bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Erythromycin Resistance Phenotype Associated with Peptidyl-tRNA Drop-Off on Early UGG and GGG Codons
Authors: Mačvanin Mirjana , Gonzalez de Valdivia Ernesto I. , Ardell David H. , Isaksson Leif A.
Published: October 2007

Expression of minigenes encoding tetra- or pentapeptides MXLX or MXLXV (E peptides), where X is a nonpolar amino acid, renders cells erythromycin resistant whereas expression of minigenes encoding tripeptide MXL does not. By using a 3A′ reporter gene system beginning with an E-peptide-encoding sequence, we asked whether the codons UGG and GGG, which are known to promote peptidyl-tRNA drop-off at early positions in mRNA, would result in a phenotype of erythromycin resistance if located after this sequence. We find that UGG or GGG, at either position +4 or +5, without a following stop codon, is associated with an erythromycin resistance phenotype upon gene induction. Our results suggest that, while a stop codon at +4 gives a tripeptide product (MIL) and erythromycin sensitivity, UGG or GGG codons at the same position give a tetrapeptide product (MILW or MILG) and phenotype of erythromycin resistance. Thus, the drop-off event on GGG or UGG codons occurs after incorporation of the corresponding amino acid into the growing peptide chain. Drop-off gives rise to a peptidyl-tRNA where the peptide moiety functionally mimics a minigene peptide product of the type previously associated with erythromycin resistance. Several genes inEscherichia colifulfill the requirements of high mRNA expression and an E-peptide sequence followed by UGG or GGG at position +4 or +5 and should potentially be able to give an erythromycin resistance phenotype.
Characterization of the Arsenate Respiratory Reductase from
Shewanella
sp. Strain ANA-3
Authors: Malasarn Davin , Keeffe Jennifer R. , Newman Dianne K.
Published: October 2007

Microbial arsenate respiration contributes to the mobilization of arsenic from the solid to the soluble phase in various locales worldwide. To begin to predict the extent to which As(V) respiration impacts arsenic geochemical cycling, we characterized the expression and activity of the
Shewanella
sp. strain ANA-3 arsenate respiratory reductase (ARR), the key enzyme involved in this metabolism. ARR is expressed at the beginning of the exponential phase and persists throughout the stationary phase, at which point it is released from the cell. In intact cells, the enzyme localizes to the periplasm. To purify ARR, a heterologous expression system was developed in
Escherichia coli
. ARR requires anaerobic conditions and molybdenum for activity. ARR is a heterodimer of ∼131 kDa, composed of one ArrA subunit (∼95 kDa) and one ArrB subunit (∼27 kDa). For ARR to be functional, the two subunits must be expressed together. Elemental analysis of pure protein indicates that one Mo atom, four S atoms associated with a
bis
-molybdopterin guanine dinucleotide cofactor, and four to five [4Fe-4S] are present per ARR. ARR has an apparent melting temperature of 41°C, a
K

m

of 5 μM, and a
V
max
of 11,111 μmol of As(V) reduced min
−1
mg of protein
−1
and shows no activity in the presence of alternative electron acceptors such as antimonite, nitrate, selenate, and sulfate. The development of a heterologous overexpression system for ARR will facilitate future structural and/or functional studies of this protein family.
HasB, theSerratia marcescensTonB Paralog, Is Specific to HasR
Authors: Benevides-Matos Najla , Wandersman Cécile , Biville Francis
Published: October 2007

Serratia marcescenspossesses two functional TonB paralogs, TonBSmand HasB, for energizing TonB-dependent transport receptors (TBDT). Previous work had shown that HasB is specific to heme uptake in the natural host and inEscherichia coliexpressing theS. marcescensTBDT receptor HasR, whereas theS. marcescensTonB andE. coliTonB proteins function equally well with various TBDT receptors for heme and siderophores. This has raised the question of the target of this specificity. HasB could be specific either to heme TBDT receptors or only to HasR. To resolve this question, we have cloned inE. colianotherS. marcescensheme receptor, HemR, and we show here that this receptor is TonB dependent and does not work with HasB. This demonstrates that HasB is not dedicated to heme TBDT receptors but rather forms a specific pair with HasR. This is the first reported case of a specific TonB protein working with only one TBDT receptor in one given species. We discuss the occurrence, possible molecular mechanisms, and selective advantages of such dedicated TonB paralogs.
Role of RelA of
Streptococcus mutans
in Global Control of Gene Expression
Authors: Nascimento Marcelle M. , Lemos José A. , Abranches Jacqueline , Lin Vanessa K. , Burne Robert A.
Published: October 2007

The production of (p)ppGpp by
Streptococcus mutans
UA159 is catalyzed by three gene products: RelA, RelP, and RelQ. Here, we investigate the role of the RelA (Rel) homologue of
S. mutans
in the stringent response and in the global control of gene expression. RelA of
S. mutans
was shown to synthesize pppGpp in vitro from GTP and ATP in the absence of added ribosomes, as well as in vivo in an
Escherichia coli relA-spoT
mutant. Mupirocin (MUP) was shown to induce high levels of (p)ppGpp production in
S. mutans
in a
relA
-dependent manner, with a concomitant reduction in GTP pools. Transcription profiling after MUP treatment of
S. mutans
revealed that 104 genes were upregulated and 130 were downregulated (
P
≤ 0.001); mainly, genes for macromolecular biosynthesis, translation, and energy metabolism were downregulated. When a derivative of UA159 carrying a complete deletion of the
relA
gene was treated with MUP, 72 genes were upregulated and 52 were downregulated (
P
≤ 0.001). The expression of 50 genes (
P
≤ 0.001) was commonly affected by MUP treatment in the two strains, suggesting that
S. mutans
can mount a
relA
-independent response to MUP. Consistent with the gene expression profiling, RelA was shown to play major roles in the regulation of phenotypic traits that are required for establishment, persistence, and virulence expression by this oral pathogen. Thus, RelA is the major (p)ppGpp synthase controlling the stringent response in
S. mutans
, and it coordinates the expression of genes and phenotypes that contribute to the pathogenic potential of the organism.
Variation in the histopathological features of patients with ascending aortic aneurysms: a study of 111 surgically excised cases
Authors: Collins M J , Dev V , Strauss B H , Fedak P W M , Butany J
Published: October 2007

Background:

Ascending aortic aneurysms (AA) are a common, though poorly understood medical condition.

Aims:

To document the histological changes in a large series of human ascending AA, and to correlate these changes with clinical variables.

Methods:

111 ascending AA were excised at surgery over a 3 year period. Each aneurysm was received as a continuous ring of tissue. Sections were taken from the anterior, posterior, greater and lesser curvature of the aorta and graded in a semi-quantitative fashion for the degree of elastin fragmentation, elastin loss, smooth muscle cell (SMC) loss, intimal changes and inflammation.

Results:

Mean patient age at surgery was 58.7 (15.6) years; there were 70 men and 41 women. 12 patients had Marfan syndrome, 34 (30.6%) had a bicuspid aortic valve (BAV), while 71 (64.0%) had a tricuspid aortic valve (TAV). Inflammatory cells were present in 28 cases (25.2%) and were confined to the adventitia. No particular region of the aortic circumference was more severely affected, however a BAV was associated with significantly less intimal change, and less fragmentation and loss of elastic tissue compared with patients with a TAV. Advanced age (>65 years), female gender and Marfan syndrome were all associated with more severe elastin degeneration and smooth muscle cell loss (p<0.05 for all).

Conclusion:

Results indicate a wide variation in the histological appearance in ascending AA, depending on patient characteristics. They suggest that the underlying aneurysm pathogenesis may also be highly variable; this warrants further investigation.
Expression of periostin in human breast cancer
Authors: Puglisi F , Puppin C , Pegolo E , Andreetta C , Pascoletti G , D’Aurizio F , Pandolfi M , Fasola G , Piga A , Damante G , Di Loreto C
Published: October 2007

Background:

Periostin is a secreted adhesion protein, normally expressed in mesenchime-derived cells. Aberrant expression of the periostin gene in epithelial tumours seems to play a role in angiogenesis and metastases.

Aims:

To investigate periostin expression in a consecutive series of breast carcinomas and correlate it with established biological and prognostic factors.

Methods:

A consecutive series of 206 breast carcinomas was investigated by immunohistochemistry with a specific antiperiostin antibody. Immunohistochemical expression of oestrogen and progesterone receptors, Ki-67 (MIB-1), HER-2/neu, VEGF-A, VEGFR-1 and VEGFR-2 was analysed. Periostin expression was also investigated in MCF-7 and MDA-468 cell lines by immunohistochemistry, western blot and quantitative RT-PCR. Localisation of periostin was investigated in MCF-7 cells by the green fluorescent protein (GFP) approach.

Results:

Periostin was highly expressed in carcinoma cells, but not in normal breast tissues. The pattern of expression was mainly cytoplasmic. However, in 12% of cases a nuclear reactivity was observed. Nuclear periostin significantly correlated with tumour size, and with expression of oestrogen receptor, progesterone receptor, VEGF-A, VEGFR-1 and VEGFR-2. A nuclear localisation of periostin was also observed in MCF-7 and MDA-468 cell lines. In MCF-7 cells the nuclear localisation of periostin was also shown by transfection of a vector expressing a GFP-periostin chimeric protein.

Conclusions:

Results indicate that the aberrant gene expression of periostin in breast cancer cells is associated with an abnormal nuclear localisation of the protein. The nuclear localisation of periostin in breast cancer may induce significant biological effects.
RESONANCES AND SPECTRAL SHIFT FUNCTION FOR THE SEMI-CLASSICAL DIRAC OPERATOR
Authors: KHOCHMAN ABDALLAH
Published: October 2007

We consider the selfadjoint operator H = H0+ V, where H0is the free semi-classical Dirac operator on ℝ3. We suppose that the smooth matrix-valued potential V = O(〈x〉-δ), δ > 0, has an analytic continuation in a complex sector outside a compact. We define the resonances as the eigenvalues of the non-selfadjoint operator obtained from the Dirac operator H by complex distortions of ℝ3. We establish an upper bound O(h-3) for the number of resonances in any compact domain. For δ > 3, a representation of the derivative of the spectral shift function ξ(λ,h) related to the semi-classical resonances of H and a local trace formula are obtained. In particular, if V is an electro-magnetic potential, we deduce a Weyl-type asymptotics of the spectral shift function. As a by-product, we obtain an upper bound O(h-2) for the number of resonances close to non-critical energy levels in domains of width h and a Breit–Wigner approximation formula for the derivative of the spectral shift function.
UPPER BOUND ON THE MASS SCALE OF SUPERPARTNERS IN MINIMAL N = 2 SUPERSYMMETRY
Authors: BRAHMACHARI BISWAJOY
Published: October 2007

If N = 2 supersymmetry breaks to N = 1 supersymmetry at an intermediate scale m2 and then, later on, N = 1 supersymmetry breaks and produces standard model at a scale m susy such that m2>m susy , renormalization group evolution of three gauge couplings are altered above the scale m2, changing the unification scale and the unified coupling. We show that when we enforce this general condition m2>m susy on the solutions of the renormalization group equations, the condition is translated into an upper bound on the scale m susy . Using presently favored values of α1(mz), α2(mz), α3(mz), we get m susy < 4.5 ×109 GeV for the central value of α3(mZ). When low energy threshold effect is present, this bound gets smeared yet remains generally stable in the 109–1010 GeV range. We also show that if we demand string unification instead of having a unified gauge theory, this constraint can be changed by exotic hypercharge normalizations.
THE EFFECTS ON S, T AND U FROM HIGHER-DIMENSIONAL FERMION REPRESENTATIONS
Authors: ZHANG HONG-HAO , CAO YUE , WANG QING
Published: October 2007

Inspired by a new class of walking technicolor models recently proposed using higher-dimensional technifermions, we consider the oblique corrections from heavy nondegenerate fermions with two classes of higher-dimensional representations of the electroweak gauge group itself. One is chiral SM-like, and the other is vector-like. In both cases, we obtain explicit expressions for S, T, U in terms of the fermion masses. We find that to keep the T parameter ultraviolet-finite, there must be a stringent constraint on the mass nondegeneracy of a heavy fermion multiplet.
APPROXIMATIVE ANALYTICAL SOLUTIONS OF THE DIRAC EQUATION IN SCHWARZSCHILD SPACETIME
Authors: COTĂESCU ION I.
Published: October 2007

Approximative analytic solutions of the Dirac equation in the geometry of Schwarzschild black holes are derived obtaining information about the discrete energy levels and the asymptotic behavior of the energy eigenspinors.
FERMION RESONANCE IN QUANTUM FIELD THEORY
Authors: GONCHAR M. O. , KALOSHIN A. E. , LOMOV V. P.
Published: October 2007

We accurately derive the fermion resonance propagator by means of Dyson summation of the self-energy contribution. It turns out that the relativistic fermion resonance differs essentially from its boson analog.
MAGNETORESISTANCE IN DOUBLE-PEROVSKITE STRUCTURE FOR Sr2FeMoO6
Authors: KOO JE HUAN , KIM JUNG-HYUN , YU DONG GEUN , CHO GUANGSUP
Published: October 2007

We investigate the magnetoresistance in double-perovskite Sr 2 FeMoO 6. In Fe -planes, ferromagnetic phases are obtained via a Kondo lattice model different from conventional ones. In Fe -planes, ferromagnetic states arise by electron–electron interactions mediated by phonon-enhanced spin flips different from bare Kondo spin flips. The appreciable magnetoresistance is mainly contributed by electrons in Fe -planes. The ferrimagnetism observed in the material Sr 2 FeMoO 6 is explained through the antiparallel alignment between the ferromagnetic spin alignments in Fe -planes and those in Mo -planes which are also driven by our theory, and the difference in magnitude of spin in Mo -planes and Fe -planes.
Ecological and hydrological aspects of peat formation
Authors: Moore P. D.
Published: October 2007

Peat formation is dependent upon an imbalance in the energetic relations of an ecosystem such that the total energy fixation by photosynthesis exceeds the total respiration on the part of the plants, animal consumers, detritivores and microbial components of the ecosystem. The imbalance comes about through the impedence of some detritivore and microbial activity as a result of the waterlogging of the environment. A knowledge of hydrological relationships in different types of mire (any freshwater wetland ecosystem in which soil organic matter accumulates) is necessary for the understanding of the rate of formation and the nature of the peat formed.

A hydrological scheme for mire classification is discussed in relation to the type of peat developed from the mire types described, particularly the proportion of inorganic material incorporated into various peatland types. Two major hydrological divisions can be distinguished—those depending entirely upon rainfall for their water intake and those receiving water both by rainfall and overland drainage. The differentiation is of profound importance in terms of the inorganic (loss on ignition; ash) content of the peat, since the rain-based (ombrotrophic) system generally has a far more limited supply of inorganic material than the flow-fed (rheotrophic) one.

One must seek models for coal-forming systems among ombrogenous tropical mires. Elevated peat-forming surfaces equivalent to the temperate raised mires are recorded from tropical areas and some of these bear vegetation whose physiognomy (general form and structure) resembles that of reconstructed coal forests. In these bog forests, peats of low ash content accumulate and such mires may prove to be the closest modern analogy to coalforming systems.
Lycopod succession in coals: an example from the Low Barnsley Seam (Westphalian B), Yorkshire, England
Authors: Bartram K. M.
Published: October 2007

Lycopsid megaspores processed from petrologically defined samples of the Low Barnsley Seam, Westphalian B, Upper Carboniferous have vertical distributions arranged in repeated successions of phases. A total of six phases was distinguished producing a more detailed pattern of succession than has previously been identified using miospores. Two important phases were recognized for the first time, designated: Phase 0, characterized by the species
Cystosporites verrucosus
Dijkstra,
Lagenicula horrida
Zerndt,
Pseudovalvisisporites nigrozonalis
(Stach & Zerndt) Lachkar and
Cystosporites giganteus
(Zerndt) Schopf, interpreted as a colonizing assemblage, and Phase 2, characterized by the species
Triangulatisporites tertius
Potonié & Kremp and
Valvisisporites auritus
(Zerndt) Potonié & Kremp which is considered to represent an association of non-arborescent lycopods.

Phases are broadly related to petrographic type(s) but changes in phases and petrography are not necessarily coincident. Phasal changes of the kind described are believed to result from the formation of a raised bog.
Gondwana coal basins of Australia and South Africa: tectonic setting, depositional systems and resources
Authors: Hobday D. K.
Published: October 2007

Upper Carboniferous and Permian coals of eastern Australia (Bowen, Sydney, Cooper, Galilee and satellite basins) and southern Africa (Karoo Basin) resemble one another in their general composition and associated clastic facies. The Australian examples, however, show more petrographic and geometric variability than their southern African Gondwana counterparts.

Critical controls on the distribution and quality of coal in both regions appear to have been (1) a near-polar location with accompanying periglacial conditions, (2) Permian through early Triassic warming independent of any significant change in palaeolatitude, (3) associated floral changes from tundra vegetation to swamps and deciduous
Glossopteris
forests, (4) variable subsidence and sedimentation rates in foredeep, rift, and epicratonic basin settings, (5) local palaeotopographic effects, (6) eustatically induced changes in base level and marine transgression, and (7) a range of depositional systems from proximal conglomeratic alluvial fans through fluvial, delta-plain, lake-margin, back-barrier, and blanket peat mires in sediment-starved basins.

In most cases, palaeotopography and depositional environment were the most important factors in determining coal seam geometry, and had considerable influence on coal quality, specifically its maceral content. Most of the commercial seams are contained in fluvial and delta-plain sequences, with thick, dip-elongate interchannel seams and really extensive coals typically overlying abandoned delta lobes. However, some important seams are juxtaposed with conglomerates of wet alluvial-fan origin or are associated with quartzose barrier sandstones; others originated in clastic-starved systems bordering shallow lakes or in blanket swamps that received moisture from groundwater discharge or direct rainfall.

Some seams display characteristics that were primarily controlled by other more regional factors such as rapid tectonic subsidence, changes in groundwater regime, or gradual marine transgression. While influencing the thickness and areal extent of seams, these factors were even more important in determining microlithotypes, maceral content, and inorganic composition of the coals.

Not only is coal mining crucial to the economies of both Australia and S Africa, with further expansion likely in the coming decades, but coal and dispersed coal particles have generated billions of barrels of commercial oil reserves along with large volumes of gas. Australian petroleum reserves are predominantly of land-plant origin, and source-reservoir relationships provide important analogues for exploring other non-marine basins.
Hardware/software tradeoffs
Authors: Randell Brian
Published: October 2007

Hardware and software are logically equivalent. Any operation performed by software can also be built directly into the hardware and any instruction executed by the hardware can also be simulated in software. The decision to put certain features in hardware and others in software is based on such factors as cost, speed, reliability and frequency of change. There are no hard and fast rules to the effect that X must go into the hardware and Y must be programmed explicitly. Designers with different goals may, and often do, make different decisions... the boundary between hardware and software is arbitrary and constantly changing. Today's software is tomorrow's hardware, and vice versa. [1]
Innovative architectures and commercial computers
Authors: Kavi Krishna M.
Published: October 2007

The session was held on May 4, 1981 in Chicago at NCC 1981. The panelists were Harvey Cragon, Pat Goldberg, Dave Patterson, Justin Rattner, Dean Earnest and Peter Denning. Krishna Kavi was the moderator. A complete report of the session is available and can be obtained by writing to the Computer Science Department, P. O. Box 44330, U.S.L., Lafayette, LA 70504.
T Cells and NKT Cells in the Pathogenesis of Asthma
Authors: Meyer Everett H. , DeKruyff Rosemarie H. , Umetsu Dale T.
Published: October 2007

Asthma is an immunological disease with multiple inflammatory and clinical phenotypes, characterized by symptoms of wheezing, shortness of breath, and coughing due to airway hyperreactivity (AHR) and reversible airway obstruction. In allergic asthma, the most common form of asthma, airway inflammation is mediated by adaptive immune recognition of protein allergens by Th2 cells, resulting in airway eosinophilia. However, in other forms of asthma, inflammation is associated with immune responses to respiratory infections and airway neutrophilia. A central feature common to all forms of asthma is AHR, the heightened responsiveness of the airways to nonspecific stimuli. AHR has been shown recently in animal models of asthma to require the presence of CD1d-restricted, invariant T cell receptor-positive, natural killer T (iNKT) cells. Although allergen-specific Th2 cells and iNKT cells have many phenotypic similarities (e.g., expression of CD4 and production of Th2 cytokines), they have complementary activities, such as production of Th2 cytokines under different conditions, differential sensitivity to corticosteroids, and responsiveness to different classes of antigen (proteins versus glycolipids). We hypothesize that Th2 cells and iNKT cells interact synergistically to induce asthma but that different forms of asthma result from distinct roles of CD4+iNKT cells versus Th2 cells.
Bacterial and Fungal Biofilm Infections
Authors: Lynch A. Simon , Robertson Gregory T.
Published: October 2007

Biofilms are communal structures of microorganisms encased in an exopolymeric coat that form on both natural and abiotic surfaces and have been associated with a variety of persistent infections that respond poorly to conventional antibiotic chemotherapy. Biofilm infections of certain indwelling medical devices by common pathogens such as staphylococci are not only associated with increased morbidity and mortality but are also significant contributors to the emergence and dissemination of antibiotic resistance traits in the nosocomial setting. Current treatment paradigms for biofilm-associated infections of semipermanent indwelling devices typically involve surgical replacement of the device combined with long-term antibiotic therapy and incur high health care costs. This review summarizes the existing data relating to the nature, prevalence, and treatment of biofilm-associated infections and highlights experimental approaches and therapies that are being pursued toward more effective treatments.
Preeclampsia and Angiogenic Imbalance
Authors: Maynard Sharon , Epstein Franklin H. , Karumanchi S. Ananth
Published: October 2007

Preeclampsia is a systemic syndrome of pregnancy that originates in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of preeclampsia was largely unknown, but recent work suggests a key role for altered expression of placental antiangiogenic factors. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These antiangiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and the role of angiogenic proteins in early placental vascular development is just beginning to be explored. These discoveries have exciting clinical implications and are likely to transform the detection and treatment of preeclampsia in the future.
The Role of Cellular Accumulation in Determining Sensitivity to Platinum-Based Chemotherapy
Authors: Hall Matthew D. , Okabe Mitsunori , Shen Ding-Wu , Liang Xing-Jie , Gottesman Michael M.
Published: October 2007

The platinum (Pt) drugs cisplatin and carboplatin are heavily employed in chemotherapy regimens; however, similar to other classes of drugs, a number of intrinsic and acquired resistance mechanisms hamper their effectiveness. The method by which Pt drugs enter cells has traditionally been attributed to simple passive diffusion. However, recent evidence suggests a number of active uptake and efflux mechanisms are at play, and altered regulation of these transporters is responsible for the reduced accumulation of drug in resistant cells. This review suggests a model that helps reconcile the disparate literature by describing multiple pathways for Pt-containing drugs into and out of the cell.
Biomarkers of Acute Kidney Injury
Authors: Vaidya Vishal S. , Ferguson Michael A. , Bonventre Joseph V.
Published: October 2007

Acute kidney injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant kidney injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.
Understanding Protein Evolution: From Protein Physics to Darwinian Selection
Authors: Zeldovich Konstantin B. , Shakhnovich Eugene I.
Published: October 2007

Efforts in whole-genome sequencing and structural proteomics start to provide a global view of the protein universe, the set of existing protein structures and sequences. However, approaches based on the selection of individual sequences have not been entirely successful at the quantitative description of the distribution of structures and sequences in the protein universe because evolutionary pressure acts on the entire organism, rather than on a particular molecule. In parallel to this line of study, studies in population genetics and phenomenological molecular evolution established a mathematical framework to describe the changes in genome sequences in populations of organisms over time. Here, we review both microscopic (physics-based) and macroscopic (organism-level) models of protein-sequence evolution and demonstrate that bridging the two scales provides the most complete description of the protein universe starting from clearly defined, testable, and physiologically relevant assumptions.
Gastrointestinal Satiety Signals
Authors: Chaudhri Owais B. , Salem Victoria , Murphy Kevin G. , Bloom Stephen R.
Published: October 2007

The increasing prevalence of obesity worldwide has imparted renewed impetus to the study of the mechanisms of appetite regulation. Digestion and nutrient absorption take place in the gastrointestinal (GI) tract, whereas food intake is controlled by neuronal circuits in the central nervous system. The need for gut-brain cross talk is therefore clear. It is now recognized that hormones released into the circulation from the GI tract in response to nutritional stimuli form a key component of this gut-brain axis. Peptides such as glucagon-like peptide-1, oxyntomodulin, pancreatic polypeptide, and peptide YY3–36reduce food intake in both animal models and in humans. Physiologically, such peptides are thought to act as satiety signals and meal terminators. Here, we review the current state of the field of the effects of gut hormone action on appetite control.
Mechanisms of Leptin Action and Leptin Resistance
Authors: Myers Martin G. , Cowley Michael A. , Münzberg Heike
Published: October 2007

The adipose tissue–derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr985 on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity. Several unique features of the arcuate nucleus of the hypothalamus may contribute to the severity of cellular leptin resistance in this region. Other mechanisms that govern feeding behavior and food reward may also underlie the inception of obesity.
Human Abilities: Emotional Intelligence
Authors: Mayer John D. , Roberts Richard D. , Barsade Sigal G.
Published: October 2007

Emotional intelligence (EI) involves the ability to carry out accurate reasoning about emotions and the ability to use emotions and emotional knowledge to enhance thought. We discuss the origins of the EI concept, define EI, and describe the scope of the field today. We review three approaches taken to date from both a theoretical and methodological perspective. We find that Specific-Ability and Integrative-Model approaches adequately conceptualize and measure EI. Pivotal in this review are those studies that address the relation between EI measures and meaningful criteria including social outcomes, performance, and psychological and physical well-being. The Discussion section is followed by a list of summary points and recommended issues for future research.
Sample Size Planning for Statistical Power and Accuracy in Parameter Estimation
Authors: Maxwell Scott E. , Kelley Ken , Rausch Joseph R.
Published: October 2007

This review examines recent advances in sample size planning, not only from the perspective of an individual researcher, but also with regard to the goal of developing cumulative knowledge. Psychologists have traditionally thought of sample size planning in terms of power analysis. Although we review recent advances in power analysis, our main focus is the desirability of achieving accurate parameter estimates, either instead of or in addition to obtaining sufficient power. Accuracy in parameter estimation (AIPE) has taken on increasing importance in light of recent emphasis on effect size estimation and formation of confidence intervals. The review provides an overview of the logic behind sample size planning for AIPE and summarizes recent advances in implementing this approach in designs commonly used in psychological research.
Adiponectin suppresses IκB kinase activation induced by tumor necrosis factor-α or high glucose in endothelial cells: role of cAMP and AMP kinase signaling
Authors: Wu Xiangdong , Mahadev Kalyankar , Fuchsel Lauren , Ouedraogo Raogo , Xu Shi-qiong , Goldstein Barry J.
Published: October 2007

Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-α (TNFα) and high glucose, activate IκB kinase (IKK)β and reduce the abundance of its substrate, inhibitor of κB (IκB)α, leading to nuclear translocation of the transcription factor NF-κB and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKKβ by either TNFα or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of IκBα protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKKβ activity, whereas both pathways were comparably active in suppressing the TNFα-induced increase in IKKβ. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNFα- and high glucose-mediated IKKβ activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin.
STAT5 mediates PAF-induced NADPH oxidase NOX5-S expression in Barrett's esophageal adenocarcinoma cells
Authors: Si Jin , Behar Jose , Wands Jack , Beer David G. , Lambeth David , Eugene Chin Y. , Cao Weibiao
Published: October 2007

We have shown that NADPH oxidase NOX5-S is overexpressed in Barrett's esophageal adenocarcinoma (EA) cells and may contribute to the progression from Barrett's esophagus (BE) to EA presumably by increasing cell proliferation and decreasing apoptosis (Fu X, Beer DG, Behar J, Wands J, Lambeth D, Cao W. J Biol Chem 281: 20368–20382, 2006). The mechanism(s) of NOX5-S overexpression in EA, however, is not fully understood. In SEG1 EA cells we found that acid treatment significantly increased platelet-activating factor (PAF) production, which in turn markedly increased NOX5-S expression and hydrogen peroxide (H2O2) production. Knockdown of NOX5-S by NOX5-S small interfering RNA (siRNA) blocked PAF-dependent H2O2production. PAF-dependent induction of NOX5-S expression and H2O2production were significantly decreased by the MAPK kinase 1 inhibitor PD-98059, by the cytosolic phospholipase A2(cPLA2) inhibitor AACOCF3, and by STAT5 downregulation with STAT5 siRNA. PAF significantly increased the phosphorylation of ERK1/2 MAPK, cPLA2, and STAT5. Using inhibitors, we demonstrated that PAF-induced STAT5 phosphorylation depends on activation of ERK1/2 MAPK and cPLA2, whereas PAF-induced cPLA2phosphorylation was associated with activation of ERK1/2 MAPK. Given that STAT5 bound to the c-sis-inducible element (TTCTGGTAA) of the NOX5-S promoter, overexpression of STAT5 significantly increased NOX5-S promoter activity. We conclude that acid-induced NOX5-S expression and H2O2production is mediated in part by production of PAF in SEG1 EA cells, and that PAF-induced increase in NOX5-S expression depends on sequential activation of ERK MAP kinases, cPLA2, and STAT5 in these cells.
Role of NKT cells in the digestive system. IV. The role of canonical natural killer T cells in mucosal immunity and inflammation
Authors: Wingender Gerhard , Kronenberg Mitchell
Published: October 2007

Lymphocytes that combine features of T cells and natural killer (NK) cells are named natural killer T (NKT) cells. The majority of NKT cells in mice bear highly conserved invariant Vα chains, and to date two populations of such canonical NKT cells are known in mice: those that express Vα14 and those that express Vα7.2. Both populations are selected by nonpolymorphic major histocompatibility complex class I-like antigen-presenting molecules expressed by hematopoietic cells in the thymus: CD1d for Vα14-expressing NKT cells and MR1 for those cells expressing Vα7.2. The more intensely studied Vα14 NKT cells have been implicated in diverse immune reactions, including immune regulation and inflammation in the intestine; the Vα7.2 expressing cells are most frequently found in the lamina propria. In humans, populations of canonical NKT cells are found to be highly similar in terms of the expression of homologous, invariant T cell antigen-receptor α-chains, specificity, and function, although their frequency differs from those in the mouse. In this review, we will focus on the role of both of these canonical NKT cell populations in the mucosal tissues of the intestine.
Exercise enhances myocardial ischemic tolerance via an opioid receptor-dependent mechanism
Authors: Dickson Eric W. , Hogrefe Christopher P. , Ludwig Paula S. , Ackermann Laynez W. , Stoll Lynn L. , Denning Gerene M.
Published: October 2007

Exercise increases serum opioid levels and improves cardiovascular health. Here we tested the hypothesis that opioids contribute to the acute cardioprotective effects of exercise using a rat model of exercise-induced cardioprotection. For the standard protocol, rats were randomized to 4 days of treadmill training and 1 day of vigorous exercise ( day 5), or to a sham exercise control group. On day 6, animals were killed, and global myocardial ischemic tolerance was assessed on a modified Langendorff apparatus. Twenty minutes of ischemia followed by 3 h of reperfusion resulted in a mean infarct size of 42 ± 4% in hearts from sham exercise controls and 21 ± 3% ( P < 0.001) in the exercised group. The cardioprotective effects of exercise were gone by 5 days after the final exercise period. To determine the role of opioid receptors in exercise-induced cardioprotection, rats were exercised according to the standard protocol; however, just before exercise on days 4 and 5, rats were injected subcutaneously with 10 mg/kg of the opioid receptor antagonist naltrexone. Similar injections were performed in the sham exercise control group. Naltrexone had no significant effect on baseline myocardial ischemic tolerance in controls (infarct size 43 ± 4%). In contrast, naltrexone treatment completely blocked the cardioprotective effect of exercise (infarct size 40 ± 5%). Exercise was also associated with an early increase in myocardial mRNA levels for several opioid system genes and with sustained changes in a number of genes that regulate inflammation and apoptosis. These findings demonstrate that the acute cardioprotective effects of exercise are mediated, at least in part, through opioid receptor-dependent mechanisms that may include changes in gene expression.
Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues
Authors: Clusin William T.
Published: October 2007

Alternation of cardiac action potential duration (APD) from beat to beat and concurrent alternation of the amplitude of the calcium transient are regarded as important arrhythmia mechanisms. These phenomena are causally interrelated and can be reliably evoked by an increase in beat frequency or by ischemia. The first part of this historical review deals with the physiology of APD alternans. Sections recounting the evolution of knowledge about calcium-activated ion currents and calcium transient alternans are interspersed among sections describing the growth of the so-called “restitution hypothesis,” which involves time-dependent recovery of potassium channels (including their passage through pre-open states) as a function of diastolic interval. Major developments are generally in chronological order, but it is necessary to move back and forth between the two theories to respect the overall time line, which runs from about l965 to the present. The concluding two sections deal with the pathophysiology of calcium transient and APD alternans during ischemia, which may be the basis for out-of-hospital cardiac arrest during the initial stages of acute myocardial infarction.
Diagnostic Value of Serological Assays in Pediatric Inflammatory Bowel Disorders
Authors: Mainardi Elsa , Villanacci Vincenzo , Bassotti Gabrio , Liserre Barbara , Rossi Elisa , Incardona Paolo , Falchetti Diego , Tonegatti Luca , Montanelli Alessandro , Barabino Arrigo , Coccia Cristina , Gambini Claudio
Published: October 2007

Background: Pediatric studies reported that the combined use of the anti-neutrophil cytoplasm autoantibodies (ANCA) and the anti-Saccharomyces cerevisiae mannan antibodies (ASCA) may be a specific useful noninvasive test in the diagnosis of inflammatory bowel diseases (IBD). Aims: To evaluate the diagnostic accuracy of ANCA and ASCA in children with suspected IBD, and to see whether different commercially available assays (indirect immunofluorescence vs. ELISA) agree well enough in terms of analytical performance. Patients and Methods: Sixty-nine children (30 males, 39 females, age range 2–18 years) with suspicion of IBD entered the study. Before colonoscopy, a blood sample was also drawn to assess ASCA and ANCA. Results: A diagnosis of IBD was established in 47 patients; the remainder had infective or other causes of colitis. For ulcerative colitis, the association ASCA–/ANCA+ had 70% sensitivity and 86% specificity, with a positive predictive value of 82%. The association ASCA+/ANCA– had 86% sensitivity and 93% specificity for Crohn’s disease, with a positive predictive value of 75%. Conclusion: Although more experience is needed to state the diagnostic power of serologic assay, determination of ANCA and ASCA in IBD children may help both in distinguish these conditions from other entitiesand ulcerative colitis from Crohn’s disease, particularly in doubtful cases.
Combinations of DSM-IV-TR Criteria Sets for Bipolar Disorders
Authors: Lieberman Daniel Z. , Peele Roger , Razavi Maryam
Published: October 2007

Background: DSM-IV-TR is the standard for making psychiatric diagnoses in many countries. The diagnostic categorization of DSM-IV-TR is valued for its reliability, however it is well accepted that patients with the same diagnosis demonstrate substantial heterogeneity. In order to quantitatively characterize the degree of possible heterogeneity that can exist, combinatorial mathematics was used to calculate the number of possible ways to satisfy symptom criteria for the diagnosis of bipolar disorder as an example of this problem. Sampling and Methods: The formula n!/(r!(n – r)!), which calculates the number of different ways of choosing an unordered number of items without repetition from a larger set, was used to calculate the number of combinations which meet the criteria for the core episodes of bipolar disorder and the specifiers. Results: The number of possible combinations for the core episodes ranged from 163 for a manic episode to 37,001 for a mixed episode. When the full collection of specifiers that DSM-IV-TR applies to bipolar disorder was used, the number of combinations was over 5 billion. Conclusions: The precision of medical communication about bipolar disorder is called into question by the billions of different ways that the criteria for this diagnosis can be met. As DSM-V is developed, the possible combinations for each diagnostic criterion should be calculated, and the effect this number has on clinical communication should be considered.
Dihydropyrimidine Dehydrogenase Activity during Long-Term Adjuvant Treatment with Oral Uracil and Tegafur for Colorectal Cancer
Authors: Sadahiro Sotaro , Suzuki Toshiyuki , Maeda Yuji , Ishikawa Kenji , Tanaka Yoichi , Yasuda Seiei , Kamijo Akemi , Makuuchi Hiroyasu , Murayama Chieko
Published: October 2007

Background: Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme for the degradation of 5-fluorouracil. The effect of long-term treatment with oral fluoropyrimidines on DPD activity has not been investigated. This study was conducted to examine changes in DPD activity in peripheral mononuclear cells (PMNC) during long-term treatment with oral uracil and tegafur (UFT) for colorectal cancer. Methods: UFT was administered for 5 consecutive days and not administered the next 2 days for 6 months after surgery. PMNC-DPD activity was measured before and 1, 2, 4 and 6 months after starting UFT administration. Results: In 70 eligible patients, there were no significant variations of PMNC-DPD activity during postoperative administration of UFT for 6 months. Grade 2 or higher adverse events were observed in significantly more patients with low DPD than with high DPD activity (p = 0.018). Conclusion: There were no significant variations of PMNC-DPD activity during the postoperative administration of UFT for 6 months. Low PMNC-DPD activity before UFT treatment was considered to be a predicting factor for toxicity.
A global assay of haemostasis which uses recombinant tissue factor and tissue-type plasminogen activator to measure the rate of fibrin formation and fibrin degradation in plasma
Authors: Zhu Kun , Skeppholm Mika , Vedin Jenny , Svensson Jan , Egberg Nils , Blombäck Margareta , He Shu
Published: October 2007

The global assay of Overall Haemostasis Potential we previously described has been refined. The coagulation cascade in plateletpoor plasma is triggered by adding a minimal dose of recombinant tissue factor together with purified phospholipids and calcium; fibrinolysis is initiated by adding recombinant tissue type-plasminogen activator in a concentration similar to what can be obtained during thrombolysis. Numerical differentials of optical densities reflecting rates of fibrin formation and degradation are calculated by a new software, and the Coagulation Profile (Cp) and the Fibrinolysis Profile (Fp) are determined. The combined effect of these counteractive systems is expressed as a ratio of Cp to Fp, called the Overall Haemostasis Index. Commercially available coagulant-deficient patient plasma samples and plasma with various amounts of added PAI-1 are examined; changes of fibrin turbidity demonstrate that this assay can determine Cp and Fp in a physiologically relevant way. Increased Cp and decreased Fp in prothrombotic patients, as well as expected effects of heparin or a thrombin inhibitor on Cp and Fp, suggest that our method can detect hypercoagulability and assist in monitoring antithrombotic treatment. Ongoing studies will show whether this simple assay can be of value in clinical routine.