bluuebunny/crossref_metadata_2025 huggingface dataset:
An Approach to Experimental Synaptic Pathology Using Green Fluorescent Protein-Transgenic Mice and Gene Knockout Mice to Show Mitochondrial Permeability Transition Pore-Driven Excitotoxicity in Interneurons and Motoneurons
Authors: Martin Lee J.
Published: March 2011

Researchers used transgenic mice expressing enhanced-green fluorescent protein (eGFP) driven by either the glycine transporter-2 gene promoter to specifically visualize glycinergic interneurons or the homeobox-9 ( Hb9) gene promoter to visualize motoneurons for assessing their vulnerabilities to excitotoxins in vivo. Stereotaxic excitotoxic lesions were made in adult male and female mouse lumbar spinal cord with the specific N-methyl- D-aspartate (NMDA) receptor agonist quinolinic acid (QA) and the non-NMDA ion channel glutamate receptor agonist kainic acid (KA). QA and KA induced large-scale degeneration of glycinergic interneurons in spinal cord. Glycinergic interneurons were more sensitive than motoneurons to NMDA receptor-mediated and non-NMDA glutamate receptor-mediated excitotoxicity. Outcome after spinal cord excitotoxicity was gender-dependent, with males showing greater sensitivity than females. Excitotoxic degeneration of spinal interneurons resembled apoptosis, while motoneuron degeneration appeared non-apoptotic. Perikaryal mitochondrial accumulation was antecedent to both NMDA and non-NMDA receptor-mediated excitotoxic stimulation of interneurons and motoneurons. Genetic ablation of cyclophilin D, a regulator of the mitochondrial permeability transition pore (mPTP), protected both interneurons and motoneurons from excitotoxicity. The results demonstrate in adult mouse spinal cord that glycinergic interneurons are more sensitive than motoneurons to excitotoxicity that stimulates mitochondrial accumulation, and that the mPTP has pro-death functions mediating apoptotic and non-apoptotic neuronal degeneration in vivo.
Recommended Neuroanatomical Sampling Practices for Comprehensive Brain Evaluation in Nonclinical Safety Studies
Authors: Switzer Robert C. , Lowry-Franssen Catherine , Benkovic Stanley A.
Published: March 2011

Adequate tissue sampling is known to reduce the likelihood that the toxicity of novel biomolecules, chemicals, and drugs might go undetected. Each organ, and often specific structurally and functionally distinct regions within it, must be assessed to detect potential site-specific toxicity. Adequate sampling of the brain requires particular consideration because of the many major substructures and more than 600 subpopulations of generally irreplaceable cells with unique functions and vulnerabilities. All known neurotoxicants affect specific subpopulations (usually neurons) rather than damaging a certain percentage of cells throughout the brain; thus, all populations should be independently assessed for lesions. Historically, the affected neural cell subpopulation has not been predictable, but it is now clear that sampling selected populations (e.g., cerebral cortex, hippocampus, cerebellar folia) cannot forecast the health of other populations. This article reviews the neuroanatomical domains affected by several model neurotoxicants to illustrate the need for more comprehensive neurohistological evaluation during nonclinical development of novel compounds. The article also describes an easily executed, cost-effective method that uses a set number of evenly spaced coronal (cross) sections to accomplish this comprehensive brain assessment during nonclinical safety studies performed in rodents, dogs, and nonhuman primates.
A Feasibility Study to Evaluate a Novel Drug Delivery Technique through Nasal/Sinus Mucosa Using a Biodegradable Polymer in a Guinea Pig Model
Authors: Jonnalagadda Sashikanth , Yu Vivian M. , Catalano Peter J.
Published: March 2011

Objective

Targeted topical pharmaceuticals have fewer side effects than systemic therapy and present an interesting option to treat chronic sinus disease. A simple, dependable, resorbable drug delivery mechanism has been elusive. The goal of this study is to examine the feasibility of a novel bioresorbable synthetic polymer for drug delivery in nose and sinuses.

Study Design

Feasibility study.

Setting

Animal study.

Subjects and Methods

Polyurethane sponges soaked in either triamcinolone or gentamicin were placed in the ethmoid cavities of 14 guinea pigs via an external approach; 2 additional animals served as controls. Serum levels of each drug were assayed at intervals up to 21 days. Histopathological examination of the relevant sinonasal anatomy of each animal was performed after 21 days.

Results

Serum levels of each drug were detectable between days 1 and 21. There were no significant differences in the histopathological examination of nasal mucosa in guinea pigs in which either drug was applied compared with control animals in which the bioabsorbable material was soaked in saline. The polyurethane sponge did not cause any foreign body reaction, granuloma, or polypoidal change to the sinus mucosa. Two animals developed a subclinical infection at the surgical site.

Conclusion

The targeted use of topical pharmaceuticals via a synthetic bioresorbable nasal sponge dressing in this guinea pig model demonstrated minimal systemic absorption and minimal histopathological changes. This technology is currently under investigation in human clinical trials.
Balloon Dilation of the Cartilaginous Eustachian Tube
Authors: Poe Dennis S. , Silvola Juha , Pyykkö Ilmari
Published: March 2011

Objectives

(1) To translate techniques developed in a previous cadaver study of balloon dilation of the cartilaginous eustachian tube (ET) into clinical treatment for refractory dilatory dysfunction and (2) to study the safety/efficacy of the technique in a pilot clinical trial.

Study Design

Prospective with subjects as their own historical controls since June 2009.

Setting

Regional academic center.

Subjects and Methods

Eleven consecutive adult patients with longstanding otitis media with effusion (OME) who were unable to autoinsufflate their ET by Valsalva, swallow, or yawn and who had previous tympanostomies (average, 4.7). At the time of intervention, 5 of 11 had a tube; 2 of 11 had a tympanic membrane (TM) perforation. Four of 11 had intact TMs, 2 with OME and tympanogram type B and 2 with TM retraction and tympanogram types B and C. Balloon dilation of the cartilaginous ET was performed with sinus dilation instruments via transnasal endoscopic approach under general anesthesia in a day surgery setting. Inflation was to a maximum of 12 atm for 1 minute. Outcome measures: ability to Valsalva, rating of ET mucosal inflammation, tympanogram, and otomicroscopy findings.

Results

All cases successfully dilated. Eleven of 11 could self‐insufflate by Valsalva (P <. 001); tympanograms were A (4/11), C (1/11), or open (6/11). All atelectases resolved. Procedures were well tolerated, without pain or complications related to dilation.

Conclusion

Dilation of the cartilaginous ET appeared to be beneficial and without significant adverse effects in the treatment of ET dilatory dysfunction. Larger controlled trials with long‐term results are now justified and needed.
Intrathyroid Parathyroid Adenoma
Authors: Goodman Arnold , Politz Doug , Lopez Jose , Norman James
Published: March 2011

Objective

It has been taught that a missing parathyroid adenoma can be within the thyroid. Therefore, thyroid lobectomy is appropriate when an adenoma cannot be found. Unfortunately, this technique is often futile. The purpose of this study is to examine the frequency of unsuccessful thyroid lobectomy in parathyroid surgery and to look at the true incidence and location of intrathyroid parathyroid adenomas (iT‐PAs).

Study Design

A retrospective chart review of 11,163 patients undergoing parathyroid surgery identifying the location of more than 40,000 parathyroid glands.

Setting

A tertiary care center specializing in parathyroid surgery.

Subjects and Methods

A total of 1163 reoperations for persistent primary hyperparathyroidism (PHPT) were examined for the incidence and outcomes of thyroid lobectomy performed to find iT‐PA. A second study examined 10,000 patients undergoing first‐time parathyroidectomy to classify the location and incidence of iT‐PA.

Results

Thyroid lobectomy had been previously unsuccessfully performed in 77% cases of PHPT undergoing reoperation. Two or fewer glands were found in 82% prior to lobectomy. The adenoma was subsequently found on the lobectomy side in 64% and on the opposite side in 36%. True iT‐PA occurred in only 0.7% of 10,000 primary cases. Another 1.2% were closely adherent to or partially within the thyroid substance. The most common location was the lower lateral quadrant of the thyroid.

Conclusion

The incidence of true iT‐PA is less than 1%, occurring in predictable locations. Thyroid lobectomy for a missing parathyroid adenoma is typically unsuccessful and should only rarely, if ever, be performed.
An evaluation of the use of Telehealth within palliative care settings across Scotland
Authors: Johnston Bridget , Kidd Lisa , Wengstrom Yvonne , Kearney Nora
Published: March 2011

There is a lack of evidence-based research in the use of Telehealth within palliative care in the UK, particularly in Scotland. The aim of this project was to evaluate the current use of Telehealth applications within palliative care across Scotland, and how these and future applications are perceived by patients, carers and professionals. This paper reports on the qualitative findings from focus groups with patients and carers in three geographical areas in Scotland, and individual interviews with key stakeholders from across Scotland, who currently work within areas of high and low Telehealth activity. The key findings indicated that Telehealth initiatives are welcomed by patients and carers but that these should be an adjunct to clinical care rather than an alternative. The stakeholder interviews revealed several notable differences between those working within areas of high and low Telehealth activity. Principally, areas of high Telehealth activity appear to be driven by national and local policy and seem to benefit from a greater level of investment in Telehealth equipment and facilities than in the more central, and hence accessible, parts of Scotland.
Changes in EEG Cross-Frequency Coupling During Cognitive Behavioral Therapy for Social Anxiety Disorder
Authors: Miskovic Vladimir , Moscovitch David A. , Santesso Diane L. , McCabe Randi E. , Antony Martin M. , Schmidt Louis A.
Published: March 2011

Coupling between EEG delta and beta oscillations is enhanced among anxious and healthy individuals during anticipatory anxiety. EEG coupling patterns associated with psychotherapy have not yet been quantified in socially anxious individuals. In this study, we used a double baseline, repeated measures design, in which 25 adults with a principal diagnosis of social anxiety disorder completed 12 weekly sessions of standardized group cognitive behavioral therapy and four EEG assessments: two at pretreatment, one at midtreatment, and one at posttreatment. Treatment was associated with reductions in symptom severity across multiple measures and informants, as well as reductions in delta-beta coupling at rest and during speech anticipation. Moreover, the clinical group exhibited greater coupling at pretreatment than did post hoc control participants with low social anxiety. The EEG cross-frequency profiles in the clinical group normalized by the posttreatment assessment. These findings provide evidence of concomitant improvement in neural and behavioral functioning among socially anxious adults undergoing psychotherapy.
In the Trenches of Real-World Self-Control
Authors: Berkman Elliot T. , Falk Emily B. , Lieberman Matthew D.
Published: March 2011

Successful goal pursuit involves repeatedly engaging self-control against temptations or distractions that arise along the way. Laboratory studies have identified the brain systems recruited during isolated instances of self-control, and ecological studies have linked self-control capacity to goal outcomes. However, no study has identified the neural systems of everyday self-control during long-term goal pursuit. The present study integrated neuroimaging and experience-sampling methods to investigate the brain systems of successful self-control among smokers attempting to quit. A sample of 27 cigarette smokers completed a go/no-go task during functional magnetic resonance imaging before they attempted to quit smoking and then reported everyday self-control using experience sampling eight times daily for 3 weeks while they attempted to quit. Increased activation in right inferior frontal gyrus, pre-supplementary motor area, and basal ganglia regions of interest during response inhibition at baseline was associated with an attenuated association between cravings and subsequent smoking. These findings support the ecological validity of neurocognitive tasks as indices of everyday response inhibition.
Treatment Foster Care for Improving Outcomes in Children and Young People: A Systematic Review
Authors: Turner William , Macdonald Geraldine
Published: March 2011

Objective: To assess the impact of treatment foster care (TFC) on psychosocial and behavioral outcomes, delinquency, placement stability, and discharge status for children and adolescents who, for reasons of severe medical, social, psychological and behavioural problems, were placed in out-of-home care in restrictive settings or at risk of placement in such settings. Method: Electronic bibliographic databases, web searches, and article reference lists were used to identify randomized controlled trials (RCTs) investigating the effectiveness of TFC with children and young people. The Cochrane Collaboration’s criteria were used to assess the methodological quality of studies that met the inclusion criteria. Wherever possible, extracted outcome data from similar studies were synthesized with random effects meta-analyses. Results: A total of 5 studies including 390 participants were included in this review. Data suggest that TFC may be a useful intervention for children and young people with complex emotional, psychological, and behavioural need, who are at risk of placements in nonfamily settings that restrict their liberty and opportunities for social inclusion. Conclusion: Although the inclusion criteria for this systematic review set a study design threshold higher than that of previous reviews, the findings mirror those of earlier reviews. While the results of individual studies generally indicate that TFC is a promising intervention for children and youth experiencing mental health problems, behavioral problems, or problems of delinquency, the evidence base is not robust and more research is needed due to the limited number of studies in this area.
Cardioprotective Effects of Glycyrrhiza uralensis Extract Against Doxorubicin- Induced Toxicity
Authors: Zhang Ling , Yang Yinxin , Yu Lingyan , Wang Yi , Liu Li , Fan Xiaohui
Published: March 2011

The purpose of the present study was to investigate the cardioprotective effects of Glycyrrhiza uralensis extract (GUE) against doxorubicin (DOX)-induced cardiotoxicity. Imprinting control region (ICR) mice were treated with saline, DOX (20 mg/kg intraperitoneal [ip] for once), GUE (100 mg/kg intragastric [ig] for 8 days), co-treatments with DOX and GUE (100 mg/kg ig for 8 days), and amifostine (100 mg/kg intravenous [iv] for once), respectively. Serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GSH-PX) activity, and glutathione (GSH) level in heart tissue were measured. Histopathologic analysis of heart tissue was also performed. Treatment with GUE significantly protected the mice from DOX-induced cardiotoxicity, indicated by decreased levels of serum LDH and CK-MB, improved heart morphology and increased GSH-PX activity and GSH level. Additionally, GUE did not compromise the tumor-inhibitory effect of DOX. In conclusion, our studies imply the potentially clinical application of GUE to overcome the cardiotoxicity of doxorubicin.
A Strategic Rationale for the Use of Sell–On Fees in European Sports
Authors: Gürtler Oliver
Published: March 2011

In European team sports, contracts that govern the transfer of a player from one club to another often contain a clause specifying a sell-on fee. Such clause ensures that the selling club profits from a future transfer of the player. This article gives possible explanations for the use of sell-on fees. Besides rather obvious explanations based on risk considerations and wealth constraints, the article shows that a sell-on fee could be used for strategic reasons. In particular, the clubs may agree on a sell-on fee since it affects the behavior of the buying club in future transfer negotiations in a favorable way.
The benefits of long-term systemic antimicrobial therapy in chronic obstructive pulmonary disease
Authors: Berim Ilya , Sethi Sanjay
Published: March 2011

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are major contributors to the morbidity and mortality associated with this disease. Current approaches that likely reduce chronic obstructive pulmonary disease (COPD) exacerbations include smoking cessation, influenza and pneumococcal vaccinations, long-acting bronchodilator and inhaled corticosteroid therapy, pulmonary rehabilitation, and mucolytic drugs. However, with optimal treatment using all of these modalities, we are only able to reduce exacerbations by about 40%. A significant proportion of COPD exacerbations are bacterial, therefore long-term antimicrobial therapy could have a role in preventing exacerbations. Long-term antibiotic treatment in COPD regimens that are being evaluated include low-dose macrolide therapy, pulsed fluoroquinolone administration and the use of inhaled antibiotics. Although initial results have been promising with significant reductions in exacerbations with these regimens, additional studies are required to identify the appropriate patient and regimen and elucidate the risk–benefit as well as cost effectiveness of long-term antibiotics in COPD.
Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis
Authors: Qu Peng , Yan Cong , Du Hong
Published: March 2011

Matrix metalloproteinase 12 (MMP12) is a macrophage-secreting proteinase. To fully understand the function of MMP12 in myeloid lineage cells, a myeloid-specific c-fms-rtTA/(TetO)7-CMV-MMP12 bitransgenic mouse model was created. In this bitransgenic system, induction of MMP12 abnormally elevated frequencies and numbers of common myeloid progenitor (CMP) and granulocyte/macrophage progenitor (GMP) populations, and decreased the frequency and number of the megakaryocyte/erythrocyte progenitor (MEP) population in the bone marrow (BM). The CD11b+/Gr-1+ immature cell population was systemically increased in multiple organs. Both in vitro and in vivo studies showed an immunosuppressive function on T-cell proliferation and function by CD11b+/Gr-1+ immature cells from MMP12-overexpressing bitransgenic mice. MMP12 directly stimulated lineage-negative (Lin−) progenitor cells to differentiate into CD11b+/Gr-1+ immature cells that showed immunosuppression on T-cell proliferation and function in vitro. Regulatory T cells (Tregs) were increased. In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression. BM chimeras confirmed that the MMP12-induced myeloid cell autonomous defect led to abnormal myelopoiesis, immune suppression, and lung adenocarcinoma.
Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase
Authors: Kazerounian Shideh , Duquette Mark , Reyes Millys A. , Lawler James T. , Song Keli , Perruzzi Carole , Primo Luca , Khosravi-Far Roya , Bussolino Federico , Rabinovitz Isaac , Lawler Jack
Published: March 2011

CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demonstrating that overexpression of CD36 in HUVECs up-regulates endogenous Syk expression. We also define a new role for TSP-1 and CD36 in the activation of the VEGFR-2 signaling pathway that requires Syk. Our findings also identify a role for Syk as a stimulator of VEGF-A–induced angiogenesis by increasing phosphorylation of Y1175 in VEGFR-2, which is a major tyrosine for promoting VEGF-A–induced endothelial cell migration. Together, these studies introduce a new signaling pathway for TSP-1, CD36, and Syk, and address the role of these proteins in regulating the angiogenic switch.
A transient definitive erythroid lineage with unique regulation of the β-globin locus in the mammalian embryo
Authors: McGrath Kathleen E. , Frame Jenna M. , Fromm George J. , Koniski Anne D. , Kingsley Paul D. , Little Jane , Bulger Michael , Palis James
Published: March 2011

A transient erythromyeloid wave of definitive hematopoietic progenitors (erythroid/myeloid progenitors [EMPs]) emerges in the yolk sac beginning at embryonic day 8.25 (E8.25) and colonizes the liver by E10.5, before adult-repopulating hematopoietic stem cells. At E11.5, we observe all maturational stages of erythroid precursors in the liver and the first definitive erythrocytes in the circulation. These early fetal liver erythroblasts express predominantly adult β-globins and the definitive erythroid-specific transcriptional modifiers c-myb, Sox6, and Bcl11A. Surprisingly, they also express low levels of “embryonic” βH1-, but not εy-, globin transcripts. Consistent with these results, RNA polymerase and highly modified histones are found associated with βH1- and adult globin, but not εy-globin, genes. E11.5 definitive proerythroblasts from mice transgenic for the human β-globin locus, like human fetal erythroblasts, express predominately human γ-, low β-, and no ε-globin transcripts. Significantly, E9.5 yolk sac–derived EMPs cultured in vitro have similar murine and human transgenic globin expression patterns. Later liver proerythroblasts express low levels of γ-globin, while adult marrow proerythroblasts express only β-globin transcripts. We conclude that yolk sac–derived EMPs, the first of 2 origins of definitive erythropoiesis, express a unique pattern of globin genes as they generate the first definitive erythrocytes in the liver of the mammalian embryo.
Carney Complex: case report and review
Authors: Borkar Shirish S , Kamath Sevagur G , Kashyap Nitin , Sagar Sunil CV , Rao Lakshmi , Warrier Raj , Chauhan Aman
Published: March 2011

Carney complex is a very rare multiple neoplasia syndrome with cardiac, cutaneous, and neural tumours with a variety of pigmented lesion of skin. We are reporting a rare case of carney complex in which left atrial myxoma with superficial angiomyxoma, giant cell tumour of bone and lentigines showed a unique association. This patient underwent successful surgical excision of left atrial myxoma under cardiopulmonary bypass.
RNAi-mediated knockdown of cyclooxygenase2 inhibits the growth, invasion and migration of SaOS2 human osteosarcoma cells: a case control study
Authors: Zhao Qinghua , Wang Chuan , Zhu Jiaxue , Wang Lei , Dong Shuanghai , Zhang Guoqiao , Tian Jiwei
Published: March 2011

Background

Cyclooxygenase2 (COX-2), one isoform of cyclooxygenase proinflammatory enzymes, is responsible for tumor development, invasion and metastasis. Due to its role and frequent overexpression in a variety of human malignancies, including osteosarcoma, COX-2 has received considerable attention. However, the function of COX-2 in the pathogenesis of cancer is not well understood. We examined the role of COX-2 in osteosarcoma.

Methods

We employed lentivirus mediated-RNA interference technology to knockdown endogenous gene COX-2 expression in human osteosarcoma cells (SaOS2) and analyzed the phenotypical changes. The effect of COX-2 treatment on the proliferation, cell cycle, invasion and migration of the SaOS2 cells were assessed using the MTT, flow cytometry, invasion and migration assays, respectively. COX-2, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) mRNA and protein expression were detected by RT-PCR and western blotting.

Results

Our results indicate that a decrease of COX-2 expression in human osteosarcoma cells significantly inhibited the growth, decreased the invasion and migration ability of SaOS2 cells. In addition, it also reduced VEGF, EGF and bFGF mRNA and protein expression.

Conclusions

The COX-2 signaling pathway may provide a novel therapeutic target for the treatment of human osteosarcoma.
The Limbs of Empire: Ahab, Santa Anna, and Moby-Dick
Authors: Taylor Christopher
Published: March 2011

Taylor reads Herman Melville's Moby-Dick (1851) through the history of the captured prosthetic limb of Mexican General Antonio López de Santa Anna. U.S. travel narratives, soldiers' accounts, and P. T. Barnum's 1847 display of the captured prosthesis in his American Museum figured the leg as a symbol of the regenerative and reembodying benefits that territorial imperialism offered to Jacksonian working classes. Melville's journalism on Barnum's exhibit evinces a deep anxiety about the enthusiasm of Barnum's working-class audience for the prosthesis of empire, scrutinizing the figurative and rhetorical modalities by which the limb gained its symbolic value and affective force. Moby-Dick, Taylor argues, turns the figurative operations that Melville isolated in his reading of Barnum into a hermeneutic for interpreting the symbolic economies governing the interclass relations that produced populist imperialism. Moby-Dick narrates how hegemonic redeployments of the working-class rhetoric of loss transformed the hands of industry, seeking autonomy through territorial imperialism, into the prostheses of an Ahabian empire.
State Killing, the Stage of Innocence, and The Exonerated
Authors: Ryan Katy
Published: March 2011

Ryan's essay analyzes the coordination of the innocence argument and sentimentality in Jessica Blank and Erik Jensen's TheExonerated (2003), a documentary play based on interviews with people sentenced to die for crimes they did not commit. The play's composition, performance, and reception reveal the challenges of creating art that is aimed at social reform and confirm the difficulty in assessing the political function or, in Fredric Jameson's sense, the political unconscious of American literature. As a celebrated example of political theater, The Exonerated also provides a forum for thinking through the contemporary terms and framework of conversations about state killing. Ryan argues that the play stimulates reform and elicits sympathy by substituting a false rhetoric of universal vulnerability for a more accurate assessment of imprisonment and judicial murder. The attempt to make the play accessible, emotional, and persuasive also sets real limits on how audience members are asked think about personal and social responsibility. Some of these efforts include a focus on the wrongly convicted instead of the guilty, a balance of white and black interviewees in the face of a racially unbalanced justice system, a rendering of pain as uplifting for audiences, and an encouragement of personal and financial solutions rather than structural and political ones.
BIMEL, an intrinsically disordered protein, is degraded by 20S proteasomes in the absence of poly-ubiquitylation
Authors: Wiggins Ceri M. , Tsvetkov Peter , Johnson Mark , Joyce Claire L. , Lamb Christopher A. , Bryant Nia J. , Komander David , Shaul Yosef , Cook Simon J.
Published: March 2011

BIM-extra long (BIMEL), a pro-apoptotic BH3-only protein and part of the BCL-2 family, is degraded by the proteasome following activation of the ERK1/2 signalling pathway. Although studies have demonstrated poly-ubiquitylation of BIMEL in cells, the nature of the ubiquitin chain linkage has not been defined. Using ubiquitin-binding domains (UBDs) specific for defined ubiquitin chain linkages, we show that BIMEL undergoes K48-linked poly-ubiquitylation at either of two lysine residues. Surprisingly, BIMELΔKK, which lacks both lysine residues, was not poly-ubiquitylated but still underwent ERK1/2-driven, proteasome-dependent turnover. BIM has been proposed to be an intrinsically disordered protein (IDP) and some IDPs can be degraded by uncapped 20S proteasomes in the absence of poly-ubiquitylation. We show that BIMEL is degraded by isolated 20S proteasomes but that this is prevented when BIMEL is bound to its pro-survival target protein MCL-1. Furthermore, knockdown of the proteasome cap component Rpn2 does not prevent BIMEL turnover in cells, and inhibition of the E3 ubiquitin ligase β-TrCP, which catalyses poly-Ub of BIMEL, causes Cdc25A accumulation but does not inhibit BIMEL turnover. These results provide new insights into the regulation of BIMEL by defining a novel ubiquitin-independent pathway for the proteasome-dependent destruction of this highly toxic protein.
Autophagy: a pathway that contributes to connexin degradation
Authors: Lichtenstein Alexandra , Minogue Peter J. , Beyer Eric C. , Berthoud Viviana M.
Published: March 2011

The function of connexins, which form gap junctions, can be rapidly modulated by degradation, because they have half-lives of only a few hours. Autophagy is a degradation pathway that has been implicated in several diseases and can be induced by cellular stresses such as starvation. We investigated the involvement of autophagy in proteolysis of the wild-type connexins CX50 and CX43, and a cataract-associated connexin mutant, CX50P88S, which forms cytoplasmic accumulations. We observed that cytoplasmic connexins were partially (cup-shaped) or completely (ring-shaped) enclosed by structures containing the autophagy-related protein LC3. Intracellular connexins also colocalized with p62, a protein that might serve as a cargo receptor for autophagic degradation. Starvation induced a decrease in connexin levels that was blocked by treatment with chloroquine, a lysosomal protease inhibitor, or by knockdown of the autophagy-related protein Atg5. These results demonstrate that autophagy can regulate cellular levels of wild-type connexins and imply that the persistence of accumulations of CX50P88S results from insufficient degradation capacity of constitutive autophagy.
Phospho-regulation of kinesin-5 during anaphase spindle elongation
Authors: Avunie-Masala Rachel , Movshovich Natalia , Nissenkorn Yael , Gerson-Gurwitz Adina , Fridman Vladimir , Kõivomägi Mardo , Loog Mart , Hoyt M. Andrew , Zaritsky Arieh , Gheber Larisa
Published: March 2011

The kinesin-5 Saccharomyces cerevisiae homologue Cin8 is shown here to be differentially phosphorylated during late anaphase at Cdk1-specific sites located in its motor domain. Wild-type Cin8 binds to the early-anaphase spindles and detaches from the spindles at late anaphase, whereas the phosphorylation-deficient Cin8-3A mutant protein remains attached to a larger region of the spindle and spindle poles for prolonged periods. This localization of Cin8-3A causes faster spindle elongation and longer anaphase spindles, which have aberrant morphology. By contrast, the phospho-mimic Cin8-3D mutant exhibits reduced binding to the spindles. In the absence of the kinesin-5 homologue Kip1, cells expressing Cin8-3D exhibit spindle assembly defects and are not viable at 37°C as a result of spindle collapse. We propose that dephosphorylation of Cin8 promotes its binding to the spindle microtubules before the onset of anaphase. In mid to late anaphase, phosphorylation of Cin8 causes its detachment from the spindles, which reduces the spindle elongation rate and aids in maintaining spindle morphology.
Chromatin folding – from biology to polymer models and back
Authors: Tark-Dame Mariliis , van Driel Roel , Heermann Dieter W.
Published: March 2011

There is rapidly growing evidence that folding of the chromatin fibre inside the interphase nucleus has an important role in the regulation of gene expression. In particular, the formation of loops mediated by the interaction between specific regulatory elements, for instance enhancers and promoters, is crucial in gene control. Biochemical studies that were based on the chromosome conformation capture (3C) technology have confirmed that eukaryotic genomes are highly looped. Insight into the underlying principles comes from polymer models that explore the properties of the chromatin fibre inside the nucleus. Recent models indicate that chromatin looping can explain various properties of interphase chromatin, including chromatin compaction and compartmentalisation of chromosomes. Entropic effects have a key role in these models. In this Commentary, we give an overview of the recent conjunction of ideas regarding chromatin looping in the fields of biology and polymer physics. Starting from simple linear polymer models, we explain how specific folding properties emerge upon introducing loops and how this explains a variety of experimental observations. We also discuss different polymer models that describe chromatin folding and compare them to experimental data. Experimentally testing the predictions of such polymer models and their subsequent improvement on the basis of measurements provides a solid framework to begin to understand how our genome is folded and how folding relates to function.
RNF41 (Nrdp1) controls type 1 cytokine receptor degradation and ectodomain shedding
Authors: Wauman Joris , De Ceuninck Leentje , Vanderroost Nele , Lievens Sam , Tavernier Jan
Published: March 2011

Cytokines, such as interferons, erythropoietin, leptin and most interleukins, signal through type 1 cytokine receptors and activate the canonical JAK–STAT pathway. Aberrant cytokine signalling underlies numerous pathologies and adequate, temporary receptor activation is therefore under tight control. Negative-feedback mechanisms are very well studied, but cellular sensitivity also depends on the number of receptors exposed at the cell surface. This is determined by the equilibrium between receptor synthesis and transport to the plasma membrane, internalisation and recycling, degradation and ectodomain shedding, but the molecular basis of how cells establish steady state receptor levels is poorly understood. Here, we report that ring finger protein 41 (RNF41, also known as E3 ubiquitin-protein ligase Nrdp1) interacts with JAK2-associated cytokine receptor complexes and modulates their cell surface exposure and signalling. Moreover, ectopic expression of RNF41 affected turnover of leptin, leukaemia inhibitory factor and interleukin-6 receptor in a dual way: it blocked intracellular cathepsin-L-dependent receptor cleavage and concomitantly enhanced receptor shedding by metalloproteases of the ADAM family. Receptor degradation and shedding are thus interconnected phenomena with a single protein, RNF41, determining the balance.
ZP2 and ZP3 cytoplasmic tails prevent premature interactions and ensure incorporation into the zona pellucida
Authors: Jimenez-Movilla Maria , Dean Jurrien
Published: March 2011

The zona pellucida contains three proteins (ZP1, ZP2, ZP3), the precursors of which possess signal peptides, ‘zona’ domains and short (9–15 residue) cytoplasmic tails downstream of a transmembrane domain. The ectodomains of ZP2 and ZP3 are sufficient to form the insoluble zona matrix and yet each protein traffics through oocytes without oligomerization. ZP2 and ZP3 were fluorescently tagged and molecular interactions were assayed by fluorescent complementation in CHO cells and growing oocytes. ZP2 and ZP3 traffic independently, but colocalize at the plasma membrane. However, protein–protein interactions were observed only after release and incorporation of ZP2 and ZP3 into the extracellular matrix surrounding mouse oocytes. In the absence of their hydrophilic cytoplasmic tails, ZP2 and ZP3 interacted within the cell and did not participate in the zona pellucida. A heterologous GPI-anchored ‘zona’ domain protein fused with the cytoplasmic tails was integrated into the zona matrix. We conclude that the cytoplasmic tails are sufficient and necessary to prevent intracellular oligomerization while ensuring incorporation of processed ZP2 and ZP3 into the zona pellucida.
Comarketing Alliances: Should You Contract on Actions or Outcomes?
Authors: Chennamaneni Pavan Rao , Desiraju Ramarao
Published: March 2011

Comarketing alliances often involve multiple partners, and a given partner's marketing efforts on behalf of the alliance can indirectly affect the demand of the other partners. Individual partners, however, can ignore the effects of such an externality and invest suboptimally to the detriment of the alliance. This paper examines the relative effectiveness of outcome- and action-based contracts in providing the alliance partners with the incentives to invest appropriately. We develop a mathematical model in which a focal firm (e.g., Sony) contracts with two partners (e.g., McDonald's and Old Navy) when each of these partners is privately informed about the impact of the alliance on its demand. Our analysis evaluates the strengths and weaknesses of outcome- (or output-) and action-based (or input-based) contracts in settings with varying levels of the demand externality. We find that when there is either no externality or a relatively weak positive externality, there is a strict preference for output-based contracts; that preference, however, is reversed with a sufficiently strong positive externality. This paper explains the underlying rationale for these findings.

This paper was accepted by Preyas Desai, marketing.
The Threat from Within: Account Managers' Concern About Opportunism by Their Own Team Members
Authors: Murtha Brian R. , Challagalla Goutam , Kohli Ajay K.
Published: March 2011

It is well known that transaction-specific investments (TSIs) made in customers by account managers makes them vulnerable to opportunism by customers (i.e., the targets of the investments). The present research shows that TSIs made in customers by account managers can also lead them to be concerned about internal opportunism by nontargets of the investments (e.g., information technology or finance specialists in their own teams). Furthermore, it shows that concern about internal opportunism leads account managers to engage in internal blocking of their own team members (i.e., restricting their access to customers and to customer information), which results in lower performance with customers. This phenomenon is a conundrum in that account managers interested in stronger performance with customers appear to block the very functional specialists who can help them attain better performance. This research also identifies two types of continuities (account manager–customer continuity and specialist–customer continuity) that moderate the relationship between TSIs and concern about internal opportunism. Building on the literature in economics and organization theory, our research suggests that cross-functional teams that are designed to bring different functional areas together are more complex to manage than previously believed.

This paper was accepted by Pradeep Chintagunta and Preyas Desai, special issue editors.

This paper was accepted by Pradeep Chintagunta and Preyas Desai, special issue editors.
An Experimental Study of Information Revelation Policies in Sequential Auctions
Authors: Cason Timothy N. , Kannan Karthik N. , Siebert Ralph
Published: March 2011

Theoretical models of information asymmetry have identified a trade-off between the desire to learn and the desire to prevent an opponent from learning private information. This paper reports a laboratory experiment that investigates if actual bidders account for this trade-off, using a sequential procurement auction with private cost information and varying information revelation policies. Specifically, the Complete Information Revelation Policy, where all submitted bids are revealed between auctions, is compared to the Incomplete Information Revelation Policy, where only the winning bid is revealed. The experimental results are largely consistent with the theoretical predictions. For example, bidders pool with other types to prevent an opponent from learning significantly more often under a Complete Information Revelation Policy. Also as predicted, the procurer pays less when employing an Incomplete Information Revelation Policy only when the market is highly competitive. Bids are usually more aggressive than the risk-neutral quantitative prediction, which is broadly consistent with risk aversion.

This paper was accepted by Teck Ho, decision analysis.
The Value of Fast Fashion: Quick Response, Enhanced Design, and Strategic Consumer Behavior
Authors: Cachon Gérard P. , Swinney Robert
Published: March 2011

A fast fashion system combines quick response production capabilities with enhanced product design capabilities to both design “hot” products that capture the latest consumer trends and exploit minimal production lead times to match supply with uncertain demand. We develop a model of such a system and compare its performance to three alternative systems: quick-response-only systems, enhanced-design-only systems, and traditional systems (which lack both enhanced design and quick response capabilities). In particular, we focus on the impact of each of the four systems on “strategic” or forward-looking consumer purchasing behavior, i.e., the intentional delay in purchasing an item at the full price to obtain it during an end-of-season clearance. We find that enhanced design helps to mitigate strategic behavior by offering consumers a product they value more, making them less willing to risk waiting for a clearance sale and possibly experiencing a stockout. Quick response mitigates strategic behavior through a different mechanism: by better matching supply to demand, it reduces the chance of a clearance sale. Most importantly, we find that although it is possible for quick response and enhanced design to be either complements or substitutes, the complementarity effect tends to dominate. Hence, when both quick response and enhanced design are combined in a fast fashion system, the firm typically enjoys a greater incremental increase in profit than the sum of the increases resulting from employing either system in isolation. Furthermore, complementarity is strongest when customers are very strategic. We conclude that fast fashion systems can be of significant value, particularly when consumers exhibit strategic behavior.

This paper was accepted by Yossi Aviv, operations management.
Advancing the Pharmacy Practice Model: Survey of New Practitioner Attitudes and Opinions
Authors: Hertig John B. , Kelley Katherine A. , Jordan Trisha A. , Tubbs Crystal R. , Casper Kristin A. , Nahata Milap C.
Published: March 2011

Purpose

As members of the future pharmacy workforce, newly practicing pharmacists will be directly involved in key changes in practice. The purpose of this study is to (a) determine the desirability of core health-system pharmacist responsibilities among new practitioners, (b) assess new practitioner satisfaction about the current state of practice, and (c) evaluate the willingness of newly practicing pharmacists to change practice.

Results

Results from this study indicate new practitioners have a greater preference for clinical, direct patient care activities compared with traditional operational functions. There is a disparity between new practitioner preferences and current practice opportunities. Respondents were satisfied with pharmacy practice at their institution (86%), yet less satisfied (56%) with the current state of health-system pharmacy practice in the United States. Satisfaction with practice at respondents' institutions was significantly associated with region, with respondents from the Great Lakes region significantly more satisfied than respondents from the Eastern, Western, and Southeastern regions ( P = .02). Respondents with postgraduate training had 2.3 times higher odds of being satisfied than those without postgraduate training ( P = .02). Survey respondents indicated a general willingness to accept change. When these results were compared to director of pharmacy responses from a 2008 survey, differences were identified between new practitioner preferences and practice availability.

Conclusion

New practitioners tend to prefer clinical functions with greater direct patient contact and are satisfied with pharmacy practice. New practitioners are willing to accept change and, therefore, will be integral to developing and implementing practice models. These findings will help the profession move forward in developing practice models that address new practitioner skills, attitudes, and opinions, successfully building the future vision of pharmacy practice.
A Perspective on the Resident-Preceptor Bond
Authors: Pierpaoli Paul G.
Published: March 2011

The central energy source in the effective training of residents resides in the bond or connection between a resident and a preceptor. It serves as the substrate for learning, mentoring, professional growth, and leadership development. This commentary explores the major dynamics of the preceptor-resident relationship, the major determinants of success, and some of the self-imposed barriers that may be counterproductive to an ideal relationship.
Functional specificity of Akt isoforms in cancer progression
Authors: Fortier Anne-Marie , Asselin Eric , Cadrin Monique
Published: March 2011

Akt/PKB kinases are central mediators of cell homeostasis. There are three highly homologous Akt isoforms, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ. Hyperactivation of Akt signaling is a key node in the progression of a variety of human cancer, by modulating tumor growth, chemoresistance and cancer cell migration, invasion and metastasis. It is now clear that, to understand the mechanisms on how Akt affects specific cancer cells, it is necessary to consider the relative importance of each of the three Akt isoforms in the altered cells. Akt1 is involved in tumor growth, cancer cell invasion and chemoresistance and is the predominant altered isoform found in various carcinomas. Akt2 is related to cancer cell invasion, metastasis and survival more than tumor induction. Most of the Akt2 alterations are observed in breast, ovarian, pancreatic and colorectal carcinomas. As Akt3 expression is limited to some tissues, its implication in tumor growth and resistance to drugs mostly occurs in melanomas, gliomas and some breast carcinomas. To explain how Akt isoforms can play different or even opposed roles, three mechanisms have been proposed: tissue-specificity expression/activation of Akt isoforms, distinct effect on same substrate as well as specific localization through the cyto-skeleton network. It is becoming clear that to develop an effective anticancer Akt inhibitor drug, it is necessary to target the specific Akt isoform which promotes the progression of the specific tumor.