bluuebunny/crossref_metadata_2025 huggingface dataset:
Academic Library Reform and the Ideal of the Librarian in England, France, and Germany in the Long Nineteenth Century
Authors: Minter Catherine
Published: February 2013

In Western Europe in the late eighteenth century, complaints were rife about the disorganization of libraries and the character of their librarians. Not only from the perspective of library users, but also from within librarians’ own ranks, the sentiment became more widespread that librarians should strive to be more industrious and effective, and that libraries should aim to be better organized in order to promote use and access. The strong ‘public service’ orientation to nineteenth-century European library theory lay at the heart of the major practical or ‘technical’ innovations — notably in the fields of classification and cataloguing — which transformed librarianship into a profession towards the end of the century.

This article aims to explore the impact of these innovations on the role and image of the librarian in the nineteenth century, with particular reference to academic libraries and librarians in England, France, and Germany. It is suggested that as a characteristic set of ‘librarianly’ virtues — prime among these being love of order, conscientiousness, selflessness, and the willingness to serve — rose to pre-eminence against the background of technical innovations in the field (and also, incidentally, as a reaction against the ‘scholar librarians’ of an earlier era), the seeds were sown of a crisis in the librarian’s professional image and self-image with implications which may even reach into the present.
miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling
Authors: Bhagat Tushar D. , Zhou Li , Sokol Lubomir , Kessel Rachel , Caceres Gisela , Gundabolu Krishna , Tamari Roni , Gordon Shanisha , Mantzaris Ioannis , Jodlowski Tomasz , Yu Yiting , Jing Xiaohong , Polineni Rahul , Bhatia Kavi , Pellagatti Andrea , Boultwood Jacqueline , Kambhampati Suman , Steidl Ulrich , Stein Cy , Ju Wenjun , Liu Gang , Kenny Paraic , List Alan , Bitzer Markus , Verma Amit
Published: February 2013

Key Points

We observed that SMAD7, a negative regulator of TGF-β receptor-I kinase, is markedly reduced in MDS, and leads to ineffective hematopoiesis. Increased levels of microRNA-21 are seen in MDS and reduce SMAD7 levels, thus overactivating TGF-β signaling.
Targeting dendritic cells—why bother?
Authors: Kreutz Martin , Tacken Paul J. , Figdor Carl G.
Published: February 2013

Vaccination is among the most efficient forms of immunotherapy. Although sometimes inducing lifelong protective B-cell responses, T-cell–mediated immunity remains challenging. Targeting antigen to dendritic cells (DCs) is an extensively explored concept aimed at improving cellular immunity. The identification of various DC subsets with distinct functional characteristics now allows for the fine-tuning of targeting strategies. Although some of these DC subsets are regarded as superior for (cross-) priming of naive T cells, controversies still remain about which subset represents the best target for immunotherapy. Because targeting the antigen alone may not be sufficient to obtain effective T-cell responses, delivery systems have been developed to target multiple vaccine components to DCs. In this Perspective, we discuss the pros and cons of targeting DCs: if targeting is beneficial at all and which vaccine vehicles and immunization routes represent promising strategies to reach and activate DCs.
Carfilzomib
Authors: Kortuem K. Martin , Stewart A. Keith
Published: February 2013

This spotlight review focuses on the second-generation proteasome inhibitor carfilzomib, which was recently approved by the US Food and Drug Administration for treatment of relapsed and refractory multiple myeloma patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. This review focuses on clinical trial data leading to drug approval and provides advice for treating physicians who are now accessing this drug for patients.
MYBBP1A suppresses breast cancer tumorigenesis by enhancing the p53 dependent anoikis
Authors: Akaogi Kensuke , Ono Wakana , Hayashi Yuki , Kishimoto Hiroyuki , Yanagisawa Junn
Published: February 2013

Background

Tumor suppressor p53 is mutated in a wide variety of human cancers and plays a critical role in anoikis, which is essential for preventing tumorigenesis. Recently, we found that a nucleolar protein, Myb-binding protein 1a (MYBBP1A), was involved in p53 activation. However, the function of MYBBP1A in cancer prevention has not been elucidated.

Methods

Relationships between MYBBP1A expression levels and breast cancer progression were examined using patient microarray databases and tissue microarrays. Colony formation, xenograft, and anoikis assays were conducted using cells in which MYBBP1A was either knocked down or overexpressed. p53 activation and interactions between p53 and MYBBP1A were assessed by immunoprecipitation and western blot.

Results

MYBBP1A expression was negatively correlated with breast cancer tumorigenesis. In vivo and in vitro experiments using the breast cancer cell lines MCF-7 and ZR-75-1, which expresses wild type p53, showed that tumorigenesis, colony formation, and anoikis resistance were significantly enhanced by MYBBP1A knockdown. We also found that MYBBP1A binds to p53 and enhances p53 target gene transcription under anoikis conditions.

Conclusions

These results suggest that MYBBP1A is required for p53 activation during anoikis; therefore, it is involved in suppressing colony formation and the tumorigenesis of breast cancer cells. Collectively, our results suggest that MYBBP1A plays a role in tumor prevention in the context of p53 activation.
CBT for depression: a pilot RCT comparing mobile phone vs. computer
Authors: Watts Sarah , Mackenzie Anna , Thomas Cherian , Griskaitis Al , Mewton Louise , Williams Alishia , Andrews Gavin
Published: February 2013

Background

This paper reports the results of a pilot randomized controlled trial comparing the delivery modality (mobile phone/tablet or fixed computer) of a cognitive behavioural therapy intervention for the treatment of depression. The aim was to establish whether a previously validated computerized program (The Sadness Program) remained efficacious when delivered via a mobile application.

Method

35 participants were recruited with Major Depression (80% female) and randomly allocated to access the program using a mobile app (on either a mobile phone or iPad) or a computer. Participants completed 6 lessons, weekly homework assignments, and received weekly email contact from a clinical psychologist or psychiatrist until completion of lesson 2. After lesson 2 email contact was only provided in response to participant request, or in response to a deterioration in psychological distress scores. The primary outcome measure was the Patient Health Questionnaire 9 (PHQ-9). Of the 35 participants recruited, 68.6% completed 6 lessons and 65.7% completed the 3-months follow up. Attrition was handled using mixed-model repeated-measures ANOVA.

Results

Both the Mobile and Computer Groups were associated with statistically significantly benefits in the PHQ-9 at post-test. At 3 months follow up, the reduction seen for both groups remained significant.

Conclusions

These results provide evidence to indicate that delivering a CBT program using a mobile application, can result in clinically significant improvements in outcomes for patients with depression.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN 12611001257954
Beliefs and attitudes towards participating in genetic research – a population based cross-sectional study
Authors: Kerath Samantha M , Klein Gila , Kern Marlena , Shapira Iuliana , Witthuhn Jennifer , Norohna Nicole , Kline Myriam , Baksh Farisha , Gregersen Peter , Taioli Emanuela
Published: February 2013

Background

Biobanks have the potential to offer a venue for chronic disease biomarker discovery, which would allow for disease early detection and for identification of carriers of a certain predictor biomarker. To assess the general attitudes towards genetic research and participation in biobanks in the Long Island/Queens area of New York, and what factors would predict a positive view of such research, participants from the NSLIJ hospital system were surveyed.

Methods

Participants were recruited at six hospital centers in the NSLIJ system during the summers of 2009 and again in 2011 (n = 1,041). Those who opted to participate were given a questionnaire containing 22 questions assessing demographics, lifestyle and attitudes towards genetic research. These questions addressed individual participant’s beliefs about the importance of genetic research, willingness to participate in genetic research themselves, and their views on informed consent issues.

Results

Respondents took a generally positive view of genetic research in general, as well as their own participation in such research. Those with reservations were most likely to cite concerns over the privacy of their medical and genetic information. Those who were married tended to view genetic research as important, while those in the younger age group viewed it as less important. Prior blood donation of respondents was found to be a predictor of their approval for genetic research. Demographic factors were not found to be predictive of personal willingness to participate in genetic research, or of approval for the opt-out approach to consent.

Conclusions

While respondents were generally inclined to approve of genetic research, and those who disapproved did not do so based on an underlying moral objection to such research, there is a disconnect between the belief in the importance of genetic research and the willingness of individuals to participate themselves. This indicates a continued concern for the ways in which genetic materials are safeguarded once they are collected. Also indicated was a general lack of understanding about the various consent processes that go along with genetic research, which should be addressed further to ensure the successful continuation of biobanks.
Substitutes of structural and non-structural autologous bone grafts in hindfoot arthrodeses and osteotomies: a systematic review
Authors: Müller Marc Andreas , Frank Alexander , Briel Matthias , Valderrabano Victor , Vavken Patrick , Entezari Vahid , Mehrkens Arne
Published: February 2013

Background

Structural and non-structural substitutes of autologous bone grafts are frequently used in hindfoot arthrodeses and osteotomies. However, their efficacy is unclear.

The primary goal of this systematic review was to compare autologous bone grafts with structural and non-structural substitutes regarding the odds of union in hindfoot arthrodeses and osteotomies.

Methods

The Medline and EMBASE and Cochrane databases were searched for relevant randomized and non-randomized prospective studies as well as retrospective comparative chart reviews.

Results

10 studies which comprised 928 hindfoot arthrodeses and osteotomies met the inclusion criteria for this systematic review. The quality of the retrieved studies was low due to small samples sizes and confounding variables. The pooled random effect odds for union were 12.8 (95% CI 12.7 to 12.9) for structural allografts, 5.7 (95% CI 5.5 to 6.0) for cortical autologous grafts, 7.3 (95% CI 6.0 to 8.6) for cancellous allografts and 6.0 (95% CI 5.7 to 6.4) for cancellous autologous grafts. In individual studies, the odds of union in hindfoot arthrodeses achieved with cancellous autologous grafts was similar to those achieved with demineralised bone matrix or platelet derived growth factor augmented ceramic granules.

Conclusion

Our results suggest an equivalent incorporation of structural allografts as compared to autologous grafts in hindfoot arthrodeses and osteotomies. There is a need for prospective randomized trials to further clarify the role of substitutes of autologous bone grafts in hindfoot surgery.
Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia
Authors: Fayyad-Kazan Hussein , Bitar Nizar , Najar Mehdi , Lewalle Philippe , Fayyad-Kazan Mohammad , Badran Rabih , Hamade Eva , Daher Ahmad , Hussein Nader , ELDirani Rim , Berri Fadwa , Vanhamme Luc , Burny Arsène , Martiat Philippe , Rouas Redouane , Badran Bassam
Published: February 2013

Background

MicroRNAs (miRNAs) are small (19-22-nt) single-stranded noncoding RNA molecules whose deregulation of expression can contribute to human disease including the multistep processes of carcinogenesis in human. Circulating miRNAs are emerging biomarkers in many diseases and cancers such as type 2 diabetes, pulmonary disease, colorectal cancer, and gastric cancer among others; however, defining a plasma miRNA signature in acute myeloblastic leukemia (AML) that could serve as a biomarker for diagnosis or in the follow-up has not been done yet.

Methods

TaqMan miRNA microarray was performed to identify deregulated miRNAs in the plasma of AML patients. Quantitative real-time RT-PCR was used to validate the results. Receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the highly and significantly identified deregulated miRNA(s) as potential candidate biomarker(s).

Results

The plasma expression level of let-7d, miR-150, miR-339, and miR-342 was down-regulated whilst that of let-7b, and miR-523 was up-regulated in the AML group at diagnosis compared to healthy controls. ROC curve analyses revealed an AUC (the areas under the ROC curve) of 0.835 (95% CI: 0.7119– 0.9581; P<0.0001) and 0.8125 (95% CI: 0.6796–0.9454; P=0.0005) for miR-150, and miR-342 respectively. Combined ROC analyses using these 2 miRNAs revealed an elevated AUC of 0.86 (95% CI: 0.7819–0.94; P<0.0001) indicating the additive effect in the diagnostic value of these 2 miRNAs. QRT-PCR results showed that the expression level of these two miRs in complete remission AML patients resembled that of healthy controls.

Conclusions

Our findings indicated that plasma miR-150 and miR-342 are novel important promising biomarkers in the diagnosis of AML. These novel and promising markers warrant validation in larger prospective studies.
Removal of cadmium (II) from simulated wastewater by ion flotation technique
Authors: Salmani Mohammad Hossein , Davoodi Mojtaba , Ehrampoush Mohammad Hassan , Ghaneian Mohammad Taghi , Fallahzadah Mohammad Hossein
Published: February 2013

A separation technique which has recently received a sharp increase in research activities is “ion flotation”. This technique has four important advantages for treating wastewaters: low energy consumption, small space requirements, small volume of sludge and acting selectively. The present study aims to optimize parameters of ion flotation for cadmium removal in simulated wastewater at laboratory scale. It was obtained on the reaction between Cd2+ and sodium dodecylesulfate (SDS) collector followed by flotation with ethanol as frother. Test solution was prepared by combining the required amount of cadmium ion, SDS and necessary frother or sodium sulfate solution. All experiments were carried out in a flotation column at laboratory temperature (27°C), adjusted pH = 4 and 120 minutes. The different parameters (namely: flow rate, cadmium, SDS and frother concentrations and ionic strength) influencing the flotation process were examined. The best removal efficiency obtained at a collector-metal ratio of 3:1 in 60 min with flow rate of 150 mL/min was 84%. The maximum cadmium removal was 92.1% where ethanol was introduced at a concentration 0.4% to flotation column with above conditions. The obtained results were promising, as both cadmium and collector were effectively removed from wastewater. Hence, the application of ion flotation for metal ions removal from effluents seems to be efficient.
Effects of human Toll-like receptor 1 polymorphisms on ageing
Authors: Uciechowski Peter , Oellig Eva Maria , Mariani Erminia , Malavolta Marco , Mocchegiani Eugenio , Rink Lothar
Published: February 2013

Background

Advanced age results in crucial alterations of the innate and adaptive immune system leading to functional defects resulting in infection and chronic diseases. Toll-like receptors (TLR) recognize pathogenic structures and are important in the immune response to infections and vaccination. However, the role of TLR single nucleotide polymorphisms (SNP) is poorly understood in the setting of human ageing. This study investigated the impact of the TLR1 SNPs A743G and T1805G on ageing in different age groups from two European populations.

Results

The TLR1 genotypes 743AA/1805GG (TLR1neg) are associated with a TLR1 negative phenotype, impaired function and susceptibility to tuberculosis. Carriers of heterozygous 743AG/1805TG and homozygous 743GG/1805TT genotypes (TLR1pos) have a TLR1 positive phenotype. By comparing healthy young and old German donors, the old group showed a tendency to carry more TLR1neg and less homozygous TLR1pos genotypes. Anti-inflammatory Interleukin (IL)-1 receptor antagonist (Ra) was significantly elevated in supernatants of mononuclear cells from old German subjects with a TLR1pos genotype in contrast to those with the 743AA genotype. Healthy old individuals and nonagenarians from Italy displayed significantly higher frequencies of TLR1pos genotypes than the old group from Germany. The data show that tumor-necrosis-factor (TNF)α, CXCL8 and CCL2 levels were higher in old donors from Germany than in plasma levels from old Italian donors. TNFα and CCL2 levels were significantly raised in old German individuals compared to Italian nonagenarians. German and Italian donors with the TLR1neg genotype basically produced more CCL2 than older European donors with TLR1pos genotypes.

Conclusion

The higher frequency of the TLR1pos genotype in elderly Italian subjects may result from different ethnic populations. Lower inflammatory mediator release of aged Italian individuals is probably due to different background in nutrition, diet, genetics and to psychological aspects. Elderly donors carrying TLR1pos genotypes basically release more anti-inflammatory IL-1Ra and less inflammatory CCL2 suggesting a decline of the pro-inflammatory status found in ageing and, therefore, this may define an anti-inflammatory phenotype. Future studies are needed to elucidate the association of a TLRpos genotype with decreased susceptibility to infections and reduced risk to develop artherosclerosis.
Serum biomarkers of papillary thyroid cancer
Authors: Makki Fawaz M , Taylor S Mark , Shahnavaz Ali , Leslie Andrew , Gallant Jeffrey , Douglas Susan , Teh Evelyn , Trites Jonathan , Bullock Martin , Inglis Karen , Pinto Devanand M , Hart Robert D
Published: February 2013

Objective

To identify serum biomarkers of papillary thyroid cancer.

Methods

Prospective analysis was performed of banked tumor and serum specimens from 99 patients with thyroid masses. Enzyme-linked immunosorbent assay (ELISA) was employed to measure levels of five serum proteins previously demonstrated to be up-regulated in papillary thyroid cancer (PTC): angiopoietin-1 (Ang-1), cytokeratin 19 (CK-19), tissue inhibitor of metalloproteinase-1 (TIMP-1), chitinase 3 like-1 (YKL-40), and galectin-3 (GAL-3). Serum levels were compared between patients with PTC and those with benign tumors.

Results

A total of 99 patients were enrolled in the study (27 men, 72 women), with a median age of 54 years. Forty-three patients had PTC and 58 cases were benign tumors. There were no statistically significant differences when comparing all five different biomarkers between PTC and other benign thyroid tumors. The p-values were 0.94, 0.48, 0.72, 0.48, and 0.90 for YKL-40, Gal-3, CK19, TIMP-1, and Ang-1, respectively.

Conclusion

Serum levels of four of the five proteins were elevated in patients with thyroid masses relative to normal values. However, the difference between benign and PTC was not significant. Two of the markers (Gal-3 & TIMP-1) displayed a greater potential difference, which may warrant further investigation. This study suggests that other serum markers should be sought. This is the first study to investigate potential serum biomarkers based on over-expressed proteins in thyroid cancer versus benign pathology.
Integrating 3D seismic curvature and curvature gradient attributes for fracture characterization: Methodologies and interpretational implications
Authors: Gao Dengliang
Published: February 2013

In 3D seismic interpretation, curvature is a popular attribute that depicts the geometry of seismic reflectors and has been widely used to detect faults in the subsurface; however, it provides only part of the solutions to subsurface structure analysis. This study extends the curvature algorithm to a new curvature gradient algorithm and integrates both algorithms for fracture detection using a 3D seismic test data set over Teapot Dome (Wyoming). In fractured reservoirs at Teapot Dome formed by tectonic folding and faulting, curvature helps define the crestal portion of reservoirs that is associated with strong seismic amplitude and high oil productivity. In contrast, curvature gradient helps define the regional northwest-trending and the cross-regional northeast-trending lineaments that are associated with weak seismic amplitude and low oil productivity. In concert with previous reports from image logs, cores, and outcrops, an integrated seismic curvature and curvature gradient analysis suggests that curvature might help define areas of enhanced potential to form tensile fractures, whereas curvature gradient might help define zones of enhanced potential to develop shear fractures. In fractured reservoirs at Teapot Dome where faulting and fault-related folding contribute dominantly to the formation and evolution of fractures, curvature and curvature gradient attributes can be potentially applied to differentiate fracture mode, to predict fracture intensity and orientation, to evaluate fracture volume and connectivity, and to model fracture networks.
Carbohydrate-Mediated Polyethylene Glycol Conjugation of TSH Improves Its Pharmacological Properties
Authors: Park Anna , Honey Denise M. , Hou Lihui , Bird Julie J. , Zarazinski Christine , Searles Michelle , Braithwaite Christian , Kingsbury Jonathan S. , Kyazike Josephine , Culm-Merdek Kerry , Greene Ben , Stefano James E. , Qiu Huawei , McPherson John M. , Pan Clark Q.
Published: February 2013

Thyrogen (thyrotropin alfa for injection), recombinant human TSH (rhTSH), has been successfully used to enhance diagnostic radioiodine scanning and thyroglobulin testing in the follow-up of patients with thyroid cancer and as an adjunctive treatment for radioiodine thyroid remnant ablation. However, the short half-life of rhTSH in the circulation requires a multidose regimen. We developed novel sialic acid-mediated and galactose-mediated conjugation chemistries for targeting polyethylene glycol (PEG) to the three N-linked glycosylation sites on the protein, to prolong plasma half-life by eliminating kidney filtration and potential carbohydrate-mediated clearance. Conjugates of different PEG sizes and copy numbers were screened for reaction yield, TSH receptor binding, and murine phamacokinetics/pharmacodynamics studies. The best performing of these products, a 40-kDa mono-PEGylated sialic acid-mediated conjugate, exhibited a 3.5-fold longer duration of action than rhTSH in rats, as a 5-fold lower affinity was more than compensated by a 23-fold extension of circulation half-life. Biochemical characterization confirmed conjugation through the sialic acids. Correlation of PEG distribution on the three N-linked glycosylation sites and the PEG effect on receptor binding supported the previously reported structure-function relationship of rhTSH glycosylation. This long-acting rhTSH has the potential to significantly improve patient convenience and provider flexibility while reducing potential side effects associated with a sudden elevation of serum TSH.
Derailed Estrogen Signaling and Breast Cancer: An Authentic Couple
Authors: Manavathi Bramanandam , Dey Oindrilla , Gajulapalli Vijay Narsihma Reddy , Bhatia Raghavendra Singh , Bugide Suresh , Kumar Rakesh
Published: February 2013

Estrogen or 17β-estradiol, a steroid hormone, plays a critical role in the development of mammary gland via acting through specific receptors. In particular, estrogen receptor-α (ERα) acts as a transcription factor and/or a signal transducer while participating in the development of mammary gland and breast cancer. Accumulating evidence suggests that the transcriptional activity of ERα is altered by the action of nuclear receptor coregulators and might be responsible, at least in part, for the development of breast cancer. In addition, this process is driven by various posttranslational modifications of ERα, implicating active participation of the upstream receptor modifying enzymes in breast cancer progression. Emerging studies suggest that the biological outcome of breast cancer cells is also influenced by the cross talk between microRNA and ERα signaling, as well as by breast cancer stem cells. Thus, multiple regulatory controls of ERα render mammary epithelium at risk for transformation upon deregulation of normal homeostasis. Given the importance that ERα signaling has in breast cancer development, here we will highlight how the activity of ERα is controlled by various regulators in a spatial and temporal manner, impacting the progression of the disease. We will also discuss the possible therapeutic value of ERα modulators as alternative drug targets to retard the progression of breast cancer.
Diabetes and Nonalcoholic Fatty Liver Disease: A Pathogenic Duo
Authors: Williams K. H. , Shackel N. A. , Gorrell M. D. , McLennan S. V. , Twigg S. M.
Published: February 2013

Recent data increasingly support a complex interplay between the metabolic condition diabetes mellitus and the pathologically defined nonalcoholic fatty liver disease (NAFLD). NAFLD predicts the development of type 2 diabetes and vice versa, and each condition may serve as a progression factor for the other. Although the association of diabetes and NAFLD is likely to be partly the result of a “common soil,” it is also probable that diabetes interacts with NAFLD through specific pathogenic mechanisms. In particular, through interrelated metabolic pathways currently only partly understood, diabetes appears to accelerate the progression of NAFLD to nonalcoholic steatohepatitis, defined by the presence of necroinflammation, with varying degrees of liver fibrosis. In the research setting, obstacles that have made the identification of clinically significant NAFLD, and particularly nonalcoholic steatohepatitis, difficult are being addressed with the use of new imaging techniques combined with risk algorithms derived from peripheral blood profiling. These techniques are likely to be used in the diabetes population in the near future. This review examines the pathogenic links between NAFLD and diabetes by exploring the epidemiological evidence in humans and also through newer animal models. Emerging technology to help screen noninvasively for differing pathological forms of NAFLD and the potential role of preventive and therapeutic approaches for NAFLD in the setting of diabetes are also examined.
FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns
Authors: Nakaya Tadashi , Alexiou Panagiotis , Maragkakis Manolis , Chang Alexandra , Mourelatos Zissimos
Published: February 2013

Dominant mutations and mislocalization or aggregation of Fused in Sarcoma (FUS), an RNA-binding protein (RBP), cause neuronal degeneration in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), two incurable neurological diseases. However, the function of FUS in neurons is not well understood. To uncover the impact of FUS in the neuronal transcriptome, we used high-throughput sequencing of immunoprecipitated and cross-linked RNA (HITS–CLIP) of FUS in human brains and mouse neurons differentiated from embryonic stem cells, coupled with RNA-seq and FUS knockdowns. We report conserved neuronal RNA targets and networks that are regulated by FUS. We find that FUS regulates splicing of genes coding for RBPs by binding to their highly conserved introns. Our findings have important implications for understanding the impact of FUS in neurodegenerative diseases and suggest that perturbations of FUS can impact the neuronal transcriptome via perturbations of RBP transcripts.
Somatostatin Derivative (smsDX) Targets Cellular Metabolism in Prostate Cancer Cells after Androgen Deprivation Therapy
Authors: Yan Lei , Xing Zhaoquan , Guo Zhaoxin , Fang Zhiqing , Jiao Wei , Guo Xiaoyu , Xu Zhonghua , Fang Zhenghui , Liu Zhaoxu
Published: February 2013

Cancer cell metabolism responsive to androgen deprivation therapy (ADT) may be involved in the development and progression of prostate cancer and the ultimate failure of androgen-deprivation therapy. To investigate the metabolism regulation effects on androgen-independent growth of prostate cancer, an established LNCaP-s cell model that resembles the clinical scenario of castration-resistant prostate cancer (CRPC), was used in this current study. This cell line was cultured from androgen-sensitive LNCaP parental cells, in an androgen-reduced condition, resembling clinical androgen deprivation therapy. To assess the effects of smsDX on the invasiveness of prostate cancer cells we used wound healing assay and Matrigel™ invasion assay. We evaluated differentially expressed proteins of the parental LNCaP cells and LNCaP-s cells after ADT by means of two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF mass spectrometric analysis. The covered area in the wound and the number of cells invading through a Matrigel chamber were significantly smaller for cells treated with smsDX than they were for control cells treated with vehicle. 56 proteins were found differentially expressed in LNCaP-s cells compared to LNCaP cells, majority of them were down-regulated after ADT treatment. 104 proteins of LNCaP cells and 86 in LNCaP-s cells, separately, were found differentially expressed after treatment with smsDX, When we explored these protein functions within the website UniProtKB/Swiss-Prot, surprisingly, most of the proteins were found to be involved in the cellular metabolism and mitochondrial function regulation. LNCaP-s as potential metastatic androgen-independent cancer cells, its metabolism and mitochondrial functions could be altered by a new somatostatin derivative smsDX, the smsDX regulatory effects on metabolism in LNCaP-s deliver more therapeutic information with the treatment of CRPC.
Activity-Dependent Spine Morphogenesis: A Role for the Actin-Capping Protein Eps8
Authors: Stamatakou Eleanna , Marzo Aude , Gibb Alasdair , Salinas Patricia C.
Published: February 2013

Neuronal activity regulates the formation and morphology of dendritic spines through changes in the actin cytoskeleton. However, the molecular mechanisms that regulate this process remain poorly understood. Here we report that Eps8, an actin-capping protein, is required for spine morphogenesis. In rat hippocampal neurons, gain- and loss-of-function studies demonstrate that Eps8 promotes the formation of dendritic spines but inhibits filopodium formation. Loss of function of Eps8 increases actin polymerization and induces fast actin turnover within dendritic spines, as revealed by free-barbed end and FRAP assays, consistent with a role for Eps8 as an actin-capping protein. Interestingly, Eps8 regulates the balance between excitatory synapses on spines and on the dendritic shaft, without affecting the total number of synapses or basal synaptic transmission. Importantly, Eps8 loss of function impairs the structural and functional plasticity of synapses induced by long-term potentiation. These findings demonstrate a novel role for Eps8 in spine formation and in activity-mediated synaptic plasticity.
Distal Pup Cues Evoke Dopamine Responses in Hormonally Primed Rats in the Absence of Pup Experience or Ongoing Maternal Behavior
Authors: Afonso Veronica M. , Shams Waqqas M. , Jin Daniel , Fleming Alison S.
Published: February 2013

During the early postpartum period or following estrogen/progesterone administration, pups elicit maternal behavior accompanied by a robust dopamine (DA) response in the nucleus accumbens (NAC) of female rats (Afonso et al., 2009). To determine whether DA responds to ostensibly “salient” stimuli in the absence of consummatory behaviors, we examined NAC shell DA responses during restricted (stimuli placed in a perforated box), and unrestricted access to pup and food stimuli. Microdialysis samples were collected from female rats that were either cycling and postpartum (Experiment 1), or after ovariectomy and treated with empty and hormone-filled capsules (Experiment 2). Relative to nonprimed controls, hormonally primed females had suppressed basal DA concentrations and facilitated pup-evoked DA responses, regardless of stimulus access condition. In contrast, food-evoked DA responses were unchanged by hormonal priming and were greater when females consumed food compared with distal (restricted) exposure to food. During pup and food restriction conditions, the lack of any “appetitive” behavioral differences, even in pup experienced postpartum females, was surprising. In Experiment 3, we confirmed that postpartum dams allocated time equivalently to restricted pup and food stimuli, even after pup deprivation. This was in sharp contrast to the effects of deprivation during the unrestricted access phase. Together, our data demonstrated that, in hormonally primed females, distal pup cues could evoke DA responses without prior stimulus experience, ongoing maternal (behavioral) responses, or clear evidence of robust pup saliency. The results suggest that NAC DA response reflects a state of responsiveness related to basal DA suppression in the hormonally primed female rat.
Signal Multiplexing and Single-Neuron Computations in Lateral Intraparietal Area During Decision-Making
Authors: Meister Miriam L. R. , Hennig Jay A. , Huk Alexander C.
Published: February 2013

Previous work has revealed a remarkably direct neural correlate of decisions in the lateral intraparietal area (LIP). Specifically, firing rate has been observed to ramp up or down in a manner resembling the accumulation of evidence for a perceptual decision reported by making a saccade into (or away from) the neuron's response field (RF). However, this link between LIP response and decision formation emerged from studies where a saccadic target was always stimulating the RF during decisions, and where the neural correlate was the averaged activity of a restricted sample of neurons. Because LIP cells are (1) highly responsive to the presence of a visual stimulus in the RF, (2) heterogeneous, and (3) not clearly anatomically segregated from large numbers of neurons that fail selection criteria, the underlying neuronal computations are potentially obscured. To address this, we recorded single neuron spiking activity in LIP during a well-studied moving-dot direction–discrimination task and manipulated whether a saccade target was present in the RF during decision-making. We also recorded from a broad sample of LIP neurons, including ones conventionally excluded in prior studies. Our results show that cells multiplex decision signals with decision-irrelevant visual signals. We also observed disparate, repeating response “motifs” across neurons that, when averaged together, resemble traditional ramping decision signals. In sum, neural responses in LIP simultaneously carry decision signals and decision-irrelevant sensory signals while exhibiting diverse dynamics that reveal a broader range of neural computations than previously entertained.
Ventromedial Prefrontal and Anterior Cingulate Cortex Adopt Choice and Default Reference Frames during Sequential Multi-Alternative Choice
Authors: Boorman Erie D. , Rushworth Matthew F. , Behrens Tim E.
Published: February 2013

Although damage to the medial frontal cortex causes profound decision-making impairments, it has been difficult to pinpoint the relative contributions of key anatomical subdivisions. Here we use function magnetic resonance imaging to examine the contributions of human ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) during sequential choices between multiple alternatives—two key features of choices made in ecological settings. By carefully constructing options whose current value at any given decision was dissociable from their longer term value, we were able to examine choices in current and long-term frames of reference. We present evidence showing that activity at choice and feedback in vmPFC and dACC was tied to the current choice and the best long-term option, respectively. vmPFC, mid-cingulate, and posterior cingulate cortex encoded the relative value between the chosen and next best option at each sequential decision, whereas dACC encoded the relative value of adapting choices from the option with the highest value in the longer term. Furthermore, at feedback we identify temporally dissociable effects that predict repetition of the current choice and adaptation away from the long-term best option in vmPFC and dACC, respectively. These functional dissociations at choice and feedback suggest that sequential choices are subject to competing cortical mechanisms.
A Mutant Prion Protein Sensitizes Neurons to Glutamate-Induced Excitotoxicity
Authors: Biasini Emiliano , Unterberger Ursula , Solomon Isaac H. , Massignan Tania , Senatore Assunta , Bian Hejiao , Voigtlaender Till , Bowman Frederick P. , Bonetto Valentina , Chiesa Roberto , Luebke Jennifer , Toselli Paul , Harris David A.
Published: February 2013

Growing evidence suggests that a physiological activity of the cellular prion protein (PrPC) plays a crucial role in several neurodegenerative disorders, including prion and Alzheimer's diseases. However, how the functional activity of PrPCis subverted to deliver neurotoxic signals remains uncertain. Transgenic (Tg) mice expressing PrP with a deletion of residues 105–125 in the central region (referred to as ΔCR PrP) provide important insights into this problem. Tg(ΔCR) mice exhibit neonatal lethality and massive degeneration of cerebellar granule neurons, a phenotype that is dose dependently suppressed by the presence of wild-type PrP. When expressed in cultured cells, ΔCR PrP induces large, ionic currents that can be detected by patch-clamping techniques. Here, we tested the hypothesis that abnormal ion channel activity underlies the neuronal death seen in Tg(ΔCR) mice. We find that ΔCR PrP induces abnormal ionic currents in neurons in culture and in cerebellar slices and that this activity sensitizes the neurons to glutamate-induced, calcium-mediated death. In combination with ultrastructural and biochemical analyses, these results demonstrate a role for glutamate-induced excitotoxicity in PrP-mediated neurodegeneration. A similar mechanism may operate in other neurodegenerative disorders attributable to toxic, β-rich oligomers that bind to PrPC.
The Auditory Sensitivity is Increased in Tinnitus Ears
Authors: Hébert Sylvie , Fournier Philippe , Noreña Arnaud
Published: February 2013

Increased auditory sensitivity, also called hyperacusis, is a pervasive complaint of people with tinnitus. The high prevalence of hyperacusis in tinnitus subjects suggests that both symptoms have a common origin. It has been suggested that they may result from a maladjusted increase of central gain attributable to sensory deafferentation. More specifically, tinnitus and hyperacusis could result from an increase of spontaneous and stimulus-induced activity, respectively. One prediction of this hypothesis is that auditory sensitivity should be increased in tinnitus compared with non-tinnitus subjects. The purpose of this study was to test this prediction by examining the loudness functions in tinnitus ears (n= 124) compared with non-tinnitus human ears (n= 106). Because tinnitus is often accompanied by hearing loss and that hearing loss makes it difficult to disentangle hypersensitivity (hyperacusis) to loudness recruitment, tinnitus and non-tinnitus ears were carefully matched for hearing loss. Our results show that auditory sensitivity is enhanced in tinnitus subjects compared with non-tinnitus subjects, including subjects with normal audiograms. We interpreted these findings as compatible with a maladaptive central gain in tinnitus.
Developmental Nicotine Exposure Alters AMPA Neurotransmission in the Hypoglossal Motor Nucleus and Pre-Bötzinger Complex of Neonatal Rats
Authors: Jaiswal Stuti J. , Pilarski Jason Q. , Harrison Caitlyn M. , Fregosi Ralph F.
Published: February 2013

Developmental nicotine exposure (DNE) impacts central respiratory control in neonates born to smoking mothers. We previously showed that DNE enhances the respiratory motor response to bath application of AMPA to the brainstem, although it was unclear which brainstem respiratory neurons mediated these effects (Pilarski and Fregosi, 2009). Here we examine how DNE influences AMPA-type glutamatergic neurotransmission in the pre-Bötzinger complex (pre-BötC) and the hypoglossal motor nucleus (XIIMN), which are neuronal populations located in the medulla that are necessary for normal breathing. Using rhythmic brainstem slices from neonatal rats, we microinjected AMPA into the pre-BötC or the XIIMN while recording from XII nerve rootlets (XIIn) as an index of respiratory motor output. DNE increased the duration of tonic activity and reduced rhythmic burst amplitude after AMPA microinjection into the XIIMN. Also, DNE led to an increase in respiratory burst frequency after AMPA injection into the pre-BötC. Whole-cell patch-clamp recordings of XII motoneurons showed that DNE increased motoneuron excitability but did not change inward currents. Immunohistochemical studies indicate that DNE reduced the expression of glutamate receptor subunits 2 and 3 (GluR2/3) in the XIIMN and the pre-BötC. Our data show that DNE alters AMPAergic synaptic transmission in both the XIIMN and pre-BötC, although the mechanism by which this occurs is unclear. We suggest that the DNE-induced reduction in GluR2/3 may represent an attempt to compensate for increased cell excitability, consistent with mechanisms underlying homeostatic plasticity.
Testosterone Depletion in Adult Male Rats Increases Mossy Fiber Transmission, LTP, and Sprouting in Area CA3 of Hippocampus
Authors: Skucas Vanessa A. , Duffy Aine M. , Harte-Hargrove Lauren C. , Magagna-Poveda Alejandra , Radman Thomas , Chakraborty Goutam , Schroeder Charles E. , MacLusky Neil J. , Scharfman Helen E.
Published: February 2013

Androgens have dramatic effects on neuronal structure and function in hippocampus. However, androgen depletion does not always lead to hippocampal impairment. To address this apparent paradox, we evaluated the hippocampus of adult male rats after gonadectomy (Gdx) or sham surgery. Surprisingly, Gdx rats showed increased synaptic transmission and long-term potentiation of the mossy fiber (MF) pathway. Gdx rats also exhibited increased excitability and MF sprouting. We then addressed the possible underlying mechanisms and found that Gdx induced a long-lasting upregulation of MF BDNF immunoreactivity. Antagonism of Trk receptors, which bind neurotrophins, such as BDNF, reversed the increase in MF transmission, excitability, and long-term potentiation in Gdx rats, but there were no effects of Trk antagonism in sham controls. To determine which androgens were responsible, the effects of testosterone metabolites DHT and 5α-androstane-3α,17β-diol were examined. Exposure of slices to 50 nmDHT decreased the effects of Gdx on MF transmission, but 50 nm5α-androstane-3α,17β-diol had no effect. Remarkably, there was no effect of DHT in control males. The data suggest that a Trk- and androgen receptor-sensitive form of MF transmission and synaptic plasticity emerges after Gdx. We suggest that androgens may normally be important in area CA3 to prevent hyperexcitability and aberrant axon outgrowth but limit MF synaptic transmission and some forms of plasticity. The results also suggest a potential explanation for the maintenance of hippocampal-dependent cognitive function after androgen depletion: a reduction in androgens may lead to compensatory upregulation of MF transmission and plasticity.
Serotonin Transporter Genotype Affects Serotonin 5-HT1ABinding in Primates
Authors: Christian Bradley T. , Wooten Dustin W. , Hillmer Ansel T. , Tudorascu Dana L. , Converse Alexander K. , Moore Colleen F. , Ahlers Elizabeth O. , Barnhart Todd E. , Kalin Ned H. , Barr Christina S. , Schneider Mary L.
Published: February 2013

Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding usingin vivoimaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor binding at the 5-HT1Areceptor site has been reported in humans, suggesting the 5-HTTLPR polymorphism may play a role in serotonin (5-HT) function. Rhesus monkeys possess a 5-HTTLPR length polymorphism similar to humans and serve as an excellent model for studying the effects of this orthologous genetic variation on behaviors and neurochemical functions related to the 5-HT system. In this study, PET imaging of [18F]mefway was performed on 58 rhesus monkeys (33l/l, 25 s-carriers) to examine the relation between 5-HT1Areceptor-specific binding and 5-HTTLPR genotypes. Significantly lower 5-HT1Abinding was found in s-carrier subjects throughout both cortical brain regions and the raphe nuclei. These results demonstrate that the underlying 5-HT neurochemical system is influenced by this functional polymorphism and illustrate the strong potential for extending the nonhuman primate model into investigating the role of this genetic variant on behavior and gene–environment interactions.
Parallel Processing via a Dual Olfactory Pathway in the Honeybee
Authors: Brill Martin F. , Rosenbaum Tobias , Reus Isabelle , Kleineidam Christoph J. , Nawrot Martin P. , Rössler Wolfgang
Published: February 2013

In their natural environment, animals face complex and highly dynamic olfactory input. Thus vertebrates as well as invertebrates require fast and reliable processing of olfactory information. Parallel processing has been shown to improve processing speed and power in other sensory systems and is characterized by extraction of different stimulus parameters along parallel sensory information streams. Honeybees possess an elaborate olfactory system with unique neuronal architecture: a dual olfactory pathway comprising a medial projection-neuron (PN) antennal lobe (AL) protocerebral output tract (m-APT) and a lateral PN AL output tract (l-APT) connecting the olfactory lobes with higher-order brain centers. We asked whether this neuronal architecture serves parallel processing and employed a novel technique for simultaneous multiunit recordings from both tracts. The results revealed response profiles from a high number of PNs of both tracts to floral, pheromonal, and biologically relevant odor mixtures tested over multiple trials. PNs from both tracts responded to all tested odors, but with different characteristics indicating parallel processing of similar odors. Both PN tracts were activated by widely overlapping response profiles, which is a requirement for parallel processing. The l-APT PNs had broad response profiles suggesting generalized coding properties, whereas the responses of m-APT PNs were comparatively weaker and less frequent, indicating higher odor specificity. Comparison of response latencies within and across tracts revealed odor-dependent latencies. We suggest that parallel processing via the honeybee dual olfactory pathway provides enhanced odor processing capabilities serving sophisticated odor perception and olfactory demands associated with a complex olfactory world of this social insect.