bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria
Authors: Charman Susan A. , Arbe-Barnes Sarah , Bathurst Ian C. , Brun Reto , Campbell Michael , Charman William N. , Chiu Francis C. K. , Chollet Jacques , Craft J. Carl , Creek Darren J. , Dong Yuxiang , Matile Hugues , Maurer Melanie , Morizzi Julia , Nguyen Tien , Papastogiannidis Petros , Scheurer Christian , Shackleford David M. , Sriraghavan Kamaraj , Stingelin Lukas , Tang Yuanqing , Urwyler Heinrich , Wang Xiaofang , White Karen L. , Wittlin Sergio , Zhou Lin , Vennerstrom Jonathan L.
Published: February 2011

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic
Plasmodium falciparum
stages with IC
50
values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures
Plasmodium berghei
-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
Number without a language model
Authors: Spaepen Elizabet , Coppola Marie , Spelke Elizabeth S. , Carey Susan E. , Goldin-Meadow Susan
Published: February 2011

Cross-cultural studies suggest that access to a conventional language containing words that can be used for counting is essential to develop representations of large exact numbers. However, cultures that lack a conventional counting system typically differ from cultures that have such systems, not only in language but also in many other ways. As a result, it is difficult to isolate the effects of language on the development of number representations. Here we examine the numerical abilities of individuals who lack conventional language for number (deaf individuals who do not have access to a usable model for language, spoken or signed) but who live in a numerate culture (Nicaragua) and thus have access to other aspects of culture that might foster the development of number. These deaf individuals develop their own gestures, called homesigns, to communicate. We show that homesigners use gestures to communicate about number. However, they do not consistently extend the correct number of fingers when communicating about sets greater than three, nor do they always correctly match the number of items in one set to a target set when that target set is greater than three. Thus, even when integrated into a numerate society, individuals who lack input from a conventional language do not spontaneously develop representations of large exact numerosities.
An adhesion protein of
Salmonella enterica
serovar Typhi is required for pathogenesis and potential target for vaccine development
Authors: Ghosh Shubhamoy , Chakraborty Krishnendu , Nagaraja Theeya , Basak Surajit , Koley Hemanta , Dutta Shanta , Mitra Utpala , Das Santasabuj
Published: February 2011

More than half of all
Salmonella enterica
serovar Typhi genes still remain unannotated. Although pathogenesis of
S
. Typhi is incompletely understood, treatment of typhoid fever is complicated by the emergence of drug resistance. Effectiveness of the currently available vaccines is also limited. In search of novel virulence proteins, we have identified several putative adhesins of
S
. Typhi through computational approaches. Our experiment shows that a 27-kDa outer membrane protein (T2544) plays a major role in bacterial adhesion to the host through high-affinity binding to laminin. Its role in bacterial pathogenesis is underscored by reduced systemic invasion and a 10-fold higher LD
50
of the mutant bacteria in mice. T2544 is strongly immunogenic as revealed by the detection of sustained high titers of serum IgG and intestinal secretory IgA in the immunized mice. In vitro, T2544 antiserum enhanced uptake and clearance of
Salmonella
by macrophages and augmented complement-mediated lysis, indicating a contribution of T2544-specific antibodies to the killing process. This correlates well with the observed protection of mice immunized with recombinant T2544 or passively immunized with T2544 antiserum against subsequent bacterial challenge, suggesting that T2544-specific antibodies are involved in protection. The present study describes an adhesion protein of
S
. Typhi that contributes to bacterial pathogenesis. Protective antibodies in mice, rapid seroconversion of naturally infected individuals with increasing titers of anti-T2544 IgG from acute to convalescent sera suggesting antibody response in humans, and wide distribution and conservation of the cell-surface adhesin in the clinical isolates of different
Salmonella
serovars make T2544 a potential vaccine candidate.
Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes
Authors: Beyer Ulrike , Moll-Rocek Julian , Moll Ute M. , Dobbelstein Matthias
Published: February 2011

TAp63, but not its homolog p53, eliminates oocytes that suffered DNA damage. An equivalent gene for guarding the male germ line is currently not known. Here we identify hitherto unknown human p63 transcripts with unique 5′-ends derived from incorporated exons upstream of the currently mapped
TP63
gene. These unique p63 transcripts are highly and specifically expressed in testis. Their most upstream region corresponds to a LTR of the human endogenous retrovirus 9 (ERV9). The insertion of this LTR upstream of the
TP63
locus occurred only recently in evolution and is unique to humans and great apes (
Hominidae
). A corresponding p63 protein is the sole p63 species in healthy human testis, and is strongly expressed in spermatogenic precursors but not in mature spermatozoa. In response to DNA damage, this human male germ-cell–encoded TAp63 protein (designated GTAp63) is activated by caspase cleavage near its carboxyterminal domain and induces apoptosis. Human testicular cancer tissues and cell lines largely lost p63 expression. However, pharmacological inhibition of histone deacetylases completely restores p63 expression in testicular cancer cells (>3,000-fold increase). Our data support a model whereby testis-specific GTAp63 protects the genomic integrity of the male germ line and acts as a tumor suppressor. In
Hominidae
, this guardian function was greatly enhanced by integration of an endogenous retrovirus upstream of the
TP63
locus that occurred 15 million years ago. By providing increased germ-line stability, this event may have contributed to the evolution of hominids and enabled their long reproductive periods.
Responses to the Assurance game in monkeys, apes, and humans using equivalent procedures
Authors: Brosnan Sarah F. , Parrish Audrey , Beran Michael J. , Flemming Timothy , Heimbauer Lisa , Talbot Catherine F. , Lambeth Susan P. , Schapiro Steven J. , Wilson Bart J.
Published: February 2011

There is great interest in the evolution of economic behavior. In typical studies, species are asked to play one of a series of economic games, derived from game theory, and their responses are compared. The advantage of this approach is the relative level of consistency and control that emerges from the games themselves; however, in the typical experiment, procedures and conditions differ widely, particularly between humans and other species. Thus, in the current study, we investigated how three primate species, capuchin monkeys, chimpanzees, and humans, played the Assurance (or Stag Hunt) game using procedures that were, to the best of our ability, the same across species, particularly with respect to training and pretesting. Our goal was to determine what, if any, differences existed in the ways in which these species made decisions in this game. We hypothesized differences along phylogenetic lines, which we found. However, the species were more similar than might be expected. In particular, humans who played using “nonhuman primate-friendly” rules did not behave as is typical. Thus, we find evidence for similarity in decision-making processes across the order
Primates
. These results indicate that such comparative studies are possible and, moreover, that in any comparison rating species’ relative abilities, extreme care must be taken in ensuring that one species does not have an advantage over the others due to methodological procedures.
Microbubbles reveal chiral fluid flows in bacterial swarms
Authors: Wu Yilin , Hosu Basarab G. , Berg Howard C.
Published: February 2011

Flagellated bacteria can swim within a thin film of fluid that coats a solid surface, such as agar; this is a means for colony expansion known as swarming. We found that micrometer-sized bubbles make excellent tracers for the motion of this fluid. The microbubbles form explosively when small aliquots of an aqueous suspension of droplets of a water-insoluble surfactant (Span 83) are placed on the agar ahead of a swarm, as the water is absorbed by the agar and the droplets are exposed to air. Using these bubbles, we discovered an extensive stream (or river) of swarm fluid flowing clockwise along the leading edge of an
Escherichia coli
swarm, at speeds of order 10 μm/s, about three times faster than the swarm expansion. The flow is generated by the action of counterclockwise rotating flagella of cells stuck to the substratum, which drives fluid clockwise around isolated cells (when viewed from above), counterclockwise between cells in dilute arrays, and clockwise in front of cells at the swarm edge. The river provides an avenue for long-range communication in the swarming colony, ideally suited for secretory vesicles that diffuse poorly. These findings broaden our understanding of swarming dynamics and have implications for the engineering of bacterial-driven microfluidic devices.
Biogenesis of the pore architecture of a voltage-gated potassium channel
Authors: Gajewski Christine , Dagcan Alper , Roux Benoit , Deutsch Carol
Published: February 2011

The pore domain of voltage-gated potassium (Kv) channels consists of transmembrane helices S5 and S6, the turret, the pore helix, the selectivity filter, and the loop preceding S6, with a tertiary reentrant structure between S5 and S6. Using biogenic intermediates, mass tagging (pegylation), and a molecular tape measure, we explored the possibility that the first stages of pore formation occur prior to oligomerization of the transmembrane core. Pegylation of introduced cysteines shows that the pore helix, but not the turret, forms a compact secondary structure in the terminal 20 Å of the ribosomal tunnel. We assessed the tertiary fold of the pore loop in monomeric constructs by determining the relative accessibilities of select cysteines using the kinetics of pegylation. Turret residues are accessible at the extracellular surface. In contrast, pore helix residues are less accessible. All-atom molecular dynamics simulations of a single Kv monomer in a solvated lipid membrane indicate that secondary and tertiary folds are stable over 650 ns. These results are consistent with acquisition of a tertiary reentrant pore architecture at the monomer stage of Kv biogenesis and begin to define a plausible sequence of folding events in the formation of Kv channels.
Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance
Authors: Fang Sungsoon , Suh Jae Myoung , Atkins Annette R. , Hong Suk-Hyun , Leblanc Mathias , Nofsinger Russell R. , Yu Ruth T. , Downes Michael , Evans Ronald M.
Published: February 2011

The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)
mRID1
in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRT
mRID1
mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRT
mRID1
mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRT
mRID1
mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases.
Fructose sensitivity is suppressed in
Arabidopsis
by the transcription factor ANAC089 lacking the membrane-bound domain
Authors: Li Ping , Wind Julia J. , Shi Xiaoliang , Zhang Honglei , Hanson Johannes , Smeekens Sjef C. , Teng Sheng
Published: February 2011

In living organisms sugars not only provide energy and carbon skeletons but also act as evolutionarily conserved signaling molecules. The three major soluble sugars in plants are sucrose, glucose, and fructose. Information on plant glucose and sucrose signaling is available, but to date no fructose-specific signaling pathway has been reported. In this study, sugar repression of seedling development was used to study fructose sensitivity in the Landsberg
erecta
(L
er
)/Cape Verde Islands (Cvi) recombinant inbred line population, and eight fructose-sensing quantitative trait loci (
QTLs
) (
FSQ1–8
) were mapped. Among them,
FSQ6
was confirmed to be a fructose-specific QTL by analyzing near-isogenic lines in which Cvi genomic fragments were introgressed in the L
er
background. These results indicate the existence of a fructose-specific signaling pathway in
Arabidopsis
. Further analysis demonstrated that the
FSQ6
-associated fructose-signaling pathway functions independently of the hexokinase1 (HXK1) glucose sensor. Remarkably, fructose-specific
FSQ6
downstream signaling interacts with abscisic acid (ABA)- and ethylene-signaling pathways, similar to HXK1-dependent glucose signaling. The Cvi allele of
FSQ6
acts as a suppressor of fructose signaling. The
FSQ6
gene was identified using map-based cloning approach, and
FSQ6
was shown to encode the transcription factor gene
Arabidopsis
NAC (petunia No apical meristem and
Arabidopsis
transcription activation factor 1, 2 and Cup-shaped cotyledon 2) domain containing protein 89 (
ANAC089
). The Cvi allele of
FSQ6/ANAC089
is a gain-of-function allele caused by a premature stop in the third exon of the gene. The truncated Cvi FSQ6/ANAC089 protein lacks a membrane association domain that is present in ANAC089 proteins from other
Arabidopsis
accessions. As a result, Cvi FSQ6/ANAC089 is constitutively active as a transcription factor in the nucleus.
Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes
Authors: Woo Yong H. , Li Wen-Hsiung
Published: February 2011

A balance between gene expression stability and evolvability is essential for the long-term maintenance of a living system. In this paper, we studied whether the genetic and epigenetic properties of the promoter affect gene expression variability. We hypothesized that upstream distance and orientation (head-to-head or head-to-tail) are important for the promoter architecture and gene expression variability. We found that in budding yeast genes with a short upstream distance tend to have low gene expression variability, and their promoter is flanked by strongly positioned nucleosomes and tends to have low nucleosome occupancy. These observations suggest that in vivo positioning of the flanking nucleosomes facilitates stable nucleosome depletion at the core promoter region and enhances gene expression stability. Head-to-head genes have, on average, lower gene expression variability, greater nucleosome depletion at the core promoter region, and more strongly positioned nucleosomes that flank the core promoter than do head-to-tail genes. These observations hold for diverse eukaryotes. In complex organisms such as mammals, only a small fraction of head-to-tail genes have retained a short upstream distance, probably because the promoter may not be flanked by a strongly positioned nucleosome on the upstream side.
In vivo
Atoh1
targetome reveals how a proneural transcription factor regulates cerebellar development
Authors: Klisch Tiemo J. , Xi Yuanxin , Flora Adriano , Wang Liguo , Li Wei , Zoghbi Huda Y.
Published: February 2011

The proneural, basic helix–loop–helix transcription factor Atoh1 governs the development of numerous key neuronal subtypes, such as cerebellar granule and brainstem neurons, inner ear hair cells, and several neurons of the proprioceptive system, as well as diverse nonneuronal cell types, such as Merkel cells and intestinal secretory lineages. However, the mere handful of targets that have been identified barely begin to account for Atoh1’s astonishing range of functions, which also encompasses seemingly paradoxical activities, such as promoting cell proliferation and medulloblastoma formation in the cerebellum and inducing cell cycle exit and suppressing tumorigenesis in the intestine. We used a multipronged approach to create a comprehensive, unbiased list of over 600 direct Atoh1 target genes in the postnatal cerebellum. We found that Atoh1 binds to a 10 nucleotide motif (AtEAM) to directly regulate genes involved in migration, cell adhesion, metabolism, and other previously unsuspected functions. This study expands current thinking about the transcriptional activities driving neuronal differentiation and provides a framework for further neurodevelopmental studies.
CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity
Authors: Cruz-Orengo Lillian , Holman David W. , Dorsey Denise , Zhou Liang , Zhang Penglie , Wright Melissa , McCandless Erin E. , Patel Jigisha R. , Luker Gary D. , Littman Dan R. , Russell John H. , Klein Robyn S.
Published: February 2011

Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood–brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1β increased, whereas interferon-γ decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS.
Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development
Authors: Lei Yu , Ripen Adiratna Mat , Ishimaru Naozumi , Ohigashi Izumi , Nagasawa Takashi , Jeker Lukas T. , Bösl Michael R. , Holländer Georg A. , Hayashi Yoshio , de Waal Malefyt Rene , Nitta Takeshi , Takahama Yousuke
Published: February 2011

Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire.
Affine fractals as boundaries and their harmonic analysis
Authors: Dutkay Dorin Ervin , Jorgensen Palle
Published: February 2011

We introduce the notion of boundary representation for fractal Fourier expansions, starting with a familiar notion of spectral pairs for affine fractal measures. Specializing to one dimension, we establish boundary representations for these fractals. We prove that as sets these fractals arise as boundaries of functions in closed subspaces of the Hardy spaceH2H^2. By this we mean that there are lacunary subsetsΓ\Gammaof the non-negative integers and associated closedΓ\Gamma-subspace in the Hardy spaceH2(D)H^2(\mathbb {D}),D\mathbb {D}denoting the disk, such that for every functionffinH2(Γ)H^2(\Gamma )and for every pointzzinD\mathbb {D},f(z)f(z)admits a boundary integral represented by an associated measureμ\mu, with integration oversupp(μ){\textrm {supp}}(\mu )placed as a Cantor subset on the circleT:=bd(D)\mathbb {T} := \mbox {bd}(\mathbb {D}).

We study families of pairs: measuresμ\muand setsΓ\Gammaof lacunary form, admitting lacunary Fourier series inL2(μ)L^2(\mu ); i.e., configurationsΓ\Gammaarranged with a geometric progression of empty spacing, missing parts, or gaps. GivenΓ\Gamma, we find corresponding generalized Szegö kernelsGΓG_\Gamma, and we compare them to the classical Szegö kernel forD\mathbb {D}.

Rather than the more traditional approach of starting withμ\muand then asking for possibilities for setsΓ\Gamma, such that we get Fourier series representations, we turn the problem upside down; now starting instead with a countably infinite discrete subsetΓ\Gammaand within a new duality framework, we study the possibilities for choices of measuresμ\mu.
What is a system of parameters?
Authors: Fouli Louiza , Huneke Craig
Published: February 2011

In this paper we discuss various refinements and generalizations of a theorem of Sankar Dutta and Paul Roberts. Their theorem gives a criterion for

d
d

elements in a

d
d

-dimensional Noetherian Cohen-Macaulay local ring to be a system of parameters, i.e., to have height

d
d

. We chiefly remove the assumption that the ring be Cohen-Macaulay and discuss similar theorems.
tigre: Transcription factor inference through gaussian process reconstruction of expression for bioconductor
Authors: Honkela Antti , Gao Pei , Ropponen Jonatan , Rattray Magnus , Lawrence Neil D.
Published: February 2011

Summary:  tigre is an R/Bioconductor package for inference of transcription factor activity and ranking candidate target genes from gene expression time series. The underlying methodology is based on Gaussian process inference on a differential equation model that allows the use of short, unevenly sampled, time series. The method has been designed with efficient parallel implementation in mind, and the package supports parallel operation even without additional software.

Availability: The tigre package is included in Bioconductor since release 2.6 for R 2.11. The package and a user's guide are available at http://www.bioconductor.org.

Contact:  antti.honkela@hiit.fi; m.rattray@sheffield.ac.uk; n.lawrence@dcs.shef.ac.uk
Ending Discrimination, Legitimating Debt: The Political Economy of Race, Gender, and Credit Access in the 1960s and 1970s
Authors: Hyman Louis
Published: February 2011

Today, in the aftermath of the subprime crisis, there is a foreboding sense that it is too easy for Americans to borrow. Living beyond our means on our cards and our mortgages, Americans borrowed at an unsustainable pace, and what put us here, the logic goes, was the unfortunate collision of lenders' greed and borrower's cupidity. Yet free-for-all borrowing defined another moment's economy as well, but without the ill consequences: the postwar period. After World War II, cheap credit underpinned the suburban prosperity, through government-insured loans, auto financing, and even department store Charga-Plates.
“Aid Where It Is Needed Most”: American Labor's Military–Industrial Complex
Authors: Wehrle Edmund F.
Published: February 2011

Between the late 1940s and mid-1960s, American organized labor emerged among the most enthusiastic supporters of the military–industrial complex. This study examines that emerging relationship, focusing on the efforts of a group of unionists to mold defense spending into a vehicle for promoting employment and addressing social and economic problems.

During the Korean War, labor representatives drafted, lobbied for, and helped administration Defense Manpower Policy #4, a policy channeling defense spending to areas suffering high rates of unemployment. With the advent of the Eisenhower administration, preferential policies fell by the wayside, but organized labor continued to press, with some success for defense spending as a general antidote to economic downturns. Late in the 1950s, the Construction Trades Department of Congress of Industrial Organizations and the American Federation of Labor (AFL-CIO), reacting to double-digit unemployment in their ranks, became an active promoter of fallout shelter construction.

Despite some initial success in reimplementing preferential policies during the early months of the Kennedy administration, organized labor's defense agenda quickly ran afoul of Secretary of Defense Robert S. McNamara's plans to systematize and rationalize the defense sector.

In the end, resistance from military and business leaders greatly impeded labor's progress. At the very least, however, labor's defense agenda reflects a larger social vision and also suggests the very real attraction to many unionists of the military–industrial complex, a malleable economic realm, open to political influence and somewhat removed from the harsh forces of the market.
Identification of New Sources of Resistance in Winter Wheat to Multiple Strains of Xanthomonas translucens pv. undulosa
Authors: Adhikari T. B. , Hansen J. M. , Gurung S. , Bonman J. M.
Published: February 2011

Bacterial leaf streak (BLS), caused by Xanthomonas translucens pv. undulosa, has re-emerged as an important disease of wheat (Triticum aestivum) in the United States. Planting resistant varieties is the best approach to manage BLS in the absence of effective bactericides. However, most of the wheat varieties currently grown in the Upper Midwest of the United States appeared to be susceptible to BLS. From the core subset of the USDA National Small Grain Collection (NSGC), a set of 605 winter wheat accessions of diverse origin and improvement status were initially inoculated with a virulent strain BLSW16 of X. translucens pv. undulosa from Casselton, ND on the flag leaf of each plant in a greenhouse. Disease reactions were assessed between 7 and 10 days after infiltration using a 0 to 6 rating scale, where ≤2.0 was considered resistant and >2.1 was considered susceptible. Resistance varied with geographic origin and was significantly (P ≤ 0.05) more frequent in accessions from North America compared to accessions from northern, eastern, and southern Europe and from south-central Asia. About 8.3% of accessions tested were resistant, and accessions with an improvement status of “cultivar” were significantly more likely to be resistant than were accessions classified as either landraces or breeding lines. Forty-two of the accessions exhibiting resistance in response to the strain BLSW16 in the first screening test were retested utilizing each of the two additional strains (BLS Cr25 and BLS Lb74 of X. translucens pv. undulosa) collected from Carrington and Lisbon, respectively. Nonparametric data analysis revealed 35 accessions were resistant, one accession, PI 266860, was susceptible to both strains, and six accessions showed differential responses. The majority of the BLS-resistant accessions also were resistant to at least one other important wheat disease based on the Germplasm Resources Information Network (GRIN) data. These results suggest that diverse and novel sources of resistance to BLS identified in this study can be utilized in winter wheat breeding programs.
Analysis of the Resistance-Breaking Ability of Different Beet necrotic yellow vein virus Isolates Loaded into a Single Polymyxa betae Population in Soil
Authors: Bornemann Kathrin , Varrelmann Mark
Published: February 2011

The genome of most Beet necrotic yellow vein virus (BNYVV) isolates is comprised of four RNAs. The ability of certain isolates to overcome Rz1-mediated resistance in sugar beet grown in the United States and Europe is associated with point mutations in the pathogenicity factor P25. When the virus is inoculated mechanically into sugar beet roots at high density, the ability depends on an alanine to valine substitution at P25 position 67. Increased aggressiveness is shown by BNYVV P type isolates, which carry an additional RNA species that encodes a second pathogenicity factor, P26. Direct comparison of aggressive isolates transmitted by the vector, Polymyxa betae, has been impossible due to varying population densities of the vector and other soilborne pathogens that interfere with BNYVV infection. Mechanical root inoculation and subsequent cultivation in soil that carried a virus-free P. betae population was used to load P. betae with three BNYVV isolates: a European A type isolate, an American A type isolate, and a P type isolate. Resistance tests demonstrated that changes in viral aggressiveness towards Rz1 cultivars were independent of the vector population. This method can be applied to the study of the synergism of BNYVV with other P. betae-transmitted viruses.
Sclerotinia Blight Resistance in Virginia-Type Peanut Transformed with a Barley Oxalate Oxidase Gene
Authors: Partridge-Telenko D. E. , Hu J. , Livingstone D. M. , Shew B. B. , Phipps P. M. , Grabau E. A.
Published: February 2011

Transgenic peanut lines expressing oxalate oxidase, a novel enzyme to peanut, were evaluated for resistance to Sclerotinia blight in naturally infested fields over a 5-year period. Area under the disease progress curve (AUDPC) for transgenic lines in single rows planted with seed from single-plant selections averaged 78, 83, and 90% lower than nontransgenic parents in 2004, 2005, and 2006, respectively. In addition, AUDPC in 14 transgenic lines planted with bulked seed in two-row plots averaged 81% lower compared with nontransgenic parents in 2005 and 86% lower in 16 transgenic lines in 2006. Six transgenic lines yielded 488 to 1,260 kg/ha greater than nontransgenic parents in 2005, and 10 lines yielded 537 to 2,490 kg/ha greater in 2006. Fluazinam (0.58 kg a.i./ha) fungicide sprays in 2008 and 2009 reduced AUDPC in transgenic and nontransgenic lines but AUDPC was lowest in transgenic lines. Without fluazinam, yields of transgenic lines averaged 1,133 to 1,578 kg/ha greater than nontransgenic lines in 2008 and 1,670 to 2,755 kg/ha greater in 2009. These results demonstrated that the insertion of barley oxalate oxidase in peanut conveyed a high level of resistance to Sclerotinia blight, and negated the need for costly fungicide sprays.
Genetic Analysis of the Resistance to Eight Anthracnose Races in the Common Bean Differential Cultivar Kaboon
Authors: Campa Ana , Giraldez Ramón , Ferreira Juan José
Published: February 2011

Resistance to the eight races (3, 7, 19, 31, 81, 449, 453, and 1545) of the pathogenic fungus Colletotrichum lindemuthianum (anthracnose) was evaluated in F3families derived from the cross between the anthracnose differential bean cultivars Kaboon and Michelite. Molecular marker analyses were carried out in the F2individuals in order to map and characterize the anthracnose resistance genes or gene clusters present in Kaboon. The analysis of the combined segregations indicates that the resistance present in Kaboon against these eight anthracnose races is determined by 13 different race-specific genes grouped in three clusters. One of these clusters, corresponding to locus Co-1 in linkage group (LG) 1, carries two dominant genes conferring specific resistance to races 81 and 1545, respectively, and a gene necessary (dominant complementary gene) for the specific resistance to race 31. A second cluster, corresponding to locus Co-3/9 in LG 4, carries six dominant genes conferring specific resistance to races 3, 7, 19, 449, 453, and 1545, respectively, and the second dominant complementary gene for the specific resistance to race 31. A third cluster of unknown location carries three dominant genes conferring specific resistance to races 449, 453, and 1545, respectively. This is the first time that two anthracnose resistance genes with a complementary mode of action have been mapped in common bean and their relationship with previously known Co- resistance genes established.
CNVnator: An approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing
Authors: Abyzov Alexej , Urban Alexander E. , Snyder Michael , Gerstein Mark
Published: February 2011

Copy number variation (CNV) in the genome is a complex phenomenon, and not completely understood. We have developed a method, CNVnator, for CNV discovery and genotyping from read-depth (RD) analysis of personal genome sequencing. Our method is based on combining the established mean-shift approach with additional refinements (multiple-bandwidth partitioning and GC correction) to broaden the range of discovered CNVs. We calibrated CNVnator using the extensive validation performed by the 1000 Genomes Project. Because of this, we could use CNVnator for CNV discovery and genotyping in a population and characterization of atypical CNVs, such as de novo and multi-allelic events. Overall, for CNVs accessible by RD, CNVnator has high sensitivity (86%–96%), low false-discovery rate (3%–20%), high genotyping accuracy (93%–95%), and high resolution in breakpoint discovery (<200 bp in 90% of cases with high sequencing coverage). Furthermore, CNVnator is complementary in a straightforward way to split-read and read-pair approaches: It misses CNVs created by retrotransposable elements, but more than half of the validated CNVs that it identifies are not detected by split-read or read-pair. By genotyping CNVs in the CEPH, Yoruba, and Chinese-Japanese populations, we estimated that at least 11% of all CNV loci involve complex, multi-allelic events, a considerably higher estimate than reported earlier. Moreover, among these events, we observed cases with allele distribution strongly deviating from Hardy-Weinberg equilibrium, possibly implying selection on certain complex loci. Finally, by combining discovery and genotyping, we identified six potential de novo CNVs in two family trios.
On the Controls of Leaf-Water Oxygen Isotope Ratios in the Atmospheric Crassulacean Acid Metabolism Epiphyte Tillandsia usneoides
Authors: Helliker Brent R.
Published: February 2011

Previous theoretical work showed that leaf-water isotope ratio (δ18OL) of Crassulacean acid metabolism epiphytes was controlled by the δ18O of atmospheric water vapor (δ18Oa), and observed δ18OL could be explained by both a non-steady-state model and a “maximum enrichment” steady-state model (δ18OL-M), the latter requiring only δ18Oa and relative humidity (h) as inputs. δ18OL, therefore, should contain an extractable record of δ18Oa. Previous empirical work supported this hypothesis but raised many questions. How does changing δ18Oa and h affect δ18OL? Do hygroscopic trichomes affect observed δ18OL? Are observations of changes in water content required for the prediction of δ18OL? Does the leaf need to be at full isotopic steady state for observed δ18OL to equal δ18OL-M? These questions were examined with a climate-controlled experimental system capable of holding δ18Oa constant for several weeks. Water adsorbed to trichomes required a correction ranging from 0.5‰ to 1‰. δ18OL could be predicted using constant values of water content and even total conductance. Tissue rehydration caused a transitory change in δ18OL, but the consequent increase in total conductance led to a tighter coupling with δ18Oa. The non-steady-state leaf water models explained observed δ18OL (y = 0.93*x − 0.07; r  2 = 0.98) over a wide range of δ18Oa and h. Predictions of δ18OL-M agreed with observations of δ18OL (y = 0.87*x − 0.99; r  2 = 0.92), and when h > 0.9, the leaf did not need to be at isotopic steady state for the δ18OL-M model to predict δ18OL in the Crassulacean acid metabolism epiphyte Tillandsia usneoides.
Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells
Authors: Habeeb Baker S. , Kitayama Joji , Nagawa Hirokazu
Published: February 2011

Adiponectin is known to have suppressive effects on tumor growth and is thought to be a key molecule in the positive correlation between obesity and cancer. However, the detailed mechanisms regulating tumor cell activity have not been elucidated. In this study, we found that both full‐length (f‐Ad) and globular adiponectin (g‐Ad) inhibited cell growth in colon cancer cell lines in glucose‐containing medium, whereas it supported cell survival in glucose‐deprived medium, with an increase in AdipoR1 and AdipoR2 expression. The latter effect of adiponectin in glucose deprivation was significantly inhibited by adding autophagy inhibitors, chloroquine, 3‐methyl adenine or a combination of pepstatin A and E‐64d, suggesting that the effect of supporting cell growth was dependent, at least in part, on the induction of autophagy. The enhancement of autophagy was confirmed morphologically using green fluorescent protein (GFP)‐microtubule‐associated protein 1 light chain 3 (LC3) fusion proteins under a fluorescence microscope using stably transfected DLD‐1 cells expressing GFP‐LC3. Western blot analysis revealed that adiponectin increased the expression of LC3‐1, LC3‐2, phosphorylated AMPKα and PPARα but decreased that of phosphorylated mTOR, insulin like growth factor (IGF)‐1, phosphorylated serine/threonine kinase (Akt) and phosphorylated phosphatidylinositol 3‐kinase (PI3K) in glucose‐deprived medium. We conclude that adiponectin supports cell survival in glucose deprivation through enhancement of the autophagic machinery by AMPKα and PPARα activation and IGF‐1/PI3k/Akt/mTOR pathway inhibition. The bimodal effects of adiponectin are thought to be clinically important in the pathophysiology of tumor development and progression. (Cancer Sci 2011; 102: 999–1006)
Histone deacetylase inhibitors block nuclear factor‐κB‐dependent transcription by interfering with RNA polymerase II recruitment
Authors: Furumai Ryohei , Ito Akihiro , Ogawa Kenji , Maeda Satoko , Saito Akiko , Nishino Norikazu , Horinouchi Sueharu , Yoshida Minoru
Published: February 2011

Histone deacetylase inhibitors (HDACi) have been shown to exhibit anti‐inflammatory activity, but their mechanism of action is poorly understood. Trichostatin A (TSA) and the cyclic tetrapeptide class inhibitor Ky‐2 inhibit both lipopolysaccharide‐induced tumor necrosis factor‐α (TNF‐α) production in rats and TNF‐α‐induced expression of inflammatory genes in HeLa cells. We assessed the molecular mechanism underlying TSA‐induced anti‐inflammatory activity by genetically dissecting activation of the nuclear factor‐κB (NF‐κB) pathway following stimulation with TNF‐α. Trichostatin A did not inhibit degradation of IκBα, nuclear translocation and DNA binding of NF‐κB; also, the drug did not affect transient expression from exogenous κB‐reporter plasmids. However, endogenous expression of inflammatory cytokines such as interleukin‐8 (IL‐8) was greatly reduced, even in the absence of de novo protein synthesis, suggesting that HDACi directly inhibits NF‐κB‐induced transcription. Indeed, chromatin immunoprecipitation (ChIP) analysis showed that events related to transcriptional activation of the IL‐8 gene region in response to TNF‐α, including recruitment of RNA polymerase II (Pol II), were compromised in the presence of TSA. These data indicate that HDAC activity is required for the efficient initiation and/or elongation of inflammatory gene transcription mediated by NF‐κB. (Cancer Sci 2011; 102: 1081–1087)
The roles of gender, age and cognitive development in children's pedestrian route selection
Authors: Barton B. K. , Ulrich T. , Lyday B.
Published: February 2011

Objective  Thousands of American children under the age of 10 years are injured annually as pedestrians. Despite the scope of this public health problem, knowledge about behavioural control and developmental factors involved in the aetiology of child pedestrian safety is limited. The present study examined the roles of gender, age and two aspects of cognitive development (visual search and efficiency of processing) in children's safe pedestrian route selection.

Methods  Measures of cognitive functioning (visual search and efficiency) and selections of risky pedestrian routes were collected from 65 children aged 5–9 years.

Results  Boys, younger children and those with less developed cognitive functioning selected riskier pedestrian routes. Cognitive functioning also subsumed age as a predictor of risky route selections.

Conclusions  Our findings suggest developmental differences, specifically less developed cognitive functioning, play important roles in children's pedestrian decision making. Directions for future examination are discussed.
Serum MMP 2 and TIMP 2 in patients with inguinal hernias
Authors: Śmigielski Jacek , Brocki Marian , Kuzdak Krzysztof , Kołomecki Krzysztof
Published: February 2011

Eur J Clin Invest 2011; 41 (6): 584–588

Background  More than sixty thousand inguinal hernia operations are performed every year in Poland. Despite many years of related research, the exact pathologic mechanism of this condition is still not fully understood. Recent studies suggested a pronounced relationship between the molecular structure of collagen fibers and the activity of metalloproteinases, the enzymes taking part in the degradation of collagen, as well as their tissue inhibitors.

Materials and methods  A prospective study has been established to measure serum levels of the matrix metalloproteinase 2 (MMP‐2) and Matrix metalloproteinase tissue inhibitor 2 (TIMP‐2) in 150 males between the ages of 26 and 70. The control group (CG) consisted of thirty healthy male volunteers of a similar age distribution.

Results  Our results indicate that MMP‐2 was highest in the direct hernia group, a statistically very significant elevation (P < 0.05) of 1562 ng mL−1 against the CG 684 ng mL−1. The highest level of TIMP, 78 ng mL−1, was found in the group with recurrent hernia, against 49.5 ng mL−1 of the CG (statistical significance of P < 0.05).

Discussion  The MMP‐2 and TIMP‐2 levels were concurrently elevated only in the recurrent hernia group.

Conclusions  The patients with inguinal hernia have a statistically significant increase in serum levels of MMP‐2. Our finding of the MMP‐2 and TIMP‐2 distinctly higher in the patients suffering from recurrence of direct inguinal hernia (reflecting a previous surgical failure) may suggest the theory that the extracellular matrix defect lies at the basis of this disorder.
Chinese primiparous women’s experiences of early motherhood: factors affecting maternal role competence
Authors: Ngai Fei‐Wan , Chan Sally WC , Holroyd Eleanor
Published: February 2011

Aim.  The aim of this study was to explore Chinese women’s perceptions of maternal role competence and factors contributing to maternal role competence during early motherhood.

Background.  Developing a sense of competence and satisfaction in the maternal role are considered critical components in maternal adaptation, which have a significant impact on parenting behaviours and the psychosocial development of the child. However, qualitative studies that address maternal role competence are limited in the Chinese population.

Design.  This was an exploratory descriptive study.

Method.  A purposive sample of 26 Chinese primiparous mothers participated in a childbirth psychoeducation programme and was interviewed at six weeks postpartum. Data were analysed using content analysis.

Results.  Women perceived a competent mother as being able to make a commitment to caring for the physical and emotional well‐being of child, while cultivating appropriate values for childhood. Personal knowledge and experience of infant care, success in breastfeeding, infant’s well‐being, availability of social support and contradictory information from various sources were major factors affecting maternal role competency.

Conclusion.  The findings highlight the importance of understanding Chinese cultural attitudes to childrearing and maternal role competence. New Chinese mothers need information on child care, positive experiences of infant care, social support and consistent information to enhance their maternal role competency. Recommendations are made for Chinese culturally specific guidelines and healthcare delivery interventions to enhance maternal role competence in early motherhood.

Relevance to clinical practice.  Nursing and midwifery care should always take into account the cultural beliefs and enable adaptation of traditional postpartum practices. Providing consistent information and positive experience on parenting skills and infant behaviour as well as enhancing effective coping strategies could strengthen Chinese women’s maternal role competency.