bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of Law to the Childhood Obesity Epidemic
Authors: Alderman Jess , Smith Jason A. , Fried Ellen J. , Daynard Richard A.
Published: March 2007

Childhood obesity is a national public health problem. Regardless of gender, race, socioeconomic status, or geographic location, children are “gaining weight to a dangerous degree and at an alarming rate.” Since 1980, the number of overweight children has doubled; among adolescents the number has almost tripled. Today, among children who are more than six years old, about nine million are obese. Many of the factors that contribute to obesity occur at a societal level, prompting the Surgeon General to conclude that preventing obesity is a “community responsibility.”

Childhood obesity is, in many important respects, a result of legal policy. Law shapes the situational and environmental influences that drive both dietary intake and physical activity. Government, public health advocates, and the food industry all use the law to alter these influences in furtherance of their respective goals. Public interest advocates attempt to persuade government and corporations to act in the interest of public health while the industry focuses on profit.
Local Venues for Change: Legal Strategies for Healthy Environments
Authors: Ashe Marice , Feldstein Lisa M. , Graff Samantha , Kline Randolph , Pinkas Debora , Zellers Leslie
Published: March 2007

Mounting evidence documents the extraordinary toll on human health resulting from the consumption of unhealthy food products and physical inactivity. Diseases related to poor nutrition – such as diabetes, heart disease, stroke, and some cancers – are among the leading causes of disability and death in the United States. Poor diet and lack of exercise come second only to tobacco use in actual causes of preventable death in this country. It is estimated that 6% of all adult health care, 7% of Medicare, and 11% of Medicaid expenditures are attributable to obesity. According to the Centers for Disease Control and Prevention, the direct medical cost associated with physical inactivity was nearly $76.6 billion in 2000.

In response to America's growing obesity problem, local policymakers have been looking for legal strategies to adopt in their communities to encourage healthful behaviors. Taking the lead from the successful tobacco control movement, nutrition advocates are seeking strategies to “denormalize” unhealthy behaviors, rather than pursuing education-based approaches that encourage individuals to change their own personal behavior.
Thermal and Storage Stability of Nutraceuticals in a Milk Beverage Dietary Supplement
Authors: Uzzan M. , Nechrebeki J. , Labuza T.P.
Published: March 2007

ABSTRACT: Under the Dietary Supplement Health and Education Act (DSHEA), fluid skim milk can be used to serve as a vehicle to deliver certain metabolites (nutraceuticals or new dietary ingredients), which provide health benefits as related to aging problems for those over 55. This opens a new avenue for an increase in milk consumption and may replace taking pills. Milk beverages enriched with various nutraceutical ingredients (soy isoflavones, glucosamine, chondroitin sulfate, creatine, and lactoferrin) were thermally processed at different combinations of temperatures from 72 to 138 °C for different holding times using a Microthermics pilot plant thermal processing unit and were incubated at refrigeration, room, or elevated storage temperatures. Residual concentrations of the active compounds were measured by high performance liquid chromatography or by immunodifusion (for lactoferrin) and degradation kinetics were determined. Results showed a very good stability of isoflavones and chondroitin sulfate in the milk environment while glucosamine, lactoferrin, and creatin showed only limited stability at either processing or storage. Glucosamine destabilized the milk protein system at boiling temperature or higher, which caused drastic precipitation in the heat exchangers. Nevertheless, all the tested nutraceutical compounds can be used to design milk beverage dietary supplements but an overrun of over 25% may be required for some of them.
The Effect of Honey Compared to Sucrose, Mixed Sugars, and a Sugar‐Free Diet on Weight Gain in Young Rats
Authors: Chepulis L.M.
Published: March 2007

ABSTRACT:  To determine whether honey, sucrose, and mixed sugars as in honey have different effects on weight gain, 40 6‐wk‐old Sprague‐Dawley rats were fed a powdered diet that was either sugar free or contained 8% sucrose, 8% mixed sugars as in honey, or 10% honey freely for 6 wk. Weight gain and food intake were assessed weekly, and at completion of the study blood samples were removed for measurement of blood sugar (HbA1c) and a fasting lipid profile. The animals were then minced and total percentage body fat and protein measured. Overall percentage weight gain was significantly lower in honey‐fed rats than those fed sucrose or mixed sugars, despite a similar food intake. Weight gains were comparable for rats fed honey and a sugar free diet although food intake was significantly higher in honey‐fed rats. HbA1c and triglyceride levels were significantly higher in all sugar treatments compared with rats fed a sugar free diet, but no other differences in lipid profiles were reported. No differences in percentage body fat or protein levels were reported.
Connecting Distributions with Power Tails on the Real Line, the Half Line and the Interval
Authors: Jones M.C.
Published: March 2007

Univariate continuous distributions have three possible types of support exemplified by: the whole real line, , the semi‐finite intervaland the bounded interval (0,1). This paper is about connecting distributions on these supports via ‘natural’ simple transformations in such a way that tail properties are preserved. In particular, this work is focussed on the case where the tails (at ±∞) of densities are heavy, decreasing as a (negative) power of their argument; connections are then especially elegant. At boundaries (0 and 1), densities behave conformably with a directly related dependence on power of argument. The transformation from (0,1) tois the standard odds transformation. The transformation fromtois a novel identity‐minus‐reciprocal transformation. The main points of contact with existing distributions are with the transformations involved in the Birnbaum–Saunders distribution and, especially, the Johnson family of distributions. Relationships between various other existing and newly proposed distributions are explored.
Proton modulation of ion channels in isolated horizontal cells of the goldfish retina
Authors: Jonz Michael G. , Barnes Steven
Published: March 2007

Transient changes in extracellular pH (pHo) occur in the retina and may have profound effects on neurotransmission and visual processing due to the pH sensitivity of ion channels. The present study characterized the effects of acidification on the activity of membrane ion channels in isolated horizontal cells (HCs) of the goldfish retina using whole‐cell patch‐clamp recording. Currents recorded from HCs were characterized by prominent inward rectification at potentials negative to −80 mV, a negative slope conductance between −70 and −40 mV, a sustained inward current, and outward rectification positive to 40 mV. Inward currents were identified as those of inward rectifier K+ (Kir) channels and Ca2+ channels by their sensitivity to 10 mm Cs+ or 20 μm Cd2+, respectively. Both of these currents were reduced when pHo decreased from 7.8 to 6.8. Glutamate (1 mm)‐activated currents were also identified, as were hemichannel currents that were enhanced by removal of extracellular Ca2+ and application of 1 mm quinidine. Both glutamate‐activated and hemichannel currents were suppressed by a similar reduction of pHo. When all of these H+‐inhibited currents were blocked, a small, sustained inward current at −60 mV increased following a decrease in pHo from 7.8 to 6.8. In addition, slope conductance between −70 and −20 mV increased during this acidification. Suppression of this H+‐activated current by removal of extracellular Na+, and an extrapolated Erev near ENa, indicated that this current was carried predominantly by Na+ ions.
Single‐channel study of the spasmodic mutation α1A52S in recombinant rat glycine receptors
Authors: Plested Andrew J. R. , Groot‐Kormelink Paul J. , Colquhoun David , Sivilotti Lucia G.
Published: March 2007

Inherited defects in glycine receptors lead to hyperekplexia, or startle disease. A mutant mouse, spasmodic, that has a startle phenotype, has a point mutation (A52S) in the glycine receptor α1 subunit. This mutation reduces the sensitivity of the receptor to glycine, but the mechanism by which this occurs is not known. We investigated the properties of A52S recombinant receptors by cell‐attached patch‐clamp recording of single‐channel currents elicited by 30–10000 μm glycine. We used heteromeric receptors, which resemble those found at adult inhibitory synapses. Activation mechanisms were fitted directly to single channel data using the HJCFIT method, which includes an exact correction for missed events. In common with wild‐type receptors, only mechanisms with three binding sites and extra shut states could describe the observations. The most physically plausible of these, the ‘flip’ mechanism, suggests that preopening isomerization to the flipped conformation that follows binding is less favoured in mutant than in wild‐type receptors, and, especially, that the flipped conformation has a 100‐fold lower affinity for glycine than in wild‐type receptors. In contrast, the efficacy of the gating reaction was similar to that of wild‐type heteromeric receptors. The reduction in affinity for the flipped conformation accounts for the reduction in apparent cooperativity seen in the mutant receptor (without having to postulate interaction between the binding sites) and it accounts for the increased EC50 for responses to glycine that is seen in mutant receptors. This mechanism also predicts accurately the faster decay of synaptic currents that is observed in spasmodic mice.
Developmental changes in potassium currents at the rat calyx of Held presynaptic terminal
Authors: Nakamura Yukihiro , Takahashi Tomoyuki
Published: March 2007

During early postnatal development, the calyx of Held synapse in the auditory brainstem of rodents undergoes a variety of morphological and functional changes. Among ionic channels expressed in the calyx, voltage‐dependent K+ channels regulate transmitter release by repolarizing the nerve terminal. Here we asked whether voltage‐dependent K+ channels in calyceal terminals undergo developmental changes, and whether they contribute to functional maturation of this auditory synapse. From postnatal day (P) 7 to P14, K+ currents became larger and faster in activation kinetics, but did not change any further to P21. Likewise, presynaptic action potentials became shorter in duration from P7 to P14 and remained stable thereafter. The density of presynaptic K+ currents, assessed from excised patch recording and whole‐cell recordings with reduced [K+]i, increased by 2–3‐fold during the second postnatal week. Pharmacological isolation of K+ current subtypes using tetraethylammonium (1 mm) and margatoxin (10 nm) revealed that the density of Kv3 and Kv1 currents underwent a parallel increase, and their activation kinetics became accelerated by 2–3‐fold. In contrast, BK currents, isolated using iberiotoxin (100 nm), showed no significant change during the second postnatal week. Pharmacological block of Kv3 or Kv1 channels at P7 and P14 calyceal terminals indicated that the developmental changes of Kv3 channels contribute to the establishment of reliable action potential generation at high frequency, whereas those of Kv1 channels contribute to stabilizing the nerve terminal. We conclude that developmental changes in K+ currents in the nerve terminal contribute to maturation of high‐fidelity fast synaptic transmission at this auditory relay synapse.
Nitroxyl increases force development in rat cardiac muscle
Authors: Dai Tieying , Tian Ye , Tocchetti Carlo Gabriele , Katori Tatsuo , Murphy Anne M. , Kass David A. , Paolocci Nazareno , Gao Wei Dong
Published: March 2007

Donors of nitroxyl (HNO), the reduced congener of nitric oxide (NO), exert positive cardiac inotropy/lusitropyin vivoandin vitro, due in part to their enhancement of Ca2+cycling into and out of the sarcoplasmic reticulum. Here we tested whether the cardiac action of HNO further involves changes in myofilament–calcium interaction. Intact rat trabeculae from the right ventricle were mounted between a force transducer and a motor arm, superfused with Krebs–Henseleit (K‐H) solution (pH 7.4, room temperature) and loaded iontophoretically with fura‐2 to determine [Ca2+]i. Sarcomere length was set at 2.2–2.3 μm. HNO donated by Angeli's salt (AS; Na2N2O3) dose‐dependently increased both twitch force and [Ca2+]itransients (from 50 to 1000 μm). Force increased more than [Ca2+]itransients, especially at higher doses (332 ± 33%versus221 ± 27%,P< 0.01 at 1000 μm). AS/HNO (250 μm) increased developed force without changing Ca2+transients at any given [Ca2+]o(0.5–2.0 mm). During steady‐state activation, AS/HNO (250 μm) increased maximal Ca2+‐activated force (Fmax, 106.8 ± 4.3versus86.7 ± 4.2 mN mm−2,n= 7–8,P< 0.01) without affecting Ca2+required for 50% activation (Ca50, 0.44 ± 0.04versus0.52 ± 0.04 μm, not significant) or the Hill coefficient (4.75 ± 0.67versus5.02 ± 1.1, not significant). AS/HNO did not alter myofibrillar Mg‐ATPase activity, supporting an effect on the myofilaments themselves. The thiol reducing agent dithiothreitol (DTT, 5.0 mm) both prevented and reversed HNO action, confirming AS/HNO redox sensitivity. Lastly, NO (from DEA/NO) did not mimic AS/HNO cardiac effects. Thus, in addition to reported changes in Ca2+cycling, HNO also acts as a cardiac Ca2+sensitizer, augmenting maximal force without altering actomyosin ATPase activity. This is likely to be due to modulation of myofilament proteins that harbour reactive thiolate groups that are targets of HNO.
Effects of lauric acid on upper gut motility, plasma cholecystokinin and peptide YY, and energy intake are load, but not concentration, dependent in humans
Authors: Feltrin Kate L. , Little Tanya J. , Meyer James H. , Horowitz Michael , Rades Thomas , Wishart Judith , Feinle‐Bisset Christine
Published: March 2007

Animal studies suggest that the effects of fatty acids on gastric emptying and pancreatic secretion are both concentration and load dependent, while their suppressive effect on energy intake is only load dependent. We postulated that, in humans, the modulation of antropyloroduodenal pressure waves, plasma cholecystokinin (CCK) and peptide YY (PYY) concentrations and energy intake by intraduodenal lauric acid, a fatty acid with 12 carbon atoms (‘C12’) would be load, but not concentration, dependent. Two groups of 12 healthy males were each studied on three separate occasions in double‐blind randomized fashion. Antropyloroduodenal pressure waves, plasma CCK and PYY, and appetite perceptions were measured during intraduodenal infusions of C12 at (1) different loads of (i) 0.2, (ii) 0.3 and (iii) 0.4 kcal min−1 (all 56 mm) for 90 min, and (2) different concentrations of (i) 40, (ii) 56 and (iii) 72 mm (all 0.4 kcal min−1) for 60 min. Energy intake at a buffet meal consumed immediately following each infusion was quantified. Suppression of antral and duodenal pressure waves, stimulation of pyloric pressure waves, stimulation of plasma CCK and PYY, and suppression of energy intake, were related to the load of C12 administered (r > 0.65, P < 0.05). In contrast, there were no concentration‐dependent effects of C12 on any of these parameters. In conclusion, in humans, the effects of intraduodenal C12 on antropyloroduodenal motility, plasma CCK and PYY and energy intake appear to be related to load, but not concentration, at least at the loads and concentrations evaluated.
Comment on "Detecting Awareness in the Vegetative State"
Authors: Nachev Parashkev , Husain Masud
Published: March 2007

In a report of a single patient in a persistent vegetative state, Owen
et al
. (Brevia, 8 September 2006, p. 1402) claimed that the presence of task-specific brain activation in response to verbal command implies both covert conscious awareness and a capacity for intention. We argue that neither can be securely inferred from the evidence presented.
Response to Comments on "Detecting Awareness in the Vegetative State"
Authors: Owen Adrian M. , Coleman Martin R. , Boly Melanie , Davis Matthew H. , Laureys Steven , Jolles Dietsje , Pickard John D.
Published: March 2007

Additional data, supported by relevant functional neuroimaging literature, confirm that the “normal” patterns of brain activity reported in a patient who was clinically diagnosed as vegetative could not have occurred “automatically” in the absence of conscious awareness. The most parsimonious explanation remains that this patient was consciously aware despite her diagnosis of vegetative state.
Was There Really an Archean Phosphate Crisis?
Authors: Konhauser Kurt O. , Lalonde Stefan V. , Amskold Larry , Holland Heinrich D.
Published: March 2007

During the Archean, massive amounts of iron were deposited in the form of banded iron formations. It has been suggested that sedimenting particles of ferric oxyhydroxide may have stripped dissolved phosphate from the oceans, causing a reduction in phytoplankton productivity. However, that model does not take into account the high concentration of dissolved silica that was present in seawater at that time. We show experimentally that silica effectively competes with phosphate for sorption sites on ferrihydrite particles. Furthermore, coprecipitation of silica with ferrihydrite reduces particle reactivity toward phosphate. Hence, Archean oceans probably contained considerably more phosphate than previously predicted.
The Focusing of Electron Flow and a Veselago Lens in Graphene
p-n
Junctions
Authors: Cheianov Vadim V. , Fal'ko Vladimir , Altshuler B. L.
Published: March 2007

The focusing of electric current by a single
p-n
junction in graphene is theoretically predicted. Precise focusing may be achieved by fine-tuning the densities of carriers on the
n
- and
p
-sides of the junction to equal values. This finding may be useful for the engineering of electronic lenses and focused beam splitters using gate-controlled
n-p-n
junctions in graphene-based transistors.
CREB-Binding Protein Modulates Repeat Instability in a
Drosophila
Model for PolyQ Disease
Authors: Jung Joonil , Bonini Nancy
Published: March 2007

Although expansion of trinucleotide repeats accounts for over 30 human diseases, mechanisms of repeat instability remain poorly understood. We show that a
Drosophila
model for the CAG/polyglutamine (polyQ) disease spinocerebellar ataxia type 3 recapitulates key features of human CAG-repeat instability, including large repeat changes and strong expansion bias. Instability is dramatically enhanced by transcription and modulated by nuclear excision repair and a regulator of DNA repair adenosine 3′,5′-monophosphate (cAMP) response element–binding protein (CREB)–binding protein—a histone acetyltransferase (HAT) whose decreased activity contributes to polyQ disease. Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability.
A Note About the Ground State of the Hydrogen Molecule
Authors: Turbiner Alexander V. , Guevara Nicolais L.
Published: March 2007

A trial function is presented for the H2 molecule which provides the most accurate (the lowest) Bohr-Oppenheimer ground state energy among few-parametric trial functions (with ≤14 parameters). It includes the electronic correlation term in the form ~ exp (γr12) where γ is a variational parameter.
Raman Spectroscopy of Nanocrystalline Li-Ti-O Spinels and Comparative DFT Calculations on TiyOz and LixTiyOz Clusters
Authors: Jirkovský Jakub , Macounová Kateřina , Dietz Hartmut , Plieth Waldfried , Krtil Petr , Záliš Stanislav
Published: March 2007

Raman spectra of cubic nanocrystalline insertion hosts in Li-Ti-O system were measured for Li1.1Ti1.9O4-δspinels and the corresponding delithiated titanium dioxide material. To interpret the measured data optimized geometries of cubic TiyOzand LixTiyOzwere calculated using the DFT cluster approach for clusters containing up to 23 atoms. The calculated geometries were used to predict the density-of-states (DOS) diagrams and vibrational spectra of the corresponding structures upon harmonic approximation. While the DFT approach reproduces satisfactorily the main structural characteristics of TiyOzclusters, the agreement in the case of LixTiyOzclusters between calculated and real structures is less satisfactory due to the small cluster size. The band gap energies obtained from DOS diagrams represent overestimates of the actual experimental band gap energies measured on cubic Li-Ti-O oxides. The agreement between calculated and measured band gap energy improves with increasing cluster size. Raman spectra calculated under harmonic approximation from the optimized geometries reproduce all important features of the experimental Raman spectra. The agreement of DFT-calculated and experimental Raman spectra improves with increasing size of the cluster.
Ibuprofen does not affect serum electrolyte concentrations after an ultradistance run
Authors: Dumke Charles L , Nieman David C , Oley Kevin , Lind Robert H
Published: March 2007

Objective:To determine the effects of ibuprofen on serum electrolyte concentrations after a 160 km running race.

Methods:Twenty nine subjects (mean (SD) age 47.9 (7.4) years) ingested 600 mg ibuprofen the day before, and 1200 mg ibuprofen during, a 160 km competitive trail running race (approximately every 4 h in 200 mg doses). Twenty five control subjects (mean (SD) age 46.8 (10.3) years) avoided ingestion of ibuprofen before or during the race. Blood was drawn on the day before the race and immediately after the race. Serum biochemical profiles were analysed by a clinical laboratory. Significant effects of treatment and time were determined with a general linear model with repeated measures.

Results:Subjects in the two groups did not differ by age, training volume, race experience, body mass index, body fat, or finishing time (25.8 (3.3) vs 25.6 (3.9) h). Body weight did not change significantly over the race (measured before, mid-race (90 km), and after). Ibuprofen ingestion did not significantly affect any of the serum markers including creatine kinase (p = 0.16). A significant decrease in serum sodium (p = 0.006), potassium (p = 0.001), chloride (p<0.001), calcium (p<0.001), albumin (p<0.001) and globulin (p<0.001) was observed after the race. Increases were seen in creatine kinase (p<0.001), creatinine (p<0.001), blood urea nitrogen (p<0.001), uric acid (p<0.001) and glucose (p<0.001) as the result of the race.

Conclusions:These data suggest that the non-specific cyclo-oxygenase inhibitor, ibuprofen, does not alter serum electrolyte concentrations during ultradistance running. However, the stress of ultradistance running appears to be related to significant changes in certain serum markers.
Bladder cancer incidence and exposure to polycyclic aromatic hydrocarbons among asphalt pavers
Authors: Burstyn Igor , Kromhout Hans , Johansen Christoffer , Langard Sverre , Kauppinen Timo , Shaham Judith , Ferro Gilles , Boffetta Paolo
Published: March 2007

Objectives:To investigate the association between exposures to polycyclic aromatic hydrocarbons (PAH) that arises during asphalt paving, and risk of bladder cancer.

Methods:7298 men included in the historical cohort were first employed between 1913 and 1999 in companies applying asphalt in Denmark, Norway, Finland and Israel. The minimal duration of employment for inclusion in the cohort was two seasons of work. Occupational histories were extracted from personnel files. A follow-up for cancer incidence was conducted through national cancer registries. The authors estimated exposures to benzo(a)pyrene as a marker for 4–6 ring PAH. Exposures were reconstructed by using information about changes in asphalt paving technology in each company over time, the modelled relation between production characteristics and exposure levels, and job histories. Relative risks and associated 95% confidence intervals were estimated using Poisson regression.

Results:48 bladder cancers among asphalt paving workers were detected; of these, 39 cases were exposed at least 15 years before the diagnosis. Cumulative exposure to PAH was not associated with the incidence of bladder cancer. The association with average exposure became stronger when 15-year lag was considered, revealing a twofold increase in relative bladder cancer risk in the two higher exposure categories. There was an indication of exposure-response association with lagged averaged exposure. Risk estimates were adjusted for age, country, duration of employment and calendar period, did not show heterogeneity among countries and did not materially change when re-estimated after excluding non-primary cancers from follow-up. Previously conducted sensitivity analysis indicates that confounding by cigarette smoking is an unlikely explanation for the observed exposure-response trends.

Conclusions:The authors were unable to control for all possible sources of confounding and bias. The results do not allow conclusion on the presence or absence of a causal link between exposures to PAH and risk of bladder cancer among asphalt workers.
Metabolic syndrome in youth: current issues and challenges
Authors: Huang Terry T.-K. , Ball Geoff D.C. , Franks Paul W.
Published: March 2007

The current paper reviews the important issues and challenges facing children and adolescents with the metabolic syndrome (MetS). Studies suggest that the MetS and its risk components may be on the rise in children along with rising rates of obesity; however, further study remains warranted. The topics reviewed encompass the definition of the syndrome, its prevalence, clustering and tracking of metabolic risk factors, the role of physical activity and diet in the development of the MetS, criticisms and utility of the MetS definition, and special considerations needed in the pediatric population. Physical activity and diet may play important roles in the MetS; however, research with precise measurements of activity, diet, and metabolic outcomes is needed. The paper concludes by emphasizing that regardless of one’s position in the ongoing debate about the MetS, the long-term risks attributable to each individual risk component are real. The abnormality of one component should automatically prompt the screening of other components. Among children and adolescents, lifestyle modification should always serve as the frontline strategy. Prevention during childhood is key to the largest possible impact on adult health at the population level.
Regulation of postprandial lipemia: an update on current trends
Authors: Paglialunga Sabina , Cianflone Katherine
Published: March 2007

People spend a large percentage of their waking hours in the postprandial state. Postprandial lipemia is associated with disruptions in lipoprotein metabolism and inflammatory factors, cardiovascular disease, MetS, and diabetes. Commonly, the dietary sources of fat exceed the actual needs and the tissues are faced with the excess, with accumulation of chylomicrons and remnant particles. This review will summarize recent findings in postprandial lipemia research with a focus on human studies. The effects of dietary factors and other meal components on postprandial lipemia leads to the following question: do we need a standardized oral lipid tolerance test (OLTT)? An overview of recent findings on FABP2, MTP, LPL, apoAV, and ASP and the effects of body habitus (sex influence and body size), as well as exercise and weight loss, on postprandial lipemia will be summarized.
Protein-protein interactions and membrane localization of the human organic solute transporter
Authors: Sun An-Qiang , Balasubramaniyan Natarajan , Xu Ke , Liu Chuan Ju , Ponamgi Vijaya M. , Liu Hongguang , Suchy Frederick J.
Published: March 2007

Two proteins that mediate bile acid export from the ileal enterocyte, organic solute transporter (OST)-α and -β, have recently been identified. It is unclear whether these two proteins associate directly and how they interact to mediate transport function and membrane localization. In this study, the protein-protein interactions, transport functions, and membrane localization of human (h)OST-α and -β proteins were examined. The results demonstrated that coexpression of hOST-α and -β in transfected cells resulted in a three- to fivefold increase of the initial rate of taurocholate influx or efflux compared with cells expressing each protein individually and nontransfected cells. Confocal microscopy demonstrated plasma membrane colocalization of hOST-α and -β proteins in cells cotransfected with hOST-α and -β cDNAs. Protein-protein interactions between hOST-α and -β were demonstrated by mammalian two-hybrid and coimmunoprecipitation analyses. Truncation of the amino-terminal 50 amino acid extracellular residues of hOST-α abolished its interaction with hOST-β and led to an intracellular accumulation of the two proteins and to only background levels of taurocholate transport. In contrast, carboxyl-terminal 28 amino acid truncated hOST-α still interacted with hOST-β, and majority of this cytoplasmic tail-truncated protein was expressed on the basolateral membrane when it was stably cotransfected with hOST-β protein in Madin-Darby canine kidney cells. In summary, hOST-α and -β proteins are physically associated. The intracellular carboxyl-terminal domain of hOST-α is not essential for this interaction with hOST-β. The extracellular amino-terminal fragment of hOST-α may contain important information for the assembly of the heterodimer and trafficking to the plasma membrane.
Amiloride-sensitive sodium absorption is different in vertebrates and invertebrates
Authors: Sobczak Katja , Willing Anne , Kusche Kristina , Bangel Nadine , Weber Wolf-Michael
Published: March 2007

Amiloride-sensitive Na+absorption is a well-described feature of numerous transporting epithelia in vertebrates. Yet, very little is known about this important physiological process regarding invertebrates. In the present paper, we compare vertebrate Na+absorption mediated by the amiloride-sensitive epithelial Na+channel (ENaC) and its invertebrate counterpart. We used the dorsal skin of the annelid Hirudo medicinalis as a model for the Na+absorption of invertebrate epithelia. In applying electrophysiological, molecular, and biochemical techniques we found striking functional and structural differences between vertebrate and invertebrate amiloride-sensitive Na+absorption. Using modified Ussing chambers, we analyzed the influence of different known blockers and effectors of vertebrate ENaC on leech epithelial Na+absorption. We demonstrate that the serine protease trypsin had no effect on the Na+transport across leech integument, while it strongly activates vertebrate ENaC. While protons, and the divalent cations Ni2+and Zn2+stimulate vertebrate ENaC, amiloride-sensitive Na+currents in leech integument were substantially reduced. For molecular studies, we constructed a cDNA library of Hirudo medicinalis and screened it with specific ENaC antibodies. We performed numerous PCR approaches using a vast number of different degenerated and specific ENaC primers to identify ENaC-like structures. Yet, both strategies did not reveal any ENaC-like sequence in leech integument. From these data we conclude that amiloride-sensitive Na+absorption in leech skin is not mediated by an ENaC-like Na+channel but by a still unknown invertebrate member of the ENaC/DEG family that we termed lENaTP (leech epithelial Na+transporting protein).
Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs
Authors: de Paula Patricia M. , Tolstykh Gleb , Mifflin Steve
Published: March 2007

Chronic exposure to intermittent hypoxia (CIH) has been used in animals to mimic the arterial hypoxemia that accompanies sleep apnea. Humans with sleep apnea and animals exposed to CIH have elevated blood pressures and augmented sympathetic nervous system responses to acute exposures to hypoxia. To test the hypothesis that exposure to CIH alters neurons within the nucleus of the solitary tract (NTS) that integrate arterial chemoreceptor afferent inputs, we measured whole cell currents induced by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors in enzymatically dispersed NTS neurons from normoxic (NORM) and CIH-exposed rats (alternating cycles of 3 min at 10% O2followed by 3 min at 21% O2between 8 AM and 4 PM for 7 days). To identify NTS neurons receiving carotid body afferent inputs the anterograde tracer 4- (4-(dihexadecylamino)styryl- N-methylpyridinum iodide (DiA) was placed onto the carotid body 1 wk before exposure to CIH. AMPA dose-response curves had similar EC50but maximal responses increased in neurons isolated from DiA-labeled CIH (20.1 ± 0.8 μM, n = 9) compared with NORM (6.0 ± 0.3 μM, n = 8) rats. NMDA dose-response curves also had similar EC50but maximal responses decreased in CIH (8.4 ± 0.4 μM, n = 8) compared with NORM (19.4 ± 0.6 μM, n = 9) rats. These results suggest reciprocal changes in the number and/or conductance characteristics of AMPA and NMDA receptors. Enhanced responses to AMPA receptor activation could contribute to enhanced chemoreflex responses observed in animals exposed to CIH and humans with sleep apnea.
Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage
Authors: Davis J. Mark , Murphy E. Angela , Carmichael Martin D. , Zielinski Mark R. , Groschwitz Claire M. , Brown Adrienne S. , Gangemi J. David , Ghaffar Abdul , Mayer Eugene P.
Published: March 2007

Downhill running is associated with fiber damage, inflammation, delayed-onset muscle soreness, and various functional deficits. Curcumin, a constituent of the Indian spice turmeric has been investigated for its anti-inflammatory activity and may offset some of the damage and functional deficits associated with downhill running. This study examined the effects of curcumin on inflammation and recovery of running performance following downhill running in mice. Male mice were assigned to downhill placebo (Down-Plac), downhill curcumin (Down-Cur), uphill placebo (Up-Plac), or uphill curcumin (Up-Cur) groups and run on a treadmill at 22 m/min at −14% or +14% grade, for 150 min. At 48 h or 72 h after the up/downhill run, mice ( experiment 1) underwent a treadmill performance run to fatigue. Another subset of mice was placed in voluntary activity wheel cages following the up/downhill run ( experiment 2) and their voluntary activity (distance, time and peak speed) was recorded. Additional mice ( experiment 3) were killed at 24 h and 48 h following the up/downhill run, and the soleus muscle was harvested for analysis of inflammatory cytokines (IL-1β, IL-6, and TNF-α), and plasma was collected for creatine kinase analysis. Downhill running decreased both treadmill run time to fatigue (48 h and 72 h) and voluntary activity (24 h) ( P < 0.05), and curcumin feedings offset these effects on running performance. Downhill running was also associated with an increase in inflammatory cytokines (24 h and 48 h) and creatine kinase (24 h) ( P < 0.05) that were blunted by curcumin feedings. These results support the hypothesis that curcumin can reduce inflammation and offset some of the performance deficits associated with eccentric exercise-induced muscle damage.
Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass
Authors: Frost Robert A. , Lang Charles H.
Published: March 2007

Although the boundaries of skeletal muscle size are fundamentally determined by genetics, this dynamic tissue also demonstrates great plasticity in response to environmental and hormonal factors. Recent work indicates that contractile activity, nutrients, growth factors, and cytokines all contribute to determining muscle mass. Muscle responds not only to endocrine hormones but also to the autocrine production of growth factors and cytokines. Skeletal muscle synthesizes anabolic growth factors such as insulin-like growth factor (IGF)-I and potentially inhibitory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and myostatin. These self-regulating inputs in turn influence muscle metabolism, including the use of nutrients such as glucose and amino acids. These changes are principally achieved by altering the activity of the protein kinase known as protein kinase B or Akt. Akt plays a central role in integrating anabolic and catabolic responses by transducing growth factor and cytokine signals via changes in the phosphorylation of its numerous substrates. Activation of Akt stimulates muscle hypertrophy and antagonizes the loss of muscle protein. Here we review the many signals that funnel through Akt to alter muscle mass.
Genioglossus muscle activity and serotonergic modulation of hypoglossal motor output in obese Zucker rats
Authors: Sood Sandeep , Liu Xia , Liu Hattie , Horner Richard L.
Published: March 2007

Obese Zucker rats have a narrower and more collapsible upper airway compared with lean controls, similar to obstructive sleep apnea (OSA) patients. Genioglossus (GG) muscle activity is augmented in awake OSA patients to compensate for airway narrowing, but the neural control of GG activity in obese Zucker rats has not been investigated to determine whether such neuromuscular compensation also occurs. This study tests the hypotheses that GG activity is augmented in obese Zucker rats compared with lean controls and that endogenous 5-hydroxytryptamine (5-HT) contributes to GG activation. Seven obese and seven lean Zucker rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and they were implanted with GG and diaphragm wires for respiratory muscle recordings. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid and the 5-HT receptor antagonist mianserin (100 μM). Compared with lean controls, respiratory rates were increased in obese rats across sleep-wake states ( P = 0.048) because of reduced expiratory durations ( P = 0.007); diaphragm activation was similar between lean and obese animals ( P = 0.632). Respiratory-related, tonic, and peak GG activities were also similar between obese and lean rats ( P > 0.139). There was no reduction in GG activity with mianserin at the hypoglossal motor nucleus, consistent with recent observations of a minimal contribution of endogenous 5-HT to GG activity. These results suggest that despite the upper airway narrowing in obese Zucker rats, these animals have a sufficiently stable airway such that pharyngeal muscle activity is normal across sleep-wake states.
Down-regulation of Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 Expression by Soy Isoflavones Enhances Prostate Cancer Radiotherapy In vitro and In vivo
Authors: Raffoul Julian J. , Banerjee Sanjeev , Singh-Gupta Vinita , Knoll Zvi E. , Fite Alemu , Zhang Hao , Abrams Judith , Sarkar Fazlul H. , Hillman Gilda G.
Published: March 2007

We previously showed that genistein, the major bioactive component of soy isoflavones, acts as a radiosensitizer and potentiates prostate tumor cell killing by radiation in vitro and in animal tumor models in vivo. However, when given alone in vivo, pure genistein promoted increased lymph node metastasis, which was not observed with a soy isoflavone mixture consisting of genistein, daidzein, and glycitein. In this study, we show that soy inhibit tumor cell growth and potentiates radiation-induced cell killing in vitro like pure genistein. In an orthotopic model, combining soy isoflavones with tumor irradiation inhibited prostate tumor growth. To determine the molecular mechanisms by which soy isoflavones potentiate radiotherapy, we investigated apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) and nuclear factor κB (NF-κB), two signaling molecules involved in survival pathways. Soy isoflavones decreased APE1/Ref-1 expression in vitro, whereas radiation up-regulated it. Pretreatment with soy isoflavones followed by radiation inhibited APE1/Ref-1 expression. APE1/Ref-1 decrease correlated with decreased DNA-binding activity of NF-κB mediated by soy isoflavones and radiation, thus promoting cell killing. In vivo treatment of prostate tumors with soy isoflavones and radiation down-regulated APE1/Ref-1 protein expression and NF-κB activity, confirming the molecular alterations observed in vitro. The down-regulation of APE1/Ref-1 and NF-κB by isoflavones, in vitro and in vivo, supports our hypothesis that these markers represent biological targets of isoflavones. Indeed, a 2-fold increase in APE1/Ref-1 expression, obtained by cDNA transfection, resulted in a 2-fold increase in NF-κB DNA-binding activity, and both of which were down-regulated by soy isoflavones, confirming the cross-talk between these molecules and, in turn, causing radiosensitization. [Cancer Res 2007;67(5):2141–9]
A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection
Authors: Suzuki Eiji , Kim Samuel , Cheung H.-Kam , Corbley Michael J. , Zhang Xiamei , Sun Lihong , Shan Feng , Singh Juswinder , Lee Wen-Cherng , Albelda Steven M. , Ling Leona E.
Published: March 2007

Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor β (TGFβ). We investigated the efficacy of a novel small-molecule TGFβ type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFβ signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC50, ∼200 nmol/L). SM16 penetrated tumor cells in vivo, suppressing tumor phosphorylated Smad2/3 levels for at least 3 h following treatment of tumor-bearing mice with a single i.p. bolus of 20 mg/kg SM16. The growth of established AB12 tumors was significantly inhibited by 5 mg/kg/d SM16 (P < 0.001) delivered via s.c. miniosmotic pumps over 28 days. The efficacy of SM16 was a result of a CD8+ antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8+ T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8+ T cells isolated from spleens of tumor-bearing mice treated with control vehicle showed minimal activity. Treatment of mice bearing large tumors with 5 mg/kg/d SM16 after debulking surgery reduced the extent of tumor recurrence from 80% to <20% (P < 0.05). SM16 was also highly effective in blocking and regressing tumors when given p.o. at doses of 0.45 or 0.65 g/kg in mouse chow. Thus, SM16 shows potent activity against established AB12 malignant mesothelioma tumors using an immune-mediated mechanism and can significantly prevent tumor recurrence after resection of bulky AB12 malignant mesothelioma tumors. These data suggest that ALK5 inhibitors, such as SM16, offer significant potential for the treatment of malignant mesothelioma and possibly other cancers. [Cancer Res 2007;67(5):2351–9]
The Asn418-Linked N-Glycan of ErbB3 Plays a Crucial Role in Preventing Spontaneous Heterodimerization and Tumor Promotion
Authors: Yokoe Shunichi , Takahashi Motoko , Asahi Michio , Lee Seung Ho , Li Wei , Osumi Daisuke , Miyoshi Eiji , Taniguchi Naoyuki
Published: March 2007

ErbB2 and ErbB3, two members of the ErbB family, form a high-affinity heregulin coreceptor that elicits potent mitogenic and transforming signals, and clinical studies indicate that these receptors play an important role in tumor incidence and progression. To determine whether N-glycosylation is involved in the function of ErbB3, a series of human ErbB3 molecules devoid of N-glycans were prepared and transfected to Flp-In-CHO cells for stable expression. A cross-linking study showed that the Asn418 to Gln mutant (N418Q) of ErbB3 underwent autodimerization without its ligand, heregulin. The wild-type or N418Q mutant of ErbB3 was next coexpressed with ErbB2 in Flp-In-CHO cells, and the effect of N-glycan on heterodimerization was examined. The N418Q mutant of ErbB3 was autodimerized with ErbB2 without ligand stimulation, and receptor tyrosine phosphorylation and subsequent extracellular signal-regulated kinase (ERK) and Akt phosphorylation were promoted in the absence of heregulin. A cell proliferation assay and a soft agar colony formation assay showed that the N418Q mutant of ErbB3 coexpressed with ErbB2 promoted cell proliferation and colony formation in soft agar in an ERK- and Akt-dependent manner. The mutation also promoted the growth of tumors in athymic mice when injected s.c. These findings suggest that the Asn418-linked N-glycan in ErbB3 plays an essential role in regulating receptor heterodimerization with ErbB2 and might have an effect on transforming activity. [Cancer Res 2007;67(5):1935–42]
Estrogen Receptors α and β Are Inhibitory Modifiers of Apc-Dependent Tumorigenesis in the Proximal Colon of Min/+ Mice
Authors: Cho Nancy L. , Javid Sara H. , Carothers Adelaide M. , Redston Mark , Bertagnolli Monica M.
Published: March 2007

Estrogen replacement therapy in postmenopausal women is associated with a reduction in colorectal cancer risk, potentially via interactions between 17β-estradiol (E2) and the estrogen receptors (ER) α and β. To study the role of E2 in intestinal tumor inhibition, we separately crossed C57BL/6J-Min/+ (Min/+) mice with Erα+/− and Erβ+/− mice to generate ER-deficient Min/+ progeny. We found an increased incidence of visible colon tumors and dysplastic microadenomas in ER-deficient Min/+ relative to Er+/+Min/+ controls. Small intestinal tumor numbers were unaffected. Invasive carcinomas were found only in Erα+/−Min/+ mice, suggesting that ERα plays additional non–cell autonomous roles that limit tumor progression. Histologic analyses of ER-deficient Min/+ colons, as well as colons from ovariectomized Min/+ mice (OvxMin/+) and E2-treated OvxMin/+ mice (OvxMin/+ +E2), revealed significant differences in crypt architecture, enterocyte proliferation, and goblet cell differentiation relative to Min/+ and Er+/+Apc+/+ (wild-type) controls. The expression of ERα and ERβ was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ERα and ERβ are inhibitory modifiers of Apc-dependent colon tumorigenesis. As a result, loss of E2 and ER signaling in postmenopausal women may contribute to colorectal cancer development. [Cancer Res 2007;67(5):2366–72]