bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesizing epidemiological and economic optima for control of immunizing infections
Authors: Klepac Petra , Laxminarayan Ramanan , Grenfell Bryan T.
Published: August 2011

Epidemic theory predicts that the vaccination threshold required to interrupt local transmission of an immunizing infection like measles depends only on the basic reproductive numberand hence transmission rates. When the search for optimal strategies is expanded to incorporate economic constraints, the optimum for disease control in a single population is determined by relative costs of infection and control, rather than transmission rates. Adding a spatial dimension, which precludes local elimination unless it can be achieved globally, can reduce or increase optimal vaccination levels depending on the balance of costs and benefits. For weakly coupled populations, local optimal strategies agree with the global cost-effective strategy; however, asymmetries in costs can lead to divergent control optima in more strongly coupled systems—in particular, strong regional differences in costs of vaccination can preclude local elimination even when elimination is locally optimal. Under certain conditions, it is locally optimal to share vaccination resources with other populations.
Leukocyte composition of human breast cancer
Authors: Ruffell Brian , Au Alfred , Rugo Hope S. , Esserman Laura J. , Hwang E. Shelley , Coussens Lisa M.
Published: August 2011

Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in “normal” breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.
Dichroic coherent diffractive imaging
Authors: Tripathi Ashish , Mohanty Jyoti , Dietze Sebastian H. , Shpyrko Oleg G. , Shipton Erik , Fullerton Eric E. , Kim Sang Soo , McNulty Ian
Published: August 2011

Understanding electronic structure at the nanoscale is crucial to untangling fundamental physics puzzles such as phase separation and emergent behavior in complex magnetic oxides. Probes with the ability to see beyond surfaces on nanometer length and subpicosecond time scales can greatly enhance our understanding of these systems and will undoubtedly impact development of future information technologies. Polarized X-rays are an appealing choice of probe due to their penetrating power, elemental and magnetic specificity, and high spatial resolution. The resolution of traditional X-ray microscopes is limited by the nanometer precision required to fabricate X-ray optics. Here we present a novel approach to lensless imaging of an extended magnetic nanostructure, in which a scanned series of dichroic coherent diffraction patterns is recorded and numerically inverted to map its magnetic domain configuration. Unlike holographic methods, it does not require a reference wave or precision optics. In addition, it enables the imaging of samples with arbitrarily large spatial dimensions, at a spatial resolution limited solely by the coherent X-ray flux, wavelength, and stability of the sample with respect to the beam. It can readily be extended to nonmagnetic systems that exhibit circular or linear dichroism. We demonstrate this approach by imaging ferrimagnetic labyrinthine domains in a Gd/Fe multilayer with perpendicular anisotropy and follow the evolution of the domain structure through part of its magnetization hysteresis loop. This approach is scalable to imaging with diffraction-limited resolution, a prospect rapidly becoming a reality in view of the new generation of phenomenally brilliant X-ray sources.
Spermless males elicit large-scale female responses to mating in the malaria mosquito
Anopheles gambiae
Authors: Thailayil Janis , Magnusson Kalle , Godfray H. Charles J. , Crisanti Andrea , Catteruccia Flaminia
Published: August 2011

Anopheles gambiae sensu stricto
is the major vector of malaria, a disease with devastating consequences for human health. Given the constant spread of the disease, alternative approaches to the use of insecticides are urgently needed to control vector populations. Females of this species undergo large behavioral changes after mating, which include a life-long refractoriness to further insemination and the induction of egg laying in blood-fed individuals. Genetic control strategies aimed at impacting
Anopheles
fertility through the release of sterile males are being advocated to reduce the size of mosquito field populations. Such strategies depend on the ability of the released sterile males to mate successfully with wild females and to switch off the female receptivity to further copulation. Here we evaluate the role of sperm in regulating female behavioral responses after mating in
An. gambiae
. We developed spermless males by RNAi silencing of a germ cell differentiation gene. These males mated successfully and preserved standard accessory gland functions. Females mated to spermless males exhibited normal postcopulatory responses, which included laying large numbers of eggs upon blood feeding and becoming refractory to subsequent insemination. Moreover, spermless males induced transcriptional changes in female reproductive genes comparable to those elicited by fertile males. Our data demonstrate that, in contrast to
Drosophila
, targeting sperm in
An. gambiae
preserves normal male and female reproductive behavior for the traits and time frame analyzed and validate the use of approaches based on incapacitation or elimination of sperm for genetic control of vector populations to block malaria transmission.
Fast-folding α-helices as reversible strain absorbers in the muscle protein myomesin
Authors: Berkemeier Felix , Bertz Morten , Xiao Senbo , Pinotsis Nikos , Wilmanns Matthias , Gräter Frauke , Rief Matthias
Published: August 2011

The highly oriented filamentous protein network of muscle constantly experiences significant mechanical load during muscle operation. The dimeric protein myomesin has been identified as an important M-band component supporting the mechanical integrity of the entire sarcomere. Recent structural studies have revealed a long α-helical linker between the C-terminal immunoglobulin (Ig) domains My12 and My13 of myomesin. In this paper, we have used single-molecule force spectroscopy in combination with molecular dynamics simulations to characterize the mechanics of the myomesin dimer comprising immunoglobulin domains My12–My13. We find that at forces of approximately 30 pN the α-helical linker reversibly elongates allowing the molecule to extend by more than the folded extension of a full domain. High-resolution measurements directly reveal the equilibrium folding/unfolding kinetics of the individual helix. We show that α-helix unfolding mechanically protects the molecule homodimerization from dissociation at physiologically relevant forces. As fast and reversible molecular springs the myomesin α-helical linkers are an essential component for the structural integrity of the M band.
Glycosylation of the enhanced aromatic sequon is similarly stabilizing in three distinct reverse turn contexts
Authors: Price Joshua L. , Powers David L. , Powers Evan T. , Kelly Jeffery W.
Published: August 2011

Cotranslational N-glycosylation can accelerate protein folding, slow protein unfolding, and increase protein stability, but the molecular basis for these energetic effects is incompletely understood. N-glycosylation of proteins at naïve sites could be a useful strategy for stabilizing proteins in therapeutic and research applications, but without engineering guidelines, often results in unpredictable changes to protein energetics. We recently introduced the enhanced aromatic sequon as a family of portable structural motifs that are stabilized upon glycosylation in specific reverse turn contexts: a five-residue type I β-turn harboring a G1 β-bulge (using a Phe–Yyy–Asn–Xxx–Thr sequon) and a type II β-turn within a six-residue loop (using a Phe–Yyy–Zzz–Asn–Xxx–Thr sequon) [Culyba EK, et al. (2011)Science331:571–575]. Here we show that glycosylating a new enhanced aromatic sequon, Phe–Asn–Xxx–Thr, in a type I′ β-turn stabilizes the Pin 1 WW domain. Comparing the energetic effects of glycosylating these three enhanced aromatic sequons in the same host WW domain revealed that the glycosylation-mediated stabilization is greatest for the enhanced aromatic sequon complementary to the type I β-turn with a G1 β-bulge. However, the portion of the stabilization from the tripartite interaction between Phe, Asn(GlcNAc), and Thr is similar for each enhanced aromatic sequon in its respective reverse turn context. Adding the Phe–Asn–Xxx–Thr motif (in a type I′ β-turn) to the enhanced aromatic sequon family doubles the number of proteins that can be stabilized by glycosylation without having to alter the native reverse turn type.
Evolution of functional nucleic acids in the presence of nonheritable backbone heterogeneity
Authors: Trevino Simon G. , Zhang Na , Elenko Mark P. , Lupták Andrej , Szostak Jack W.
Published: August 2011

Multiple lines of evidence support the hypothesis that the early evolution of life was dominated by RNA, which can both transfer information from generation to generation through replication directed by base-pairing, and carry out biochemical activities by folding into functional structures. To understand how life emerged from prebiotic chemistry we must therefore explain the steps that led to the emergence of the RNA world, and in particular, the synthesis of RNA. The generation of pools of highly pure ribonucleotides on the early Earth seems unlikely, but the presence of alternative nucleotides would support the assembly of nucleic acid polymers containing nonheritable backbone heterogeneity. We suggest that homogeneous monomers might not have been necessary if populations of heterogeneous nucleic acid molecules could evolve reproducible function. For such evolution to be possible, function would have to be maintained despite the repeated scrambling of backbone chemistry from generation to generation. We have tested this possibility in a simplified model system, by using a T7 RNA polymerase variant capable of transcribing nucleic acids that contain an approximately 1∶1 mixture of deoxy- and ribonucleotides. We readily isolated nucleotide-binding aptamers by utilizing an in vitro selection process that shuffles the order of deoxy- and ribonucleotides in each round. We describe two such RNA/DNA mosaic nucleic acid aptamers that specifically bind ATP and GTP, respectively. We conclude that nonheritable variations in nucleic acid backbone structure may not have posed an insurmountable barrier to the emergence of functionality in early nucleic acids.
Chloroplast Omp85 proteins change orientation during evolution
Authors: Sommer Maik S. , Daum Bertram , Gross Lucia E. , Weis Benjamin L. M. , Mirus Oliver , Abram Lars , Maier Uwe-G. , Kühlbrandt Werner , Schleiff Enrico
Published: August 2011

The majority of outer membrane proteins (OMPs) from Gram-negative bacteria and many of mitochondria and chloroplasts are β-barrels. Insertion and assembly of these proteins are catalyzed by the Omp85 protein family in a seemingly conserved process. All members of this family exhibit a characteristic N-terminal polypeptide-transport–associated (POTRA) and a C-terminal 16-stranded β-barrel domain. In plants, two phylogenetically distinct and essential Omp85's exist in the chloroplast outer membrane, namely Toc75-III and Toc75-V. Whereas Toc75-V, similar to the mitochondrial Sam50, is thought to possess the original bacterial function, its homolog, Toc75-III, evolved to the pore-forming unit of the TOC translocon for preprotein import. In all current models of OMP biogenesis and preprotein translocation, a topology of Omp85 with the POTRA domain in the periplasm or intermembrane space is assumed. Using self-assembly GFP-based in vivo experiments and in situ topology studies by electron cryotomography, we show that the POTRA domains of both Toc75-III and Toc75-V are exposed to the cytoplasm. This unexpected finding explains many experimental observations and requires a reevaluation of current models of OMP biogenesis and TOC complex function.
Transformations, transport, and potential unintended consequences of high sulfur inputs to Napa Valley vineyards
Authors: Hinckley Eve-Lyn S. , Matson Pamela A.
Published: August 2011

Unintended anthropogenic deposition of sulfur (S) to forest ecosystems has a range of negative consequences, identified through decades of research. There has been far less study of purposeful S use in agricultural systems around the world, including the application of elemental sulfur (S
0
) as a quick-reacting fungicide to prevent damage to crops. Here we report results from a three-year study of the transformations and flows of applied S
0
in soils, vegetation, and hydrologic export pathways of Napa Valley, CA vineyards, documenting that all applied S is lost from the vineyard ecosystem on an annual basis. We found that S
0
oxidizes rapidly to sulfate (

) on the soil surface where it then accumulates over the course of the growing season. Leaf and grape tissues accounted for only 7–13% of applied S whereas dormant season cover crops accounted for 4–10% of applications. Soil S inventories were largely

and ester-bonded sulfates; they decreased from 1,623 ± 354 kg ha
-1
during the dry growing season to 981 ± 526 kg ha
-1
(0–0.5 m) during the dormant wet season. Nearly all S applied to the vineyard soils is transported offsite in dissolved oxidized forms during dormant season rainstorms. Thus, the residence time of reactive S is brief in these systems, and largely driven by hydrology. Our results provide new insight into how S use in vineyards constitutes a substantial perturbation of the S cycle in Northern California winegrowing regions and points to the unintended consequences that agricultural S use may have at larger scales.
Hemagglutinin–neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets
Authors: Yen Hui-Ling , Liang Chi-Hui , Wu Chung-Yi , Forrest Heather L. , Ferguson Angela , Choy Ka-Tim , Jones Jeremy , Wong Diana Dik-Yan , Cheung Peter Pak-Hang , Hsu Che-Hsiung , Li Olive T. , Yuen Kit M. , Chan Renee W. Y. , Poon Leo L. M. , Chan Michael C. W. , Nicholls John M. , Krauss Scott , Wong Chi-Huey , Guan Yi , Webster Robert G. , Webby Richard J. , Peiris Malik
Published: August 2011

A novel reassortant derived from North American triple-reassortant (TRsw) and Eurasian swine (EAsw) influenza viruses acquired sustained human-to-human transmissibility and caused the 2009 influenza pandemic. To identify molecular determinants that allowed efficient transmission of the pandemic H1N1 virus among humans, we evaluated the direct-contact and respiratory-droplet transmissibility in ferrets of representative swine influenza viruses of different lineages obtained through a 13-y surveillance program in southern China. Whereas all viruses studied were transmitted by direct contact with varying efficiency, respiratory-droplet transmissibility (albeit inefficient) was observed only in the TRsw-like A/swine/Hong Kong/915/04 (sw915) (H1N2) virus. The sw915 virus had acquired the M gene derived from EAsw and differed from the gene constellation of the pandemic H1N1 virus by the neuraminidase (NA) gene alone. Glycan array analysis showed that pandemic H1N1 virus A/HK/415742/09 (HK415742) and sw915 possess similar receptor-binding specificity and affinity for α2,6-linked sialosides. Sw915 titers in differentiated normal human bronchial epithelial cells and in ferret nasal washes were lower than those of HK415742. Introducing the NA from pandemic HK415742 into sw915 did not increase viral replication efficiency but increased respiratory-droplet transmissibility, despite a substantial amino acid difference between the two viruses. The NA of the pandemic HK415742 virus possessed significantly higher enzyme activity than that of sw915 or other swine influenza viruses. Our results suggest that a unique gene constellation and hemagglutinin–neuraminidase balance play a critical role in acquisition of efficient and sustained human-to-human transmissibility.
The conserved GTPase Gem1 regulates endoplasmic reticulum–mitochondria connections
Authors: Kornmann Benoît , Osman Christof , Walter Peter
Published: August 2011

Mitochondria are connected to the endoplasmic reticulum (ER) through specialized protein complexes. We recently identified the ER–mitochondria encounter structure (ERMES) tethering complex, which plays a role in phospholipid exchange between the two organelles. ERMES also has been implicated in the coordination of mitochondrial protein import, mitochondrial DNA replication, and mitochondrial dynamics, suggesting that these interorganelle contact sites play central regulatory roles in coordinating various aspects of the physiology of the two organelles. Here we purified ERMES complexes and identified the Ca
2+
-binding Miro GTPase Gem1 as an integral component of ERMES. Gem1 regulates the number and size of the ERMES complexes. In vivo, association of Gem1 to ERMES required the first of Gem1’s two GTPase domains and the first of its two functional Ca
2+
-binding domains. In contrast, Gem1’s second GTPase domain was required for proper ERMES function in phospholipid exchange. Our results suggest that ERMES is not a passive conduit for interorganellar lipid exchange, but that it can be regulated in response to physiological needs. Furthermore, we provide evidence that the metazoan Gem1 ortholog Miro-1 localizes to sites of ER–mitochondrial contact, suggesting that some of the features ascribed to Gem1 may be evolutionarily conserved.
Visualization of dynein-dependent microtubule gliding at the cell cortex: implications for spindle positioning
Authors: Gusnowski Eva M. , Srayko Martin
Published: August 2011

Dynein motors move along the microtubule (MT) lattice in a processive “walking” manner. In the one-cell Caenorhabditis elegans embryo, dynein is required for spindle-pulling forces during mitosis. Posteriorly directed spindle-pulling forces are higher than anteriorly directed forces, and this imbalance results in posterior spindle displacement during anaphase and an asymmetric division. To address how dynein could be asymmetrically activated to achieve posterior spindle displacement, we developed an assay to measure dynein’s activity on individual MTs at the embryo cortex. Our study reveals that cortical dynein motors maintain a basal level of activity that propels MTs along the cortex, even under experimental conditions that drastically reduce anaphase spindle forces. This suggests that dynein-based MT gliding is not sufficient for anaphase spindle-pulling force. Instead, we find that this form of dynein activity is most prominent during spindle centering in early prophase. We propose a model whereby different dynein–MT interactions are used for specific spindle-positioning tasks in the one-cell embryo.
Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells
Authors: Wan Qi , Kozhaya Lina , ElHed Aimee , Ramesh Radha , Carlson Thaddeus J. , Djuretic Ivana M. , Sundrud Mark S. , Unutmaz Derya
Published: August 2011

Human memory T cells (TM cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6+ and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)–using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6+, but not CCR6−, TM cells, even in CCR6+ cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6+ TM cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.
Outcomes and Genetic Relatedness of Carbapenem-Resistant Enterobacteriaceae at Detroit Medical Center
Authors: Marchaim Dror , Chopra Teena , Perez Federico , Hayakawa Kayoko , Lephart Paul R. , Bheemreddy Suchitha , Blunden Christopher , Hujer Andrea M. , Rudin Susan , Shango Maryann , Campbell Michelle , Varkey Jastin , Slim Jessica , Ahmad Farah , Patel Diixa , Chen Ting-Yi , Pogue Jason M. , Salimnia Hossein , Dhar Sorabh , Bonomo Robert A. , Kaye Keith S.
Published: August 2011

Background.

Carbapenem-resistant Enterobacteriaceae (CRE) are rapidly emerging in hospitals in the United States and are posing a significant threat. To better understand the transmission dynamics and the acquisition of resistant strains, a thorough analysis of epidemiologic and molecular characteristics was performed.

Methods.

CRE isolated at Detroit Medical Center were analyzed from September 2008 to September 2009. blaKPC genes were investigated by polymerase chain reaction (PCR), and repetitive extragenic palindromic PCR (rep-PCR) was used to determine genetic similarity among strains. Epidemiologic and outcomes analyses were performed.

Results.

Ninety-two unique patient CRE isolates were recovered. Sixty-eight strains (74%) were Klebsiella pneumoniae, 7 were Klebsiella oxytoca, 15 were Enterobacter species, and 2 were Escherichia coli. Fifteen isolates (16%) were resistant to Colistin, 14 (16%) were resistant to tigecycline, and 2 were resistant to all antimicrobials tested. The mean ± standard deviation age of patients was 63 ± 2 years. Sixty patients (68%) were admitted to the hospital from long-term care facilities. Only 70% of patients received effective antimicrobial therapy when infection was suspected, with a mean time to appropriate therapy of 120 ± 23 hours following sample culturing. The mean length of hospitalization after sample culturing was 18.6 ± 2.5 days. Of 57 inpatients, 18 (32%) died in the hospital. Independent predictors for mortality were intensive care unit stay (odds ratio [OR], 15.8; P = .003) and co-colonization with CRE and either Acinetobacter baumannii or Pseudomonas aeruginosa (OR, 17.2; P = .006). Among K. pneumoniae CRE, rep-PCR revealed 2 genetically related strains that comprised 70% and 20% of isolates, respectively.

Conclusions.

In this large U.S. cohort of patients with CRE infection, which reflects the modern continuum of medical care, co-colonization with CRE and A. baumannii or P. aeruginosa was associated with increased mortality. Two predominant clones of K. pneumoniae accounted for the majority of cases of CRE infection.
Achievement of 500 keV negative ion beam acceleration on JT-60U negative-ion-based neutral beam injector
Authors: Kojima A. , Hanada M. , Tanaka Y. , Kawai M. , Akino N. , Kazawa M. , Komata M. , Mogaki K. , Usui K. , Sasaki S. , Kikuchi K. , Seki N. , Nemoto S. , Oshima K. , Simizu T. , Kubo N. , Oasa K. , Inoue T. , Watanabe K. , Taniguchi M. , Kashiwagi M. , Tobari H. , Umeda N. , Kobayashi S. , Yamano Y. , Grisham L.R.
Published: August 2011

Hydrogen negative ion beams of 507 keV, 1 A and 486 keV, 2.8 A have been successfully produced in the JT-60U negative ion source with a three-stage accelerator by overcoming a poor voltage holding of the accelerator with large-size grids of ∼2 m2. This is the first result of H− beam acceleration up to 500 keV at a high current of over 1 A. In order to improve the voltage holding capability, the breakdown voltages of the large-size grids and small-size electrodes with uniform and locally strong electric fields were examined by changing the gap length. It was found that the voltage holding of the large-size grids was below half of that of the small-size electrodes with a uniform electric field which was used in the design of the accelerator. This degradation was found to be caused by the local electric field concentrations in addition to the size. Based on the results of the voltage holding tests and beam optics calculations, the gap lengths of the large-size grids were tuned to have a capability to sustain 600 kV. As a result, the gap tuning realized stable voltage holding during beam accelerations without significant degradations of the beam optics and stripping loss. These results indicated that stable 500 keV beam accelerations required for JT-60SA are feasible and this gap tuning is also applicable for the design of ITER accelerator.
Avoidance of disruptions at high βN in ASDEX Upgrade with off-axis ECRH
Authors: Esposito B. , Granucci G. , Maraschek M. , Nowak S. , Gude A. , Igochine V. , Lazzaro E. , McDermott R. , Poli E. , Stober J. , Suttrop W. , Treutterer W. , Zohm H. , Brunetti D.
Published: August 2011

Experiments on disruption avoidance have been carried out in H-mode ASDEX Upgrade plasmas: the localized perpendicular injection of ECRH (1.5 MW ∼ 0.2P
tot) onto the q = 2 resonant surface has led to the delay and/or complete avoidance of disruptions in a high βN scenario (I
p = 1 MA, B
t = 2.1 T, q
95 ∼ 3.6, with NBI ∼7.5 MW). In these discharges (at low q
95 and low density) neoclassical tearing modes (NTMs) are excited: the growth and locking of the m/n = 2/1 mode leads to the disruption. The scheme of the experiment is successfully applied in the same way as in previous disruption avoidance experiments in FTU and ASDEX Upgrade. As soon as the disruption precursor signal (the locked mode detector and/or the loop voltage) reaches the preset threshold, the ECRH power is triggered by real-time control. A poloidal scan in deposition location (ρdep) has been carried out by setting the poloidal launching mirrors at different angles in each discharge. The results depend on ρdep: complete disruption avoidance can be achieved when the power is injected close to or onto the 2/1 island. When ECRH is injected outside the island (either at radii inside or outside the q = 2 surface), the discharge is disrupted as in the reference case.
Real-time physics-model-based simulation of the current density profile in tokamak plasmas
Authors: Felici F. , Sauter O. , Coda S. , Duval B.P. , Goodman T.P. , Moret J-M. , Paley J.I.
Published: August 2011

A new paradigm is presented to reconstruct the plasma current density profile in a tokamak in real-time. The traditional method of basing the reconstruction on real-time diagnostics combined with a real-time Grad–Shafranov solver suffers from the difficulty of obtaining reliable internal current profile measurements with sufficient spatial and temporal accuracy to have a complete picture of the profile evolution at all times. A new methodology is proposed in which the plasma current density profile is simulated in real-time by solving the first-principle physics-based equations determining its evolution. Effectively, an interpretative transport simulation similar to those run today in post-plasma shot analysis is performed in real-time. This provides real-time reconstructions of the current density profile with spatial and temporal resolution constrained only by the capabilities of the computational platform used and not by the available diagnostics or the choice of basis functions. The diagnostic measurements available in real-time are used to constrain and improve the accuracy of the simulated profiles. Estimates of other plasma quantities, related to the current density profile, become available in real-time as well. The implementation of the proposed paradigm in the TCV tokamak is discussed, and its successful use in plasma experiments is demonstrated. This framework opens up the possibility of unifying q profile reconstructions across different tokamaks using a common physics model and will support a wealth of applications in which improved real-time knowledge of the plasma state is used for feedback control, disruption avoidance, scenario monitoring and external disturbance estimation.
𝐶^{𝛼}-classical solutions for abstract non-autonomous integro-differential equations
Authors: Hernández Eduardo
Published: August 2011

In this paper we study the existence of strict and classical solutions for a class of abstract non-autonomous integro-differential equations in Banach spaces. Some applications of the abstract results are considered.
Atlas of products for wave-Sobolev spaces on ℝ¹⁺³
Authors: D’Ancona Piero , Foschi Damiano , Selberg Sigmund
Published: August 2011

The wave-Sobolev spaces

H

s
,
b

H^{s,b}

are

L
2

L^2

-based Sobolev spaces on the Minkowski space-time

R

1
+
n

\mathbb {R}^{1+n}

, with Fourier weights adapted to the symbol of the d’Alembertian. They are a standard tool in the study of regularity properties of nonlinear wave equations, and in such applications the need arises for product estimates in these spaces. Unfortunately, it seems that with every new application some estimates come up which have not yet appeared in the literature, and then one has to resort to a set of well-established procedures for proving the missing estimates. To relieve the tedium of having to constantly fill in such gaps “by hand”, we make here a systematic effort to determine the complete set of estimates in the bilinear case. We determine a set of necessary conditions for a product estimate

H

s
1

,

b
1

⋅

H

s
2

,

b
2

↪

H

−

s
0

,
−

b
0

H^{s_1,b_1} \cdot H^{s_2,b_2} \hookrightarrow H^{-s_0,-b_0}

to hold. These conditions define a polyhedron

Ω
\Omega

in the space

R

6

\mathbb {R}^6

of exponents

(

s
0

,

s
1

,

s
2

,

b
0

,

b
1

,

b
2

)

(s_0,s_1,s_2,b_0,b_1,b_2)

. We then show, in space dimension

n
=
3

n=3

, that all points in the interior of

Ω
\Omega

, and all points on the faces minus the edges, give product estimates. We can also allow some but not all points on the edges, but here we do not claim to have the sharp result. The corresponding results for

n
=
2

n=2

and

n
=
1

n=1

will be published elsewhere.
Ground state and non-ground state solutions of some strongly coupled elliptic systems
Authors: Bonheure Denis , Moreira dos Santos Ederson , Ramos Miguel
Published: August 2011

We study an elliptic system of the formLu=|v|p−1vLu = \left | v\right |^{p-1} vandLv=|u|q−1uLv=\left | u\right |^{q-1} uinΩ\Omegawith homogeneous Dirichlet boundary condition, whereLu:=−ΔuLu:=-\Delta uin the case of a bounded domain andLu:=−Δu+uLu:=-\Delta u + uin the cases of an exterior domain or the whole spaceRN\mathbb {R}^N. We analyze the existence, uniqueness, sign and radial symmetry of ground state solutions and also look for sign changing solutions of the system. More general non-linearities are also considered.
Whose Fast and Whose Feast? Intrahousehold Asymmetries in Dietary Diversity Response Among East African Pastoralists
Authors: Villa Kira M. , Barrett Christopher B. , Just David R.
Published: August 2011

This article explores intrahousehold dietary diversity allocation within pastoralist households in eastern Africa. We estimate income elasticities of dietary diversity for demographic cohorts allowing asymmetric behavior depending on household circumstances. We find that household heads disproportionately bear the nutritional burden when household income is below mean, while other cohorts disproportionately enjoy the nutritional gains when it is above mean. The commonly assumed symmetric framework masks this intrahousehold behavior and produces biased elasticity estimates. Stochastic dominance tests show adult daughters as better‐off than other household members in their dietary diversity, sons as worse off, and little difference between male heads and their wives.
Inferring disease and gene set associations with rank coherence in networks
Authors: Hwang TaeHyun , Zhang Wei , Xie Maoqiang , Liu Jinfeng , Kuang Rui
Published: August 2011

Motivation: To validate the candidate disease genes identified from high-throughput genomic studies, a necessary step is to elucidate the associations between the set of candidate genes and disease phenotypes. The conventional gene set enrichment analysis often fails to reveal associations between disease phenotypes and the gene sets with a short list of poorly annotated genes, because the existing annotations of disease-causative genes are incomplete. This article introduces a network-based computational approach called rcNet to discover the associations between gene sets and disease phenotypes. A learning framework is proposed to maximize the coherence between the predicted phenotype–gene set relations and the known disease phenotype-gene associations. An efficient algorithm coupling ridge regression with label propagation and two variants are designed to find the optimal solution to the objective functions of the learning framework.

Results: We evaluated the rcNet algorithms with leave-one-out cross-validation on Online Mendelian Inheritance in Man (OMIM) data and an independent test set of recently discovered disease–gene associations. In the experiments, the rcNet algorithms achieved best overall rankings compared with the baselines. To further validate the reproducibility of the performance, we applied the algorithms to identify the target diseases of novel candidate disease genes obtained from recent studies of Genome-Wide Association Study (GWAS), DNA copy number variation analysis and gene expression profiling. The algorithms ranked the target disease of the candidate genes at the top of the rank list in many cases across all the three case studies.

Availability:  http://compbio.cs.umn.edu/dgsa_rcNet

Contact:  kuang@cs.umn.edu
Delineating the habitat of demersal fish assemblages with acoustic seabed technologies
Authors: van der Kooij Jeroen , Kupschus Sven , Scott Beth E.
Published: August 2011

van der Kooij, J., Kupschus, S., and Scott, B. E. 2011. Delineating the habitat of demersal fish assemblages with acoustic seabed technologies. – ICES Journal of Marine Science, 68: 1973–1985. Habitats influence species distribution and, although the seabed is an important habitat factor for demersal species, traditional sampling methods often provide no practical solution to investigating the seabed over large areas. The ability of a multivariate method that utilizes single-beam acoustic seabed data combined with species composition data to define demersal fish habitats was tested. The best model explained 19.4% of the variance observed in the species data and was robust between years. Ten biotopes were identified, each containing species that, either alone or in combination with others, were indicative of that biotope. Using unclassified acoustic seabed data as explanatory variables, discrepancies between the numbers of acoustically distinct classes and species assemblages, as previously reported in the literature, were avoided, while utilizing their relationship with community structure. The study focused on the relationship between simultaneously recorded species composition and seabed data from fishing stations, but because continuous acoustic data along the survey tracks were available between stations, the model could be used to predict the spatial extent of the biotopes. Although the method was developed with the eventual aim of providing a meaningful foundation to the spatial management of mixed fisheries, it could also contribute to applications in spatial planning.
The structure of demersal fish assemblages in a cold, highly stratified environment
Authors: Chouinard P-M. , Dutil J-D.
Published: August 2011

Chouinard, P-M., and Dutil, J-D. 2011. The structure of demersal fish assemblages in a cold, highly stratified environment. – ICES Journal of Marine Science, 68: 1896–1908. Fish are a major component of marine ecosystems, with many species co-occuring in the same habitats. Potential interactions among species and with the environment can be studied through the identification of species assemblages. Data from bottom trawl surveys (2004–2008) conducted in the estuary and northern Gulf of St Lawrence were analysed using multivariate methods (cluster, multidimensional scaling, and detrended canonical correspondence analysis) to describe the structure and composition of demersal fish assemblages, including rare and smaller non-commercial species. The spatial variability in environmental conditions that characterizes the study area has a significant impact on the composition of fish assemblages in the region. In all, 35 taxa were classified as key, and 6 main fish assemblages were described, based on catch in numbers. These assemblages had a coherent spatial distribution in the study area, associated with either depth, salinity and temperature, or dissolved oxygen. The analyses showed overall strong correlations between species abundance and prevalent environmental conditions and explained 18.4% of the variance in species abundance data and 79.2% of the variance in the species–environment relationship.
An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance
Authors: Zuber Johannes , Rappaport Amy R. , Luo Weijun , Wang Eric , Chen Chong , Vaseva Angelina V. , Shi Junwei , Weissmueller Susann , Fellman Christof , Taylor Meredith J. , Weissenboeck Martina , Graeber Thomas G. , Kogan Scott C. , Vakoc Christopher R. , Lowe Scott W.
Published: August 2011

Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations—a phenomenon dubbed “oncogene addiction.” Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9—a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.
Return to youth with Sox17: Figure 1.
Authors: Chhabra Akanksha , Mikkola Hanna K.A.
Published: August 2011

Maturation of hematopoietic stem cells (HSCs) from fetal to adult state and differentiation to progenitors are thought to follow a one-way street. In this issue of Genes & Development, He and colleagues (pp. 1613–1627) show that overexpression of Sox17 can convert adult multipotential progenitors to self-renewing HSCs that possess fetal properties. These findings challenge the irreversibility of hematopoietic development, and open up new perspectives to understand the different forms of HSC self-renewal at distinct stages of ontogeny and during transformation.
Sustained activation of the HER1–ERK1/2–RSK signaling pathway controls myoepithelial cell fate in human mammary tissue
Authors: Pasic Lejla , Eisinger-Mathason T.S. Karin , Velayudhan Bisi T. , Moskaluk Christopher A. , Brenin David R. , Macara Ian G. , Lannigan Deborah A.
Published: August 2011

Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 signal intensity. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) effector RSK prevents the EGF-induced myoepithelial expansion. Notably, mouse mammary organoids are much less responsive to HER1 ligands. Little is known about the myoepithelial lineage or about growth factor effects on mammary progenitor differentiation, and our studies provide an important window into human mammary development that reveals unexpected differences from the mouse model.
Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors
Authors: He Shenghui , Kim Injune , Lim Megan S. , Morrison Sean J.
Published: August 2011

A key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self-renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilineage reconstitution that resembled fetal hematopoiesis, including increased erythropoiesis, increased myelopoiesis, and decreased lymphopoiesis. Long-term ectopic expression of Sox17 eventually led to leukemogenesis. These data demonstrate that SOX17 is sufficient to confer fetal HSC characteristics to adult hematopoietic progenitors and is therefore a key determinant of fetal HSC identity.
Evaluation of [125I]IPOS as a molecular imaging probe for hypoxia‐inducible factor‐1‐active regions in a tumor: Comparison among single‐photon emission computed tomography/X‐ray computed tomography imaging, autoradiography, and immunohistochemistry
Authors: Ueda Masashi , Kudo Takashi , Mutou Yasuko , Umeda Izumi Ogihara , Miyano Azusa , Ogawa Kei , Ono Masahiro , Fujii Hirofumi , Kizaka‐Kondoh Shinae , Hiraoka Masahiro , Saji Hideo
Published: August 2011

To image hypoxia‐inducible factor‐1 (HIF‐1)‐active tumors, we previously developed a chimeric protein probe ([123/125I]IPOS) that is degraded in the same manner as HIF‐1α under normoxic conditions. In the present study, we aim to show that the accumulation of radioiodinated POS reflects the expression of HIF‐1. In vivo single‐photon emission computed tomography (SPECT)/X‐ray CT (CT) imaging, autoradiography, and double‐fluorescent immunostaining for HIF‐1α and pimonidazole (PIMO) were carried out 24 h after the injection of [125I]IPOS. Tumor metabolite analysis was also carried out. A tumor was clearly visualized by multi‐pinhole, high‐resolution SPECT/CT imaging with [125I]IPOS. The obtained images were in accordance with the corresponding autoradiograms and with the results of ex vivo biodistribution. A metabolite analysis revealed that 77% of the radioactivity was eluted in the macromolecular fraction, suggesting that the radioactivity mainly existed as [125I]IPOS in the tumors. Immunohistochemistry revealed that the HIF‐1α‐positive areas and PIMO‐positive areas were not always identical, only some of the regions were positive for both markers. The areas showing [125I]IPOS accumulation were positively and significantly correlated with the HIF‐1α‐positive areas (R = 0.75, P < 0.0001). The correlation coefficient between [125I]IPOS‐accumulated areas and HIF‐1α‐positive areas was significantly greater than that between the [125I]IPOS‐accumulated areas and the PIMO‐positive areas (P < 0.01). These findings indicate that [125I]IPOS accumulation reflects HIF‐1 expression. Thus, [123/125I]IPOS can serve as a useful probe for the molecular imaging of HIF‐1‐active tumors. (Cancer Sci 2011; 102: 2090–2096)
Weaning infants with phenylketonuria: a review
Authors: MacDonald A. , Evans S. , Cochrane B. , Wildgoose J.
Published: August 2011

How to cite this article
 MacDonald A., Evans S., Cochrane B. & Wildgoose J. (2012) Weaning infants with phenylketonuria: a review. J Hum Nutr Diet.25, 103–110

Careful weaning is particularly important in phenylketonuria (PKU). Dietary phenylalanine intake is severely restricted, and the diet is supplemented with phenylalanine‐free amino acids and special low protein foods. In PKU, there are no evidence‐based weaning guidelines and no studies assessing the introduction of solid foods. We critically review the literature and examine current UK weaning practices. Ideally, weaning in PKU should closely reflect the ‘model’ for healthy infants. However, the requirement for optimal blood phenylalanine control and the demands of diet therapy overshadow the social aspects of weaning. Solid food intake is established with very low protein foods first, and then 50 mg phenylalanine exchanges (equivalent to 1 g of intact protein) gradually replace breast/formula feeds. Introducing solids before the recommended 6 months of age may be advantageous because there is a less persistent neophobic food response, possibly leading to better food acceptance. Infants with PKU also require a special phenylalanine‐free protein substitute. Between 6 and 12 months, a second concentrated source of phenylalanine‐free protein substitute is required. This is commonly given as an additional liquid, although the prescribed volume may adversely affect appetite. Alternatively, a second‐stage protein substitute administered as a paste may better suit feeding development. Further research aiming to examine the weaning process in PKU with a focus on biological, maternal, infant, social and environmental factors is required. This will help provide evidence for the effect of protein substitute on appetite and help in the development of evidence‐based guidelines.