bluuebunny/crossref_metadata_2025 huggingface dataset:
Conditional gene inactivation reveals roles for Fgf10 and Fgfr2 in establishing a normal pattern of epithelial branching in the mouse lung
Authors: Abler Lisa L. , Mansour Suzanne L. , Sun Xin
Published: July 2009

Fibroblast growth factor 10 (FGF10) signaling through FGF receptor 2 (FGFR2) is required for lung initiation. While studies indicate that Fgf10 and Fgfr2 are also important at later stages of lung development, their roles in early branching events remain unclear. We addressed this question through conditional inactivation of both genes in mouse subsequent to lung initiation. Inactivation of Fgf10 in lung mesenchyme resulted in smaller lobes with a reduced number of branches. Inactivation of Fgfr2 in lung epithelium resulted in disruption of lobes and small epithelial outgrowths that arose arbitrarily along the main bronchi. In both mutants, there was an increase in cell death. Also, the expression patterns of key signaling molecules implicated in branching morphogenesis were altered and a proximal lung marker was expanded distally. Our results indicate that both Fgf10 and Fgfr2 are required for a normal branching program and for proper proximal–distal patterning of the lung.Developmental Dynamics 238:1999–2013, 2009. © 2009 Wiley‐Liss, Inc.
Obesity: Is it a mental disorder?
Authors: Marcus Marsha D. , Wildes Jennifer E.
Published: July 2009

Objective:

Using Wakefield's conceptualization of mental disorder as “harmful mental dysfunction” (Wakefield, Am Psychol, 47, 373–388, 1992), we examined the evidence for including obesity as a mental disorder in DSM‐V.

Method:

We searched computer databases and examined reference lists from review articles published in the last 10 years to identify empirical papers relevant to the present review.

Results:

Obesity is a condition of heterogeneous etiology that is harmful for most individuals. However, there is scant evidence that obesity, in general, is caused by mental dysfunction. Although recent work examining the neurocircuitry of energy balance has suggested that mental dysfunction may be involved in the etiology of specific obesity phenotypes, findings are too preliminary to support classification of obesity as a mental disorder. Nevertheless, there is evidence that obesity is related to mental disorder and many of the medications used to treat psychiatric illness.

Discussion:

There is little evidence for including obesity as a mental disorder in DSM‐V. However, results confirm the importance of monitoring adiposity routinely among patients with psychiatric illness. © 2009 American Psychiatric Association. (Int J Eat Disord 2009)
Validity and utility of the current definition of binge eating
Authors: Wolfe Barbara E. , Baker Christina Wood , Smith Adrian T. , Kelly‐Weeder Susan
Published: July 2009

Objective

Binge eating, a cardinal symptom of bulimia nervosa (BN) and binge eating disorder (BED), continues to pose challenges in terms of its definition and thus construct validity and clinical utility. This article reviews the available empirical data that support or refute the current DSM‐IV‐TR defined characteristics of a binge episode.

Method

A systematic literature review was conducted using Medline/PubMed electronic database on DSM‐IV‐TR defined binge characteristics and associated attributes.

Results

Data support the current DSM guidelines indicating that binge episodes typically occur in less than 2 h. Size of binge episodes has variability across BN and BED diagnostic groups. Loss of control (LOC) continues to be a core feature of binge eating. Negative affect is the most widely reported antecedent. Strikingly, little is known about binge episodes among individuals with anorexia nervosa‐binge/purge subtype.

Discussion

Available empirical evidence supports the current DSM duration and LOC attributes of a binge episode in BN and BED. However, a more controversial issues is the extent to which size is important in the definition of a binge episode (e.g., subjective vs. objective episodes) across diagnostic categories and the extent to which binge size informs prognosis, treatment, and clinical outcomes. Further study of binge eating attributes in AN is needed. © 2009 American Psychiatric Association. Int J Eat Disord 2009
Rapid release of cytoplasmic IL‐15 from tumor‐associated macrophages is an initial and critical event in IL‐12‐initiated tumor regression
Authors: Watkins Stephanie K. , Li Bing , Richardson Katharine S. , Head Kimberly , Egilmez Nejat K. , Zeng Qun , Suttles Jill , Stout Robert D.
Published: July 2009

This study reveals that the IL‐15 rapidly released into serum upon IL‐12 injection into tumor‐bearing mice is critical for the subsequent leukocytic infiltration of the tumor and tumor‐bearing tissue. The increase in serum IL‐15 occurs within 2 h after IL‐12 injection concomitantly with a decrease in cytoplasmic IL‐15 in tumor‐associated Mϕ (TAM). Injection of anti‐IL‐15 one hour prior to IL‐12 abrogates subsequent leukocytic infiltration into the tumor and prevents the IL‐12‐induced reduction of primary tumor mass and the clearance of metastases. Administration of anti‐IL‐15 18 h after IL‐12 did not have a detectable impact on IL‐12‐induced leukocytic infiltration of the tumor. Deletion of NK cells had no impact on the IL‐12‐induced change in the functional phenotype of TAM or on the subsequent initiation of leukocytic infiltration of the tumor. In concert with our previous studies demonstrating that IL‐12 reduces tumor‐supportive activities of TAM, the current study supports the hypothesis that functional re‐programming of TAM not only undermines Mϕ support for tumor growth but also contributes to a critical step in the initiation of anti‐tumor immune responses. In this context, the functional plasticity and pro‐immunogenic potential of TAM may constitute a significant and unappreciated target in existing cytokine therapies.
Strategies for optimizing targeting and delivery of mucosal HIV vaccines
Authors: Ahlers Jeffrey D. , Belyakov Igor M.
Published: July 2009

Effective frontline defenses against HIV‐1 will require targeting vaccines to mucosal tissue in order to induce αβ CD8+ lymphocytes in mucosal effector sites (lamina propria and intraepithelial compartment) as well as antibody secreting plasma cells that can neutralize and limit free virus. A concerted second wave of assault against the virus will require the activation and recruitment of antigen specific memory CD4+ and CD8+ T cells in mesenteric lymph nodes and distal secondary lymphoid organs. New delivery strategies targeting the “right” DC subsets in combination with delivery of mucosal adjuvants and innate signals for activating DC will be essential for mucosal vaccines in order to circumvent the naturally tolerogenic environment and the induction of Tregs. Mucosal delivery of antigen in combination with inflammatory signals has been shown to empower systemic immunization by directing responses to mucosal sites for imprinting optimum mucosal memory. Here, we discuss novel vaccine strategies and adjuvants for optimizing mucosal delivery of HIV vaccines.
Human CD8+CXCR3+ T cells have the same function as murine CD8+CD122+ Treg
Authors: Shi Zhe , Okuno Yusuke , Rifa'i Muhaimin , Endharti Agustina Tri , Akane Kazuyuki , Isobe Ken‐ichi , Suzuki Haruhiko
Published: July 2009

The importance of CD8+CD122+ Treg in the maintenance of immune homeostasis has been previously demonstrated in mice. Because the expression pattern of CD8 and CD122 in humans is different from that in mice, human CD8+ Treg that correspond to the murine CD8+CD122+ Treg have not been identified. In this study, we performed DNA microarray analyses to compare the gene expression profiles of CD8+CD122+ cells and CD8+CD122− cells in mice and found that CXCR3 was preferentially expressed in CD8+CD122+ cells. When we analyzed the expression of CD122 and CXCR3 in murine CD8+ cells, we observed a definite population of CD122+CXCR3+ cells. CD8+CXCR3+ cells in mice showed similar regulatory activities to CD8+CD122+ cells by in vivo and in vitro assays. While CD8+CD122+CXCR3+ cells are present in mice, CD8+CXCR3+ cells, but not CD8+CD122+ cells, are present in humans. In the in vitro assay, human CD8+CXCR3+ cells showed the regulatory activity of producing IL‐10 and suppressing IFN‐γ production from CD8+CXCR3− cells. These results suggest that human CD8+CXCR3+ T cells are the counterparts of murine CD8+CD122+ Treg.
Structural remodeling of gray matter astrocytes in the neonatal pig brain after hypoxia/ischemia
Authors: Sullivan Susan M. , Björkman S. Tracey , Miller Stephanie M. , Colditz Paul B. , Pow David V.
Published: July 2009

Astrocytes play a vital role in the brain; their structural integrity and sustained function are essential for neuronal viability, especially after injury or insult. In this study, we have examined the response of astrocytes to hypoxia/ischemia (H/I), employing multiple methods (immunohistochemistry, iontophoretic cell injection, Golgi‐Kopsch staining, and D‐aspartate uptake) in a neonatal pig model of H/I. We have identified morphological changes in cortical gray matter astrocytes in response to H/I. Initial astrocytic changes were evident as early as 8 h post‐insult, before histological evidence for neuronal damage. By 72 h post‐insult, astrocytes exhibited significantly fewer processes that were shorter, thicker, and had abnormal terminal swellings, compared with astrocytes from control brains that exhibited a complex structure with multiple fine branching processes. Quantification and image analysis of astrocytes at 72 h post‐insult revealed significant decreases in the average astrocyte size, from 686 μm2 in controls to 401 μm2 in H/I brains. Sholl analysis revealed a significant decrease (>60%) in the complexity of astrocyte branching between 5 and 20 μm from the cell body. D‐Aspartate uptake studies revealed that the H/I insult resulted in impaired astrocyte function, with significantly reduced clearance of the glutamate analog, D‐aspartate. These results suggest that astrocytes may be involved in the pathophysiological events of H/I brain damage at a far earlier time point than first thought. Developing therapies that prevent or reverse these astrocytic changes may potentially improve neuronal survival and thus might be a useful strategy to minimize brain damage after an H/I insult. © 2009 Wiley‐Liss, Inc.
Olfactory mucosa for transplant‐mediated repair: A complex tissue for a complex injury?
Authors: Lindsay Susan L. , Riddell John S. , Barnett Susan C.
Published: July 2009

Damage to the brain and spinal cord leads to permanent functional disability because of the very limited capacity of the central nervous system (CNS) for repair. Transplantation of cells into regions of CNS damage represents one approach to enhancing this repair. At present, the ideal cell type for transplant‐mediated repair has not been identified but autologous transplantation would be advantageous. Olfactory tissue, in part because of its capacity for regeneration, has emerged as a promising source of cells and several clinical centers are using olfactory cells or tissues in the treatment of CNS damage. Until now, the olfactory ensheathing cell, a specialized glial cell of the olfactory system has been the main focus of attention. Transplants of this cell have been shown to have a neuroprotective function, support axonal regeneration, and remyelinate demyelinated axons. However, the olfactory mucosa is a heterogeneous tissue, composed of a variety of cells supporting both its normal function and its regenerative capacity. It is therefore possible that it contains several cell types that could participate in CNS repair including putative stem cells as well as glia. Here we review the cellular composition of the olfactory tissue and the evidence that equivalent cell types exist in both rodent and human olfactory mucosa suggesting that it is potentially a rich source of autologous cells for transplant‐mediated repair of the CNS. © 2009 Wiley‐Liss, Inc.
Blockade of IL‐15 activity inhibits microglial activation through the NFκB, p38, and ERK1/2 pathways, reducing cytokine and chemokine release
Authors: Gomez‐Nicola Diego , Valle‐Argos Beatriz , Nieto‐Sampedro Manuel
Published: July 2009

Reactive glia formation is one of the hallmarks of damage to the CNS, but little information exists on the signals that direct its activation. Microglial cells are the main regulators of both innate and adaptative immune responses in the CNS. The proinflammatory cytokine IL‐15 is involved in regulating the response of T and B cells, playing a key role in regulating nervous system inflammatory events. We have used a microglial culture model of inflammation induced by LPS and IFNγ to evaluate the role of IL‐15 in the proinflammatory response. Our results indicate that IL‐15 is necessary for the reactive response, its deficiency (IL‐15‐/‐) leading to the development of a defective proinflammatory response. Blockade of IL‐15, both with blocking antibodies or with the ganglioside Neurostatin, inhibited the activation of the NFκB pathway, decreasing iNOS expression and NO production. Inhibiting IL‐15 signaling also blocked the activation of the mitogen‐activated protein kinase (MAPK) pathways ERK1/2 and p38. The major consequence of these inhibitory effects, analyzed using cytokine antibody arrays, was a severe decrease in the production of chemokines, cytokines and growth factors, like CCL17, CCL19, IL‐12, or TIMP‐1, that are essential for the development of the phenotypic changes of glial activation. In conclusion, activation of the IL‐15 system seems a necessarystep for the development of glial reactivity and the regulation of the physiology of glial cells. Modulating IL‐15 activity opens the possibility of developing new strategies to control gliotic events upon inflammatory stimulation. © 2009 Wiley‐Liss, Inc.
The neural origins of superficial and individuated judgments about ingroup and outgroup members
Authors: Freeman Jonathan B. , Schiller Daniela , Rule Nicholas O. , Ambady Nalini
Published: July 2009

We often form impressions of others based on superficial information, such as a mere glimpse of their face. Given the opportunity to get to know someone, however, our judgments are allowed to become more individuated. The neural origins of these two types of social judgment remain unknown. We used functional magnetic resonance imaging to dissociate the neural mechanisms underlying superficial and individuated judgments. Given behavioral evidence demonstrating impairments in individuating others outside one's racial group, we additionally examined whether these neural mechanisms are race‐selective. Superficial judgments recruited the amygdala. Individuated judgments engaged a cortical network implicated in mentalizing and theory of mind. One component of this mentalizing network showed selectivity to individuated judgments, but exclusively for targets of one's own race. The findings reveal the distinct—and race‐selective—neural bases of our everyday superficial and individuated judgments of others. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.
Progressive fatigue effects on manual lifting factors
Authors: Banks Anthony D. , Aghazadeh Fereydoun
Published: July 2009

The purpose of this study was to evaluate the effect of progressive fatigue on factors that previously have been associated with increased risk of low back pain in various occupational settings, during a repetitive lifting task where a freestyle lifting technique was used. A laboratory experiment was conducted to evaluate electromyography amplitude, kinematic, and kinetic parameters of repetitive freestyle lifting during a 2‐hour lifting period. Subjective fatigue rating increased over time, indicating that the participant “felt” increasingly fatigued as the experiment progressed. Static composite strength decreased an average of 20% from the beginning to the end of the experiment. Effect of lifting posture (semi‐squat, semi‐stoop, and stoop) was observed on peak trunk flexion angle, trunk flexion angle at initiation of the lift, and knee angle at initiation of the lift indicating that, in freestyle lifting, participants assume quantitatively different lifting techniques. A significant effect of the time–posture interaction was observed on the dynamic leg lift floor to knuckle height strength, indicating that dynamic strength may change over time depending on lifting posture selected. © 2009 Wiley Periodicals, Inc.
Efficacy and safety of quetiapine for depressive symptoms in patients with schizophrenia
Authors: Lee Kyoung‐Uk , Jeon Yang‐Whan , Lee Hae‐Kook , Jun Tae‐Youn
Published: July 2009

Objective

To investigate the efficacy and safety of quetiapine for depressive symptoms in patients with schizophrenia.

Method

Thirty‐nine patients fulfilling DSM‐IV‐TR diagnostic criteria for schizophrenia and had depressive symptoms were studied in a prospective 6‐week open‐label design using quetiapine monotherapy. The brief psychiatric rating scale (BPRS), 17‐item Hamilton depression rating scale (HAMD‐17), Simpson–Angus rating scale, and the Barnes Akathisia rating scale (BARS) were used to assess patients at baseline, week 1, 2, 4, and 6.

Results

Thirty patients (76.9%) completed this study. The dose of quetiapine at endpoint was 583 (±235 SD) mg/day. Treatment with Quetiapine was associated with significantly reduced depressive symptoms (HAMD‐17 total score and BPRS depression/anxiety subscale) from the first week of treatment. Changes of mean score from baseline to endpoint were 7.8 ± 6.2 for HAMD‐17 total score and 3.4 ± 3.6 for BPRS depression/anxiety subscale (LOCF, n = 39, p < 0.001). Quetiapine was well tolerated, with minimal extrapyramidal symptoms and non‐significant increase in body weight (mean increase of 0.8 kg).

Conclusions

While the interpretation of findings from the open‐label design of this study warrants appropriate caution, the results suggest that quetiapine may be an effective and tolerable treatment for depression in patients with schizophrenia. Copyright © 2009 John Wiley & Sons, Ltd.
Hydrodynamic modelling of a large flood‐prone river system in India with limited data
Authors: Patro Shivananda , Chatterjee Chandranath , Singh Rajendra , Raghuwanshi Narendra Singh
Published: July 2009

The article presents a detailed review on the issues and constraints of hydrodynamic modelling of floods in data‐poor countries with large flood‐prone rivers. A one‐dimensional (1D) hydrodynamic model is used to simulate the river flows with limited available data in the delta region of Mahanadi River basin in India. The shuttle radar topography mission digital elevation models (SRTM DEM) was analyzed and compared with the elevations derived from available topomaps and measured river cross‐sections. Subsequently, the SRTM‐derived river cross‐section elevation values are refined for use in the hydrodynamic model. The 1D hydrodynamic model is set up and calibrated using the refined cross‐sections derived from SRTM DEM along with the measured ones and all available river discharge as well as water‐level data at different gauging sites for the monsoon period (June–September) of the year 2004. The calibrated set up is validated using both discharge and water‐level data for the same period for the years 2001 and 2002. The performance of the calibration and validation results of the hydrodynamic model is evaluated for all the years using different performance indices. The model‐simulated discharge and water levels are found to be in close agreement with the observed ones. The study demonstrates the usefulness of using the SRTM DEM to derive river cross‐sections for use in hydrodynamic modelling studies. Copyright © 2009 John Wiley & Sons, Ltd.
Enhancement of in vivo bone regeneration efficacy of osteogenically undifferentiated human cord blood mesenchymal stem cells
Authors: Kang Jin Muk , Kang Sun‐Woong , La Wan‐Geun , Yang Yoon‐Sun , Kim Byung‐Soo
Published: July 2009

We hypothesized that bone morphogenetic protein‐2 (BMP‐2) would significantly enhance in vivo bone formation efficacy of osteogenically undifferentiated human cord blood mesenchymal stem cells (hCBMSCs). To test this hypothesis, poly(lactic‐co‐glycolic acid)/hydroxyapatite (PLGA/HA) scaffolds (group 1), BMP‐2‐loaded PLGA/HA scaffolds (group 2), undifferentiated hCBMSCs seeded on PLGA/HA scaffolds (group 3), undifferentiated hCBMSCs seeded on BMP‐2‐loaded PLGA/HA scaffolds (group 4), and osteogenically differentiated hCBMSCs seeded on PLGA/HA scaffolds (group 5) were implanted into dorsal, subcutaneous spaces of athymic mice for 8 weeks. Histological analysis showed that group 4 exhibited the largest bone formation area. RT‐PCR analysis showed that human mRNA expression of osteoblastic markers such as ALP and osteocalcin in group 4 was higher than that of the other groups. Mouse osteoblastic markers of the host cells in the implants were also expressed more in group 4 than in the other groups. This study demonstrated that hCBMSCs that were not differentiated osteogenically in vitro prior to transplantation regenerate bone negligibly in vivo and that transplantation of osteogenically undifferentiated hCBMSCs with BMP‐2 delivery results in much more extensive bone formation in vivo than that of undifferentiated or osteogenically differentiated hCBMSCs. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Patterning N‐type and S‐type neuroblastoma cells with Pluronic F108 and ECM proteins
Authors: Corey Joseph M. , Gertz Caitlyn C. , Sutton Thomas J. , Chen Qiaoran , Mycek Katherine B. , Wang Bor‐Shuen , Martin Abbey A. , Johnson Sara L. , Feldman Eva L.
Published: July 2009

Influencing cell shape using micropatterned substrates affects cell behaviors, such as proliferation and apoptosis. Cell shape may also affect these behaviors in human neuroblastoma (NBL) cancer, but to date, no substrate design has effectively patterned multiple clinically important human NBL lines. In this study, we investigated whether Pluronic F108 was an effective antiadhesive coating for human NBL cells and whether it would localize three NBL lines to adhesive regions of tissue culture plastic or collagen I on substrate patterns. The adhesion and patterning of an S‐type line, SH‐EP, and two N‐type lines, SH‐SY5Y and IMR‐32, were tested. In adhesion assays, F108 deterred NBL adhesion equally as well as two antiadhesive organofunctional silanes and far better than bovine serum albumin. Patterned stripes of F108 restricted all three human NBL lines to adhesive stripes of tissue culture plastic. We then investigated four schemes of applying collagen and F108 to different regions of a substrate. Contact with collagen obliterates the ability of F108 to deter NBL adhesion, limiting how both materials can be applied to substrates to produce high fidelity NBL patterning. This patterned substrate design should facilitate investigations of the role of cell shape in NBL cell behavior. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Tissue engineering of composite grafts: Cocultivation of human oral keratinocytes and human osteoblast‐like cells on laminin‐coated polycarbonate membranes and equine collagen membranes under different culture conditions
Authors: Glaum R. , Wiedmann‐Al‐Ahmad M. , Huebner U. , Schmelzeisen R.
Published: July 2009

In complex craniomaxillofacial defects, the simultaneous reconstruction of hard and soft tissue is often necessary. Until now, oral keratinocytes and osteoblast‐like cells have not been cocultivated on the same carrier. For the first time, the cocultivation of human oral keratinocytes and human osteoblast‐like cells has been investigated in this study. Different carriers (laminin‐coated polycarbonate and equine collagen membranes) and various culture conditions were examined. Human oral keratinocytes and human osteoblast‐like cells from five patients were isolated from tissue samples, seeded on the opposite sides of the carriers and cultivated for 1 and 2 weeks under static conditions in an incubator and in a perfusion chamber. Proliferation and morphology of the cells were analyzed by EZ4U‐tests, light microscopy, and scanning electron microscopy. Cocultivation of both cell‐types seeded on one carrier was possible. Quantitative and qualitative growth was significantly better on collagen membranes when compared with laminin‐coated polycarbonate membranes independent of the culture conditions. Using perfusion culture in comparison to static culture, the increase of cell proliferation after 2 weeks of cultivation when compared with the proliferation after 1 week was significantly lower, independent of the carriers used. In conclusion, the contemporaneous cultivation of human oral keratinocytes and human osteoblast‐like cells on the same carrier is possible, a prerequisite for planned in vivo studies. As carrier collagen is superior to laminin‐coated polycarbonate membranes. Regarding the development over time, the increase of proliferation rate is lower in perfusion culture. Examinations of cellular differentiation over time under various culture conditions will be subject of further investigations. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Bone formation on rough, but not polished, subcutaneously implanted Ti surfaces is preceded by macrophage accumulation
Authors: Chehroudi Babak , Ghrebi Salem , Murakami Hiroshi , Waterfield John Douglas , Owen Gethin , Brunette Donald Maxwell
Published: July 2009

Implanted rough surfaces have long been associated with the accumulation of macrophages and other cells of the monocytic lineage such as foreign body giant cells and osteoclasts. As cells of the moncytic lineage are part of the immune system, the response of this cell family to biomaterials has attracted wide concern. This study compared events at the interface of implant surface topographies with varied roughness in a rat subcutaneous model. Titanium‐coated epoxy replicas of machined, etched, blasted, titanium‐plasma‐sprayed (TPS), sandblasted‐and‐etched (SLA), micromachined, and polished surfaces were implanted for up to 11 weeks, and processed for light or electron microscopy or immunohistochemistry for ED1, a marker for recruited macrophages. Initially, healing appeared similar among all surfaces, the frequency of mineralization followed the order of SLA, micromachined, TPS, machined, etched, blasted, and polished surfaces. On the SLA surface macrophages, as identified by both ultrastructural morphology and immunohistochemistry were the predominant cell type at 1 week and persisted until mineralization occurred as early as 2 weeks. On smoother surfaces collagenous matrix predominated at 2 weeks and subsequently increased with time. There, thus, appears to be two routes to bone‐like tissue formation on Ti implants in this rat subcutaneous model; macrophage‐mediated and macrophage‐independent dense collagenous‐matrix‐associated. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Designing novel antitrypanosomal agents from a mixed graph‐theoretical substructural approach
Authors: Planche Alejandro Speck , Scotti Marcus Tulius , Emerenciano Vicente de Paulo , López América García , Pérez Enrique Molina , Uriarte Eugenio
Published: July 2009

Chagas disease is nowadays the most serious parasitic health problem. This disease is caused by Trypanosoma cruzi. The great number of deaths and the insufficient effectiveness of drugs against this parasite have alarmed the scientific community worldwide. In an attempt to overcome this problem, a model for the design and prediction of new antitrypanosomal agents was obtained. This used a mixed approach, containing simple descriptors based on fragments and topological substructural molecular design descriptors. A data set was made up of 188 compounds, 99 of them characterized an antitrypanosomal activity and 88 compounds that belong to other pharmaceutical categories. The model showed sensitivity, specificity and accuracy values above 85%. Quantitative fragmental contributions were also calculated. Then, and to confirm the quality of the model, 15 structures of molecules tested as antitrypanosomal compounds (that we did not include in this study) were predicted, taking into account the information on the abovementioned calculated fragmental contributions. The model showed an accuracy of 100% which means that the “in silico” methodology developed by our team is promising for the rational design of new antitrypanosomal drugs. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
Quantitative composition of vitellogenin‐derived yolk proteins and their effects on viability of embryos and larvae of common dentex (Dentex dentex), a marine pelagophil teleost
Authors: Samaee Seyed‐Mohammadreza , Lahnsteiner Franz , Giménez Gemma , Estévez Alicia , Sarg Bettina , Lindner Herbert
Published: July 2009

To evaluate the importance of the quantitative composition of vitellogenin (Vtg)‐derived egg yolk proteins during initial events of Dentex dentex life, viable eggs were obtained from captive broodstocks. Viability parameters (VPs; egg buoyancy (FR), hatching rate (HR), and larval survival rate (SR) at 0, 3, and 5 days posthatch (dph)) were determined for 70 egg batches. Vtg‐derived yolk proteins were purified from the eggs using cation‐exchange chromatography, separated and detected by SDS‐PAGE, identified and characterized using mass spectrometry, quantified using image densitometry, and finally correlated to VPs. The 77.97, 57.22, 22.22, 17.69 and 16.95 kDa proteins were identified as proteolytic products resulted from both VtgA and B. All the Vtg‐derived yolk proteins were significantly correlated to VPs with a maximum explanatory effect (R2) of 0.634. The concentration of the 57.22 kDa protein was significantly correlated with FR, the 77.97, 57.22, 22.22, 17.69 and 16.95 kDa proteins with HR and SR at 0 dph, the 22.22, 17.69 and 16.95 kDa proteins with SR at 3 and 5 dph. The results showed the importance of yolk protein content in the egg for embryogenesis and early larval development and indicated its potential use to predict egg quality in teleosts. J. Exp. Zool. 311A:504–520, 2009. © 2009 Wiley‐Liss, Inc.
Subcellular distribution of urea transporter in the collecting tubule of shark kidney is dependent on environmental salinity
Authors: Yamaguchi Yoko , Takaki Shin , Hyodo Susumu
Published: July 2009

In the kidney of marine elasmobranchs, urea reabsorption from filtered urine is essential for maintaining high levels of urea in the body. In the kidney of the houndshark, Triakis scyllium, we previously found that a facilitative urea transporter (UT) is localized to a specific nephron segment, the collecting tubule, suggesting that the collecting tubule has an important role in the urea reabsorption process. To elucidate the roles of UT, we transferred T. scyllium to high (130%) and low (30%) salinity, and examined UT mRNA levels and UT distribution patterns in the kidney using real‐time PCR and semi‐quantitative fluorescence immunohistochemistry, respectively. Following transfer to low and high salinity, houndshark decreased and increased plasma urea concentrations, respectively, in order to control plasma osmolality. The abundance of UT mRNA did not differ among the experimental groups, whereas that of UT protein in the collecting tubule was significantly decreased in 30% seawater (SW). Furthermore, the subcellular UT distribution was dramatically changed. UT in the apical plasma membrane of collecting tubule almost disappeared in 30% SW, whereas it slightly increased in 130% SW compared with 100% SW. Conversely, reverse transfer of fish from 30 to100% SW restored UT in the apical membrane. These results indicate that the accumulation of UT to the apical plasma membrane of the collecting tubule of Triakis is an important factor for regulating urea reabsorption in the kidney. J. Exp. Zool. 311A: 705–718, 2009. © 2009 Wiley‐Liss, Inc.
Temperature, phenotype, and the evolution of temperature‐dependent sex determination: how do natural incubations compare to laboratory incubations?
Authors: Paitz Ryan T. , Gould Amelia C. , Holgersson Mikael C.N. , Bowden Rachel M.
Published: July 2009

Phenotypic variation is a fundamental component of the process of evolution and understanding the factors that create this variation is critical to investigations of this process. We test the hypothesis that phenotypic variation created under natural incubation conditions will differ from that created under constant laboratory conditions in a reptile species with temperature‐dependent sex determination (TSD), the red‐eared slider turtle (Trachemys scripta). Using a split clutch design, we demonstrate that offspring morphology, behavior, and sex differed between hatchlings incubated in the field and those from the laboratory, but immune response did not. The interactions between different phenotypic parameters will ultimately determine how natural selection acts upon offspring, and consequently our data suggest that offspring developing under these differing conditions should have different fitnesses. The relationship between offspring sex and phenotype serves as the theoretical foundation on which most investigations into the evolution of TSD are built. Thus, it may be necessary to use natural incubation conditions to accurately examine how offspring sex relates to other phenotypic parameters if we are to understand the evolution of this sex determining mechanism. J. Exp. Zool. (Mol. Dev. Ecol.) 314B:86–93, 2010. © 2009 Wiley‐Liss, Inc.
Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis
Authors: Sone Jun , Niwa Jun‐ichi , Kawai Kaori , Ishigaki Shinsuke , Yamada Shin‐ichi , Adachi Hiroaki , Katsuno Masahisa , Tanaka Fumiaki , Doyu Manabu , Sobue Gen
Published: July 2009

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive motor neuron degeneration and leads to death within a few years of diagnosis. One of the pathogenic mechanisms of ALS is proposed to be a dysfunction in the protein quality‐control machinery. Dorfin has been identified as a ubiquitin ligase (E3) that recognizes and ubiquitinates mutant SOD1 proteins, thereby accelerating their degradation and reducing their cellular toxicity. We examined the effects of human Dorfin overexpression in G93A mutant SOD1 transgenic mice, a mouse model of familial ALS. In addition to causing a decrease in the amount of mutant SOD1 protein in the spinal cord, Dorfin overexpression ameliorated neurological phenotypes and motor neuron degeneration. Our results indicate that Dorfin overexpression or the activation or induction of E3 may be a therapeutic avenue for mutant SOD1‐associated ALS. © 2009 Wiley‐Liss, Inc.
Parkin reverses intracellular β‐amyloid accumulation and its negative effects on proteasome function
Authors: Rosen Kenneth M. , Moussa Charbel E.‐H. , Lee Han‐Kyu , Kumar Pravir , Kitada Tohru , Qin Gangjian , Fu Qinghao , Querfurth Henry W.
Published: July 2009

The significance of intracellular β‐amyloid (Aβ42) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Aβ removal mechanisms that have attracted attention include IDE/neprilysin degradation and antibody‐mediated uptake by immune cells. However, the role of the ubiquitin‐proteasome system (UPS) in the disposal of cellular Aβ has not been fully explored. The E3 ubiquitin ligase Parkin targets several proteins for UPS degradation, and Parkin mutations are the major cause of autosomal recessive Parkinson's disease. We tested whether Parkin has cross‐function to target misfolded proteins in AD for proteasome‐dependent clearance in SH‐SY5Y and primary neuronal cells. Wild‐type Parkin greatly decreased steady‐state levels of intracellular Aβ42, an action abrogated by proteasome inhibitors. Intracellular Aβ42 accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Aβ or Parkin did not account for their effects on the proteasome. Parkin knock‐down led to accumulation of Aβ. In AD brain, Parkin was found to interact with Aβ and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Aβ through a proteasome‐dependent pathway. © 2009 Wiley‐Liss, Inc.
Postnatal development of NT3 and TrkC in mouse ventral cochlear nucleus
Authors: Feng J. , Bendiske J. , Morest D.K.
Published: July 2009

In the developing nervous system, neurotrophin 3 (NT3) and brain‐derived neurotrophic factor (BDNF) have been shown to interact with each other and with different parts of a neuron or glia and over considerable distances in time and space. The auditory system provides a useful model for analyzing these events, insofar as it is subdivided into well‐defined groups of specific neuronal types that are readily related to each other at each stage of development. Previous work in our laboratory suggested that NT3 and its receptor TrkC in the mouse cochlear nucleus (CN) may be involved in directing neuronal migration and initial targeting of inputs from cochlear nerve axons in the embryo. NT3 is hard to detect soon after birth, but TrkC lingers longer. Here we found NT3 and TrkC around P8 and the peak around P30. Prominent in ventral CN, associated with globular bushy cells and stellate cells, they were localized to different subcellular sites. The TrkC immunostain was cytoplasmic, and that of NT3 was axonal and perisomatic. TrkC may be made by CN neurons, whereas NT3 has a cochlear origin. The temporal pattern of their development and the likelihood of activity‐dependent release of NT3 from cochlear axons suggest that it may not be critical in early synaptogenesis; it may provide long‐term trophic effects, including stabilization of synapses once established. Activity‐related regulation could coordinate the supply of NT3 with inner ear activity. This may require interaction with other neurotrophins, such as BDNF. © 2009 Wiley‐Liss, Inc.
NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network
Authors: Uittenbogaard Martine , Baxter Kristin K. , Chiaramello Anne
Published: July 2009

During neurogenesis, expression of the basic helix‐loop‐helix NeuroD6/Nex1/MATH‐2 transcription factor parallels neuronal differentiation and is maintained in differentiated neurons in the adult brain. To dissect NeuroD6 differentiation properties further, we previously generated a NeuroD6‐overexpressing stable PC12 cell line, PC12‐ND6, which displays a neuronal phenotype characterized by spontaneous neuritogenesis, accelerated NGF‐induced differentiation, and increased regenerative capacity. Furthermore, we reported that NeuroD6 promotes long‐term neuronal survival upon serum deprivation. In this study, we identified the NeuroD6‐mediated transcriptional regulatory pathways linking neuronal differentiation to survival, by conducting a genome‐wide microarray analysis using PC12‐ND6 cells and serum deprivation as a stress paradigm. Through a series of filtering steps and a gene‐ontology analysis, we found that NeuroD6 promotes distinct but overlapping gene networks, consistent with the differentiation, regeneration, and survival properties of PC12‐ND6 cells. By using a gene‐set‐enrichment analysis, we provide the first evidence of a compelling link between NeuroD6 and a set of heat shock proteins in the absence of stress, which may be instrumental in conferring stress tolerance on PC12‐ND6 cells. Immunocytochemistry results showed that HSP27 and HSP70 interact with cytoskeletal elements, consistent with their roles in neuritogenesis and preserving cellular integrity. HSP70 also colocalizes with mitochondria located in the soma, growing neurites, and growth cones of PC12‐ND6 cells prior to and upon stress stimulus, consistent with its neuroprotective functions. Collectively, our findings support the notion that NeuroD6 links neuronal differentiation to survival via the network of molecular chaperones and endows the cells with increased stress tolerance. © 2009 Wiley‐Liss, Inc.
Down‐regulation of microglia and NG2‐positive cells reaction in trimethyltin‐injured hippocampus of rats treated with myelin basic protein‐reactive T cells: Possible contribution to the neuroprotective effect of T cells
Authors: Kurkowska‐Jastrzębska Iwona , Zaremba Małgorzata , Członkowska Anna , Oderfeld‐Nowak Barbara
Published: July 2009

In our previous investigations, we demonstrated that CD4+ antimyelin basic protein (MBP) T cells protect hippocampal neurons against trimethyltin‐induced damage. We hypothesized involvement of T cells, interacting with the various glial populations activated during the neurodegeneration process. In this study, we employ immunocytochemical methods to investigate the influence of administration of T cells on the response of microglia and of NG2+ cells to trimethyltin (TMT)‐induced damage. Female Lewis rats were treated with anti‐MBP CD4+ T cells (4 million per animal, i.v) 24 hr after TMT (8 mg/kg, i.p) intoxication. TMT caused degeneration of CA4 hipppocampal neurons and evoked an abundant reaction of microglial and NG2+ cells in the injured region. The cells changed morphology into the activated state, and the number of OX42+ and NG2+ cells increased about 4.5‐fold and 3‐fold, respectively, relative to controls as assessed on day 21 after TMT treatment. Additionally, the cells of ameboid morphology, which expressed NG2 or microglial antigens, appeared in the zone of neurodegeneration. Furthermore, certain cells of ameboid phenotype shared both antigens. In rats treated with T cells, down‐regulation of the activation of both glial classes and reduction of formation of their ameboid forms was observed. The number of the total OX42+ and NG2+ cells decreased by 21% and 54%, respectively, and the number of their ameboid forms decreased by 46% and 73%, respectively. Our data suggest that the diminished activation of microglia and NG2+ cells, particularly the reduced number of their ameboid forms, may contribute to the neuroprotective effect of T cells. © 2009 Wiley‐Liss, Inc.
International tourism and economic development in South Africa: a Granger causality test
Authors: Akinboade Oludele A. , Braimoh Lydia A.
Published: July 2009

One of the major objectives of macroeconomic policies in many developing countries is sustained economic growth, and South Africa has been striving to achieve and maintain this in various ways. One of these is through international tourism. Although international tourism contributes to the growth of many economies, it is in turn, impacted by growth in many developed countries. Real gross domestic product (GDP), international tourism earnings, real effective exchange rate and exports were analysed within a multivariate vector auto regressive model using annual data covering 1980–2005. The main focus of this study therefore was to demonstrate the direction of causality between international tourism earnings and long‐run economic growth of South Africa, among other variables, using Granger causality analysis. The result obtained showed a unidirectional causality running from international tourism earnings to real GDP, both in the short run and in the long run. The error correction mechanism carried out also supported this causality. Copyright © 2009 John Wiley & Sons, Ltd.
Some Remarks on Dodgson's Voting Rule
Authors: Brandt Felix
Published: July 2009

Sparked by a remarkable result due to Hemaspaandra et al. [9], the voting rule attributed to Charles Dodgson (aka Lewis Carroll) has become one of the most studied voting rules in computational social choice. However, the computer science literature often neglects that Dodgson's rule has some serious shortcomings as a choice procedure. This short note contains four examples revealing Dodgson's deficiencies (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Hybrid Elections Broaden Complexity‐Theoretic Resistance to Control
Authors: Hemaspaandra Edith , Hemaspaandra Lane A. , Rothe Jörg
Published: July 2009

Electoral control refers to attempts by an election's organizer (“the chair”) to influence the outcome by adding/deleting/partitioning voters or candidates. The important paper of Bartholdi, Tovey, and Trick [1] that introduces (constructive) control proposes computational complexity as a means of resisting control attempts: Look for election systems where the chair's task in seeking control is itself computationally infeasible.

We introduce and study a method of combining two or more candidate‐anonymous election schemes in such a way that the combined scheme possesses all the resistances to control (i.e., all the NP‐hardnesses of control) possessed by any of its constituents: It combines their strengths. From this and new resistance constructions, we prove for the first time that there exists a neutral, anonymous election scheme (whose winner problem is computable in polynomial time) that is resistant to all twenty standard types of electoral control (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Sincere‐Strategy Preference‐Based Approval Voting Fully Resists Constructive Control and Broadly Resists Destructive Control
Authors: Erdélyi Gábor , Nowak Markus , Rothe Jörg
Published: July 2009

We study sincere‐strategy preference‐based approval voting (SP‐AV), a system proposed by Brams and Sanver [1] and here adjusted so as to coerce admissibility of the votes (rather than excluding inadmissible votes a priori), with respect to procedural control. In such control scenarios, an external agent seeks to change the outcome of an election via actions such as adding/deleting/partitioning either candidates or voters. SP‐AV combines the voters' preference rankings with their approvals of candidates, where in elections with at least two candidates the voters' approval strategies are adjusted – if needed – to approve of their most‐preferred candidate and to disapprove of their least‐preferred candidate. This rule coerces admissibility of the votes even in the presence of control actions, and hybridizes, in effect, approval with pluralitiy voting. We prove that this system is computationally resistant (i.e., the corresponding control problems are NP‐hard) to 19 out of 22 types of constructive and destructive control. Thus, SP‐AV has more resistances to control than is currently known for any other natural voting system with a polynomial‐time winner problem. In particular, SP‐AV is (after Copeland voting, see Faliszewski et al. [2, 3]) the second natural voting system with an easy winner‐determination procedure that is known to have full resistance to constructive control, and unlike Copeland voting it in addition displays broad resistance to destructive control (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Ernest Everett Just, Johannes Holtfreter, and the origin of certain concepts in embryo morphogenesis
Authors: Byrnes W. Malcolm
Published: July 2009

Ernest E. Just (1883–1941) is best known for his discovery of the “wave of negativity” that sweeps of the sea urchin egg during fertilization, and his elucidation of what are known as the fast and slow blocks to polyspermy. Just's contemporary Johannes Holtfreter (1901–1992) is known for his pioneering work in amphibian morphogenesis, which helped to lay the foundation for modern vertebrate developmental biology. This paper, after briefly describing the life and scientific contributions of Just, argues that his work and ideas strongly influenced two of the concepts for which Holtfreter is best known: tissue affinity and autoneuralization (or autoinduction). Specifically, this paper argues that, first, Just's experiments demonstrating developmental stage‐specific changes in the adhesiveness of the blastomeres of cleavage embryos helped lay the foundation for Holtfreter's concept of tissue affinity and, second, Just's notion of the intrinsic irritability of the egg cell, which is evident in experimental parthenogenesis, strongly informed Holtfreter's concept of the nonspecific induction of neural tissue formation in amphibian gastrula ectoderm explants, a phenomenon known as autoinduction. Acknowledgment of these contributions by Just in no way diminishes the importance of Holtfreter's groundbreaking work. It does, however, extend the impact of Just's work into the area of embryo morphogenesis. It connects Just to Holtfreter and positions his work as an antecedent to embryo research that continues to this day. Mol. Reprod. Dev. 76: 912–921, 2009. © 2009 Wiley‐Liss, Inc.