacteria break down the manure in these warm and oxygen-free tanks.

The biogas from the manure can be used for electricity and hot water production. With some further treatment it can also be stored as a compressed natural gas, for heating or even vehicle fuel.

PigsLim says a larger scale digester could supply a farm’s energy needs and also be sold to the grid to provide electricity to the community.

There are other benefits to anaerobic digestion in addition to energy generation. The digested manure retains the nutrients to be good fertilizer while becoming a more consistent product. Also, the digester can reduce odor emissions.

“When the manure is treated by the digester process the odor concentration is significantly reduced,” Lim said. “There is still going to be odor, but it’s going to be much lower and less fluctuation than the raw manure.”

A Lot of Pork

The swine industry is big in the United States – there are 73,150 pork farms in America with 120 million pigs marketed each year.

Before the 1960s, most pork in the U.S. was raised in outside lots or on pasture systems. With the development of slotted floors and liquid manure handling equipment, it became possible for producers to more easily care for larger numbers of animals. Enclosed buildings overcame most weather problems and predators, and minimized the potential pollution from outside lot runoff.

Typically, pig odor is a localized air quality problem, with low concentrations of odorous gases such as p-cresol. Odor problems are often a starting point for litigation. Many farmers can go out of business just fighting a lawsuit.

An Important Part of Future Farms?

There are challenges to anaerobic digestion, the biggest being cost and management. In a commercial setting the digester would be 100 times larger than the one at MU’s swine research facility.

Lim pointed out that industry leaders and scientists believe anaerobic digesters will be an important piece of future farms, both to mitigate odor and for generating renewable energy.  The cost is a major obstacle now. The team is working closely with industry experts from Martin Machinery, a Missouri company who specializes in biogas generators and control systems.

MU researchers are using the scaled down digester to find ways to make digesters more affordable and easier to manage. They are also using it as an education tool to show producers the potentials, what it takes to process the manure, and to train people how to properly run a system like this.

Source: Cafnr

SETTLING FOR ‘MR. RIGHT NOW’ BETTER THAN WAITING FOR ‘MR. RIGHT’

Evolutionary researchers have determined that settling for “Mr. Okay” is a better evolutionary strategy than waiting for “Mr. Perfect.” When studying the evolution of risk aversion researchers found that it is in our nature – traced back to the earliest humans – to take the safe bet when stakes are high, such as whether or not we will mate. Photo by D.L. Turner

Evolutionary researchers have determined that settling for “Mr. Okay” is a better evolutionary strategy than waiting for “Mr. Perfect.”

When studying the evolution of risk aversion, Michigan State University researchers found that it is in our nature – traced back to the earliest humans – to take the safe bet when stakes are high, such as whether or not we will mate.

“Primitive humans were likely forced to bet on whether or not they could find a better mate,” said Chris Adami, MSU professor of microbiology and molecular genetics and co-author of the paper.

“They could either choose to mate with the first, potentially inferior, companion and risk inferior offspring, or they could wait for Mr. or Ms. Perfect to come around,” he said. “If they chose to wait, they risk never mating.”

Adami and his co-author Arend Hintze, MSU research associate, used a computational model to trace risk-taking behaviors through thousands of generations of evolution with digital organisms. These organisms were programmed to make bets in high-payoff gambles, which reflect the life-altering decisions that natural organisms must make, as for example choosing a mate.

“An individual might hold out to find the perfect mate but run the risk of coming up empty and leaving no progeny,” Adami said. “Settling early for the sure bet gives you an evolutionary advantage, if living in a small group.”

Adami and his team tested many variables that influence risk-taking behavior and concluded that certain conditions influence our decision-making process. The decision must be a rare, once-in-a-lifetime event and also have a high payoff for the individual’s future – such as the odds of producing offspring.

How risk averse we are correlates to the size of the group in which we were raised. If reared in a small group – fewer than 150 people – we tend to be much more risk averse than those who were part of a larger community.

It turns out that primitive humans lived in smaller groups, about 150 individuals. Because resources tend to be more scarce in smaller communities, this environment helps promote risk aversion.

“We found that it is really the group size, not the total population size, which matters in the evolution of risk aversion,” Hintze said.

However, not everyone develops the same level of aversion to risk. The study also found that evolution doesn’t prefer one single, optimal way of dealing with risk, but instead allows for a range of less, and sometimes more-risky, behaviors to evolve.

“We do not all evolve to be the same,” Adami said. “Evolution creates a diversity in our acceptance of risk, so you see some people who are more likely to take bigger risks than others. We see the same phenomenon in our simulations.”

The research was part of an interdisciplinary collaboration with Ralph Hertwig of the Max Planck Institute for Human Development in Berlin.

Also contributing to the study was Randal Olson, graduate student, MSU Department of Computer Science and Engineering and BEACON Center for the Study of Evolution in Action.

Source: Michigan State University

Climate change accelerates maturing of grape in wine production

                             Johann Martínez-Lüscher , Nafarroako Unibertsitatea

The increase in temperatures and of CO2 levels – the consequences of climate change – accelerates the maturing of grapes in wine production, affecting colour and possibly aromas”. This was the conclusion of the PhD thesis defended by Johann Martínez-Lüscher, undertaken jointly by the University of Navarra and the University of Bordeaux.

The biologist explained that if the forecasts by the Intergovernmental Panel on Climate Change of a level of 700ppm of carbon dioxide and a temperature increase of 4ºC are proved correct, “the accumulation of sugars could be so rapid that the rest of these processes that depend on this will not be capable of keeping up. This will mean that, on comparing grapes with the same concentration of sugars or degree of alcohol, the crops under climate change conditions will have poorer colouration and this will be noticed in the wine”.

In fact, “it is increasingly more frequent to find wines with a higher alcoholic degree due to the over maturing of the grape”. Nonetheless, in the framework of climate change, the consequences can vary. “For example, the changes in levels of ultraviolet radiation or the decrease in rainfall may have antagonistic effects to those caused by an increase in temperature or CO2 levels. Thus, there are many unknowns about what the future holds”, he added.

Wine in a new scenario

In this way wine production will have to find solutions in order to confront environmental challenges. “The use of slower maturing ‘clones’ (sub-varieties) could be one of the possible strategies. It would also be very tempting to substitute the varieties planted in each location by others better adapted to warmer climates, but this would to a great extent mean giving up the typical characteristics of each variety of our wines – something unthinkable to date”.

Nevertheless, as this expert pointed out, climate change can provide new opportunities: for example, the production of a type of wine in cooler climes where it was not possible before. “This is the case of the incipient wine industry in the United Kingdom where I intend to continue working”, stated the researcher.

Mr. Martínez-Lüscher’s research has been financed by the University of Navarra, the Navarre-Aquitane Cross-Border Cooperation Programme, the Spanish Ministry of Science and Innovation, and the 7th European Union Framework Programme.

Source: Elhuyar Fundazioa

New Molecular Target Identified for Treating Cerebral Malaria

                                                             Mosquito Anopheles

A drug already approved for treating other diseases may be useful as a treatment for cerebral malaria, according to researchers at Harvard T. H. Chan School of Public Health. They discovered a novel link between food intake during the early stages of infection and the outcome of the disease, identifying two molecular pathways that could serve as new targets for treatment.

“We have known for a long time that nutrition can affect the course of infectious disease, but we were surprised at how rapidly a mild reduction in food intake could improve outcome in a mouse malaria model,” said senior author James Mitchell, associate professor of genetics and complex diseases. “However, the real importance of this work is the identification of unexpected molecular pathways underlying cerebral malaria that we can now target with existing drugs.”

The study appears online January 30, 2015 in Nature Communications.

Cerebral malaria — a severe form of the disease — is the most serious consequence of infection by the parasite Plasmodium falciparum, resulting in seizures, coma, and death. Currently there is a lack of safe treatment options for cerebral malaria, particularly for use in children, who represent the majority of cases. Even patients who receive early treatment with standard antimalarial chemotherapeutic agents run a high risk of dying, despite clearance of the parasite. Moreover, around 25% of survivors develop neurological complications and cognitive impairment.

Lead authors Pedro Mejia and J. Humberto Treviño-Villarreal, both researchers at Harvard T.H. Chan School of Public Health, found that leptin—a hormone secreted from fat tissue with roles in suppressing appetite, but also in activating adaptive immune and inflammatory responses—is increased upon infection in a mouse model of cerebral malaria, and turns out to be a major bad actor in promoting neurological symptoms and death. Remarkably, Mejia, Treviño-Villarreal and colleagues showed that reducing leptin using a variety of means, either genetically, pharmacologically, or nutritionally by reducing food intake during the first two days of infection, protected against cerebral malaria.

The researchers also found that leptin acted primarily on cytotoxic T cells by turning on the well-studied mTOR protein, for which pharmacologic inhibitors are readily available. In their animal model, treating mice with the mTOR inhibitor rapamycin protected them against the neurological complications of cerebral malaria. Protection was due in part to a preservation of the blood brain barrier, which prevented the entry of blood cells carrying the parasites into the brain. As rapamycin is already FDA-approved for use in humans, trials in humans for cerebral malaria treatment with this drug may be possible, according to the researchers.

This study was the result of an ongoing collaboration between the Mitchell lab in the Department of Genetics and Complex Diseases and the labs of Manoj Duraisingh and Dyann Wirth in the Department of Immunology and Infectious Diseases. Other Harvard T.H. Chan School of Public Health authors included  Christopher Hine, Eylul Harputlugil, Samantha Lang, Ediz Calay and Rick Rogers.

This study was supported in part by grants from NIH (DK090629 and AG036712) and the Glenn Foundation for Medical Research to J.R.M.; a Harvard T.H. Chan School of Public Health Yerby postdoctoral fellowship to Mejia, and financial support from the Universidad Auto´noma de Nuevo Leo´n to Treviño-Villarreal.

Source: Harvard

Studying patterns in bacterial organization

credit to Gerard Wong, of the California NanoSystems Institute

Bacterial biofilms, at first glance, may seem to be spontaneous, random phenomena from which we have no power to protect our environment or ourselves.

They’re potentially useful as an aid to wastewater treatment, but they also cause infections that account for $6 billion a year in health care costs. Biofilms are also more resistant to antibiotic drugs, making them difficult to eradicate.

Dr. Kun Zhao, of the California NanoSystems Institute at UCLA, refuses to see biofilms as arbitrary: he emphasizes the fact that biofilms are communities of bacteria in self-produced polymeric matrices of polysaccharides, and using a biophysical approach, he studies the pattern behind their organization.

Central questions in Zhao’s research include how bacterial colonies transition from reversible to irreversible attachment, how they migrate, and how they ultimately disperse. Specifically, Zhao examines the polysaccharide Psl, which poses a positive feedback loop because it is both secreted by moving bacteria and serves as a chemo-attractant for future bacteria movement. The positive feedback creates an inherent pattern, as bacteria are more likely to visit a location they have been to before.

Zhao and colleagues have also discovered that bacterial mutants that cannot produce Psl exhibit more random and uniform movement.

To better quantify bacterial movement,Zhao has created a computer algorithm that shows the full movement history of each individual bacterium on a dish, and that provides a “search engine” allowing researchers to find every bacterium performing specific life cycle activities, like division.

Zhao has postulated a “rich get richer” mechanism for biofilms. He compares bacterial organization to Wall Street because concentrated movement ensures that some cells become extremely enriched. In the future, he hopes to model colloidal structures for biological problems, like the growth of the bacterial cell wall. Zhao currently uses colloids, which in physics are used as models for atomic systems, to observe how shapes affect self-assembly. He also would like to look at cell-substrate interactions, which are implicated in bacterial territoriality and social interactions.

by Olivia Zhu

Source: Duke University

Description of Telamoptilia grewiae sp. n. and the consequences for the definition of the genera Telamoptilia and Spulerina (Lepidoptera, Gracillariidae, Gracillariinae)

Adult, host plant and mines of Telamoptilia grewiae sp. n. 1 Adult in habitus, paratype 2 Live adult 3 Host plant 4 Linear mines by early instar larvae 5 Blotch mine by later instar larva 6 Seriously damaged leaves found in September. Credit: Zookeys

The genus Telamoptilia Kumata & Kuroko, 1988 is globally represented by five species that may be found in the Oriental and African regions. The type species T. cathedraea (Meyrick, 1908) is geographically shared by the Oriental Region and Madagascar (De Prins and De Prins 2014). Three species are currently known from China, including T. cathedraea, T. hemistacta (Meyrick, 1924), and T. prosacta (Meyrick, 1918).

The larvae of Telamoptilia species are leaf miners. Three plant families are known as hosts for Telamoptilia: Malvaceae, Amaranthaceae and Convolvulaceae (De Prins and De Prins 2014). Vári (1961) briefly described the biology of T. geyeri (Vári, 1961). Kumata et al. (1988) described the biology and the larval body chaetotaxy of three species: T. cathedraea, T. prosacta and T. tiliae (Kumata & Ermolaev, 1988). However, no larval head chaetotaxy and pupal features of Telamoptilia have been described so far.

Telamoptilia grewiae sp. n. is associated with Malvaceae and is described in the present paper from adult external characters, male and female genitalia, wing venation and immature stages. The larval head and pupal features are described for the first time in Telamoptilia.

Methods

Field investigations were carried out in Mt. Baxian National Nature Reserves (40°11'N, 117°32'E), 300−600 m, Tianjin, China, from May to September in 2013 and June 2014. Leaves containing mines with larvae were placed in sealed plastic bags, or rearing containers with moist cotton. Larvae removed from mines were immersed in nearly boiling water for 30 seconds, and then were kept in 75% ethanol for morphological examination. Last instar larval skins, pupae, and exuviae were kept in 75% ethanol. Pupae in rearing containers were placed outdoors to overwinter, and were transferred into the laboratory at 20 °C on February 6, 2014. Emergence successively occurred from March 9 to early-April 2014. Adults were collected chiefly by rearing from immature stages, and occasionally by light trap.

Adult photographs were taken with a Leica M250A stereo microscope. Genitalia and wings were dissected and mounted according to the methods introduced by Li (2002), but stained with Eosin Y and/or Chlorazol Black, and the illustrations were prepared by using a Leica DM750 microscope, and refined in Photoshop® CS4 software. For scanning electron microscopy, larvae and pupae were dehydrated in gradient ethanol, dried in vacuum and coated with gold in a SCD 005 Sputter Coater (BAL-TEC), then operated with a voltage of 15 kV using Quanta 200 environmental scanning electron microscope (SEM) (FEI, Oregon). Line drawings were outlined from the photos taken by the Leica M250A stereo microscope, using path tool in Adobe Photoshop® CS4 software. Photographs of host plant, mines and a live adult were taken in the field using Canon PowerShot G10 digital camera.

Terminology of immature stages follows Davis and De Prins (2011) and De Prins et al. (2013), and that of adults follows Kumata et al. (1988). Thoracic segments I−III and abdominal segments 1−10 are abbreviated as TI−TIII and A1−A10, respectively.

All the specimens studied, including the types of the new species and the vouchered larvae and pupae, are deposited in the Insect Collection, Nankai University, Tianjin, China.

Taxonomy

Adults (Figs 1–2) with wing span 6.0−8.0 mm. Head silvery white, tinged with gray on face. Labial palpus grayish white, colored blackish gray on outer surface of distal half of second segment and before apex of third segment. Maxillary palpus white, with middle or distal half blackish fuscous. Antenna with scape white on posterior half, blackish gray on anterior half and distal portion, flap blackish gray tinged with white, as wide as scape in frontal view; flagellum silvery grayish fuscous, with each unit blackish distally. Thorax and tegula blackish gray mixed with white. Legs mostly white; foreleg with coxa blackish fuscous basally and distally, femur and tibia blackish fuscous, tarsus blackish gray distally on each except last segment; midleg with coxa blackish fuscous distally, femur blackish fuscous, except white medially and distally on dorsal surface, with ventral scale expansion blackish fuscous, tibia blackish fuscous basally and distally, white medially, tarsus white, each except last segment dotted blackish fuscous distally; hindleg with coxa blackish fuscous distally, femur blackish fuscous distally on outer surface, tibia blackish fuscous basally and distally, tarsus with basal three segments blackish fuscous distally, fourth segment dotted blackish fuscous dorso-distally. Forewing grayish fuscous to blackish fuscous; costal margin with a white spot basally at about 1/10 and one before apex, the former sometimes touching fold posteriorly, with white stria at distal 3/10 and 1/6 obliquely outward, reaching middle of wing and near termen respectively; transverse white fascia from costal 1/3 and 1/2 obliquely outward, reaching dorsal 1/2 and before end of fold respectively, edged with blackish fuscous to black scales, inner fascia wider than outer one, widened on posterior half; small white dot on distal end of M3, two or three small white dots along termen; apex blackish fuscous; cilia mostly blackish fuscous basally, gray distally, white adjacent to white markings, white on basal 1/4, black on median part, gray distally at apex, gray along dorsal margin. Hindwing and cilia uniformly gray.

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Three new species of saddled loricariid catfishes, and a review of Hemiancistrus, Peckoltia, and allied genera (Siluriformes)

(Figs 2–4). CORBIDI 14685, an adult male (Figs 2–4) from 13.5806 S, 75.2449 W (WGS84), Chicchobamba, upstream of Represa Negrayccassa, upper drainage of the Huaytará river, 3900 m, Provincia Huaytará, Región Huancavelica, Peru, collected by A. Catenazzi, V. Vargas García, and M. Jaico Huayanay

We describe a new species of Telmatobius from the Pacific slopes of the Andes in central Peru. Specimens were collected at 3900 m elevation near Huaytará, Huancavelica, in the upper drainage of the Pisco river. The new species has a snout–vent length of 52.5 ± 1.1 mm (49.3–55.7 mm, n = 6) in adult females, and 48.5 mm in the single adult male. The new species has bright yellow and orange coloration ventrally and is readily distinguished from all other central Peruvian Andean species of Telmatobius but T. intermedius by having vomerine teeth but lacking premaxillary and maxillary teeth, and by its slender body shape and long legs. The new species differs from T. intermedius by its larger size, flatter head, and the absence of cutaneous keratinized spicules (present even in immature females of T. intermedius), and in males by the presence of minute, densely packed nuptial spines on dorsal and medial surfaces of thumbs (large, sparsely packed nuptial spines in T. intermedius). The hyper-arid coastal valleys of Peru generally support low species richness, particularly for groups such as aquatic breeding amphibians. The discovery of a new species in this environment, and along a major highway crossing the Andes, shows that much remains to be done to document amphibian diversity in Peru.

The Tropical Andes are characterized by a large diversification of the aquatic frogs of the genus Telmatobius Wiegmann, 1834. Sixty-two species are currently recognized in this genus (AmphibiaWeb 2014; Aguilar and Valencia 2009; Frost 2014; including species previously assigned to Batrachophrynus Peters, 1873). The altitudinal distribution of Telmatobius ranges from 1000 m to 5400 m (De la Riva and Harvey 2003; Seimon et al. 2007), and its longitudinal distribution extends from the equator (T. niger Barbour & Noble, 1920, whose populations have been extirpated in Ecuador; Merino-Viteri et al. 2005) to 29°S, on the eastern slopes of the Argentinean Andes (T. contrerasi Cei, 1977). Twenty-eight species of Telmatobius are distributed in Peru (Lehr 2005; AmphibiaWeb 2014), but of these only five [T. arequipensis Vellard, 1955; T. intermedius Vellard, 1955; T. jelskii (Peters, 1873); T. peruvianus Wiegmann, 1834; T. rimac Schmidt, 1954] are known to occur in the hyper-arid coastal valleys that drain directly into the Pacific Ocean.

During October 2012 we made several surveys for the Biodiversity and Monitoring Assessment Program of the Smithsonian Conservation Biology Institute’s Center for Conservation Education and Sustainability (Catenazzi et al. 2013a; Catenazzi et al. 2013b). During one of these surveys, we found a population of Telmatobius in the upper drainage of the Huaytará river (Region of Huancavelica), a tributary of the Pisco river in the Pacific slopes of the central Peruvian Andes. Individuals of this population possess traits that do not correspond to the morphological characteristics of other species found in the arid coastal valleys of central Peru (Fig. 1), namely T. rimac to the north and T. intermedius to the south (Vellard 1951; Schmidt 1954; Lehr 2005). Therefore, here we describe the new species and provide a diagnosis to differentiate it from congeneric forms.

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EGFR-Mediated Beclin 1 Phosphorylation in Autophagy Suppression, Tumor Progression, and Tumor Chemoresistance

EGFR negatively regulates autophagy by binding to Beclin 1.
Active EGFR phosphorylates Beclin 1 and alters its interactome.
EGFR suppression of Beclin 1 may contribute to tumor progression in lung cancer.

Lung cancer responses to EGFR inhibitors may involve activation of Beclin 1. Image Credit: Cell Press

Summary
Cell surface growth factor receptors couple environmental cues to the regulation of cytoplasmic homeostatic processes, including autophagy, and aberrant activation of such receptors is a common feature of human malignancies. Here, we defined the molecular basis by which the epidermal growth factor receptor (EGFR) tyrosine kinase regulates autophagy. Active EGFR binds the autophagy protein Beclin 1, leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased Beclin 1-associated VPS34 kinase activity. EGFR tyrosine kinase inhibitor (TKI) therapy disrupts Beclin 1 tyrosine phosphorylation and binding to its inhibitors and restores autophagy in non-small-cell lung carcinoma (NSCLC) cells with a TKI-sensitive EGFR mutation. In NSCLC tumor xenografts, the expression of a tyrosine phosphomimetic Beclin 1 mutant leads to reduced autophagy, enhanced tumor growth, tumor dedifferentiation, and resistance to TKI therapy. Thus, oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery, which may contribute to tumor progression and chemoresistance.

Introduction
Epidermal growth factor receptor (EGFR), an oncogenic receptor tyrosine kinase, links extracellular signals to cellular homeostasis. In normal cells, EGFR signaling is triggered by the binding of growth factors, such as epidermal growth factor (EGF), leading to homodimerization or heterodimerization with other EGFR family members (such as HER2/neu) and autophosphorylation of the intracellular domain (Lemmon and Schlessinger, 2010). The phosphotyrosines formed serve as a docking site for adaptor molecules, which results in the activation of signaling pathways including the Ras/MAPK pathway, the PI3K/Akt pathway, and STAT signaling pathways. In tumor cells, the tyrosine kinase activity of EGFR may be dysregulated by EGFR gene mutation, increased EGFR gene copy number, or EGFR protein overexpression, leading to aberrant EGFR signaling and increased tumor cell survival, proliferation, invasion, and metastasis ( Ciardiello and Tortora, 2008). EGFR signaling is deregulated in many human cancers, including those of the lung, head and neck, colon, pancreas, and brain.

The deregulation of EGFR in human cancers has led to the development of anticancer agents that target EGFR, including: (1) anti-EGFR antibodies that inhibit ligand binding and (2) small-molecule receptor tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, that block EGFR intracellular tyrosine kinase activity. Although the EGFR TKIs have shown limited clinical benefit in the majority of solid tumors, they are effective in non-small-cell lung carcinomas (NSCLCs) that harbor specific mutations in the tyrosine kinase domain of EGFR (most commonly, in-frame deletion in exon 19 around codons 746–750 or single-base substitution, L858R, in exon 21) (Ciardiello and Tortora, 2008, Lynch et al., 2004 and Pao and Chmielecki, 2010). Most patients with NSCLCs with EGFR mutations initially respond favorably to erlotinib or gefitinib, suggesting these mutations drive tumorigenesis. However, among tumors that initially respond to EGFR TKIs, most eventually acquire resistance, often due to the emergence of a secondary mutation, T790M, in the kinase domain of EGFR (Pao and Chmielecki, 2010).

Several studies have shown that EGFR signaling regulates autophagy, a lysosomal degradation pathway that functions in cellular homeostasis and protection against a variety of diseases, including cancer (Levine and Kroemer, 2008). The downstream targets of EGFR—PI3K, Akt, and mammalian target of rapamycin (mTOR)—are well-established negative regulators of autophagy (Botti et al., 2006). Moreover, EGFR inhibitors induce autophagy in NSCLCs (Gorzalczany et al., 2011 and Han et al., 2011) and other cancer cells (Fung et al., 2012). However, the links between EGFR signaling and autophagy remain poorly understood, particularly (1) the molecular mechanisms by which EGFR signaling suppresses autophagy, (2) the role of EGFR suppression of autophagy in lung cancer pathogenesis, and (3) the role of autophagy induction in the response to TKI therapy. EGFR inhibitor-induced autophagy in lung cancer cells has been postulated to exert either cytoprotective (Han et al., 2011) or cytotoxic (Gorzalczany et al., 2011) effects.

Conflicting results regarding the role of autophagy in the response or resistance to EGFR TKI treatment reflects broader uncertainties in the role of autophagy in cancer therapy (Rubinsztein et al., 2012). It is not understood in what contexts autophagy induction contributes to tumor progression or suppression and to tumor chemoresistance or chemosensitivity. There is a general consensus that autophagy prevents tumor initiation, as loss-of-function mutations of several different autophagy genes results in spontaneous tumorigenesis (beclin 1, Atg5, and Atg7) and/or increased chemical-induced tumorigenesis (Atg4C) in mice ( Rubinsztein et al., 2012). Despite this inhibitory role in tumor initiation, it has been proposed that autophagy may promote the growth of established tumors and contribute to chemoresistance, principally through its actions to prolong the survival of metabolically stressed neoplastic cells ( Rubinsztein et al., 2012).

To understand the relationship between oncogenic signaling, autophagy, and distinct stages of tumorigenesis, it is important to define the molecular mechanisms by which oncogenic signaling regulates autophagy. We recently showed that the oncogene Akt inhibits autophagy independently of mTOR signaling via serine phosphorylation of the essential autophagy protein, Beclin 1 (Wang et al., 2012), a haploinsufficient tumor suppressor protein frequently monoallelically deleted in human breast and ovarian cancer (Levine and Kroemer, 2008). Moreover, Akt-mediated phosphorylation of Beclin 1 contributes to Akt-dependent fibroblast transformation, supporting the concept that inactivation of Beclin 1-dependent autophagy plays a role in tumor initiation. However, it is not known whether oncogenic inactivation of Beclin 1 (or other autophagy proteins) influences progression of established tumors and/or their response to therapy.


Here, we identify the molecular basis by which EGFR tyrosine kinase activity regulates autophagy. We show that active EGFR binds to Beclin 1, leading to its tyrosine phosphorylation, alteration of its interactome, and inhibition of its autophagy function. A mutant of Beclin 1 containing phosphomimetic mutations in the EGFR-dependent tyrosine phosphorylation sites enhances autophagy suppression in EGFR-mutated NSCLC cells, resulting in enhanced tumor progression, altered tumor cell differentiation, and partial tumor resistance to EGFR TKI therapy. These findings demonstrate a heretofore unknown link between oncogenic receptor tyrosine kinases and the autophagy machinery, which may contribute to tumor progression and resistance to targeted therapy.

Source: Full Artical At - CELL PRESS

Why do zebras have stripes?

A mother zebra with a foal in Tanzania’s Tarangire National Park. Credit: Brenda Larison/UCLA

One of nature’s fascinating questions is how zebras got their stripes.

A team of life scientists led by UCLA’s Brenda Larison has found at least part of the answer: The amount and intensity of striping can be best predicted by the temperature of the environment in which zebras live.

In the January cover story of the Royal Society’s online journal, Open Science, the researchers make the case that the association between striping and temperature likely points to multiple benefits — including controlling zebras’ body temperature and protecting them from diseases carried by biting flies.

“While past studies have typically focused their search for single mechanisms, we illustrate in this study how the cause of this extraordinary phenomenon is actually likely much more complex than previously appreciated, with temperature playing an important role,” said Thomas B. Smith, professor of ecology and evolutionary biology in the UCLA College and senior author of the research.

Larison, a researcher in UCLA’s department of ecology and evolutionary biology and the study’s lead author, and her colleagues examined the plains zebra, which is the most common of three zebra species and has a wide variety of stripe patterns. On zebras in warmer climes, the stripes are bold and cover the entire body. On others — particularly those in regions with colder winters such as South Africa and Namibia — the stripes are fewer in number and are lighter and narrower. In some cases, the legs or other body parts have virtually no striping.

Zebras evolved from horses more than 2 million years ago, biologists have found. Scientists have previously hypothesized that zebras’ stripes evolved for one, or a combination of, four main reasons: confusing predators, protecting against disease-carrying insects, controlling body temperature and social cohesion. And while numerous previous studies of the phenomenon focused on a single hypothesis, the Larison-led study was the first to fully test a large set of hypotheses against one another.

Analyzing zebras at 16 locations in Africa and considering more two dozen environmental factors, the researchers found that temperature was the strongest predictor of zebras’ striping. The finding provides the first evidence that controlling body temperature, or thermoregulation, is the main reason for the stripes and the patterns they form.
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Separate research by Daniel Rubenstein, a Princeton University professor of ecology and evolutionary biology and a co-author of the Open Science paper, and Princeton undergraduate Damaris Iriondo strongly suggests that boldly striped zebras have external body temperatures about five degrees Fahrenheit cooler than other animals of the same size — like antelopes — that do not have stripes but live in the same areas. The Rubenstein study is not yet published, but it is cited in the Open Science paper.

Larison has studied many zebras during her field work throughout Africa — including in Kenya, South Africa, Tanzania, Uganda and Zimbabwe. Using the fact that their stripes are unique like fingerprints, she is able to distinguish one zebra from another.

In addition to Rubenstein, arguably the world’s leading expert on zebras, the study’s co-authors were Alec Chan-Golston and Elizabeth Li, former UCLA undergraduates in mathematics; Ryan Harrigan, an assistant adjunct professor in UCLA’s Center for Tropical Research; and Henri Thomassen, a former UCLA postdoctoral scholar and current research associate at the Institute for Evolution and Ecology at Germany’s University of Tübingen.

The research was supported by the National Geographic Society Committee for Research and Exploration.

Larison and her research team have also collected zebra tissue samples and have used cutting-edge technology to sequence zebra DNA to try to identify which genes code for striping. The team is continuing to study the benefits stripes provide.

Source: UCLA

Drug combo supresses growth of late-stage prostate cancer turmors

By Natalie van Hoose

Low doses of metformin, a widely used diabetes medication, and a gene inhibitor known as BI2536 can successfully halt the growth of late-stage prostate cancer tumors, a Purdue University study finds.

Prostate cancer causes the second-highest number of cancer-related deaths in men in the U.S., and methods of treating advanced prostate cancer are limited.

Xiaoqi Liu (pronounced zhow-CHEE' LEE'-oo), associate professor of biochemistry and cancer research, and fellow researchers found that the drugs metformin and BI2536 can work together to suppress the spread of prostate cancer that resists all other available treatments, potentially prolonging patients' lives.

"We've found a promising way to treat late-stage prostate cancer," Liu said. "By combining low levels of two well-tolerated drugs, the progression of this disease could be significantly delayed. Completely curing the cancer at the advanced stage is pretty much impossible, but this treatment might manage it for a while - that's exciting."

A number of treatments exist for the earlier stages of prostate cancer, which grows slowly compared with many other cancers. Because prostate cancer cells need the male sex hormone androgen to develop, one way to treat the disease is to suppress androgen - a process known as castration. If the cancer continues to spread, the patient often undergoes chemotherapy. As a last resort, drugs that block the synthesis of androgen by prostate cancer cells can be used, but these medications only extend a patient's lifespan for several months.

New approaches to treating the most persistent forms of prostate cancer are "urgently needed," Liu said.

Adding to the challenge is the fact that castration treatment can inadvertently encourage the cancer to get tougher. It can heighten oxidative stress on the prostate gland, which increases the expression of Plk1, a gene that has been linked to many cancers. Over-expression of Plk1 can also trigger the synthesis of androgen.

"The goal of castration is to block androgen synthesis," Liu said. "But cancer cells eventually become 'smart' enough to make androgen anyhow, which is why the cancer continues to grow."

Additionally, castration can disrupt the body's metabolism and lead to insulin resistance, which also can stimulate the production of androgen. The cancer will spread until both of these side effects are stopped, Liu said.

Previous studies showed that metformin - an inexpensive, antidiabetic drug that has been commonly used for more than 40 years - is particularly potent to prostate cancer tumors.

Working with fellow researchers from Purdue, the University of Wisconsin-Madison and the Indiana University School of Medicine, Liu found that a combination of low levels of metformin and BI2536, a drug that stifles the activity of Plk1, could work in tandem to slow the growth of prostate tumors too advanced for current treatments by promoting the self-destruction of cancer cells and preventing androgen synthesis.

The drugs did not impact healthy prostate cells, a "key finding," Liu said. "Ideally, cancer therapy will have minimal effects on normal cells."

Because metformin helps regulate metabolism, it may reverse some of the metabolic damage caused by castration, he said.

The researchers tested the drugs in a classical cell culture assay of prostate cancer cells and in advanced prostate tumors in mice. Low concentrations of the drugs significantly slowed the development of cancer in both trials. The mice tumors were grown from the tumor cells of a late-stage prostate cancer patient, suggesting that the treatment would prove effective in humans.

"Those results were amazing," Liu said. "These are the first data we've generated from a real patient, so I was almost jumping in the air when I saw that it worked."

Liu said that the next step in the research is to test the combination of drugs in clinical trials. Further research is also needed to understand the underlying mechanism of metformin and why it is effective at suppressing prostate cancer

Source: Purdue Univesity

Stanford bioengineers develop tool for reprogramming genetic code

Stanford bioengineers have developed a new tool that allows them to preferentially activate or deactivate genes in living cells. VITSTUDIO/SHUTTERSTOCK

Biology relies upon the precise activation of specific genes to work properly. If that sequence gets out of whack, or one gene turns on only partially, the outcome can often lead to a disease.

Now, bioengineers at Stanford and other universities have developed a sort of programmable genetic code that allows them to preferentially activate or deactivate genes in living cells. The work is published in the current issue of Cell, and could help usher in a new generation of gene therapies.

The technique is an adaptation of CRISPR, itself a relatively new genetic tool that makes use of a natural defense mechanism that bacteria evolved over millions of years to slice up infectious virus DNA.

Standard CRISPR consists of two components: a short RNA that matches a particular spot in the genome, and a protein called Cas9 that snips the DNA in that location. For the purposes of gene editing, scientists can control where the protein snips the genome, insert a new gene into the cut and patch it back together.

Inserting new genetic code, however, is just one way to influence how the genome is expressed. Another involves telling the cell how much or how little to activate a particular gene, thus controlling how much protein a cell produces from that gene and altering its behavior.

It's this action that Lei Stanley Qi, an assistant professor of bioengineering and of chemical and systems biology at Stanford, and his colleagues aim to manipulate.

Influencing the genome
In the new work, the researchers describe how they have designed the CRISPR molecule to include a second piece of information on the RNA, instructing the molecule to either increase (upregulate) or decrease (downregulate) a target gene's activity, or turn it on/off entirely.

Additionally, they designed it so that it could affect two different genes at once. In a cell, the order or degree in which multiple genes are activated can produce different metabolic products.

"It's like driving a car. You control the wheel to control direction, and the engine to control the speed, and how you balance the two determines how the car moves," Qi said. "We can do the same thing in the cell by up- or downregulating genes, and produce different outcomes."

As a proof of principle, the scientists used the technique to take control of a yeast metabolic pathway, turning genes on and off in various orders to produce four different end products. They then tested it on two mammalian genes that are important in cell mobility, and were able to control the cell's direction and how fast it moved.

Future therapies
The ability to control genes is an attractive approach in designing genetic therapies for complex diseases that involve multiple genes, Qi said, and the new system may overcome several of the challenges of existing experimental therapies.

"Our technique allows us to directly control multiple specific genes and pathways in the genome without expressing new transgenes or uncontrolled behaviors, such as producing too much of a protein, or doing so in the wrong cells," Qi said. "We could eventually synthesize tens of thousands of RNA molecules to control the genome over a whole organism."

Next, Qi plans to test the technique in mice and refine the delivery method. Currently the scientists use a virus to insert the molecule into a cell, but he would eventually like to simply inject the molecules into an organism's blood.

"That is what is so exciting about working at Stanford, because the School of Medicine's immunology group is just around the corner, and working with them will help us address how to do this without triggering an immune response," said Qi, who is a member of the interdisciplinary Stanford ChEM-H institute. "I'm optimistic because everything about this system comes naturally from cells, and should be compatible with any organism."

Source: Stanford university

On the ups and downs of the seemingly idle brain

Cortical colors Inhibitory cells abound in the barrel cortex of the mouse, where three main types were labeled to fluoresce in different colors: PV (red), SOM (blue), and 5HT3aR, which includes VIP and NPY, (green). Image: Connors lab/Brown University

Even when it seems not to be doing much, the brain maintains a baseline of activity in the form of up and down states of bustle and quiet. To accomplish this seemingly simple cycle, it maintains a complex balance between the activity of many excitatory and inhibitory cells, Brown University scientists report in the Journal of Neuroscience.

PROVIDENCE, R.I. [Brown University] — Even in its quietest moments, the brain is never “off.” Instead, while under anesthesia, during slow-wave sleep, or even amid calm wakefulness, the brain’s cortex maintains a cycle of activity and quiet called “up” and “down” states. A new study by Brown University neuroscientists probed deep into this somewhat mysterious cycle in mice, to learn more about how the mammalian brain accomplishes it.

In addition to an apparent role in maintaining a baseline of brain activity, the up and down cycling serves as a model for other ways in which activity across the cortex is modulated, said Garrett Neske, graduate student and lead author. To study how the brain maintains this cycling, he found, is to learn how the brain walks a healthy line between excitement and inhibition as it strives to be idle but ready, a bit like a car at a stoplight.

Garrett Neske To study how the brain maintains up and down cycles is to learn how the brain strives to be idle but ready, a bit like a car at a stoplight. Photo: David Orenstein/Brown University

“It is very important to regulate that balance of excitation and inhibition,” said senior author Barry Connors, professor and chair of neuroscience at Brown. “Too much excitation relative to inhibition you get a seizure, too little you become comatose. So whether you are awake and active and processing information or whether you are in some kind of idling state of the brain, you need to maintain that balance.”

The cycling may seem simple, but what Neske and Connors found in their investigation, published in the Journal of Neuroscience, is that it involves a good deal of complexity. They focused on five different types of cells in a particular area of the mouse cortex and found that all five appear to contribute uniquely to the ups and downs.

Cells in a barrel

Specifically the researchers, including Saundra Patrick, neuroscience research associate and second author, looked at the activity of excitatory pyramidal cells and four kinds of inhibitory interneurons (PV, SOM, VIP and NPY) in different layers of the barrel cortex. That part of the cortex is responsible for processing sensations on the face, including the whiskers.

Neske induced up and down cycles in slices of tissue from the barrel cortex and recorded each cell type’s electrical properties and behaviors, such as its firing rate and the amounts of excitation and inhibition they received from other neurons.

The picture that emerged is that all types of interneurons were active. This included the most abundant interneuron subtype (the fast-spiking PV cell), and the various more slowly spiking subtypes (SOM, VIP, NPY). In fact, Connors said, the latter cells were active at levels similar to or higher than neighboring excitatory cells, contributing strong inhibition during the up state.

One way such findings are important is in how they complement recent ones by another research group at Yale University. In that study scientists looked at a different part of the cortex called the entorhinal cortex. There they found that only one inhibitory neuron, PV, seemed to be doing anything in the up state to balance out the excitement of the pyramidal neurons. The other inhibitory neurons stayed virtually silent. In his study, Neske replicated those results.

Taken together, the studies indicate that even though up and down cycles occur throughout the cortex, they may be regulated differently in different parts.

“It suggests that inhibition plays different roles in persistent activity in these two regions of cortex and it calls for more comparative work to be done among cortical areas,” Neske said. “You can’t just use one cortical region as the model for all inhibitory interneuron function.”

From observation to manipulation

Since observing the different behaviors of the neuron types, Neske has moved on to manipulating them to see what role each of them plays. Using the technique of optogenetics, in which the firing of different neuron types can be activated or suppressed with pulses of colored light, Neske is experimenting with squelching different interneurons to see how their enforced abstention affects the up and down cycle.

When the work is done, he should emerge with an even clearer idea of the brain’s intricate and diligent efforts to remain balanced between excitation and inhibition.

The National Institutes of Health (grants NS-050434, MH-086400, and T32NS062443) and the Defense Advanced Research Projects Agency (grant DARPA-BAA-09-27) supported the research.

Source: Brown University

Reducing Myc gene activity extends healthy lifespan in mice

No bones about it Young mice have good bone density whether they have two copies (top row; +/+) or one copy (bottom row; +/-) of the Myc gene. As they age, researchers found, mice with just one copy maintain better bone density and stay healthy longer. Sedivy lab/Brown University

Mice with one rather than the normal two copies of the gene Myc (also found in humans) lived 15 percent longer and had considerably healthier lives than normal mice, according to a new Brown University-led study in Cell.

PROVIDENCE, R.I. [Brown University] — A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice, the first such finding regarding this gene in a mammalian species.

Myc is found in the genomes of all animals, ranging from ancestral single-celled organisms to humans. It is a major topic of biomedical research and has been shown to be a central regulator of cell proliferation, growth, and death. It is of such widespread and fundamental importance that animals cannot live without it. But in humans and mice, too much expression of the protein that Myc encodes has been closely linked to cancer, making it a well-known but elusive target of drug developers.

In a new study in the journal Cell, the scientists report that when they bred laboratory mice to have only one copy of the gene, instead of the normal two, thus reducing the expression of the encoded protein, those mice lived 15 percent longer on average — 20 percent longer for females and 10 percent longer among males — than normal mice. Moreover, the experimental mice showed many signs of better health into old age.

The experimental — “heterozygous” — mice grew to be about 15 percent smaller than the normal mice (a probable disadvantage in the wild) but that was the only discernable downside found to date for lacking a second copy of the gene, said senior author John Sedivy, the Hermon C. Bumpus Professor of Biology and professor of medical science at Brown.

“The animals are definitely aging slower,” he said. “They are maintaining the function of their organs and tissues for longer periods of time.”

Physiological differences

That assessment is based on detailed studies of the physiology — down to the molecular level — of the heterozygous and normal mice. The researchers conducted these experiments to try to understand the longevity difference between the two groups.

John Sedivy “The animals are definitely aging slower [and[ they are maintaining the function of their organs and tissues for longer periods of time.”

Co-lead author Jeffrey Hoffman, a medical and doctoral student, led the studies of the health of the mice, including various bodily systems. In many cases they were just like their normal counterparts. They reproduced just as well, for example.

“These mice are incredibly normal, yet they are really long-lived,” Sedivy said. “The reason why we were struck by that is because in many other longevity models like caloric restriction or treatment with rapamycin, the animals live longer but they also have some health issues.”

Instead the Myc heterozygous mice simply experienced fewer problems of aging. They did not develop osteoporosis, they maintained a healthier balance of immune system T cells, had less cardiac fibrosis, were more active, experienced less age-related slowing of their metabolic rate, produced less cholesterol, and exhibited better coordination.

Graduate student and co-lead author Xiaoai Zhao, meanwhile, led the molecular analysis of several pathways known to be involved in regulating longevity to find out how they might be different. Sure enough, heterozygous mice exhibited changes in IGF-1 signaling and nutrient and energy-sensing pathways, but how Myc engages those mechanisms is still not clear. Of particular interest, heterozygous mice showed less protein synthesis in several tissues. Regulation of this process is known to be under direct Myc control, and its reduction by a variety of means is known to extend lifespan in diverse species from yeast to mammals.

Genome-wide patterns of gene expression showed that Myc heterozygotes had significant differences in pathways related to metabolism and the immune system. Those patterns, however, only overlapped somewhat with patterns seen in other lifespan extending interventions.

Zhao and Hoffman’s studies also argue against a role for Myc in an oft-cited paradigm of greater longevity: upregulation of a variety of stress defense mechanisms. Their experimental mice seemed to suffer from as much stress and consequences of stress as normal mice.

The different benefits of Myc reduction compared to other laboratory longevity extenders shows that just as there are many ways the body can break down with aging, Sedivy said, there may be many ways to forestall that.

“There is more than one way to become long-lived,” Sedivy said.

Help for humans?

In the long term, Sedivy said he is optimistic that the findings about Myc could prove to matter to human health.

Finding the right target for a drug in one of Myc’s key metabolic or immune system pathways may or may not extend human lifespan, he said, but it might help people stay healthier as they age — for example, if it can reduce osteoporosis in people the way it does in mice. In particular, Sedivy said, it emphasizes the importance of the process of protein synthesis as a target of interventions that are likely to have widespread benefits on many organ systems.

And the study also offers encouragement to companies seeking to develop cancer drugs that block Myc overexpression. As important as normal Myc expression is to physiology, it appears that at least in mice there were many substantial benefits in reducing it by, say, half. Thus, Sedivy said, any drug that can target Myc directly is likely to find many applications beyond cancer.

In addition to Sedivy, Hoffman, and Zhao, the paper’s other authors are Marco De Cecco, Abigail Peterson, Luca Paglilaroli, Jayameenakshi Manivannan Bin Feng, Thomas Serre, Kevin Bath, Haiyan Xu, and Nicola Neretti of Brown; Gene Hubbard, Wenbo Qi, and Holly Van Remmen of the University of Texas; Yongqing Zhang and Rafael de Cabo of the National Institute on Aging; and Richard Miller of the University of Michigan.

The National Institutes of Health (grants R37AG016694, F30AG035592), the Ellison Medical Foundation, and the Glenn Award for Research on the Biological Mechanism of Aging supported the research. Some experiments were conducted in the Brown University molecular pathology and genomics cores.

Not just a longer life, but a healthier, stronger body “Do you think she might be a Myc hypomorph?” Drawing: Emma Sedivy

Source: Brown University

An Advanced Method of DNA Nanostructure Formation Developed

Figure 1: Uni-molecular magnetic tweezers orchestrating the DNA nanostructure formation

Professor Tae-Young Yoon’s research team from the Department of Physics at KAIST has developed a new method to form DNA nanostructures by using magnetic tweezers to observe and to induce the formation of the structure in real time.

Unlike traditional designs of "DNA origami" which relies on thermal or chemical annealing methods, the new technology utilizes a completely different dynamic in DNA folding. This allows the folding to be done within only ten minutes.

Developed in 2006, the "DNA origami" allows a long skeleton of DNA to be folded into an arbitrary structure by using small stapler DNA pieces. This has been a prominent method in DNA nanotechnology.
 

Figure 2: The evolution of DNA nanostructure formation using magnetic tweezers. The DNA nanostructure with a 21-nanometer size was formed in about eight minutes.

However, the traditional technology which adopts thermal processes could not control the DNA formation during the folding because every interaction among DNAs occurs simultaneously. Thus, the thermal processes, which take dozens of hours to complete, had to be repeated multiple times in order to find the optimal condition.

The research team designed a DNA folding using uni-molecular magnetic tweezers that applied force to a single DNA molecule while measuring the state of the DNA. Through this technology, they were able to induce the formation of DNA nanostructure and observe it at the same time.

During high temperature heat treatment, the first stage of conventional thermal processes, the internal structure of the long skeleton DNA untangles. To induce such state, after attaching one side of the skeleton DNA to the surface of glass and the other side to a magnetic material, the team unfolded the internal structure of the DNA by pulling the two sides apart with magnetic force.

Unlike the conventional thermal processes, this method lets the stapler DNA swiftly adhere to the skeleton DNA within a minute because the sites are revealed at room temperature.

After the stapler pieces connected to the skeleton, the team removed the magnetic force. Next, the structure folded through self-assembly as the stapler DNAs stuck to different sites on the skeleton DNA.

Professor Yoon said, “With the existing thermal methods, we could not differentiate the reactions of the DNA because the response of each DNA pieces mutually interacted with each other.” He added that “Using the magnetic tweezers, we were able to sort the process of DNA nanostructure formation into a series of reactions of DNA molecules that are well known, and shorten the time taken for formation in only ten minutes.”

He commented, “This nanostructure formation method will enable us to create more intricate and desirable DNA nanostructures by programming the folding of DNA origami structures.”

Conducted by Dr. Woori Bae under the guidance of Professor Yoon, the research findings were published online in the December 4th issue of Nature Communications.


Source: KAIST