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Liu E.,University of Colorado at Denver | Lee H.-S.,University of South Florida | Aronsson C.A.,Lund University | Hagopian W.A.,Pacific Northwest Diabetes Research Institute | And 8 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS: We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS: The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowestrisk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS: Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. Copyright © 2014 Massachusetts Medical Society.

News Article | November 11, 2015

Molecular biologist Nina Dudnik was studying rice in Côte d'Ivoire when she realized the logistical challenge of doing research in the developing world. “I was trying to conduct research in a country an ocean away from where the equipment manufacturers and reagent suppliers were,” she says. “We had to wait months to get them.” When she returned to start her PhD course at Harvard University in Cambridge, Massachusetts, she led a group of fellow students to collect surplus equipment and supplies for labs in need in developing countries. Eventually, her volunteer work became a non-profit business, and in 2007, she founded Seeding Labs in Boston, Massachusetts. The firm provides scientific training and refurbished equipment to research institutions. “We work with a large network of corporations and research institutions that donate their surplus equipment to us, and we distribute it to the labs that need it,” Dudnik says. Since its inception Seeding has partnered with scientists in 22 nations, and in 2015 it was hailed by Fast Company magazine as one of the world's top ten most innovative non-profit organizations. Dudnik expects to ship equipment to about 15 university departments next year. In support of her goal, last year she won a US$3-million grant from the US Agency for International Development. She has four full-time employees and next year expects to hire a fifth. The non-profit sector appealed to Dudnik because of its vast potential for helping others. “This is a problem with great social impact,” she says of labs in developing nations that struggle with insufficient and worn-out equipment and resources. “My desire to solve it has nothing to do with becoming rich and famous.” This objective represents the biggest difference between for-profit and non-profit businesses: non-profit groups are driven by their mission rather than by the need to bolster the bottom line. “They're interested in solving problems,” says Joanne Kamens, who is executive director at Addgene, a non-profit organization in Cambridge, Massachusetts, that operates a plasmid repository for the research community. For that reason, scientists often thrive in non-profit organizations, Kamens says, because they value knowledge and solutions. Roles for scientists in the non-profit sector are as diverse as the types of organizations that exist in it. Scientists might, for example, do bench research, manage large-scale community projects, work with disease-advocacy groups or become science communicators at professional societies. Finding the type of non-profit that dovetails with one's interests requires an understanding of how the organizations operate and the opportunities that they offer. Networking contacts and online job sites, such as Idealist (, can help to provide this information, says Dudnik. She recommends talking with a broad cross-section of employees in the sector to get a clear idea of their organization's mission and available jobs, internships and volunteer posts. Scientists are increasingly deciding that they are a good fit with the sector: the number of PhD holders from the life and physical sciences who enter it is rising, according to the US National Science Foundation's biennial Survey of Doctoral Recipients ( In 2003, 5% of science-doctorate holders were working in the non-profit sector; the rate increased to about 7% by 2013. Employment opportunities in the sector are also on the increase, according to a survey this year from Nonprofit HR, a US human-resources group based in Washington DC that serves the sector. The survey found that about half of non-profit organizations in the United States and Canada planned to create new positions this year. Those who hope to land a professional post at a non-profit business should have volunteer or internship experience, both to provide a flavour of working in the sector and to deflect possible scepticism from potential co-workers. Some non-scientist employees in the sector may perceive a researcher as someone who can only pipette or peer into a microscope. “Having any kind of volunteering or interning experience is really, really vital,” says Dudnik. “It will demonstrate that you are capable of more than research and that you have a passion for helping others.” Scientists in non-profit organizations often find themselves becoming part of a local community. Residents of Assen, the Netherlands, needed help to improve safety for cyclists along a canal at night, so the city turned to its regional science shop. Such 'shops' are non-profit groups that are usually linked to a university and provide research in response to local concerns. With help from the municipal government and volunteers, science-shop researchers found that green lights illuminated cyclists' paths without unduly disturbing the area's wildlife. “It was a cooperation between different stakeholders that are involved in this specific problem,” says Norbert Steinhaus, coordinator and international contact for Living Knowledge, which coordinates the international science-shop network. Many scientists who work at non-profit groups enjoy a latitude that would be unlikely in the for-profit sector. Aimee Dudley, a lab group leader at the non-profit Pacific Northwest Diabetes Research Institute in Seattle, Washington, says that she has considerable freedom in her research programme. “I consider myself the head of my own small business,” she says. “I determine the direction of the lab, get funding, make sure it has the money to pay people and do experiments.” Dudley maintains an affiliate faculty post in the University of Washington's genome-sciences department, which links her with colleagues and their research. It also provides her with access to the university's library and subscriptions, as well as to graduate students, who can perform their thesis research work in her lab. “I enjoy teaching and supervising in the lab, and think it's important to help the next generation of researchers,” she says. For her, hosting students and providing on-site training is another aspect of her flexibility. “If I wasn't interested in having students, I wouldn't,” she says. Autonomy has also been valuable to Cristina Eisenberg, a lead scientist at the Boston-based Earthwatch Institute. In the past year, she has travelled twice to the Pacaya-Samiria National Reserve in Peru's Amazonian region, where she oversees Earthwatch's projects, including a decade-long study of climate-change effects in the Amazon. “This position enables me to have far more impact on science and sustainability than if I was at a university teaching classes,” she says. Joseph Jerry is science director at the non-profit Pioneer Valley Life Sciences Institute (PVSLI) in Springfield, Massachusetts, as well as a faculty member at the University of Massachusetts Amherst. This means that he can augment his basic research into breast cancer at the university with more-translational research at PVSLI, where he says he gets to work closely with patients and advocates. The opportunity to interact directly with clinical patients has been an eye-opening experience for Jerry, who admits that as a scientist, he has been most comfortable in the lab. “I don't consider myself a people person, but working with patients is a wonderful experience,” he says. “I've learned a lot about how to communicate better.” Yet for all of their upsides, non-profit organizations are hardly perfect; like any other business, they are vulnerable to a faltering economy. Historically, they have depended on a philanthropic business model: supported by hefty and regular donations, they provided a service or product for which consumers or clients did not pay. But that model has weakened along with the global economy, and non-profits are seeking other ways to secure funds. Seeding Labs, for example, no longer depends entirely on philanthropy — it charges clients a fee to cover part of the cost of doing business. The fee also increases the likelihood that Seeding's services will be more highly valued, Dudnik says. Still, notes Kamens, in a shifting economic landscape, researchers may be especially desirable for non-profit posts that require fundraising because they typically have substantial experience of writing grants. “It's very hard to find people who are good at development work,” she says. Ultimately, researchers who work at non-profit groups become part of a community of people who care deeply about the organization's goals. That was the reason that Eisenberg left her academic post for Earthwatch in the first place. For her, working at a non-profit meant more than spending time in the jungle or the lab. “We work together,” she says, “to advance our mission — science”.

Buchner D.A.,Case Western Reserve University | Nadeau J.H.,Pacific Northwest Diabetes Research Institute
Genome Research | Year: 2015

Quantitative trait loci (QTLs) are being used to study genetic networks, protein functions, and systems properties that underlie phenotypic variation and disease risk in humans, model organisms, agricultural species, and natural populations. The challenges are many, beginning with the seemingly simple tasks of mapping QTLs and identifying their underlying genetic determinants. Various specialized resources have been developed to study complex traits in many model organisms. In the mouse, remarkably different pictures of genetic architectures are emerging. Chromosome Substitution Strains (CSSs) reveal many QTLs, large phenotypic effects, pervasive epistasis, and readily identified genetic variants. In contrast, other resources as well as genome-wide association studies (GWAS) in humans and other species reveal genetic architectures dominated with a relatively modest number of QTLs that have small individual and combined phenotypic effects. These contrasting architectures are the result of intrinsic differences in the study designs underlying different resources. The CSSs examine contextdependent phenotypic effects independently among individual genotypes, whereas with GWAS and other mouse resources, the average effect of each QTL is assessed among many individuals with heterogeneous genetic backgrounds. We argue that variation of genetic architectures among individuals is as important as population averages. Each of these important resources has particular merits and specific applications for these individual and population perspectives. Collectively, these resources together with high-throughput genotyping, sequencing and genetic engineering technologies, and information repositories highlight the power of the mouse for genetic, functional, and systems studies of complex traits and disease models. © 2015 Buchner and Nadeau.

Ortiz D.,University of Washington | Bryan J.,Pacific Northwest Diabetes Research Institute
Frontiers in Endocrinology | Year: 2015

ATP-sensitive K+ (KATP) channels composed of potassium inward-rectifier type 6.2 and sulfonylurea receptor type 1 subunits (Kir6.2/SUR1)4 are expressed in various cells in the brain and endocrine pancreas where they couple metabolic status to membrane potential. In β-cells, increases in cytosolic [ATP/ADP]c inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively. SUR1 is reported to be a Mg2+-dependent ATPase. A prevailing model posits that ATP hydrolysis at SUR1 is required to stimulate openings of the pore. However, recent work shows nucleotide binding, without hydrolysis, is sufficient to switch SUR1 to stimulatory conformations. The actions of nucleotides, ATP and ADP, on ND (SUR1E1506D) and CHI (SUR1E1506K) mutants, without Kir6.2, were compared to assess both models. Both substitutions significantly impair hydrolysis in SUR1 homologues. SUR1E1506D has greater affinity for MgATP than wildtype; SUR1E1506K has reduced affinity. Without Mg2+, SUR1E1506K has a greater affinity for ATP4- consistent with electrostatic attraction between ATP4-, unshielded by Mg2+, and the basic lysine. Further analysis of ND and CHI ABCC8 mutants in the second transmembrane and nucleotide binding domains (TMD2 & NBD2), found a relation between their affinities for ATP (± Mg2+) and their clinical phenotype. Increased affinity for ATP is associated with ND; decreased affinity with CHI. In contrast, MgADP showed a weaker relationship. Diazoxide, known to reduce insulin release in some CHI cases, potentiates switching of CHI mutants from non-stimulatory to stimulatory states consistent with diazoxide stabilizing a nucleotide-bound conformation. The results emphasize the greater importance of nucleotide binding vs hydrolysis in the regulation of KATP channels in vivo. © 2015 Bryan and Ortiz.

Hickman M.A.,University of Minnesota | Hickman M.A.,Emory University | Paulson C.,University of Minnesota | Dudley A.,Pacific Northwest Diabetes Research Institute | And 2 more authors.
Genetics | Year: 2015

The opportunistic pathogen Candida albicans has a large repertoire of mechanisms to generate genetic and phenotypic diversity despite the lack of meiosis in its life cycle. Its parasexual cycle enables shifts in ploidy, which in turn facilitate recombination, aneuploidy, and homozygosis of whole chromosomes to fuel rapid adaptation. Here we show that the tetraploid state potentiates ploidy variation and drives population heterogeneity. In tetraploids, the rate of losing a single heterozygous marker [loss of heterozygosity (LOH)] is elevated ∼30-fold higher than the rate in diploid cells. Furthermore, isolates recovered after selection for LOH of one, two, or three markers were highly aneuploid, with a broad range of karyotypes including strains with a combination of di-, tri-, and tetrasomic chromosomes. We followed the ploidy trajectories for these tetraploid- and aneuploid-derived isolates, using a combination of flow cytometry and double-digestion restriction-site-associated DNA analyzed with next-generation sequencing. Isolates derived from either tetraploid or aneuploid isolates predominately resolved to a stable euploid state. The majority of isolates reduced to the conventional diploid state; however, stable triploid and tetraploid states were observed in ∼30% of the isolates. Notably, aneuploid isolates were more transient than tetraploid isolates, resolving to a euploid state within a few passages. Furthermore, the likelihood that a particular isolate will resolve to the same ploidy state in replicate evolution experiments is only ∼50%, supporting the idea that the chromosome loss process of the parasexual cycle is random and does not follow trajectories involving specific combinations of chromosomes. Together, our results indicate that tetraploid progenitors can produce populations of progeny cells with a high degree of genomic diversity, from altered ploidy to homozygosis, providing an excellent source of genetic variation upon which selection can act. © 2015 by the Genetics Society of America.

Nadeau J.H.,Pacific Northwest Diabetes Research Institute
Genome Biology | Year: 2015

Not so fast. The Iqbal et. al. study and the associated Whitelaw commentary highlight the appropriately high standards of study design and interpretation needed to obtain good evidence for or against epigenetic inheritance. Please see related article: © 2015 Nadeau.

Cromie G.A.,Pacific Northwest Diabetes Research Institute | Dudley A.M.,Pacific Northwest Diabetes Research Institute
Current Biology | Year: 2015

Individuals, and cells, vary in their ability to tolerate aneuploidy, an unbalanced chromosome complement. Tolerance mechanisms can be karyotype-specific or general. General tolerance mechanisms may allow cells to benefit from the phenotypic plasticity conferred by access to multiple aneuploid states. © 2015 Elsevier Ltd. All rights reserved.

Vallerie S.N.,Harvard University | Vallerie S.N.,Pacific Northwest Diabetes Research Institute | Hotamisligil G.S.,Harvard University
Science Translational Medicine | Year: 2010

The stress-activated c-Jun amino-terminal kinase (JNK) plays a pivotal role in metabolic conditions such as obesity, insulin resistance, and type 2 diabetes. Intricate tissue-specific tweaking of JNK activity in preclinical models of metabolic diseases reveals a complex interplay among local and systemic effects on carbohydrate and lipid metabolism. Synthesis of these entangled effects illustrates that for JNK inhibitors to have therapeutic impact, they must function in multiple cell types to modulate JNK activity.

News Article | March 28, 2016

Do you find Swiss and Belgian chocolates tastier than your country's own chocolate? If so, you might thank the yeast present in your chocolate for giving that distinctive taste. Diverse yeast population may give the difference in taste of chocolates and coffee that can be seen from different parts of the world, researchers said. The authors sought to know which human activity have influenced the yeasts in the coffee and cacaos fermentation came from. According to the study, wine production differs from the production of chocolate and coffee in a few vital aspects. Initially, the production of wine uses vessels in its fermentation like oak barrels, are exported to new areas where their yeast are native from its origin. As compared to chocolates and coffee, wherein the fermentation style used might have a population of yeast which is different from the area of origin. "Humans have transported and cultivated the plants, but at least for one important species, their associated microbes have arisen from transport and mingling in events that are independent of the transport of the plants themselves," said Aimee Dudley of Pacific Northwest Diabetes Research Institute in Seattle, U.S.A. The researchers fermented the cacao beans' surrounding pulp through a microbe-driven process. The microbe-driven process used lactic acid bacteria and acetic acid bacteria to digest the surrounding pectinaceous pulp of the beans. The process has a vital role in the different characteristics of the beans such as flavor and color. On the other hand, researchers found that the microbiota of coffee beans showed little yeasts in its fermentation. As compared to the natural way of fermenting the coffee through the digestion of its cherry pulp by coffee growers, the researchers attempted to culture live yeasts through unroasted coffee and cacao beans derived from different geographical and ecological niches. Researchers said that the yeast strains seen from the chocolate and coffee making shows greater diversity than those yeast associated in making wines. The findings published in the journal Current Biology, showed that the coffee and cocoa strains have multiple origins and the approach used in it can also isolate other microorganisms. Coffee trees and cacao beans are now commonly grown across the "bean belt" which surrounds the equator but originally cultivated in Ethiopia and Amazon rain forest.

News Article | March 24, 2016

In comparison to the yeasts found in vineyards around the world, the new work shows that those associated with coffee and cacao beans show much greater diversity. The findings suggest that those differences may play an important role in the characteristics of chocolate and coffee from different parts of the world. "Our study suggests a complex interplay between human activity and microbes involved in the production of coffee and chocolate," says Aimée Dudley of the Pacific Northwest Diabetes Research Institute in Seattle. "Humans have transported and cultivated the plants, but at least for one important species, their associated microbes have arisen from transport and mingling in events that are independent of the transport of the plants themselves." Coffee and cacao trees originally grew in Ethiopia and the Amazon rainforest. They are now widely cultivated across the "bean belt" that surrounds the equator. After they are picked, both cacao and coffee beans are fermented for a period of days to break down the surrounding pulp. This microbe-driven process also has an important influence on the character and flavor of the beans. Dudley and her colleagues wanted to know where the yeasts in these human-associated fermentations came from. Had coffee- or cacao-specific yeast strains been unknowingly transported along with the plants? Or, do particular regions of the world harbor novel yeast populations? To find out, the researchers bought unroasted coffee and cacao beans grown in Central and South America, Africa, Indonesia, or the Middle East and isolated the associated yeast in their Seattle laboratory. Genetic analysis of those yeast strains revealed that yeasts from coffee and cacao beans were substantially more diverse than the wine yeasts. Interestingly, the genetic signatures of the yeast strains strongly clustered according to the geographic origin of the beans. In fact, Dudley says, this association was so strong that they were able to accurately determine the origin of the beans solely from the DNA sequences of their associated yeasts. The findings show that the yeast strains associated with coffee and cacao have multiple, independent origins. In other words, not all coffee strains are related, nor are all cacao strains. What's more, the yeast strains associated with coffee or cacao in specific places appear to be hybrids that resulted from the mixing of strains from different parts of the world. In fact, one of those strains is closely related to the yeast used to make wine. "The ancient and continuing global traffic in yeasts associated with wine fermentation may have set the stage for subsequent mingling and admixture events that gave rise to the yeasts that are now associated with the production of coffee and chocolate," Dudley says. The researchers say the findings could lead to improvements in chocolate and coffee. Studies of wine production have shown that the yeasts associated with fermentation significantly influence the properties of the wine, including its flavor and aroma. "Given that the yeast strains associated with coffee and cacao fermentations are substantially more genetically diverse than the wine strains, they could play an even larger role in the properties of coffee and cacao produced in different regions of the globe," Dudley says. Explore further: Finally, a way to authenticate premium chocolate More information: Current Biology, Ludlow et al.:"Independent Origins of Yeast Associated with Coffee and Cacao Fermentation"

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