bluuebunny/crossref_metadata_2025 huggingface dataset:
Search for a Gene Expression Signature of Breast Cancer Local Recurrence in Young Women
Authors: Servant Nicolas , Bollet Marc A. , Halfwerk Hans , Bleakley Kevin , Kreike Bas , Jacob Laurent , Sie Daoud , Kerkhoven Ron M. , Hupé Philippe , Hadhri Rim , Fourquet Alain , Bartelink Harry , Barillot Emmanuel , Sigal-Zafrani Brigitte , van de Vijver Marc J.
Published: January 2012

Purpose: A gene expression signature, predictive for local recurrence after breast-conserving treatment, has previously been identified from a series of 165 young patients with breast cancer. We evaluated this signature on both another platform and an independent series, compared its performance with other published gene-sets, and investigated the gene expression profile of a larger data set.

Experimental Design: Gene expression tumor profiles were obtained on 148 of the initial 165 Dutch patients and on an independent validation series of 195 French patients. Both unsupervised and supervised classifications were used to study the gene expression profile of the 343 breast cancers and to identify subgroups that differ for their risk of local recurrence.

Results: The previous local recurrence signature was validated across platforms. However, when applied to the French patients, the signature did not reproduce its reported performance and did not better classify the patients than other published gene sets. Hierarchical clustering of all 343 breast cancers did not show any grouping reflecting local recurrence status. Genes related to proliferation were found differentially expressed between patients with or without local recurrence only in triple-negative tumors. Supervised classification revealed no significant gene set predictive for local recurrence or able to outperform classification based on clinical variables.

Conclusions: Although the previously identified local recurrence signature was robust on another platform, we were neither able to validate it on an independent data set, nor able to define a strong gene expression classifier for local recurrence using a larger data set. We conclude that there are no significant differences in gene expression pattern in tumors from patients with and without local recurrence after breast-conserving treatment. Clin Cancer Res; 18(6); 1704–15. ©2012 AACR.
Profilin as an Aeroallergen by Means of Conjunctival Allergen Challenge with Purified Date Palm Profilin
Authors: Núñez R. , Carballada F. , Lombardero M. , Jimeno L. , Boquete M.
Published: January 2012

Background: The role of profilin as a food allergen is well established, but little research has been done about its ability to elicit respiratory disease. Profilin is considered more of a confounding allergen on skin testing with whole pollen extracts than other airborne allergens. Our aim was to find out whether or not profilin can cause symptoms in sensitized individuals, which would be compatible with its role as an airborne allergen. Methods: We performed conjunctival allergen challenges with date palm profilin in a series of consecutive pollen-allergic patients with rhino-conjunctivitis, divided in two groups: profilin sensitized (n = 17) and not sensitized (n = 14), who served as controls. We investigated the possible association between profilin sensitization and profilin allergy in these groups of patients. Results: None of the patients from the not profilin-sensitized group had a positive result in conjunctival allergen challenges. In contrast, 65% of profilin sensitized patients had a positive conjunctival allergen challenge and were considered allergic to profilin. We found a significant statistical association between being profilin allergic and being profilin sensitized (χ2 = 10.39, p < 0.005). Conclusions: Profilin seems to work as an aeroallergen in a significant proportion of profilin-sensitized patients. This might explain the uselessness of conjunctival challenges with whole pollen extracts to disclose genuine sensitization. In the future, the possibility of quantifying this allergen in pollen immunotherapy vaccines should be considered.
Arl6ip1 Plays a Role in Proliferation during Zebrafish Retinogenesis
Authors: Huang Hsing-Yen , Liu Jeng-Ting , Yan Hong-Young , Tsai Huai-Jen
Published: January 2012

Objective: Arl6ip1 has been reported to play a role in ocular development, but its regulatory function as it relates to proliferation is unclear. Therefore, this study aimed to evaluate how Arl6ip1 may regulate the proliferative behavior of retinal progenitor cells during zebrafish embryogenesis. Method: Arl6ip1 was specifically knocked down by introducing morpholino nucleic acid oligomers. The DNA content of cells dissociated from morphant eyes was analyzed by fluorescence-activated cell sorting (FACS). Retinal cells in the S- and late G2/M-phase were detected by labeling with BrdU and then immunostaining with anti-BrdU antibody and by immunostaining with phospho-histone H3 antibody, respectively. We also examined the expressions of shh,p57kip2, and cyclin D1 in retinas of experimental animals. The bidirectional plasmid pGFP:HSE:p57kip2 was used to rescue the defect in cell cycle exit. Results: FACS analysis showed that the >2C DNA content per cell in the eyes of arl6ip1 morphants was 2-fold greater than that of the wild type. Following functional Arl6ip1 knockdown, anti-BrdU- and anti-phospho-histone H3-positive signals were higher and the retinal progenitors kept expressing cyclin D1 but not shh or p57kip2, suggesting that eye progenitor cells remained in an early progenitor state and could not exit the cell cycle to progress to differentiation. Interestingly, overexpression of p57kip2, which enables exit from the cell cycle, led to a reduction of anti-BrdU-positive signals in the retinas of arl6ip1 morphants. Conclusion: Arl6ip1 not only affects signals controlling eye development but also plays an important role in the proliferation of retinal progenitor cells.
Epstein-Barr Virus Genotypes and Strains in Central Nervous System Demyelinating Disease and Epstein-Barr Virus-Related Illnesses in Australia
Authors: Lay Meav-Lang J. , Lucas Robyn M. , Toi Cheryl , Ratnamohan Mala , Ponsonby Anne-Louise , Dwyer Dominic E. ,   The Ausimmune Investigator Group
Published: January 2012

Objectives: To identify Epstein-Barr virus (EBV) genotypes and strains in samples from individuals with and without a first diagnosis of central nervous system (CNS) demyelinating disease (a possible precursor to multiple sclerosis) and patients with EBV-associated diseases in Australia. Methods: Samples from 55 EBV DNA and serology positive subjects including individuals with (n = 17) and without (n = 21) a first clinical diagnosis of CNS demyelination and patients with EBV-related diseases (n = 17) were examined. EBV genotype and strain were identified by sequence mutations within the Epstein-Barr nuclear antigen-2 region (EBNA-2) using DNA sequence analysis. Results: Both EBV genotypes, A and B, were detected (genotype A, 54/55, 98.2%; genotype B, 1/55, 1.8%). Within genotype A, GD1 was the most commonly detected strain (42/54, 77.7%), followed by B95-8 (9/54, 16.7%) and M-ABA (3/54, 5.6%). Genotype B, strain AG876, was found in one individual with CNS demyelinating disease. Conclusions: EBV genotype A and the GD1 strain were the common EBV genotypes isolated from individuals with and without CNS demyelinating disease, and in subjects with various EBV-related diseases. Although disease-specific genotypes or strains were not identified, this study provides useful insights into the molecular epidemiology of EBV infection in Australia.
High-Risk Human Papillomavirus Infection in Bowen’s Disease of the Nail Unit: Report of Three Cases and Review of the Literature
Authors: Grundmeier Natalie , Hamm Henning , Weissbrich Benedikt , Lang Sabrina Christine , Bröcker Eva-Bettina , Kerstan Andreas
Published: January 2012

Background: Bowen’s disease (BD) of the nail unit is associated with human papillomavirus (HPV) infection. Objective: This study aimed to investigate the frequency of high-risk HPV infection, gender, age and digital distribution in this condition. Methods: Biopsy specimens of 3 consecutive cases with periungual BD were investigated for the presence of HPV DNA by in situ hybridization and by polymerase chain reaction (PCR). Furthermore, 74 cases of ungual BD conducted with HPV genotyping as reported in the literature were reviewed. Results: PCR of biopsy specimens revealed in 2 cases infection with HPV-16 and in 1 case with HPV-73. Additionally, in 1 HPV-16-positive case HPV-31/33 was detected by in situ hybridization. In line, review of the literature demonstrated a clear association of HPV-positive BD with high-risk HPV types. Interestingly, age at diagnosis was significantly lower in women. Whereas in both genders the second to fourth fingers on both hands were commonly diseased, only in men the thumbs were also prominently affected. Conclusions: Infection with high-risk HPV types is common in BD of the nail unit suggesting the aetiological cause. Therefore, patients and partners should be closely followed up for digital and genital HPV-associated lesions.
Update on Kleefstra Syndrome
Authors: Willemsen M.H. , Vulto-van Silfhout A.T. , Nillesen W.M. , Wissink-Lindhout W.M. , van Bokhoven H. , Philip N. , Berry-Kravis E.M. , Kini U. , van Ravenswaaij-Arts C.M.A. , Delle Chiaie B. , Innes A.M.M. , Houge G. , Kosonen T. , Cremer K. , Fannemel M. , Stray-Pedersen A. , Reardon W. , Ignatius J. , Lachlan K. , Mircher C. , Helderman van den Enden P.T.J.M. , Mastebroek M. , Cohn-Hokke P.E. , Yntema H.G. , Drunat S. , Kleefstra T.
Published: January 2012

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.
Effects of Reduced
Gcm1
Expression on Trophoblast Morphology, Fetoplacental Vascularity, and Pregnancy Outcomes in Mice
Authors: Bainbridge Shannon A. , Minhas Abhijeet , Whiteley Kathie J. , Qu Dawei , Sled John G. , Kingdom John C.P. , Adamson S. Lee
Published: January 2012

Preeclampsia is a life-threatening disorder characterized by maternal gestational hypertension and proteinuria that results from placental dysfunction. Placental abnormalities include abnormal syncytiotrophoblast and a 50% reduction in placental expression of the transcription factor
Gcm1
. In mice, homozygous deletion of
Gcm1
prevents syncytiotrophoblast differentiation and is embryonic lethal. We used heterozygous
Gcm1
mutants (
Gcm1
+/−
) to test the hypothesis that hypomorphic expression of placental
Gcm1
causes defective syncytiotrophoblast differentiation and maternal and placental phenotypes that resemble preeclampsia. We mated wild-type female mice with
Gcm1
+/−
fathers to obtain wild-type mothers carrying ≈50%
Gcm1
+/−
conceptuses.
Gcm1
+/−
placentas had syncytiotrophoblast abnormalities including reduced gene expression of
Gcm1
-regulated
SynB
, elevated expression of
sFlt1
, a thickened interhemal membrane separating maternal and fetal circulations, and electron microscopic evidence in syncytiotrophoblast of necrosis and impaired maternal-fetal transfer. Fetoplacental vascularity was quantified by histomorphometry and microcomputed tomography imaging. In
Gcm1
+/−
, it was ≈30% greater than wild-type littermates, whereas placental vascular endothelial growth factor A (
Vegfa
) expression and fetal and placental weights did not differ. Wild-type mothers carrying
Gcm1
+/−
conceptuses developed late gestational hypertension (118±2 versus 109.6±0.7 mm Hg in controls;
P
<0.05). We next correlated fetoplacental vascularity with placental
Gcm1
expression in human control and pathological pregnancies and found that, as in mice, fetoplacental vascularity increased when GCM1 protein expression decreased (
R
2
=−0.45;
P
<0.05). These results support a role for reduced placental
Gcm1
expression as a causative factor in defective syncytiotrophoblast differentiation and maternal and placental phenotypes in preeclampsia in humans.
The Postmodern Beauty of Fractals
Authors: Garousi Mehrdad
Published: January 2012

Fractal art, one of the significant conjunctions of art, modern mathematics and computer technology, has been the author's primary art medium for the past five years. After presenting an introduction to the general properties of fractal art, the author explains certain visual aspects and processes of creating such art using examples from his own work.
Social, Sexual and Economic Networks of Prostitution
Authors: Holme Petter
Published: January 2012

This article discusses the networks of prostitution, in particular those that can be extracted from online data, and what they can teach us about prostitution itself, disease spreading, cultural differences and a broader spectrum of socio-economical phenomena.
Assessing Tracer Transport Algorithms and the Impact of Vertical Resolution in a Finite-Volume Dynamical Core
Authors: Kent James , Jablonowski Christiane , Whitehead Jared P. , Rood Richard B.
Published: January 2012

Modeling the transport of trace gases is an essential part of any atmospheric model. The tracer transport scheme in the Community Atmosphere Model finite-volume dynamical core (CAM-FV), which is part of the National Center for Atmospheric Research’s (NCAR’s) Community Earth System Model (CESM1), is investigated using multidimensional idealized advection tests. CAM-FV’s tracer transport algorithm makes use of one-dimensional monotonic limiters. The Colella–Sekora limiter, which is applied to increase accuracy where the data are smooth, is implemented into the CAM-FV framework, and compared with the more traditional monotonic limiter of the piecewise parabolic method (the default limiter). For 2D flow, CAM-FV splits dimensions, allowing overshoots and undershoots, with the Colella–Sekora limiter producing larger overshoots than the default limiter.

The impact of vertical resolution is also explored. A vertical Lagrangian coordinate is used in CAM-FV, and is periodically remapped back to a fixed Eulerian grid. For purely vertical motion, it is found that less-frequent remapping of the Lagrangian coordinate in CAM-FV improves results. For full 3D tests, the vertical component of the tracer transport dominates the error and limits the overall accuracy. If the vertical resolution is inadequate, increasing the horizontal resolution has almost no effect on accuracy. This is because the vertical resolution currently used in CAM version 5 may not be sufficiently fine enough to resolve some atmospheric tracers and provide accurate vertical advection. Idealized tests using tracers in a gravity wave agree with these results.
Partial Replacement of ω‐6 Fatty Acids With Medium‐Chain Triglycerides, but Not Olive Oil, Improves Colon Cytokine Response and Damage in Experimental Colitis
Authors: Bertevello Pedro L. , De Nardi Leticia , Torrinhas Raquel S. , Logullo Angela F. , Waitzberg Dan L.
Published: January 2012

Background: Soybean oil is rich in ω‐6 fatty acids, which are associated with higher incidence and more severe cases of inflammatory bowel diseases. The authors evaluated whether partial replacement of soybean oil by medium‐chain triglycerides (MCTs) or olive oil influenced the incidence and severity of experimental ulcerative colitis by using different parenteral lipid emulsions (LEs). Methods: Wistar rats (n = 40) were randomized to receive parenteral infusion of the following LE: 100% soybean oil (SO), 50% MCT mixed with 50% soybean oil (MCT/SO), 80% olive oil mixed with 20% soybean oil (OO/SO), or saline (CC). After 72 hours of infusion, acetic acid experimental colitis was induced. After 24 hours, colon histology and cytokine expression were analyzed. Results: SO was not significantly associated with overall tissue damage. MCT/SO was not associated with necrosis (P < .005), whereas OO/SO had higher frequencies of ulcer and necrosis (P < .005). SO was associated with increased expression of interferon‐γ (P = .005) and OO/SO with increased interleukin (IL)–6 and decreased tumor necrosis factor–α expression (P < .05). MCT/SO appeared to decrease IL‐1 (P < .05) and increase IL‐4 (P < .001) expression. Conclusions: Parenteral SO with high concentration of ω‐6 fatty acids was not associated with greater tissue damage in experimental colitis. SO partial replacement with MCT/SO decreased the frequency of histological necrosis and favorably modulated cytokine expression in the colon; however, replacement with OO/SO had unfavorable effects.
Thermal Injury Activates the eEF2K‐Dependent eEF2 Pathway in Pediatric Patients
Authors: Song Juquan , Finnerty Celeste C. , Herndon David N. , Kraft Robert , Boehning Darren , Brooks Natasha C. , Tompkins Ronald G. , Jeschke Marc G.
Published: January 2012

Background:

Burn induces a hypermetabolic state characterized by alterations in protein metabolism, which is associated with increased morbidity and mortality. Eukaryotic elongation factor 2 (eEF2) plays a crucial role in regulating protein synthesis in many diseases, but whether it participates in burn‐induced hypermetabolism is unclear. The aim of this study was to determine the expression of eEF2 and the upstream eEF2‐inactivating kinase, eEF2K, in severely burned pediatric patients.

Methods:

Eight pediatric patients (> 40% total body surface area) and 3 nonburned pediatric volunteers were enrolled. Muscle and skin biopsies were collected at early (0–10 days postburn [dpb]), middle (11–49 dpb), and late (50–365 dpb) time points. Resting energy expenditure (REE), body composition, and muscle protein fractional synthesis rate (FSR) were measured. Proteins were extracted and analyzed by Western blotting. To further investigate the protein synthesis pathway, microarray data from muscle and skin were examined from 22 nonburned and 20 burned children.

Results:

Burn patients exhibited a profound hypermetabolic response, as seen by a significant increase in REE (P < .05) and loss of lean body mass without altered muscle FSR, indicating a shift to catabolism after thermal injury. In muscle, the phosphorylation of eEF2K‐dependent eEF2 was down regulated early and middle postburn. Similar changes in eEF2K and eEF2 levels occurred in skin at the early time point. Total amounts of eEF2 and eEF2K were not altered.

Conclusion:

Burn induces prolonged activation of eEF2K and eEF2. Alterations in these mediators may contribute to profound hypermetabolism in severely burned patients.
Faith-Based Organizations and Development: Prospects and Constraints
Authors: Olarinmoye Omobolaji Ololade
Published: January 2012

The failure of development as expressed in the high level of poverty in African states and the consequent emphasis of bilateral and multilateral aid agencies on participatory development and decentralization has brought to the fore the role of Non-governmental organization, of which Faith-based organizations (FBOs) are among the most useful, in the development process in Africa. Not much is known about FBOs and their development activities. This paper explores the various forms and dimensions of FBO engagement with development in Nigeria and their interaction with other development aid actors in Nigeria. Most importantly, it examines their interaction with donors and the Nigerian state. It concludes that FBOs are important but silent actors in development whose success is closely tied to their religious nature and whose activities can be further enhances if the constraints arising out of their religious nature can be reconciled with the logic of the state.
Infrastructure, Economic Growth and Poverty Reduction in Africa
Authors: Jerome Afeikhena
Published: January 2012

The relationship between infrastructure, growth and poverty is empirically robust in the macro- economic and microeconomic literature as well as in the rapidly evolving randomised field evaluation studies. This article appraises the role of infrastructure in economic growth and poverty alleviation in Africa. It notes that Africa’s infrastructure is still much below international standards in terms of quantity and quality. Access, affordability and quality of service continue to be key issues in all infrastructure sectors. Poverty was also not carefully addressed as part of the regulatory and other reform packages implemented during the 1990s. Not surprisingly, the infrastructure needs of the poor, the majority of who reside in rural and peri-urban areas have not been met and they continue to rely on unsafe, unreliable and often overpriced alternatives to compensate for the policy failures. Unlike the reforms of the 1990s which were shaped by ideological cleavages and blame game, there is gradually a coalescing of opinions on the reform agenda in the twenty-first century. The choice is no longer between a segregation of public and private provision but mutual collaboration between both actors. The public sector is now expected to play a much more important role in financing infrastructure than previously acknow-ledged, while the private sector should assist in meeting the significant needs associated with infrastructure construction, operation, and to some extent, financing in sectors such as telecommunications, energy generation, and transport services in which commercial and political risks are much lower.

JEL Classification: F3, L3, L9, N17, 055
Impact of Pubertal Development and Physical Activity on Heart Rate Variability in Overweight and Obese Children in Taiwan
Authors: Chen Su-Ru , Chiu Hung-Wen , Lee Yann-Jinn , Sheen Tzong-Chi , Jeng Chii
Published: January 2012

Child obesity is frequently associated with dysfunction of autonomic nervous system. Children in pubertal development were suggested to be vulnerable to autonomic nervous system problems such as decrease of heart rate variability from dysregulation of metabolic control. This study explored the influence of pubertal development on autonomic nervous system function in overweight and obese children and the concurrent effects of their physical activity. Eighty-four overweight or obese children and 87 normal weighted controls were recruited. Autonomic nervous system function was studied by measuring heart rate variability. Results showed that the overweight/obese children had significantly lower heart rate variability. Overweight/obese children in puberty had significantly lower heart rate variability which was positively correlated with their physical activity levels. In conclusion, overweight/obesity adversely affects the autonomic nervous system function of children especially during their pubertal development. Overweight/obese children should be encouraged to engage in physical activities during puberty to improve their autonomic nervous system function.
The Children Are Listening
Authors: Thaller Jonel
Published: January 2012

Familicide is a rare but troubling event that can be difficult to recount, especially for residents of the community were it occurred. The author of this piece combines her academic and practitioner knowledge of family violence with her personal experience, recalling the events leading up to the murder of a classmate nearly 20 years ago. The author reframes these memories through her current knowledge of risk assessment for domestic lethality as well as the safety behaviors women typically employ to protect themselves and their children. Further emphasis is placed on the need for children and young people to be involved in coordinated community efforts to detect and disclose incidents of family violence. Public education on this topic, for both adults and young people, can be useful in reducing stigma and coordinating efforts for intervention.
Renal transitional-cell carcinoma in two cats with chronic kidney disease
Authors: Hanzlicek Andrew S , Ganta Chanran , Myers Carl B , Grauer Gregory F
Published: January 2012

Two 12-year-old cats were diagnosed with chronic kidney disease (CKD) based on physical examination, clinicopathologic data and, in one case, abdominal ultrasound findings. Approximately 1 year after the initial diagnosis of CKD both cats developed renal transitional cell carcinoma (TCC) — bilateral in one cat. Based on post-mortem examination, one cat had no evidence of metastasis and the other had metastasis to the large intestine, heart and lungs. This is the first report of de novo bilateral renal TCC in a cat, as well as the first report of renal TCC developing in cats with previous history of confirmed CKD.
The tribological study of novel phosphorous–nitrogen type phosphoramidate additives in rapeseed oil
Authors: Yan Jincan , Bu Junmin , Bai Xuefeng , Li Jing , Ren Tianhui , Zhao Yidong
Published: January 2012

Two novel phosphorous–nitrogen type phosphoramidate derivatives, dibutyl octadecylphosphoramidate and dimethyl 4-dodecylphenylphosphoramidate, were synthesized and applied as lubricant additives in rapeseed oil. Using a four-ball machine and standard method, the tribological behaviors of these additives in rapeseed oil were compared with commercial lubricant additives dodecan-1-aminium butyl 7-methyloctyl phosphate (coded T308B) and dibutyl phosphonate (coded T304). The results show that the phosphoramidate derivatives possess excellent antiwear, friction-reducing properties and good extreme pressure capacities. The tribological mechanism was investigated by X-ray absorption near edge structure spectroscopy. It is proposed that the prepared compounds as additives in rapeseed oil form a protective film on the rubbed surface, and the film contains phosphate and/or polyphosphate which can affect the tribological behavior.
Self-reported panic attacks in adulthood: Relationship with injury, location and disclosure of childhood sexual abuse
Authors: Renner Lynette M , Coohey Carol , Ruch Gillian , O’Leary Patrick
Published: January 2012

• Summary: Children’s long-term response to sexual abuse is likely to be influenced by its context, such as the location of the abuse, the severity of the abuse, their relationship to the abuser, and whether they disclose the abuse. In this study, we examine whether these factors increase the likelihood that children will experience panic attacks during adulthood.

• Findings: This secondary analysis relied on a convenience sample of 92 participants who were recruited through community advertisements. In the multivariate model, adults who were injured during the sexual abuse, were sexually abused outside their home, who reported the sexual abuse was incest, and who were in midlife were more likely to experience panic attacks. Disclosing abuse and wanting to disclose abuse, but being unable to, were not related to panic attacks.

• Applications: The results of this exploratory study need to be verified by other researchers using a larger sample. For children, discussing the location of the abuse could lead to a conversation about safe spaces and protective strategies.
Comment: Is Self–Other Overlap the Key to Understanding Empathy?
Authors: Eisenberg Nancy , Sulik Michael J.
Published: January 2012

Preston and Hofelich (2012) suggested that researchers disagree on the role of self–other overlap in empathy due to a failure to differentiate among neural overlap, subjective resonance, and personal distress; they also developed a framework for tying neural and subjective overlap to various aspects of functioning they include in the construct of empathy. Although we found their discussion of different processes that have been labeled empathy interesting and helpful, we found their discussion of self–other overlap to be somewhat less useful for conceptualizing differences among empathy-related processes. In addition, we provide an alternative perspective to their reasoning regarding the role of experience and neural overlap in an aspect of empathy-related responding (e.g., concern or compassion).
Author reply: Empathy Does Provide Rational Support for Decisions. But Is It the Right Decision?
Authors: Breithaupt Fritz
Published: January 2012

This article examines the relation of empathy and rational judgment. When people observe a conflict most are quick to side with one of the parties. Once a side has been taken, empathy with that party further solidifies this choice. Hence, it will be suggested that empathy is not neutral to judgment and rational decision-making. This does not mean, however, that the one who empathizes will necessarily have made the best choice.
Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer
Authors: Buchlis George , Podsakoff Gregory M. , Radu Antonetta , Hawk Sarah M. , Flake Alan W. , Mingozzi Federico , High Katherine A.
Published: January 2012

In previous work we transferred a human factor IX–encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier who died of causes unrelated to gene transfer. Using Western blot, IHC, and immunofluorescent staining, we show persistent factor IX expression in injected muscle tissue. F.IX transcripts were detected in injected skeletal muscle using RT-PCR, and isolated whole genomic DNA tested positive for the presence of the transferred AAV vector sequence. This is the longest reported transgene expression to date from a parenterally administered AAV vector, with broad implications for the future of muscle-directed gene transfer.
IMWG consensus on maintenance therapy in multiple myeloma
Authors: Ludwig Heinz , Durie Brian G. M. , McCarthy Philip , Palumbo Antonio , San Miguel Jésus , Barlogie Bart , Morgan Gareth , Sonneveld Pieter , Spencer Andrew , Andersen Kenneth C. , Facon Thierry , Stewart Keith A. , Einsele Hermann , Mateos Maria-Victoria , Wijermans Pierre , Waage Anders , Beksac Meral , Richardson Paul G. , Hulin Cyrille , Niesvizky Ruben , Lokhorst Henk , Landgren Ola , Bergsagel P. Leif , Orlowski Robert , Hinke Axel , Cavo Michele , Attal Michel
Published: January 2012

Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.
Developing a powerful In Silico tool for the discovery of novel caspase-3 substrates: a preliminary screening of the human proteome
Authors: Ayyash Muneef , Tamimi Hashem , Ashhab Yaqoub
Published: January 2012

Background

Caspases are a family of cysteinyl proteases that regulate apoptosis and other biological processes. Caspase-3 is considered the central executioner member of this family with a wide range of substrates. Identification of caspase-3 cellular targets is crucial to gain further insights into the cellular mechanisms that have been implicated in various diseases including: cancer, neurodegenerative, and immunodeficiency diseases. To date, over 200 caspase-3 substrates have been identified experimentally. However, many are still awaiting discovery.

Results

Here, we describe a powerful bioinformatics tool that can predict the presence of caspase-3 cleavage sites in a given protein sequence using a Position-Specific Scoring Matrix (PSSM) approach. The present tool, which we call CAT3, was built using 227 confirmed caspase-3 substrates that were carefully extracted from the literature. Assessing prediction accuracy using 10 fold cross validation, our method shows AUC (area under the ROC curve) of 0.94, sensitivity of 88.83%, and specificity of 89.50%. The ability of CAT3 in predicting the precise cleavage site was demonstrated in comparison to existing state-of-the-art tools. In contrast to other tools which were trained on cleavage sites of various caspases as well as other similar proteases, CAT3 showed a significant decrease in the false positive rate. This cost effective and powerful feature makes CAT3 an ideal tool for high-throughput screening to identify novel caspase-3 substrates.

The developed tool, CAT3, was used to screen 13,066 human proteins with assigned gene ontology terms. The analyses revealed the presence of many potential caspase-3 substrates that are not yet described. The majority of these proteins are involved in signal transduction, regulation of cell adhesion, cytoskeleton organization, integrity of the nucleus, and development of nerve cells.

Conclusions

CAT3 is a powerful tool that is a clear improvement over existing similar tools, especially in reducing the false positive rate. Human proteome screening, using CAT3, indicate the presence of a large number of possible caspase-3 substrates that exceed the anticipated figure. In addition to their involvement in various expected functions such as cytoskeleton organization, nuclear integrity and adhesion, a large number of the predicted substrates are remarkably associated with the development of nerve tissues.
Characterization of the C. elegans erlin homologue
Authors: Hoegg Maja B , Robbins Stephen M , McGhee James D
Published: January 2012

Background

Erlins are highly conserved proteins associated with lipid rafts within the endoplasmic reticulum (ER). Biochemical studies in mammalian cell lines have shown that erlins are required for ER associated protein degradation (ERAD) of activated inositol-1,4,5-trisphosphate receptors (IP3Rs), implying that erlin proteins might negatively regulate IP3R signalling. In humans, loss of erlin function appears to cause progressive intellectual disability, motor dysfunction and joint contractures. However, it is unknown if defects in IP3R ERAD are the underlying cause of this disease phenotype, whether ERAD of activated IP3Rs is the only function of erlin proteins, and what role ERAD plays in regulating IP3R-dependent processes in the context of an intact animal or embryo. In this study, we characterize the erlin homologue of the nematode Caenorhabditis elegans and examine erlin function in vivo. We specifically set out to test whether C. elegans erlin modulates IP3R-dependent processes, such as egg laying, embryonic development and defecation rates. We also explore the possibility that erlin might play a more general role in the ERAD pathway of C. elegans.

Results

We first show that the C. elegans erlin homologue, ERL-1, is highly similar to mammalian erlins with respect to amino acid sequence, domain structure, biochemical properties and subcellular location. ERL-1 is present throughout the C. elegans embryo; in adult worms, ERL-1 appears restricted to the germline. The expression pattern of ERL-1 thus only partially overlaps with that of ITR-1, eliminating the possibility of ERL-1 being a ubiquitous and necessary regulator of ITR-1. We show that loss of ERL-1 does not affect overall phenotype, or alter brood size, embryonic development or defecation cycle length in either wild type or sensitized itr-1 mutant animals. Moreover we show that ERL-1 deficient worms respond normally to ER stress conditions, suggesting that ERL-1 is not an essential component of the general ERAD pathway.

Conclusions

Although loss of erlin function apparently causes a strong phenotype in humans, no such effect is seen in C. elegans. C. elegans erlin does not appear to be a ubiquitous major modulator of IP3 receptor activity nor does erlin appear to play a major role in ERAD.
An R package "VariABEL" for genome-wide searching of potentially interacting loci by testing genotypic variance heterogeneity
Authors: Struchalin Maksim V , Amin Najaf , Eilers Paul HC , van Duijn Cornelia M , Aulchenko Yurii S
Published: January 2012

Background

Hundreds of new loci have been discovered by genome-wide association studies of human traits. These studies mostly focused on associations between single locus and a trait. Interactions between genes and between genes and environmental factors are of interest as they can improve our understanding of the genetic background underlying complex traits. Genome-wide testing of complex genetic models is a computationally demanding task. Moreover, testing of such models leads to multiple comparison problems that reduce the probability of new findings. Assuming that the genetic model underlying a complex trait can include hundreds of genes and environmental factors, testing of these models in genome-wide association studies represent substantial difficulties.

We and Pare with colleagues (2010) developed a method allowing to overcome such difficulties. The method is based on the fact that loci which are involved in interactions can show genotypic variance heterogeneity of a trait. Genome-wide testing of such heterogeneity can be a fast scanning approach which can point to the interacting genetic variants.

Results

In this work we present a new method, SVLM, allowing for variance heterogeneity analysis of imputed genetic variation. Type I error and power of this test are investigated and contracted with these of the Levene's test. We also present an R package, VariABEL, implementing existing and newly developed tests.

Conclusions

Variance heterogeneity analysis is a promising method for detection of potentially interacting loci. New method and software package developed in this work will facilitate such analysis in genome-wide context.
Expression profiling reveals Spot 42 small RNA as a key regulator in the central metabolism of Aliivibrio salmonicida
Authors: Hansen Geir Å , Ahmad Rafi , Hjerde Erik , Fenton Christopher G , Willassen Nils-Peder , Haugen Peik
Published: January 2012

Background

Spot 42 was discovered in Escherichia coli nearly 40 years ago as an abundant, small and unstable RNA. Its biological role has remained obscure until recently, and is today implicated in having broader roles in the central and secondary metabolism. Spot 42 is encoded by the spf gene. The gene is ubiquitous in the Vibrionaceae family of gamma-proteobacteria. One member of this family, Aliivibrio salmonicida, causes cold-water vibriosis in farmed Atlantic salmon. Its genome encodes Spot 42 with 84% identity to E. coli Spot 42.

Results

We generated a A. salmonicida spf deletion mutant. We then used microarray and Northern blot analyses to monitor global effects on the transcriptome in order to provide insights into the biological roles of Spot 42 in this bacterium. In the presence of glucose, we found a surprisingly large number of ≥ 2X differentially expressed genes, and several major cellular processes were affected. A gene encoding a pirin-like protein showed an on/off expression pattern in the presence/absence of Spot 42, which suggests that Spot 42 plays a key regulatory role in the central metabolism by regulating the switch between fermentation and respiration. Interestingly, we discovered an sRNA named VSsrna24, which is encoded immediately downstream of spf. This new sRNA has an expression pattern opposite to that of Spot 42, and its expression is repressed by glucose.

Conclusions

We hypothesize that Spot 42 plays a key role in the central metabolism, in part by regulating the pyruvat dehydrogenase enzyme complex via pirin.
Luteolin decreases IGF-II production and downregulates insulin-like growth factor-I receptor signaling in HT-29 human colon cancer cells
Authors: Lim Do Young , Cho Han Jin , Kim Jongdai , Nho Chu Won , Lee Ki Won , Park Jung Han Yoon
Published: January 2012

Background

Luteolin is a 3',4',5,7-tetrahydroxyflavone found in various fruits and vegetables. We have shown previously that luteolin reduces HT-29 cell growth by inducing apoptosis and cell cycle arrest. The objective of this study was to examine whether luteolin downregulates the insulin-like growth factor-I receptor (IGF-IR) signaling pathway in HT-29 cells.

Methods

In order to assess the effects of luteolin and/or IGF-I on the IGF-IR signaling pathway, cells were cultured with or without 60 μmol/L luteolin and/or 10 nmol/L IGF-I. Cell proliferation, DNA synthesis, and IGF-IR mRNA levels were evaluated by a cell viability assay, [3H]thymidine incorporation assays, and real-time polymerase chain reaction, respectively. Western blot analyses, immunoprecipitation, and in vitro kinase assays were conducted to evaluate the secretion of IGF-II, the protein expression and activation of IGF-IR, and the association of the p85 subunit of phophatidylinositol-3 kinase (PI3K) with IGF-IR, the phosphorylation of Akt and extracellular signal-regulated kinase (ERK)1/2, and cell division cycle 25c (CDC25c), and PI3K activity.

Results

Luteolin (0 - 60 μmol/L) dose-dependently reduced the IGF-II secretion of HT-29 cells. IGF-I stimulated HT-29 cell growth but did not abrogate luteolin-induced growth inhibition. Luteolin reduced the levels of the IGF-IR precursor protein and IGF-IR transcripts. Luteolin reduced the IGF-I-induced tyrosine phosphorylation of IGF-IR and the association of p85 with IGF-IR. Additionally, luteolin inhibited the activity of PI3K activity as well as the phosphorylation of Akt, ERK1/2, and CDC25c in the presence and absence of IGF-I stimulation.

Conclusions

The present results demonstrate that luteolin downregulates the activation of the PI3K/Akt and ERK1/2 pathways via a reduction in IGF-IR signaling in HT-29 cells; this may be one of the mechanisms responsible for the observed luteolin-induced apoptosis and cell cycle arrest.
HPV type-related chromosomal profiles in high-grade cervical intraepithelial neoplasia
Authors: Bierkens Mariska , Wilting Saskia M , van Wieringen Wessel N , van de Wiel Mark A , Ylstra Bauke , Meijer Chris JLM , Snijders Peter JF , Steenbergen Renske DM
Published: January 2012

Background

The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected.

Methods

Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (≥ 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58.

Results

Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2).

Conclusions

Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.
"Now we are in a different time; various bad diseases have come." understanding men's acceptability of male circumcision for HIV prevention in a moderate prevalence setting
Authors: Kelly Angela , Kupul Martha , Fitzgerald Lisa , Aeno Herick , Neo James , Naketrumb Richard , Siba Peter , Kaldor John M , Vallely Andrew ,   of the Male Circumcision Acceptability and Impact Study (MCAIS) team
Published: January 2012

Background

Adult male surgical circumcision (MC) has been shown to reduce HIV acquisition in men and is recommended by the WHO for inclusion in comprehensive national HIV prevention programs in high prevalence settings. Only limited research to date has been conducted in countries experiencing moderate burden epidemics, where the acceptability, operational feasibility and potential epidemiological impact of MC remain unclear.

Methods

A multi-method qualitative research study was conducted at four sites in Papua New Guinea (PNG), with 24 focus group discussions and 65 in-depth interviews carried out among 276 men.

Results

The majority of men were in favour of MC being introduced for HIV prevention in PNG and considered improved genital hygiene, enhanced sexual pleasure and culturally appropriateness key factors in the acceptability of a future intervention. A minority of men were against the introduction of MC, primarily due to concerns regarding sexual risk compensation and that the intervention went against prevailing cultural and religious beliefs.

Conclusion

This is one of the first community-based MC acceptability studies conducted in a moderate prevalence setting outside of Africa. Research findings from this study suggest that a future MC program for HIV prevention would be widely accepted by men in PNG.