bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of the Human Prefrontal Cortex in Social Cognition and Moral Judgment
Authors: Forbes Chad E. , Grafman Jordan
Published: June 2010

Results from functional magnetic resonance imaging and lesion studies indicate that the prefrontal cortex (PFC) is essential for successful navigation through a complex social world inundated with intricate norms and moral values. This review examines regions of the PFC that are critical for implicit and explicit social cognitive and moral judgment processing. Considerable overlap between regions active when individuals engage in social cognition or assess moral appropriateness of behaviors is evident, underscoring the similarity between social cognitive and moral judgment processes in general. Findings are interpreted within the framework of structured event complex theory, providing a broad organizing perspective for how activity in PFC neural networks facilitates social cognition and moral judgment. We emphasize the dynamic flexibility in neural circuits involved in both implicit and explicit processing and discuss the likelihood that neural regions thought to uniquely underlie both processes heavily interact in response to different contextual primes.
Sodium Channels in Normal and Pathological Pain
Authors: Dib-Hajj Sulayman D. , Cummins Theodore R. , Black Joel A. , Waxman Stephen G.
Published: June 2010

Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated sodium channels, Nav1.1–Nav1.9, are essential for generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several channels as pivotal for signal transmission along the pain axis, including Nav1.3, Nav1.7, Nav1.8, and Nav1.9, with the latter three preferentially expressed in peripheral sensory neurons and Nav1.3 being upregulated along pain-signaling pathways after nervous system injuries. Nav1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these sodium channel isoforms to pain.
The Subplate and Early Cortical Circuits
Authors: Kanold Patrick O. , Luhmann Heiko J.
Published: June 2010

The developing mammalian cerebral cortex contains a distinct class of cells, subplate neurons (SPns), that play an important role during early development. SPns are the first neurons to be generated in the cerebral cortex, they reside in the cortical white matter, and they are the first to mature physiologically. SPns receive thalamic and neuromodulatory inputs and project into the developing cortical plate, mostly to layer 4. Thus SPns form one of the first functional cortical circuits and are required to relay early oscillatory activity into the developing cortical plate. Pathophysiological impairment or removal of SPns profoundly affects functional cortical development. SPn removal in visual cortex prevents the maturation of thalamocortical synapses, the maturation of inhibition in layer 4, the development of orientation selective responses and the formation of ocular dominance columns. SPn removal also alters ocular dominance plasticity during the critical period. Therefore, SPns are a key regulator of cortical development and plasticity. SPns are vulnerable to injury during prenatal stages and might provide a crucial link between brain injury in development and later cognitive malfunction.
Wallerian Degeneration, WldS, and Nmnat
Authors: Coleman Michael P. , Freeman Marc R.
Published: June 2010

Traditionally, researchers have believed that axons are highly dependent on their cell bodies for long-term survival. However, recent studies point to the existence of axon-autonomous mechanism(s) that regulate rapid axon degeneration after axotomy. Here, we review the cellular and molecular events that underlie this process, termed Wallerian degeneration. We describe the biphasic nature of axon degeneration after axotomy and our current understanding of how WldS—an extraordinary protein formed by fusing a Ube4b sequence to Nmnat1—acts to protect severed axons. Interestingly, the neuroprotective effects of WldS span all species tested, which suggests that there is an ancient, WldS-sensitive axon destruction program. Recent studies with WldS also reveal that Wallerian degeneration is genetically related to several dying back axonopathies, thus arguing that Wallerian degeneration can serve as a useful model to understand, and potentially treat, axon degeneration in diverse traumatic or disease contexts.
Genomes in Conflict: Maintaining Genome Integrity During Virus Infection
Authors: Weitzman Matthew D. , Lilley Caroline E. , Chaurushiya Mira S.
Published: June 2010

The cellular surveillance network for sensing and repairing damaged DNA prevents an array of human diseases, and when compromised it can lead to genomic instability and cancer. The carefully maintained cellular response to DNA damage is challenged during viral infection, when foreign DNA is introduced into the cell. The battle between virus and host generates a genomic conflict. The host attempts to limit viral infection and protect its genome, while the virus deploys tactics to eliminate, evade, or exploit aspects of the cellular defense. Studying this conflict has revealed that the cellular DNA damage response machinery comprises part of the intrinsic cellular defense against viral infection. In this review we examine recent advances in this emerging field. We identify common themes used by viruses in their attempts to commandeer or circumvent the host cell's DNA repair machinery, and highlight potential outcomes of the conflict for both virus and host.
Vaccines to Prevent Infections by Oncoviruses
Authors: Schiller John T. , Lowy Douglas R.
Published: June 2010

It has been estimated that viruses are etiological agents in approximately 12% of human cancers. Most of these cancers can be attributed to infections by human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), and Kaposi's sarcoma–associated herpesvirus (KSHV). Prophylactic vaccines against other pathogenic viruses have an excellent record as public health interventions in terms of safety, effectiveness, and ability to reach economically disadvantaged populations. These considerations should prompt efforts to develop and implement vaccines against oncoviruses. Safe and effective HBV and HPV vaccines, based on virus-like particles, are commercially available, and the major focus is now on vaccine delivery, especially to low-resource settings. HCV and EBV vaccines are under active development, but few clinical trials have been conducted, and none of the candidate vaccines has proven to be sufficiently effective to warrant commercialization. Efforts to develop KSHV vaccines have been more limited.
Molecular Insights into Burkholderia pseudomallei and Burkholderia mallei Pathogenesis
Authors: Galyov Edouard E. , Brett Paul J. , DeShazer David
Published: June 2010

Burkholderia pseudomallei and Burkholderia mallei are closely related gram-negative bacteria that can cause serious diseases in humans and animals. This review summarizes the current and rapidly expanding knowledge on the specific virulence factors employed by these pathogens and their roles in the pathogenesis of melioidosis and glanders. In particular, the contributions of recently identified virulence factors are described in the context of the intracellular lifestyle of these pathogens. Throughout this review, unique and shared virulence features of B. pseudomallei and B. mallei are discussed.
Structure, Function, and Evolution of Linear Replicons in Borrelia
Authors: Chaconas George , Kobryn Kerri
Published: June 2010

Spirochetes of the genus Borrelia include important human pathogens that cause Lyme borreliosis and relapsing fever. The genomes of Borrelia species can be composed of up to 24 DNA molecules, most of which are linear. The plasmid content and linear replicon sequence arrangement vary widely between isolates. The linear replicons are terminated by covalently closed DNA hairpins or hairpin telomeres. Replication of these elements involves a unique reaction, called telomere resolution, to produce hairpin telomeres from replicative intermediates. The telomere resolvase, ResT, is thought to contribute to the genetic flux of the linear molecules by promoting stabilized telomere fusions. Telomere resolvases are related to the tyrosine recombinases and ResT can generate the crucial reaction intermediate of this class of enzyme, the Holliday junction. This observation has led to the proposal that telomere resolvases evolved from tyrosine recombinases inducing DNA linearization in the genomes that acquired them.
CRISPR/Cas System and Its Role in Phage-Bacteria Interactions
Authors: Deveau Hélène , Garneau Josiane E. , Moineau Sylvain
Published: June 2010

Clustered regularly interspaced short palindromic repeats (CRISPRs) along with Cas proteins is a widespread system across bacteria and archaea that causes interference against foreign nucleic acids. The CRISPR/Cas system acts in at least two general stages: the adaptation stage, where the cell acquires new spacer sequences derived from foreign DNA, and the interference stage, which uses the recently acquired spacers to target and cleave invasive nucleic acid. The CRISPR/Cas system participates in a constant evolutionary battle between phages and bacteria through addition or deletion of spacers in host cells and mutations or deletion in phage genomes. This review describes the recent progress made in this fast-expanding field.
Viruses, microRNAs, and Host Interactions
Authors: Skalsky Rebecca L. , Cullen Bryan R.
Published: June 2010

One of the most significant recent advances in biomedical research has been the discovery of the ∼22-nt-long class of noncoding RNAs designated microRNAs (miRNAs). These regulatory RNAs provide a unique level of posttranscriptional gene regulation that modulates a range of fundamental cellular processes. Several viruses, especially herpesviruses, also encode miRNAs, and over 200 viral miRNAs have now been identified. Current evidence indicates that viruses use these miRNAs to manipulate both cellular and viral gene expression. Furthermore, viral infection can exert a profound impact on the cellular miRNA expression profile, and several RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Here we discuss our current knowledge of viral miRNAs and virally influenced cellular miRNAs and their relationship to viral infection.
TonB-Dependent Transporters: Regulation, Structure, and Function
Authors: Noinaj Nicholas , Guillier Maude , Barnard, Travis J. , Buchanan Susan K.
Published: June 2010

TonB-dependent transporters (TBDTs) are bacterial outer membrane proteins that bind and transport ferric chelates, called siderophores, as well as vitamin B12, nickel complexes, and carbohydrates. The transport process requires energy in the form of proton motive force and a complex of three inner membrane proteins, TonB-ExbB-ExbD, to transduce this energy to the outer membrane. The siderophore substrates range in complexity from simple small molecules such as citrate to large proteins such as serum transferrin and hemoglobin. Because iron uptake is vital for almost all bacteria, expression of TBDTs is regulated in a number of ways that include metal-dependent regulators, σ/anti-σ factor systems, small RNAs, and even a riboswitch. In recent years, many new structures of TBDTs have been solved in various states, resulting in a more complete understanding of siderophore selectivity and binding, signal transduction across the outer membrane, and interaction with the TonB-ExbB-ExbD complex. However, the transport mechanism is still unclear. In this review, we summarize recent progress in understanding regulation, structure, and function in TBDTs and questions remaining to be answered.
Persister Cells
Authors: Lewis Kim
Published: June 2010

Persisters are dormant variants of regular cells that form stochastically in microbial populations and are highly tolerant to antibiotics. High persister (hip) mutants of Pseudomonas aeruginosa are selected in patients with cystic fibrosis. Similarly, hip mutants of Candida albicans are selected in patients with an oral thrush biofilm. These observations suggest that persisters may be the main culprit responsible for the recalcitrance of chronic infectious disease to antimicrobial therapy. Screening knockout libraries has not produced mutants lacking persisters, indicating that dormancy mechanisms are redundant. Toxin/antitoxin (TA) modules are involved in persister formation in Escherichia coli. The SOS response leads to overexpression of the TisB toxin and persister formation. TisB is a membrane-acting peptide that apparently sends cells into dormancy by decreasing the proton motive force and ATP levels. Stress responses may act as general activators of persister formation. Proteins required for maintaining persisters may represent realistic targets for discovery of drugs capable of effectively treating chronic infections.
Neural Mechanisms for Interacting with a World Full of Action Choices
Authors: Cisek Paul , Kalaska John F.
Published: June 2010

The neural bases of behavior are often discussed in terms of perceptual, cognitive, and motor stages, defined within an information processing framework that was originally inspired by models of human abstract problem solving. Here, we review a growing body of neurophysiological data that is difficult to reconcile with this influential theoretical perspective. As an alternative foundation for interpreting neural data, we consider frameworks borrowed from ethology, which emphasize the kinds of real-time interactive behaviors that animals have engaged in for millions of years. In particular, we discuss an ethologically-inspired view of interactive behavior as simultaneous processes that specify potential motor actions and select between them. We review how recent neurophysiological data from diverse cortical and subcortical regions appear more compatible with this parallel view than with the classical view of serial information processing stages.
Motor Neuron Diversity in Development and Disease
Authors: Kanning Kevin C. , Kaplan Artem , Henderson Christopher E.
Published: June 2010

Although often considered as a group, spinal motor neurons are highly diverse in terms of their morphology, connectivity, and functional properties and differ significantly in their response to disease. Recent studies of motor neuron diversity have clarified developmental mechanisms and provided novel insights into neurodegeneration in amyotrophic lateral sclerosis (ALS). Motor neurons of different classes and subtypes—fast/slow, alpha/gamma—are grouped together into motor pools, each of which innervates a single skeletal muscle. Distinct mechanisms regulate their development. For example, glial cell line–derived neurotrophic factor (GDNF) has effects that are pool-specific on motor neuron connectivity, column-specific on axonal growth, and subtype-specific on survival. In multiple degenerative contexts including ALS, spinal muscular atrophy (SMA), and aging, fast-fatigable (FF) motor units degenerate early, whereas motor neurons innervating slow muscles and those involved in eye movement and pelvic sphincter control are strikingly preserved. Extrinsic and intrinsic mechanisms that confer resistance represent promising therapeutic targets in these currently incurable diseases.
Genetic, hormonal, and metabolomic influences on social behavior and sex preference of XXY mice
Authors: Liu Peter Y. , Erkkila Krista , Lue YanHe , Jentsch J. David , Schwarcz Monica Dorin , Abuyounes Deena , Hikim Amiya Sinha , Wang Christina , Lee Paul W.-N. , Swerdloff Ronald S.
Published: June 2010

XXY men (Klinefelter syndrome) are testosterone deficient, socially isolated, exhibit impaired gender identity, and may experience more homosexual behaviors. Here, we characterize social behaviors in a validated XXY mouse model to understand mechanisms. Sociability and gender preference were assessed by three-chambered choice tasks before and after castration and after testosterone replacement. Metabolomic activities of brain and blood were quantified through fractional synthesis rates of palmitate and ribose (GC-MS). XXY mice exhibit greater sociability than XY littermates, particularly for male mice. The differences in sociability disappear after matching androgen exposure. Intact XXY, compared with XY, mice prefer male mice odors when the alternatives are ovariectomized female mice odors, but they prefer estrous over male mice odors, suggesting that preference for male mice may be due to social, not sexual, cues. Castration followed by testosterone treatment essentially remove these preferences. Fractional synthesis rates of palmitate are higher in the hypothalamus, amygdala, and hippocampus of XXY compared with XY mice but not with ribose in these brain regions or palmitate in blood. Androgen ablation in XY mice increases fractional synthesis rates of fatty acids in the brain to levels indistinguishable from those in XXY mice. We conclude that intact XXY mice exhibit increased sociability, differences in gender preference for mice and their odors are due to social rather than sexual cues and, these differences are mostly related to androgen deficiency rather than genetics. Specific metabolic changes in brain lipids, which are also regulated by androgens, are observed in brain regions that are involved in these behaviors.
Insulin-sensitive obesity
Authors: Klöting Nora , Fasshauer Mathias , Dietrich Arne , Kovacs Peter , Schön Michael R. , Kern Matthias , Stumvoll Michael , Blüher Matthias
Published: June 2010

The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulin-resistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 ± 1.3 kg/m2 were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 ± 27 vs. 316 ± 91 cm2), number of macrophages in omental adipose tissue (4.9 ± 0.8 vs. 13.2 ± 1.4%), mean omental adipocyte size (528 ± 76 vs. 715 ± 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values <0.05), and higher serum adiponectin (6.9 ± 3.4 vs. 3.4 ± 1.7 ng/ml) and omental adipocyte insulin sensitivity (all P values <0.01). The strongest predictors of insulin sensitivity by far were macrophage infiltration together with circulating adiponectin ( r2 = 0.98, P < 0.0001). In conclusion, independently of total body fat mass, increased visceral fat accumulation and adipose tissue dysfunction are associated with IR obesity. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity.
Role of Intrinsic Properties in Drosophila Motoneuron Recruitment During Fictive Crawling
Authors: Schaefer Jennifer E. , Worrell Jason W. , Levine Richard B.
Published: June 2010

Motoneurons in most organisms conserve a division into low-threshold and high-threshold types that are responsible for generating powerful and precise movements. Drosophila 1b and 1s motoneurons may be analogous to low-threshold and high-threshold neurons, respectively, based on data obtained at the neuromuscular junction, although there is little information available on intrinsic properties or recruitment during behavior. Therefore in situ whole cell patch-clamp recordings were used to compare parameters of 1b and 1s motoneurons in Drosophila larvae. We find that resting membrane potential, voltage threshold, and delay-to-spike distinguish 1b from 1s motoneurons. The longer delay-to-spike in 1s motoneurons is a result of the shal-encoded A-type K+ current. Functional differences between 1b and 1s motoneurons are behaviorally relevant because a higher threshold and longer delay-to-spike are observed in MNISN-1s in pairwise whole cell recordings of synaptically evoked activity during bouts of fictive locomotion.
Chronic reduction in cardiac output induces hypoxic signaling in larval zebrafish even at a time when convective oxygen transport is not required
Authors: Kopp Renate , Schwerte Thorsten , Egg Margit , Sandbichler Adolf Michael , Egger Bernhard , Pelster Bernd
Published: June 2010

In the present study, the zebrafish breakdance mutant ( bre) was used to assess the role of blood flow in development because it has been previously shown that bre larvae have a chronically reduced cardiac output as a result of ventricular contraction following only every second atrial contraction in addition to an atrial bradycardia. We confirmed a 50% reduction compared with control fish and further showed that blood flow in the caudal part of the dorsal aorta decreased by 80%. Associated with these reductions in blood flow were indications of developmental retardation in bre mutants, specifically delayed hatching, reduced cell proliferation, and a transiently decreased growth rate. Surprisingly, an increased red blood cell concentration and an earlier appearance of trunk vessels in bre larvae indicated some compensation to convective oxygen transport, although in previous studies it has been shown that zebrafish larvae at this stage obtain oxygen by bulk diffusion. In bre animals immunohistochemical analyses showed a significant increase in hypoxia inducible factor 1 (HIF)-α protein expression, comparable with wild-type larvae that were raised under hypoxic conditions. Accordingly, the expression of some hif downstream genes was affected. Furthermore, Affymetrix microarray analyses revealed a large number of genes that were differently expressed comparing control and bre larvae, and the number even increased with proceeding development. The results showed that a chronic reduction in blood flow generated hypoxic molecular signals despite partial compensation by increased oxygen carrying capacity and transiently slowed the overall development of zebrafish bre larvae.
Naturally occurring mutations in the canine CFTR gene
Authors: Spadafora Domenico , Hawkins Eleanor C. , Murphy Keith E. , Clark Leigh Anne , Ballard Stephen T.
Published: June 2010

Naturally occurring cystic fibrosis (CF)-causing mutations in the CFTR gene have not been identified in any nonhuman animal species. Since domestic dogs are known to develop medical conditions associated with atypical CF in humans (e.g., bronchiectasis and pancreatitis), we hypothesized that dogs with these disorders likely have a higher expression rate of CFTR mutations than the at-large population. Temporal temperature-gradient gel electrophoresis (TTGE) was used to screen canine CFTR in 400 animals: 203 dogs diagnosed with pancreatitis, 23 dogs diagnosed with bronchiectasis, and 174 dogs admitted to clinics for any illness (at-large dogs). Twenty-eight dogs were identified with one of four CFTR missense mutations. P1281T and P1464H mutations occur in relatively unconserved residues. R1456W is analogous to the human R1453W mutation, which has ∼20% of normal CFTR function and is associated with pancreatitis and panbronchiolitis. R812W disrupts a highly conserved protein kinase A recognition site within the regulatory domain. We conclude that naturally occurring CFTR mutations are relatively common in domestic dogs and can be detected with TTGE. No substantive differences in mutation frequency were observed between the at-large, pancreatitis, and bronchiectasis dogs.
Controversies in Surgical Staging of Endometrial Cancer
Authors: Seracchioli R. , Solfrini S. , Mabrouk M. , Facchini C. , Di Donato N. , Manuzzi L. , Savelli L. , Venturoli S.
Published: June 2010

Endometrial cancer is the most common gynaecological malignancy and its incidence is increasing. In 1998, international federation of gynaecologists and obstetricians (FIGO) required a change from clinical to surgical staging in endometrial cancer, introducing pelvic and paraaortic lymphadenectomy. This staging requirement raised controversies around the importance of determining nodal status and impact of lymphadenectomy on outcomes. There is agreement about the prognostic value of lymphadenectomy, but its extent, therapeutic value, and benefits in terms of survival are still matter of debate, especially in early stages. Accurate preoperative risk stratification can guide to the appropriate type of surgery by selecting patients who benefit of lymphadenectomy. However, available preoperative and intraoperative investigations are not highly accurate methods to detect lymph nodes and a complete surgical staging remains the most precise method to evaluate extrauterine spread of the disease. Laparotomy has always been considered the standard approach for endometrial cancer surgical staging. Traditional and robotic‐assisted laparoscopic techniques seem to provide equivalent results in terms of disease‐free survival and overall survival compared to laparotomy. These minimally invasive approaches demonstrated additional benefits as shorter hospital stay, less use of pain killers, lower rate of complications and improved quality of life.
Evaluation of Cytotoxicity and Genotoxicity ofInula viscosaLeaf Extracts with Allium Test
Authors: Aşkin Çelik Tülay , Aslantürk Özlem Sultan
Published: June 2010

I. viscosahas been used for years in folk medicine for its anti-inflammatory, antipyretic, antiseptic, and paper antiphlogistic activities. In this study, cytotoxic and genotoxic effects ofI. viscosaleaf extracts on the root meristem cells ofAllium cepahave been examined. Onion bulbs were exposed to 2.5 mg/ml, 5 mg/ml, and 10 mg/ml concentrations of the extracts for macroscopic and microscopic analysis. Tap water has been used as a negative control and Ethyl methanesulfonate (EMS) ( M) has been used as a positive control. The test concentrations have been determined according to doses which are recommended for use in alternative medicine. There has been statistically significant () inhibition of root growth depending on concentration by the extracts when compared with the control groups. All the tested extracts have been observed to have cytotoxic effects on cell division inA. cepa. I. viscosaleaf extract induces the total number of chromosomal aberrations and micronuclei (MNC) formations inA. ceparoot tip cells significantly when compared with control groups. Also, this paper shows for the first time the induction of cell death, ghost cells, cells with membrane damage, and binucleated cells by extract treatment. These results suggest the cytotoxic and genotoxic effects of theI. viscosaleaf extracts onA. cepa.
Reduced Noise Effect in Nonlinear Model Estimation Using Multiscale Representation
Authors: Nounou Mohamed N. , Nounou Hazem N.
Published: June 2010

Nonlinear process models are widely used in various applications. In the absence of fundamental models, it is usually relied on empirical models, which are estimated from measurements of the process variables. Unfortunately, measured data are usually corrupted with measurement noise that degrades the accuracy of the estimated models. Multiscale wavelet‐based representation of data has been shown to be a powerful data analysis and feature extraction tool. In this paper, these characteristics of multiscale representation are utilized to improve the estimation accuracy of the linear‐in‐the‐parameters nonlinear model by developing a multiscale nonlinear (MSNL) modeling algorithm. The main idea in this MSNL modeling algorithm is to decompose the data at multiple scales, construct multiple nonlinear models at multiple scales, and then select among all scales the model which best describes the process. The main advantage of the developed algorithm is that it integrates modeling and feature extraction to improve the robustness of the estimated model to the presence of measurement noise in the data. This advantage of MSNL modeling is demonstrated using a nonlinear reactor model.
Investigation of Tinnitus Patients in Italy: Clinical and Audiological Characteristics
Authors: Martines Francesco , Bentivegna Daniela , Di Piazza Fabiola , Martines Enrico , Sciacca Vincenzo , Martinciglio Gioacchino
Published: June 2010

Objective. 312 tinnitus sufferers were studied in order to analyze: the clinical characteristics of tinnitus; the presence of tinnitus-age correlation and tinnitus-hearing loss correlation; the impact of tinnitus on subjects' life and where possible the etiological/predisposing factors of tinnitus.Results. There is a slight predominance of males. The highest percentage of tinnitus results in the decades 61–70. Of the tinnitus sufferers, 197 (63.14%) have a hearing deficit (light hearing loss in 37.18% of cases). The hearing impairment results of sensorineural type in 74.62% and limited to the high frequencies in 58.50%. The tinnitus is referred as unilateral in 59.93%, a pure tone in 66.99% and 10 dB above the hearing threshold in 37.7%. It is limited to high frequencies in 72.10% of the patients with sensorineural hearing loss (SNHL) while the 88.37% of the patients with high-frequency SNHL have a high-pitched tinnitus ( ).Conclusion. Hearing status and age represent the principal tinnitus related factors; there is a statistically significant association between high-pitched tinnitus and high-frequency SNHL. There is no significant correlation between tinnitus severity and tinnitus loudness confirming the possibility that neural connection involved in evoking tinnitus-related negative reactions are governed by conditioned reflexes.
How Do Cells Make Decisions: Engineering Micro- and Nanoenvironments for Cell Migration
Authors: Ngalim Siti Hawa , Magenau Astrid , Le Saux Guillaume , Gooding J. Justin , Gaus Katharina
Published: June 2010

Cell migration contributes to cancer metastasis and involves cell adhesion to the extracellular matrix (ECM), force generation through the cell's cytoskeletal, and finally cell detachment. Both adhesive cues from the ECM and soluble cues from neighbouring cells and tissue trigger intracellular signalling pathways that are essential for cell migration. While the machinery of many signalling pathways is relatively well understood, how hierarchies of different and conflicting signals are established is a new area of cellular cancer research. We examine the recent advances in microfabrication, microfluidics, and nanotechnology that can be utilized to engineer micro- and nanoscaled cellular environments. Controlling both adhesive and soluble cues for migration may allow us to decipher how cells become motile, choose the direction for migration, and how oncogenic transformations influences these decision-making processes.
Modeling the Effect of Plants and Peat on Evapotranspiration in Constructed Wetlands
Authors: Chazarenc Florent , Naylor Simon , Comeau Yves , Merlin Gérard , Brisson Jacques
Published: June 2010

Evapotranspiration (ET) in constructed wetlands (CWs) represents a major factor affecting hydrodynamics and treatment performances. The presence of high ET was shown to improve global treatment performances, however ET is affected by a wide range of parameters including plant development and CWs age. Our study aimed at modelling the effect of plants and peat on ET in CWs; since we hypothesized peat could behave like the presence of accumulated organic matter in old CWs. Treatment performances, hydraulic behaviour, and ET rates were measured in eight 1 m2CWs mesocosm (1 unplanted, 1 unplanted with peat, 2 planted withPhragmites australis, 2 planted withTypha latifoliaand 2 planted withPhragmites australiswith peat). Two models were built using first order kinetics to simulate COD and TKN removal with ET as an input. The effect of peat was positive on ET and was related to the better growth conditions it offered to macrophytes. Removal efficiency in pilot units with larger ET was higher for TKN. On average, results show for COD ak20value of 0.88d-1and 0.36d-1for TKN. We hypothesized that the main effect of ET was to concentrate effluent, thus enhancing degradation rates.
Effect of Postdeposition Heat Treatment on the Crystallinity, Size, and Photocatalytic Activity of TiO2 Nanoparticles Produced via Chemical Vapour Deposition
Authors: Othman Siti Hajar , Abdul Rashid Suraya , Mohd Ghazi Tinia Idaty , Abdullah Norhafizah
Published: June 2010

Titanium dioxide (TiO2) nanoparticles were produced using chemical vapour deposition (CVD) at different deposition temperatures (300–700°C). All the samples were heat treated at their respective deposition temperatures and at a fixed temperature of 400°C. A scanning electron microscope (SEM), a transmission electron microscope (TEM), and X‐ray diffraction (XRD) were used to characterize the nanoparticles in terms of size and crystallinity. The photocatalytic activity was investigated via degradation of methylene blue under UV light. The effects of post deposition heat treatment are discussed in terms of crystallinity, nanoparticle size as well as photocatalytic activity. Crystallinity was found to have a much larger impact on photocatalytic activity compared to nanoparticle size. Samples having a higher degree of crystallinity were more photocatalytically active despite being relatively larger in size. Surprisingly, the photocatalytic activity of the samples reduced when heat treated at temperatures lower than the deposition temperature despite showing an improvement in crystallinity.
Relapsing Polychondritis Following Alopecia Areata
Authors: Starr John C. , Taneja Nidhika , Brasher George W.
Published: June 2010

A case of alopecia areata followed by relapsing polychondritis is presented. Similar cases from the literature are reviewed and speculation about the relationship of these diseases is offered. Although the occurrence of these diseases together could be coincidental, an association seems immunologically plausible. Thus, relapsing polychondritis might be an unusual systemic manifestation of alopecia areata.
A ComprehensiveIn SilicoAnalysis of the Functional and Structural Impact of SNPs in theIGF1RGene
Authors: de Alencar S. A. , Lopes Julio C. D.
Published: June 2010

Insulin-like growth factor 1 receptor (IGF1R) acts as a critical mediator of cell proliferation and survival. Many single nucleotide polymorphisms (SNPs) found in theIGF1Rgene have been associated with various diseases, including both breast and prostate cancer. The genetics of these diseases could be better understood by knowing the functions of these SNPs. In this study, we performed a comprehensive analysis of the functional and structural impact of all known SNPs in this gene using publicly available computational prediction tools. Out of a total of 2412 SNPs inIGF1Rretrieved from dbSNP, we found 32 nsSNPs, 58 sSNPs, 83 mRNA3′UTR SNPs, and 2225 intronic SNPs. Among the nsSNPs, a total of six missense nsSNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (PolyPhen), and one nonsense nsSNP was found. Further, we modeled mutant proteins and compared the total energy values with the native IGF1R protein, and showed that a mutation from arginine to cysteine at position 1216 (rs61740868) on the surface of the protein caused the greatest impact on stability. Also, the FASTSNP tool suggested that 31 sSNPs and 3 intronic SNPs might affect splicing regulation. Based on our investigation, we report potential candidate SNPs for future studies onIGF1Rmutations.
Mechanism of Catch Force: Tethering of Thick and Thin Filaments by Twitchin
Authors: Butler Thomas M. , Siegman Marion J.
Published: June 2010

Catch is a mechanical state occurring in some invertebrate smooth muscles characterized by high force maintenance and resistance to stretch during extremely slow relaxation. During catch, intracellular calcium is near basal concentration and myosin crossbridge cyctng rate is extremely slow. Catch force is relaxed by a protein kinase A-mediated phosphorylation of sites near the N- and C- temini of the minititin twitchin (~526 kDa). Some catch force maintenance car also occur together with cycling myosin crossbridges at submaximal calcium concentrations, but not when the muscle is maximally activated. Additionally, the link responsible for catch can adjust during shortening of submaximally activated muscles and maintain catch force at the new shorter length. Twitchin binds to both thick and thin filaments, and the thin filament binding shown by both the N- and Cterminal portions of twitchin is decreased by phosphorylation of the sites that regulate catch. The data suggest that the twitchin molecule itself is the catch force beanng tether between thick and thin filaments. We present a model for the regulation of catch in which the twitchin tether can be displaced from thin filaments by both (a) the phosphorylation of twitchin and (b) the attachment of high force myosin crossbridges.
Neighborhood Rough Set Reduction-Based Gene Selection and Prioritization for Gene Expression Profile Analysis and Molecular Cancer Classification
Authors: Hou Mei-Ling , Wang Shu-Lin , Li Xue-Ling , Lei Ying-Ke
Published: June 2010

Selection of reliable cancer biomarkers is crucial for gene expression profile-based precise diagnosis of cancer type and successful treatment. However, current studies are confronted with overfitting and dimensionality curse in tumor classification and false positives in the identification of cancer biomarkers. Here, we developed a novel gene-ranking method based on neighborhood rough set reduction for molecular cancer classification based on gene expression profile. Comparison with other methods such as PAM, ClaNC, Kruskal-Wallis rank sum test, and Relief-F, our method shows that only few top-ranked genes could achieve higher tumor classification accuracy. Moreover, although the selected genes are not typical of known oncogenes, they are found to play a crucial role in the occurrence of tumor through searching the scientific literature and analyzing protein interaction partners, which may be used as candidate cancer biomarkers.
Loss of the Desmosomal Component Perp Impairs Wound Healing In Vivo
Authors: Beaudry Veronica G. , Ihrie Rebecca A. , Jacobs Suzanne B. R. , Nguyen Bichchau , Pathak Navneeta , Park Eunice , Attardi Laura D.
Published: June 2010

Epithelial wound closure is a complex biological process that relies on the concerted action of activated keratinocytes and dermal fibroblasts to resurface and close the exposed wound. Modulation of cell‐cell adhesion junctions is thought to facilitate cellular proliferation and migration of keratinocytes across the wound. In particular, desmosomes, adhesion complexes critical for maintaining epithelial integrity, are downregulated at the wound edge. It is unclear, however, how compromised desmosomal adhesion would affect wound reepithelialization, given the need for a delicate balance between downmodulating adhesive strength to permit changes in cellular morphology and maintaining adhesion to allow coordinated migration of keratinocyte sheets. Here, we explore the contribution of desmosomal adhesion to wound healing using mice deficient for the desmosomal component Perp. We find that Perp conditional knockout mice display delayed wound healing relative to controls. Furthermore, we determine that while loss of Perp compromises cell‐cell adhesion, it does not impair keratinocyte proliferation and actually enhances keratinocyte migration in in vitro assays. Thus, Perp′s role in promoting cell adhesion is essential for wound closure. Together, these studies suggest a role for desmosomal adhesion in efficient wound healing.
Global Behavior of a Higher‐Order Difference Equation
Authors: Li Tuo , Jia Xiu-Mei
Published: June 2010

This paper is concerned with the global behavior of higher‐order difference equation of the form , n = 0,1, 2…, y−k, y−k+1, …, y0 ∈ (0,1). Under some certain assumptions, it is proved that the positive equilibrium is globally asymptotical stable.
DC-HIL/Glycoprotein Nmb Promotes Growth of Melanoma in Mice by Inhibiting the Activation of Tumor-Reactive T Cells
Authors: Tomihari Mizuki , Chung Jin-Sung , Akiyoshi Hideo , Cruz Ponciano D. , Ariizumi Kiyoshi
Published: June 2010

DC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA–transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL–knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8+ T cells to melanoma-associated antigens on parental B16F10 cells. Using an assay examining the spread to the lung following i.v. injection, DC-HIL–knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy. Cancer Res; 70(14); 5778–87. ©2010 AACR.
Dysregulation of p53/Sp1 Control Leads to DNA Methyltransferase-1 Overexpression in Lung Cancer
Authors: Lin Ruo-Kai , Wu Chiu-Yi , Chang Jer-Wei , Juan Li-Jung , Hsu Han-Shui , Chen Chih-Yi , Lu Yun-Yueh , Tang Yen-An , Yang Yi-Chieh , Yang Pan-Chyr , Wang Yi-Ching
Published: June 2010

Overexpression of DNA 5′-cytosine-methyltransferases (DNMT), which are enzymes that methylate the cytosine residue of CpGs, is involved in many cancers. However, the mechanism of DNMT overexpression remains unclear. Here, we showed that wild-type p53 negatively regulated DNMT1 expression by forming a complex with specificity protein 1 (Sp1) protein and chromatin modifiers on the DNMT1 promoter. However, the stoichiometry between p53 and Sp1 determined whether Sp1 acts as a transcription activator or corepressor. Low level of exogenous Sp1 enhanced the repressive activity of endogenous p53 on the DNMT1 promoter whereas high level of Sp1 upregulated DNMT1 gene expression level in A549 (p53 wild-type) cells. In H1299 (p53 null) cells, exogenous Sp1 induced DNMT1 expression in a dose-dependent manner. We also discovered a new mechanism whereby high level of Sp1, via its COOH-terminal domain, induced interaction between p53 and MDM2, resulting in degradation of p53 by MDM2-mediated ubiquitination. Clinical data from 102 lung cancer patients indicated that overexpression of DNMT1 was associated with p53 mutation (P = 0.014) and high expression of Sp1 protein (P = 0.006). In addition, patients with overexpression of both DNMT1 and Sp1 proteins showed poor prognosis (P = 0.037). Our cell and clinical data provided compelling evidence that deregulation of DNMT1 is associated with gain of transcriptional activation of Sp1 and/or loss of repression of p53. DNMT1 overexpression results in epigenetic alteration of multiple tumor suppressor genes and ultimately leads to lung tumorigenesis and poor prognosis. Cancer Res; 70(14); 5807–17. ©2010 AACR.
Altered Dynamics of Intestinal Cell Maturation in Apc1638N/+ Mice
Authors: Wang Donghai , Pezo Rossanna C. , Corner Georgia , Sison Cristina , Lesser Martin L. , Shenoy Shailesh M. , Mariadason John M. , Singer Robert H. , Augenlicht Leonard H.
Published: June 2010

Novel imaging of active transcription sites in interphase nuclei of intestinal epithelial cells in situ showed that key genes associated with Wnt and Notch signaling were dynamically regulated as the cells underwent normal maturation during their migration along the mouse crypt-villus axis (CVA). However, oscillating patterns of activation of these genes were displaced along this axis in the histologically normal intestinal mucosa of Apc1638N/+ mice before tumor development. Gene expression profiling then showed that the normal reprogramming of cells along the CVA was dampened in the Apc1638N/+ mice, with an overrepresentation of c-myc target genes among those loci affected in the mutant mice. Moreover, in the Apc1638N/+ mice, there was a perturbed pattern of expression of lineage-specific markers along the CVA consistent with transcription site repression of the Math1 gene, and genes encoding enzymes of every step of the tricarboxylic acid cycle were downregulated in the crypt of Apc1638N/+ mice compared with WT, but not in the villus. These changes may alter energy metabolism and generate a pseudohypoxic state, suggested by elevated expression of Hif1α and its target genes. Thus, although intestinal tumors develop in Apc1638N/+ mice on focal loss or inactivation of the WT allele, our results show that in the Apc1638N/+ mouse, inheritance of only a single WT Apc allele perturbs the dynamic and complex reprogramming underlying normal cell maturation, which links epithelial function and homeostasis with architectural organization of the intestine. Cancer Res; 70(13); 5348–57. ©2010 AACR.
Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes
Authors: Movahedi Kiavash , Laoui Damya , Gysemans Conny , Baeten Martijn , Stangé Geert , Van den Bossche Jan , Mack Matthias , Pipeleers Daniel , In't Veld Peter , De Baetselier Patrick , Van Ginderachter Jo A.
Published: June 2010

Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6ChiCX3CR1low monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally “re-educating” the TAM compartment. Cancer Res; 70(14); 5728–39. ©2010 AACR.