bluuebunny/crossref_metadata_2025 huggingface dataset:
Sample-morphology effects on x-ray photoelectron peak intensities
Authors: Powell Cedric J. , Tougaard Sven , Werner Wolfgang S. M. , Smekal Werner
Published: January 2013

The authors have used the National Institute of Standards and Technology Database for the Simulation of Electron Spectra for Surface Analysis to simulate photoelectron spectra from the four sample morphologies considered by Tougaard [J. Vac. Sci. Technol. A 14, 1415 (1996)]. These simulations were performed for two classes of materials, two instrument configurations, and two conditions, one in which elastic scattering is neglected (corresponding to the Tougaard results) and the other in which it is included. The authors considered the Cu/Au morphologies analyzed by Tougaard and similar SiO2/Si morphologies since elastic-scattering effects are expected to be smaller in the latter materials than the former materials. Film thicknesses in the simulations were adjusted in each case to give essentially the same chosen Cu 2p3/2 or O 1s peak intensity. Film thicknesses with elastic scattering switched on were systematically less than those with elastic scattering switched off by up to about 25% for the Cu/Au morphologies and up to about 14% for the SiO2/Si morphologies. For the two morphologies in which the Cu 2p3/2 or O 1s peak intensity was attenuated by an overlayer, the ratios of film thicknesses with elastic scattering switched on to those with elastic scattering switched off varied approximately linearly with the single-scattering albedo, a convenient measure of the strength of elastic scattering. This variation was similar to that of the ratio of the effective attenuation length to the inelastic mean free path for the photoelectrons in the overlayer film. For the two morphologies in which the Cu 2p3/2 or O 1s photoelectrons originated from an overlayer film, the ratios of film thicknesses with elastic scattering switched on to those with elastic scattering switched off varied more weakly with the single-scattering albedo. This weaker variation was attributed to the weaker effects of elastic scattering for photoelectrons originating predominantly from near-surface atoms than for photoelectrons that travel through an overlayer film.
BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of
FoxC2
and Stimulate Adipocyte Differentiation
Authors: Yao Yixin , Suraokar Milind , Darnay Bryant G. , Hollier Brett G. , Shaiken Tattym E. , Asano Takayuki , Chen Chien-Hung , Chang Benny H.-J. , Lu Yiling , Mills Gordon B. , Sarbassov Dos , Mani Sendurai A. , Abbruzzese James L. , Reddy Shrikanth A. G.
Published: January 2013

Activation of Akt1 during adipocyte differentiation requires a binding partner called BSTA.
The Akt DUBbed InAktive
Authors: Lin Kui
Published: January 2013

Deubiquitination limits the kinase activity of Akt in the absence of growth factor stimulation.
Regulation in Reserve
Authors: Ferrarelli Leslie K.
Published: January 2013

Sequestered microRNAs serve as a regulatory reserve pool to enable quiescent cells to effectively respond to mitogenic signals.
Therapy for Fibrotic Diseases: Nearing the Starting Line
Authors: Friedman Scott L. , Sheppard Dean , Duffield Jeremy S. , Violette Shelia
Published: January 2013

An emerging consensus indicates that fibrotic diseases in lung, liver, and kidney exhibit common underlying mechanisms, which can be targeted therapeutically.
FcγRs Muscle Up Dendritic Cell Cross-Presentation
Authors: Anandasabapathy Niroshana
Published: January 2013

Targeting FCγ receptors may improve dendritic cell–mediated vaccination.
Inspired by Porcupines
Authors: Collier Joel H.
Published: January 2013

Porcupine quills inspire new design concepts for hypodermic needles.
A Better Pacemaker: Transdifferentiation of Myocytes to Pacemaker Cells
Authors: Nahrendorf Matthias
Published: January 2013

Transdifferentiation of heart cells with a key transcription factor generates functional pacemaker cells in situ, a new approach to correcting heart failure.
Targeted Amino Acid Substitutions Impair Streptolysin O Toxicity and Group A
Streptococcus
Virulence
Authors: Chiarot Emiliano , Faralla Cristina , Chiappini Nico , Tuscano Giovanna , Falugi Fabiana , Gambellini Gabriella , Taddei Annarita , Capo Sabrina , Cartocci Elena , Veggi Daniele , Corrado Alessia , Mangiavacchi Simona , Tavarini Simona , Scarselli Maria , Janulczyk Robert , Grandi Guido , Margarit Immaculada , Bensi Giuliano
Published: January 2013

Streptolysin O is a potent pore-forming toxin produced by group A
Streptococcus
. The aims of the present study were to dissect the relative contributions of different structural domains of the protein to hemolytic activity, to obtain a detoxified form of streptolysin O amenable to human vaccine formulation, and to investigate the role of streptolysin O-specific antibodies in protection against group A
Streptococcus
infection. On the basis of
in silico
structural predictions, we introduced two amino acid substitutions, one in the proline-rich domain 1 and the other in the conserved undecapeptide loop in domain 4. The resulting streptolysin O derivative showed no toxicity, was highly impaired in binding to eukaryotic cells, and was unable to form organized oligomeric structures on the cell surface. However, it was fully capable of conferring consistent protection in a murine model of group A
Streptococcus
infection. When we engineered a streptococcal strain to express the double-mutated streptolysin O, a drastic reduction in virulence as well as a diminished capacity to kill immune cells recruited at the infection site was observed. Furthermore, when mice immunized with the toxoid were challenged with the wild-type and mutant strains, protection only against the wild-type strain, not against the strain expressing the double-mutated streptolysin O, was obtained. We conclude that protection occurs by antibody-mediated neutralization of active toxin.

IMPORTANCE
We present a novel example of structural design of a vaccine antigen optimized for human vaccine use. Having previously demonstrated that immunization of mice with streptolysin O elicits a protective immune response against infection with group A
Streptococcus
strains of different serotypes, we developed in this study a double-mutated nontoxic derivative that represents a novel tool for the development of protective vaccine formulations against this important human pathogen. Furthermore, the innovative construction of an isogenic strain expressing a functionally inactive toxin and its use in infection and opsonophagocytosis experiments allowed us to investigate the mechanism by which streptolysin O mediates protection against group A
Streptococcus
. Finally, the ability of this toxin to directly attack and kill host immune cells during infection was studied in an air pouch model, which allowed parallel quantification of cellular recruitment, vitality, and cytokine release at the infection site.
Broad Conditions Favor the Evolution of Phase-Variable Loci
Authors: Palmer M. E. , Lipsitch M. , Moxon E. R. , Bayliss C. D.
Published: January 2013

Simple sequence repeat (SSR) tracts produce stochastic
on
-
off
switching, or phase variation, in the expression of a panoply of surface molecules in many bacterial commensals and pathogens. A change to the number of repeats in a tract may alter the phase of the translational reading frame, which toggles the
on
-
off
state of the switch. Here, we construct an
in silico
SSR locus with mutational dynamics calibrated to those of the
Haemophilus influenzae mod
locus. We simulate its evolution in a regimen of two alternating environments, simultaneously varying the selection coefficient,
s
, and the epoch length,
T
. Some recent work in a simpler (two-locus) model suggested that stochastic switching in a regimen of two alternating environments may be evolutionarily favored only if the selection coefficients in the two environments are nearly equal (“symmetric”) or selection is very strong. This finding was puzzling, as it greatly restricted the conditions under which stochastic switching might evolve. Instead, we find agreement with other recent theoretical work, observing selective utility for stochastic switching if the product
sT
is large enough for the favored state to nearly fix in both environments. Symmetry is required neither in
s
nor in
sT
. Because we simulate finite populations and use a detailed model of the SSR locus, we are also able to examine the impact of population size and of several SSR locus parameters. Our results indicate that conditions favoring evolution and maintenance of SSR loci in bacteria are quite broad.

IMPORTANCE
Bacteria experience frequent changes of environment during the infection cycle. One means to rapidly adapt is stochastic switching: a bacterial lineage will stochastically produce a variety of genotypes, so that some descendants will survive if the environment changes. Stochastic switching mediated by simple sequence repeat (SSR) loci is widespread among bacterial commensals and pathogens and influences critical interactions with host surfaces or immune effectors, thereby affecting host persistence, transmission, and virulence. Here, we use the most detailed
in silico
model of an SSR locus to date, with its phase variation calibrated to match the
mod
locus of
Haemophilus influenzae
. The type III restriction-modification system encoded by
mod
participates in the regulation of multiple other genes; thus, SSR-mediated phase variation of
mod
has far-reaching
cis
-regulatory effects. This coupling of phase-variable switching to complex phenotypic effects has been described as the “phasevarion” and is central to understanding the infection cycle of bacterial commensals and pathogens.
Characterization of a Diffusible Signaling Factor from Xylella fastidiosa
Authors: Beaulieu Ellen D. , Ionescu Michael , Chatterjee Subhadeep , Yokota Kenji , Trauner Dirk , Lindow Steven
Published: January 2013

Cell-cell signaling in
Xylella fastidiosa
has been implicated in the coordination of traits enabling colonization in plant hosts as well as insect vectors. This cell density-dependent signaling has been attributed to a diffusible signaling factor (DSF) produced by the DSF synthase RpfF. DSF produced by related bacterial species are unsaturated fatty acids, but that of
X. fastidiosa
was thought to be different from those of other taxa. We describe here the isolation and characterization of an
X. fastidiosa
DSF (
Xf
DSF) as 2(
Z
)-tetradecenoic acid. This compound was isolated both from recombinant
Erwinia herbicola
expressing
X. fastidiosa rpfF
and from an
X. fastidiosa rpfC
deletion mutant that overproduces DSF. Since an
rpfF
mutant is impaired in biofilm formation and underexpresses the hemagglutinin-like protein-encoding genes
hxfA
and
hxfB
, we demonstrate that these traits can be restored by ca. 0.5 µM
Xf
DSF but not by myristic acid, the fully saturated tetradecenoic acid. A
phoA
-based
X. fastidiosa
biosensor that assesses DSF-dependent expression of
hxfA
or
hxfB
revealed a high level of molecular specificity of DSF signaling.

IMPORTANCE
X. fastidiosa
causes diseases in many important plants, including grape, where it incites Pierce’s disease. Virulence of
X. fastidiosa
for grape is coordinated by cell-cell signaling molecules, designated DSF (Diffusible Signaling Factor). Mutants blocked in DSF production are hypervirulent for grape, suggesting that virulence is suppressed upon DSF accumulation and that disease could be controlled by artificial elevation of the DSF level in plants. In this work, we describe the isolation of the DSF produced by
X. fastidiosa
and the verification of its biological activity as an antivirulence factor. We also have developed
X. fastidiosa
DSF biosensors to evaluate the specificity of cell-cell signaling to be investigated.
Brain dead or not? CT angiogram yielding false-negative result on brain death confirmation
Authors: Johnston Robyn , Kaliaperumal Chandrasekaran , Wyse Gerald , Kaar George
Published: January 2013

We describe a case of severe traumatic brain injury with multiple facial and skull fractures where CT angiogram (CTA) failed to yield a definite result of brain death as an ancillary test. A 28-year-old man was admitted following a road traffic accident with a Glasgow Coma Score (GCS) of 3/15 and fixed pupils. CT brain revealed uncal herniation and diffuse cerebral oedema with associated multiple facial and skull fractures. 72 h later, his clinical condition remained the same with high intracranial pressure refractory to medical management. Clinical confirmation on brain death was not feasible owing to facial injuries. A CTA, performed to determine brain perfusion, yielded a ‘false-negative’ result. Skull fractures have possibly led to venous prominence in the cortical and deep venous drainage system. This point needs to be borne in mind while considering CTA as an ancillary test to confirm brain death.
Thiamine-responsive pulmonary hypertension
Authors: Asakura Takanori , Kodera Satoshi , Kanda Junji , Ikeda Masayuki
Published: January 2013

The aim of this report is to call attention to a poorly recognised cause of pulmonary hypertension, thiamine deficiency. A 78-year-old woman without alcoholism or malabsorption presented with progressive dyspnoea and generalised oedema. Echocardiography showed signs of right ventricular overload with an estimated systolic pulmonary artery pressure of 50 mm Hg. Increased lactate concentrations prompted us to investigate thiamine deficiency. A 3-month history of picky eating, relying exclusively on white rice as the staple food, and low blood concentrations of thiamine confirmed the diagnosis. She recovered fully after 12 days of intravenous thiamine administration. Thiamine deficiency should be considered in all patients with pulmonary hypertension of unknown origin.
Imaging challenges of carotid artery in-stent restenosis
Authors: Pizzolato Raffaella , Hirsch Joshua A , Romero Javier M
Published: January 2013

Internal carotid artery stenosis is an established risk factor for stroke. Therefore, carotid artery revascularization has an important role in the prevention and treatment of stroke. For the treatment of carotid artery stenosis, carotid artery stenting (CAS) has currently gained acceptance as a safe alternative to carotid endarterectomy (CEA), particularly in patients at high surgical risk. Duplex ultrasonography (DUS) is a non-invasive technique with standardized criteria used for the diagnosis of carotid atheromatous disease as well as for the detection of restenosis after carotid revascularization. Restenosis rates vary widely in the literature. Different studies indicated that restenosis following CAS was higher than following CEA, although the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) reported similar restenosis frequency after 2 years of follow-up. Given these results, DUS may have a significant role in the follow-up of CAS patients. Conventional carotid artery DUS velocity criteria are thought to be less accurate in patients who have undergone CAS and many authors proposed different criteria for grading in-stent restenosis (ISR). This review presents the advantages of CAS, the current practice of carotid revascularization, CAS complications and risks, and DUS criteria for carotid artery ISR. After analyzing multiple relevant studies that proposed sonographic criteria for grading at least 70% ISR, we can conclude that a peak systolic velocity value of 300–350 cm/s could be used as a relatively good and sensitive predictor of high grade ISR.
Audit of HIV testing frequency and behavioural interventions for men who have sex with men: policy and practice in sexual health clinics in England
Authors: Desai Monica , Desai Sarika , Sullivan Ann Kathleen , Mohabeer Malika , Mercey Danielle , Kingston Margaret A , Thng Caroline , McCormack Sheena , Gill O Noel , Nardone Anthony ,   On behalf of GUMNet
Published: January 2013

Background

National guidance recommends targeted behavioural interventions and frequent HIV testing for men who have sex with men (MSM). We reviewed current policy and practice for HIV testing and behavioural interventions (BI) in England to determine adherence to guidance.

Methods

25 sexual health clinics were surveyed using a semistructured audit asking about risk ascertainment for MSM, HIV testing and behavioural intervention policies. Practice was assessed by reviewing the notes of the first 40 HIV-negative MSM aged over 16 who attended from 1 June 2010, in a subset of 15 clinics.

Results

24 clinics completed the survey: 18 (75%) defined risk for MSM and 17 used unprotected anal intercourse (UAI) as an indication of high risk. 21 (88%) offered one or more structured BI. Of 598 notes reviewed, 199 (33%) MSM reported any UAI. BI, including safer sex advice, was offered to and accepted by 251/598 (42%) men. A low proportion of all MSM (52/251: 21%) accepted a structured one-to-one BI as recommended by national guidance and uptake was still low among higher risk MSM (29/107: 27%). 92% (552/598) of men had one or more HIV test over a 1-year period.

Conclusions

In 2010, the number of HIV tests performed met the national minimum standard but structured behavioural interventions were being offered to and accepted by only a small proportion of MSM, including those at a higher risk of infection. Reasons for not offering behavioural interventions to higher risk MSM, whether due to patient choice, a lack of staff training or resource shortage, need to be investigated and addressed.
A CLOSED-FORM EXTENSION TO THE BLACK-COX MODEL
Authors: ALFONSI AURÉLIEN , LELONG JÉRÔME
Published: January 2013

In the Black-Cox model, a firm defaults when its value hits an exponential barrier. Here, we propose an hybrid model that generalizes this framework. The default intensity can take two different values and switches when the firm value crosses a barrier. Of course, the intensity level is higher below the barrier. We get an analytic formula for the Laplace transform of the default time. This result can be also extended to multiple barriers and intensity levels. Then, we explain how this model can be calibrated to Credit Default Swap prices and show its tractability on different kinds of data. We also present numerical methods to numerically recover the default time distribution.
IN-ARREARS TERM STRUCTURE PRODUCTS: NO ARBITRAGE PRICING BOUNDS AND THE CONVEXITY ADJUSTMENTS
Authors: CHEN AN , SANDMANN KLAUS
Published: January 2013

When pricing an in-arrears term structure product, the valuation usually boils down to determining the price of a vanilla product and of some additional part. To computer the price of the additional part, sometimes a specific term structure (like Gaussian or LIBOR) is assumed. Sometimes approximation methods are applied to achieve model-independent valuation formulae. In the present paper, we show that these valuation formulae (the price of vanilla products plus convexity adjustments resulting from approximation) are in effect model-independent pricing bounds in every arbitrage-free model. More specifically, they are proven to be a lower pricing bound for in-arrears payer swaps and in-arrears caps and an upper bound for in-arrears receiver swaps and in-arrears floors. To address the goodness/tightness issue of the bounds, convexity adjustments are compared with the exact pricing formulae obtained in LIBOR market model.
CONSTRUCTION OF MULTIFRACTAL FRACTIONAL RANDOM WALKS WITH HURST INDEX SMALLER THAN 1/2
Authors: PERPÈTE NICOLAS
Published: January 2013

We construct the Multifractal Fractional Random Walks with Hurst index 0 < H < 1/2 as the limits in C[0, 1], when l goes to 0, of the processes [Formula: see text] being the continuous cascade defined by Bacry and Muzy. This work completes the available literature, mainly dedicated to the case 1/2 ≤ H < 1. It is of particular interest for applications in a variety of areas, such as turbulence or finance.
CONFORMATIONAL PROPERTIES AND INTRAMOLECULAR HYDROGEN BONDING OF 3-AMINO-PROPENESELENAL: ANAB INITIOAND DENSITY FUNCTIONAL THEORY STUDIES
Authors: RAISSI HEIDAR , FARZAD FARZANEH , ESLAMDOOST SHAHIRA , MOLLANIA FARIBA
Published: January 2013

In the present work a conformational analysis of 3-amino-propeneselenal (APS) was performed using several computational methods, including DFT (B3LYP), MP2 and G2MP2. Harmonic vibrational frequencies were estimated at the same levels to confirm the nature of the stationary points found and also to account for the zero point vibrational energy (ZPVE) correction. Two intramolecular hydrogen bonds (HBs) established between the polar groups were identified by the structural geometric parameters. The excited-state properties of intramolecular hydrogen bonding in hydrogen bonded systems have been investigated theoretically using the time dependent density functional theory (TDDFT) method. The influence of the solvent on the stability order of conformers and the strength of intramolecular hydrogen bonding was considered using the polarized continuum model (PCM), the self-consistent isodensity polarized continuum model (SCI-PCM) and the integral equation formalism-polarizable continuum model (IEF-PCM) methods. The "atoms in molecules" theory of Bader was used to analyze critical points and to study the nature of HB in these systems. Natural bond orbital (NBO) analysis was also performed for better understanding the nature of intramolecular interactions. The calculated the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies show that charge transfer occur within the molecule. Further verification of the obtained transition state structures were implemented via intrinsic reaction coordinate (IRC) analysis. Calculations of the1H NMR chemical shift at GIAO/B3LYP/6–311++G** level of theory are also presented.
THE PREPARATION OF SOLVENT-FREE MULTIWALL CARBON NANOTUBES/SILICA HYBRID NANOMATERIAL WITH LIQUID-LIKE BEHAVIOR
Authors: ZHANG JIAO-XIA , JANG KE-MAO , ZHENG YA-PING , WU FEI , LI YU-QING
Published: January 2013

The solvent-free hybrid nanomaterial consisting of multiwall carbon nanotubes (MWNTs) and silica nanoparticles are prepared by a facile route. The content of MWNTs/silica nanoparticles is up to 20 wt.%. The hybrid nanomaterial exhibits liquid-like behavior in the absence of solvent at room temperature.
Integrated Genomic Approaches to Enhance Genetic Resistance in Chickens
Authors: Cheng Hans H. , Kaiser Pete , Lamont Susan J.
Published: January 2013

The chicken has led the way among agricultural animal species in infectious disease control and, in particular, selection for genetic resistance. The generation of the chicken genome sequence and the availability of other empowering tools and resources greatly enhance the ability to select for enhanced disease resistance via genetic markers and to understand more deeply the biological basis of host resistance. In this review, we discuss how integrated genomic approaches are able to identify specific genes and genetic markers associated with disease resistance, give select examples of contemporary work involving various genomic strategies to identify disease resistance genes, and finish by giving some final thoughts on predicted applications in the near future.
Endophenotypes in Psychopathology Research: Where Do We Stand?
Authors: Miller Gregory A. , Rockstroh Brigitte
Published: January 2013

Endophenotypes for psychopathology have been conceived as latent, unobserved, but measureable manifestations of phenomena that causally connect genetic liability to clinical disorder. Several decades of research have led to refinement of the construct and identification of some candidate endophenotypes, but rather limited progress on finding the genes involved or the mechanisms by which endophenotypes are driven by genetic and environmental factors and in turn drive psychopathology. Currently promising avenues for research involve development of transdiagnostic concepts not limited to traditional diagnostic categories, measures of endophenotypic and manifest psychopathology that have higher validity than those categories, and methods for modeling complex relationships among diverse contributors to etiology. With more grounding in animal neuroscience and other aspects of basic biological and psychological science, exemplified in the Research Domain Criteria initiative, there is every reason to anticipate that the endophenotype concept will grow more central in the psychopathology literature.
Interpersonal Processes in Depression
Authors: Hames Jennifer L. , Hagan Christopher R. , Joiner Thomas E.
Published: January 2013

Humans have an intrinsic need for social connection; thus, it is crucial to understand depression in an interpersonal context. Interpersonal theories of depression posit that depressed individuals tend to interact with others in a way that elicits rejection, which increases their risk for future depression. In this review, we summarize the interpersonal characteristics, risk factors, and consequences of depression in the context of the relevant theories that address the role of interpersonal processes in the onset, maintenance, and chronicity of depression. Topics reviewed include social skills, behavioral features, communication behaviors, interpersonal feedback seeking, and interpersonal styles as they relate to depression. Treatment implications are discussed in light of the current research on interpersonal processes in depression, and the following future directions are discussed: developing integrative models of depression, improving measurement of interpersonal constructs, examining the association between interpersonal processes in depression and suicide, and tailoring interventions to target interpersonal processes in depression.
Glass Transition Thermodynamics and Kinetics
Authors: Stillinger Frank H. , Debenedetti Pablo G.
Published: January 2013

The remarkable kinetic slowdown experienced by liquids as they are cooled toward their glass transition is not accompanied by any obvious structural change. Understanding the origin of this behavior is a major scientific challenge. At present, this area of condensed matter theory is characterized by an abundance of divergent viewpoints that attempt to describe well-defined physical phenomena. We review representative theoretical views on the unusual kinetics of liquid supercooling, which fall into two broad competing categories: thermodynamic and kinetic. In the former, an apparent “ideal,” thermodynamic, glass transition caused by rapid loss of entropy in the supercooled liquid underlies kinetic slowdown; in the latter, purely kinetic constraints are responsible for loss of ergodicity. The possible existence of an ideal thermodynamic glass transition is discussed and placed in its proper statistical mechanical context.
Nutrimetabonomics:Applications for Nutritional Sciences, with Specific Reference to Gut Microbial Interactions
Authors: Claus Sandrine P. , Swann Jonathan R.
Published: January 2013

Understanding the role of the diet in determining human health and disease is one major objective of modern nutrition. Mammalian biocomplexity necessitates the incorporation of systems biology technologies into contemporary nutritional research. Metabonomics is a powerful approach that simultaneously measures the low-molecular-weight compounds in a biological sample, enabling the metabolic status of a biological system to be characterized. Such biochemical profiles contain latent information relating to inherent parameters, such as the genotype, and environmental factors, including the diet and gut microbiota. Nutritional metabonomics, or nutrimetabonomics, is being increasingly applied to study molecular interactions between the diet and the global metabolic system. This review discusses three primary areas in which nutrimetabonomics has enjoyed successful application in nutritional research: the illumination of molecular relationships between nutrition and biochemical processes; elucidation of biomarker signatures of food components for use in dietary surveillance; and the study of complex trans-genomic interactions between the mammalian host and its resident gut microbiome. Finally, this review illustrates the potential for nutrimetabonomics in nutritional science as an indispensable tool to achieve personalized nutrition.
Off-Flavor Precursors in Soy Protein Isolate and Novel Strategies for their Removal
Authors: Damodaran Srinivasan , Arora Akshay
Published: January 2013

Off-flavors remain a major hurdle in expanding the use of soy protein isolate (SPI) in mainstream food applications. The complexity in solving this problem arises from the presence of protein-bound precursors in SPI. Among the most predominant sources of off-flavors in SPI is the residual amount of phospholipids that contain polyunsaturated fatty acids (PUFAs). Autoxidation of PUFAs generates several classes of volatile compounds that contribute to the beany, grassy, or green odor of SPI. In addition, several polyphenolic compounds, such as isoflavones, saponins, phenolic acids, etc., impart bitter and astringent tastes to SPI. Traditional methods for removing protein-bound precursors from SPI and their limitations are reviewed. The most notable trade-off of conventional methods is the loss of protein functionality to some degree. Therefore, pursuit of gentler treatments to overcome SPI off-flavor has been the focus of industry and academia alike. Novel approaches that employ β-cyclodextrin to remove both SPI-bound precursors and volatile compounds are described.
Interleukin-4- and Interleukin-13-Mediated Alternatively Activated Macrophages: Roles in Homeostasis and Disease
Authors: Van Dyken Steven J. , Locksley Richard M.
Published: January 2013

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair.
The Potential of HDAC Inhibitors as Cognitive Enhancers
Authors: Gräff Johannes , Tsai Li-Huei
Published: January 2013

Histone acetylation is a prominent epigenetic modification of the central nervous system that is unequivocally associated with an increase in the rate of gene transcription. Because gene transcription, in turn, plays an important role in long-lasting forms of memory, histone acetylation generally favors long-term memory, whereas histone deacetylation impinges on it. Histone acetylation is also amenable to pharmacological interventions—predominantly by the use of histone deacetylase (HDAC) inhibitors—and has therefore spurred considerable interest as a putative target of cognitive enhancement. Because of the ubiquitous presence of histone acetylation, HDAC inhibitors have great potential not only to treat cognitive impairment resulting from neurodevelopmental and neurodegenerative disorders but also to serve as cognitive enhancers for the cognitively healthy. In this review, we summarize the state of the art of HDAC inhibitors as cognitive treatments or cognitive enhancers; describe a new model of their mode of action, epigenetic priming; and caution against their unsupervised usage, despite their overall great promise.
Pluripotent Stem Cell–Derived Hepatocytes: Potential and Challenges in Pharmacology
Authors: Szkolnicka Dagmara , Zhou Wenli , Lucendo-Villarin Balta , Hay David C.
Published: January 2013

The liver is a fascinating organ and performs a wide range of functions necessary for life. Because the hepatocyte is the major functional cell type found in the liver, it is important that we better understand its role in health and disease. Functional hepatocytes have been derived from many sources, including human stem cell populations. These models offer new opportunities to further our understanding of human liver biology from diverse genotypes and, in the future, to facilitate the development of novel medicines or cell-based therapies. This review discusses limitations in current cell-based models and the advantages offered by pluripotent stem cell–derived hepatocytes.
Recent Advances in Singlet Fission
Authors: Smith Millicent B. , Michl Josef
Published: January 2013

A survey is provided of recent progress in the understanding of singlet fission, a spin-allowed process in which a singlet excited molecule shares its energy with a ground-state neighbor to produce two triplet excited molecules. It has been observed to occur in single-crystal, polycrystalline, and amorphous solids, on timescales from 80 fs to 25 ps, producing triplet yields as high as 200%. Photovoltaic devices using the effect have shown external quantum efficiencies in excess of 100%. Almost all the efficient materials are alternant hydrocarbons of the acene series or their simple derivatives, and it is argued that a wider structural variety would be desirable. The current state of the development of molecular structure design rules, based on first-principles theoretical considerations, is described along with initial examples of implementation.
Water Interfaces, Solvation, and Spectroscopy
Authors: Geissler Phillip L.
Published: January 2013

Liquid water consistently expands our appreciation of the rich statistical mechanics that can emerge from simple molecular constituents. Here I review several interrelated areas of recent work on aqueous systems that aim to explore and explain this richness by revealing molecular arrangements, their thermodynamic origins, and the timescales on which they change. Vibrational spectroscopy of OH stretching features prominently in these discussions, with an emphasis on efforts to establish connections between spectroscopic signals and statistics of intermolecular structure. For bulk solutions, the results of these efforts largely verify and enrich existing physical pictures of hydrogen-bond network connectivity, dynamics, and response. For water at interfaces, such pictures are still emerging. As an important example I discuss the solvation of small ions at the air-water interface, whose surface propensities challenge a basic understanding of how aqueous fluctuations accommodate solutes in heterogeneous environments.
HIV Prevention Among Women in Low- and Middle-Income Countries: Intervening Upon Contexts of Heightened HIV Risk
Authors: Strathdee Steffanie A. , Wechsberg Wendee M. , Kerrigan Deanna L. , Patterson Thomas L.
Published: January 2013

Women's vulnerability to HIV infection is influenced by contextual factors in the risk environment that operate at multiple levels (i.e., physical, social, economic, policy). We present three case studies that illustrate combination approaches to HIV prevention among women who are at heightened risk for infection, especially sex workers, in low- and middle-income countries (LMICs). Lessons learned from these case studies are consistent with international literature promoting interventions that combine sexual risk reduction, condom promotion, and improved access to sexually transmitted infection (STI) treatment in the context of structural interventions, including policy change and empowerment of sex workers to reduce their vulnerability to HIV/STIs. We suggest avenues for future research and new intervention targets as well as a more nuanced approach to understanding the structural and social vulnerability of women to HIV infection in these settings.
Stress and Cardiovascular Disease: An Update on Current Knowledge
Authors: Steptoe Andrew , Kivimäki Mika
Published: January 2013

Considerable progress has been made during the past decade in research on cardiovascular effects of stress. Early-life stressors, such as childhood abuse and early socioeconomic adversity, are linked to increased cardiovascular morbidity in adulthood. Our updated meta-analyses of prospective studies published until 2011 show a 1.5-fold (95% confidence interval 1.2–1.9) increased risk of coronary heart disease among adults experiencing social isolation and a 1.3-fold (1.2–1.5) excess risk for workplace stress; adverse metabolic changes are one of the underlying plausible mechanisms. Stress, anger, and depressed mood can act as acute triggers of major cardiac events; the pooled relative risk of acute coronary syndrome onset being preceded by stress is 2.5 (1.8–3.5) in case-crossover studies. Stress is also implicated in the prognosis of cardiovascular disease and in the development of stress (takotsubo) cardiomyopathy. A major challenge over the next decade is to incorporate stress processes into the mainstream of cardiovascular pathophysiological research and understanding.
Role of RACK1 in the differential proliferative effects of neuropeptide Y1–36 and peptide YY1–36 in SHR vs. WKY preglomerular vascular smooth muscle cells
Authors: Cheng Dongmei , Zhu Xiao , Gillespie Delbert G. , Jackson Edwin K.
Published: January 2013

Previous studies show that neuropeptide Y1–36 (NPY1–36) and peptide YY1–36 (PYY1–36), by engaging Y1 receptors, stimulate proliferation of spontaneous hypertensive rat (SHR) preglomerular vascular smooth muscle cells (PGVSMCs). In contrast, these peptides have little effect on proliferation of Wistar-Kyoto (WKY) PGVSMCs. Why SHR and WKY PGVSMCs differ in this regard is unknown. Because receptor for activated C kinase 1 (RACK1) can modulate cell proliferation, we tested the hypothesis that differences in RACK1 levels/localization may explain the differential response of SHR vs. WKY PGVSMCs to NPY1–36 and PYY1–36. Western blotting for RACK1 in subcellular fractions of cultured SHR and WKY PGVSMCs demonstrated increased levels of RACK1 in the membrane and cytoskeletal subcellular fractions of SHR vs. WKY PGVSMCs. NPY1–36 and PYY1–36 stimulated proliferation of SHR PGVSMCs, and siRNA knockdown of RACK1 abrogated this effect. Neither NPY1–36 nor PYY1–36 stimulated the proliferation of WKY PGVSMCs. However, in WKY PGVSMCs treated with a RACK1 plasmid, both NPY1–36 and PYY1–36 stimulated proliferation. In SHR PGVSMCs, inhibitors of the Gi/phospholipase C/PKC pathway (a pathway known to be organized by RACK1) attenuated the ability of NPY1–36 to stimulate the proliferation of SHR PGVSMCs. Our results suggest that RACK1 modulates the ability of PGVSMCs to respond to the proliferative actions of NPY1–36 and PYY1–36 and differences in RACK1 levels/localization account for, in part, differential proliferative responses to NPY1–36 and PYY1–36 in SHR vs. WKY PGVSMCs. Because dipeptidyl peptidase IV inhibitors increase NPY1–36 and PYY1–36 levels, our findings have implications for the use of such drugs in diabetic patients.
Quantitative characterization of changes in the cardiac mitochondrial proteome during anesthetic preconditioning and ischemia
Authors: Bienengraeber Martin , Pellitteri-Hahn Molly , Hirata Naoyuki , Baye Tesfaye M. , Bosnjak Zeljko J. , Olivier Michael
Published: January 2013

Changes in mitochondrial bioenergetics have been proposed to be critical for triggering and effecting anesthetic-induced preconditioning (APC) against cardiac ischemia and reperfusion injury. The objective of this study was to analyze changes in mitochondrial protein levels and link those changes to potential functional changes. A 18O-labeling method was applied for relative comparison of cardiac mitochondrial samples from control and isoflurane exposed rats before and after ischemia and reperfusion. Wistar rats were exposed to isoflurane for 30 min (APC) or did not receive the anesthetic (control). Rats were subjected to 30 min coronary occlusion and 15 min reperfusion without (ischemia) or after APC (ischemia + APC). The following comparisons were made: control vs. APC, control vs. ischemia, and APC vs. ischemia + APC. Proteins were analyzed by liquid chromatography-mass spectrometry. A total of 98 proteins currently annotated as mitochondrial proteins in the UniProt database were positively identified from three replicate experiments. Most of the changes during APC and ischemia occur in complexes of the electron transport chain. Overall, fewer changes in ETC complexes were found when comparing APC with APC + ischemia than when comparing control and ischemia. This corresponds to the preservation of bioenergetics due to APC after ischemia and reperfusion as indicated by preserved ATP level and generation. APC itself induced changes in complex I, but those changes were not correlated with activity changes in mitochondria after APC. Thus, a proteomic mass spectral approach does not only assess quantitative changes without prior knowledge of proteins, but also allows insight into the mechanisms of ischemia and reperfusion injury and APC.
Role of Phospholipids in Endocytosis, Phagocytosis, and Macropinocytosis
Authors: Bohdanowicz Michal , Grinstein Sergio
Published: January 2013

Endocytosis, phagocytosis, and macropinocytosis are fundamental processes that enable cells to sample their environment, eliminate pathogens and apoptotic bodies, and regulate the expression of surface components. While a great deal of effort has been devoted over many years to understanding the proteins involved in these processes, the important contribution of phospholipids has only recently been appreciated. This review is an attempt to collate and analyze the rapidly emerging evidence documenting the role of phospholipids in clathrin-mediated endocytosis, phagocytosis, and macropinocytosis. A primer on phospholipid biosynthesis, catabolism, subcellular distribution, and transport is presented initially, for reference, together with general considerations of the effects of phospholipids on membrane curvature and charge. This is followed by a detailed analysis of the critical functions of phospholipids in the internalization processes and in the maturation of the resulting vesicles and vacuoles as they progress along the endo-lysosomal pathway.
Regulation of Small GTPases by GEFs, GAPs, and GDIs
Authors: Cherfils Jacqueline , Zeghouf Mahel
Published: January 2013

Small GTPases use GDP/GTP alternation to actuate a variety of functional switches that are pivotal for cell dynamics. The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated by GDIs and GDI-like proteins. The structures and core mechanisms of representative members of small GTPase regulators from most families have now been elucidated, illuminating their general traits combined with scores of unique features. Recent studies reveal that small GTPase regulators have themselves unexpectedly sophisticated regulatory mechanisms, by which they process cellular signals and build up specific cell responses. These mechanisms include multilayered autoinhibition with stepwise release, feedback loops mediated by the activated GTPase, feed-forward signaling flow between regulators and effectors, and a phosphorylation code for RhoGDIs. The flipside of these highly integrated functions is that they make small GTPase regulators susceptible to biochemical abnormalities that are directly correlated with diseases, notably a striking number of missense mutations in congenital diseases, and susceptible to bacterial mimics of GEFs, GAPs, and GDIs that take command of small GTPases in infections. This review presents an overview of the current knowledge of these many facets of small GTPase regulation.
Gastric Acid, Calcium Absorption, and Their Impact on Bone Health
Authors: Kopic Sascha , Geibel John P.
Published: January 2013

Calcium balance is essential for a multitude of physiological processes, ranging from cell signaling to maintenance of bone health. Adequate intestinal absorption of calcium is a major factor for maintaining systemic calcium homeostasis. Recent observations indicate that a reduction of gastric acidity may impair effective calcium uptake through the intestine. This article reviews the physiology of gastric acid secretion, intestinal calcium absorption, and their respective neuroendocrine regulation and explores the physiological basis of a potential link between these individual systems.
New Fundamentals in Hemostasis
Authors: Versteeg Henri H. , Heemskerk Johan W. M. , Levi Marcel , Reitsma Pieter H.
Published: January 2013

Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surrounding tissue. The first important component that contributes to hemostasis is the coagulation system, while the second important component starts with platelet activation, which not only contributes to the hemostatic plug, but also accelerates the coagulation system. Eventually, coagulation and platelet activation are switched off by blood-borne inhibitors and proteolytic feedback loops. This review summarizes new concepts of activation of proteases that regulate coagulation and anticoagulation, to give rise to transient thrombin generation and fibrin clot formation. It further speculates on the (patho)physiological roles of intra- and extravascular receptors that operate in response to these proteases. Furthermore, this review provides a new framework for understanding how signaling and adhesive interactions between endothelial cells, leukocytes, and platelets can regulate thrombus formation and modulate the coagulation process. Now that the key molecular players of coagulation and platelet activation have become clear, and their complex interactions with the vessel wall have been mapped out, we can also better speculate on the causes of thrombosis-related angiopathies.
Hypoxia and Adipose Tissue Function and Dysfunction in Obesity
Authors: Trayhurn Paul
Published: January 2013

The rise in the incidence of obesity has led to a major interest in the biology of white adipose tissue. The tissue is a major endocrine and signaling organ, with adipocytes, the characteristic cell type, secreting a multiplicity of protein factors, the adipokines. Increases in the secretion of a number of adipokines occur in obesity, underpinning inflammation in white adipose tissue and the development of obesity-associated diseases. There is substantial evidence, particularly from animal studies, that hypoxia develops in adipose tissue as the tissue mass expands, and the reduction in Po2is considered to underlie the inflammatory response. Exposure of white adipocytes to hypoxic conditions in culture induces changes in the expression of >1,000 genes. The secretion of a number of inflammation-related adipokines is upregulated by hypoxia, and there is a switch from oxidative metabolism to anaerobic glycolysis. Glucose utilization is increased in hypoxic adipocytes with corresponding increases in lactate production. Importantly, hypoxia induces insulin resistance in fat cells and leads to the development of adipose tissue fibrosis. Many of the responses of adipocytes to hypoxia are initiated at Po2levels above the normal physiological range for adipose tissue. The other cell types within the tissue also respond to hypoxia, with the differentiation of preadipocytes to adipocytes being inhibited and preadipocytes being transformed into leptin-secreting cells. Overall, hypoxia has pervasive effects on the function of adipocytes and appears to be a key factor in adipose tissue dysfunction in obesity.