bluuebunny/crossref_metadata_2025 huggingface dataset:
X-radiation inhibits histone deacetylase 1 and 2, upregulates Axin expression and induces apoptosis in non-small cell lung cancer
Authors: Han Yang , Zhang Yong , Yang Lian-he , Mi Xiao-yi , Dai Shun-dong , Li Qing-chang , Xu Hong-tao , Yu Juan-han , Li Guang , Zhao Jing , Han Chong , Yuan Xi-ming , Wang En-hua
Published: October 2012

Background

Histone deacetylase (HDAC) plays an important role in the deacetylation of histone, which can alter gene expression patterns and affect cell behavior associated with malignant transformation. The aims of this study were to investigate the relationships between HDAC1, HDAC2, clinicopathologic characteristics, patient prognosis and apoptosis, to clarify the mechanism of upregulation of the Axis inhibitor Axin (an important regulator of the Wnt pathway) by X-radiation and to elucidate the effect of siRNA on radiation therapy of non-small cell lung cancer (NSCLC).

Methods

HDAC1 and HDAC2 expression levels were measured by immunohistochemistry and reverse transcription PCR. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling and fluorescence activated cell sorting. BE1 cells expressing Axin were exposed to 2 Gy of X-radiation.

Results

Expression of HDAC1 and that of HDAC2 were correlated, and significantly higher in NSCLC tissues than in normal lung tissues (P < 0.05). HDAC1 and HDAC2 expression was correlated with pTNM stage and negatively correlated with differentiation of NSCLC and apoptotic index (P < 0.05). The prognosis of patients with low expression of HDAC1 and HDAC2 was better than that of those with high expression. X-radiation and siRNA inhibited HDAC1 and HDAC2 expression in NSCLC cells and Axin levels were significantly higher in BE1 cells.

Conclusions

X-radiation and siRNA inhibit expression of HDAC1 and HDAC2, weaken the inhibitory effect of HDAC on Axin, upregulate Axin expression and induce apoptosis of lung cancer cells. Inhibition of HDAC1 and HDAC2 is a means of enhancing the radiosensitivity of NSCLC.
Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina
Authors: Luo Jing , Uribe Rosa A , Hayton Sarah , Calinescu Anda-Alexandra , Gross Jeffrey M , Hitchcock Peter F
Published: October 2012

Background

Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina’s stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish.

Results

The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype.

Conclusions

These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins.
Effects of personality traits on the manifestations of irritable bowel syndrome
Authors: Tayama Jun , Nakaya Naoki , Hamaguchi Toyohiro , Tomiie Tadaaki , Shinozaki Masae , Saigo Tatsuo , Shirabe Susumu , Fukudo Shin
Published: October 2012

Objective

Previous studies have reported that patients with irritable bowel syndrome (IBS) show high neuroticism. However, the precise association between the IBS subtypes and the degree of neuroticism in younger populations is largely unknown. We tested our hypothesis that subjects with diarrhea-predominant IBS may have a higher degree of neuroticism than subjects without IBS or those with other subtypes of IBS. We also verified the additional hypothesis that the severity of neuroticism might be correlated with the severity of IBS in younger populations.

Methods

We conducted a cross-sectional survey of 557 university students, ranging in age from 18 to 21 years. Presence/ absence of IBS and determination of the IBS subtype was by the Rome II Modular Questionnaire, while the severity of IBS was determined by the IBS severity index (IBS-SI). The degree of neuroticism was evaluated using the Maudsely Personality Inventory (MPI). The presence/absence of psychological distress was measured with the K6 scale.

Results

Neuroticism scores in the subjects with diarrhea-predominant IBS were significantly higher than those in the non-IBS subjects or subjects with constipation-predominant IBS. The neuroticism scores were significantly correlated with the IBS-SI scores in all subjects with IBS.

Conclusion

These results suggest that neuroticism is involved in the pathophysiology of IBS in young subjects, especially in that of the diarrhea-predominant subtype.
MetabR: an R script for linear model analysis of quantitative metabolomic data
Authors: Ernest Ben , Gooding Jessica R , Campagna Shawn R , Saxton Arnold M , Voy Brynn H
Published: October 2012

Background

Metabolomics is an emerging high-throughput approach to systems biology, but data analysis tools are lacking compared to other systems level disciplines such as transcriptomics and proteomics. Metabolomic data analysis requires a normalization step to remove systematic effects of confounding variables on metabolite measurements. Current tools may not correctly normalize every metabolite when the relationships between each metabolite quantity and fixed-effect confounding variables are different, or for the effects of random-effect confounding variables. Linear mixed models, an established methodology in the microarray literature, offer a standardized and flexible approach for removing the effects of fixed- and random-effect confounding variables from metabolomic data.

Findings

Here we present a simple menu-driven program, “MetabR”, designed to aid researchers with no programming background in statistical analysis of metabolomic data. Written in the open-source statistical programming language R, MetabR implements linear mixed models to normalize metabolomic data and analysis of variance (ANOVA) to test treatment differences. MetabR exports normalized data, checks statistical model assumptions, identifies differentially abundant metabolites, and produces output files to help with data interpretation. Example data are provided to illustrate normalization for common confounding variables and to demonstrate the utility of the MetabR program.

Conclusions

We developed MetabR as a simple and user-friendly tool for implementing linear mixed model-based normalization and statistical analysis of targeted metabolomic data, which helps to fill a lack of available data analysis tools in this field. The program, user guide, example data, and any future news or updates related to the program may be found athttp://metabr.r-forge.r-project.org/.
Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies
Authors: Laming Eleanor , Melzi Eleonora , Scholes Sandra FE , Connelly Maira , Bell Charlotte R , Ballingall Keith T , Dagleish Mark P , Rocchi Mara S , Willoughby Kim
Published: October 2012

Background

Bovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows (“BNP dams”). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and β-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured in vitro from sternal biopsies taken at 24 hours and 6 days post-challenge.

Results

Clonogenic assay demonstrated that CFU-GEMM (colony forming unit-granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post-challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced.

Conclusion

This study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types.
DNA copy number alterations and PPARG amplification in a patient with multifocal bladder urothelial carcinoma
Authors: Conconi Donatella , Panzeri Elena , Redaelli Serena , Bovo Giorgio , Volante Marco , Viganò Paolo , Strada Guido , Dalprà Leda , Bentivegna Angela
Published: October 2012

Background

Bladder cancer is the seventh most common cancer worldwide and over 90% are transitional cell carcinoma (TCC). At the first time of diagnosis at least 70% of TCC present as superficial bladder cancer. Because the clinical outcome of superficial bladder tumors is relatively unpredictable, there is a pressing need to identify markers that may predict tumor recurrence and progression and new treatment strategies.

Case presentation

We present a unique case of a 67-year old male who underwent total cystectomy after repeated trans-urethral resections of the bladder for multifocal non-muscle invasive bladder cancer. The first and the third tumor were diagnosed as high grade non-infiltrating (HGNI), while the second as carcinoma in situ (CIS). We performed both array comparative genomic hybridization and a targeted chromosomal profile by UroVysion in order to detect copy number variations (CNVs) that may be involved with tumor recurrence and progression. The overall data from this study provide new evidence for the monoclonal origin of urothelial tumor multifocality as several genetic changes were found in different tumors of the same patient. From the analysis of shared CNVs two gained regions emerged at 3p25.2 and 12q23.2, including PPARG and ASCL1 genes, respectively. The copy number level of these genes would seem inversely mutually correlated and highly dependent on histological grade, because the highest level of amplification at 3p25.2 was evidenced in the two HGNI samples, while the highest level of copy number gain at 12q23.2 was reported in the CIS.

Conclusion

We provide new evidence on the role of PPARG in initiation and maintenance of bladder cancer. For the first time we also suggest a possible explanation for the elevated expression of PPARG in this type of tumor through a focal high level amplification at 3p25.2. Furthermore, a new gene, ASCL1, emerged as a potential candidate to assist PPARG in bladder carcinogenesis.
Key factors influencing canine heartworm, Dirofilaria immitis, in the United States
Authors: Brown Heidi E , Harrington Laura C , Kaufman Phillip E , McKay Tanja , Bowman Dwight D , Nelson C Thomas , Wang Dongmei , Lund Robert
Published: October 2012

An examination of the Companion Animal Parasite Council’s (CAPC) canine heartworm data to clarify the spatial prevalence of heartworm in the United States. Factors thought to influence the spatial risk of disease, as identified in a recent CAPC workshop, are discussed.
Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women
Authors: Walter Kimberly N , Corwin Elizabeth J , Ulbrecht Jan , Demers Laurence M , Bennett Jeanette M , Whetzel Courtney A , Klein Laura Cousino
Published: October 2012

Background

Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes.

Objective

We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism.

Methods

We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/− 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels.

Results

All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH-cortisol relationship was maintained for TSH levels (uIU/L) ≤4.0, ≤3.5, ≤3.0, and ≤2.5 but not ≤2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels.

Conclusions

Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study.
A comparative assessment of alternatives to the full-leg radiograph for determining knee joint alignment
Authors: Navali Amir M , Bahari Leila Azhar Shekoufeh , Nazari Behrouz
Published: October 2012

Background

The purpose of this study was to assess the concurrent validity of alternative measures of frontal plane knee alignment, namely the radiographic anatomic axis and two clinical measures in patients complaining of knee malalignment as compared with the mechanical axis on full-length radiograph of lower limbs.

Methods

The knee-alignment angle was measured in 100 knees of 50 subjects with the chief complaint of frontal knee malalignment according to the following methods: lower-limb mechanical axis on radiograph, lower-limb anatomic axis on radiograph, distance between medial femoral condyles or medial malleoli using a calliper and lower-limb alignment using a goniometer. Data were analyzed using Pearson’s correlation coefficient and simple linear regression.

Results

The anatomic axis best correlated with the mechanical axis (r = 0.93, P<0.001), followed closely by the intercondylar/intermalleolar distance measured by calliper (r = 0.89, P<0.001). Significant correlation was also found between the mechanical-axis angle and the lower limb axis measured by goniometer (r = 0.67, P<0.001).

Conclusions

The anatomic axis on radiograph, the calliper method and to a lesser extent the goniometer measurement appear to be valid alternatives to the mechanical axis on full-leg radiograph for determining frontal plane knee alignment. These alternative measures have the potential to provide useful information regarding knee alignment and may increase the assessment of this parameter by clinicians and researchers.
International Congress on Transposable Elements (ICTE) 2012 in Saint Malo and the sea of TE stories
Authors: Ainouche Abdelkader , Bétermier Mireille , Chandler Mick , Cordaux Richard , Cristofari Gaël , Deragon Jean-Marc , Lesage Pascale , Panaud Olivier , Quesneville Hadi , Vaury Chantal , Vieira Cristina , Vitte Clémentine
Published: October 2012

An international conference on Transposable Elements (TEs) was held 21–24 April 2012 in Saint Malo, France. Organized by the French Transposition Community (GDR Elements Génétiques Mobiles et Génomes, CNRS) and the French Society of Genetics (SFG), the conference’s goal was to bring together researchers from around the world who study transposition in diverse organisms using multiple experimental approaches. The meeting drew more than 217 attendees and most contributed through poster presentations (117), invited talks and short talks selected from poster abstracts (48 in total). The talks were organized into four scientific sessions, focused on: impact of TEs on genomes, control of transposition, evolution of TEs and mechanisms of transposition. Here, we present highlights from the talks given during the platform sessions. The conference was sponsored by Alliance pour les sciences de la vie et de la santé (Aviesan), Centre national de la recherche scientifique (CNRS), Institut national de la santé et de la recherche médicale (INSERM), Institut de recherche pour le développement (IRD), Institut national de la recherche agronomique (INRA), Université de Perpignan, Université de Rennes 1, Région Bretagne and Mobile DNA.

Chair of the organization committee

Jean-Marc Deragon

Organizers

Abdelkader Ainouche, Mireille Bétermier, Mick Chandler, Richard Cordaux, Gaël Cristofari, Jean-Marc Deragon, Pascale Lesage, Didier Mazel, Olivier Panaud, Hadi Quesneville, Chantal Vaury, Cristina Vieira and Clémentine Vitte
Large scale screening of commonly used Iranian traditional medicinal plants against urease activity
Authors: Nabati Farzaneh , Mojab Faraz , Habibi-Rezaei Mehran , Bagherzadeh Kowsar , Amanlou Massoud , Yousefi Behnam
Published: October 2012

Background and purpose of the study

H. pylori infection is an important etiologic impetus usually leading to gastric disease and urease enzyme is the most crucial role is to protect the bacteria in the acidic environment of the stomach. Then urease inhibitors would increase sensitivity of the bacteria in acidic medium.

Methods

137 Iranian traditional medicinal plants were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 50% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined.

Results

37 plants out of the 137 crude extracts revealed strong urease inhibitory activity (more than 70% inhibition against urease activity at 10 mg/ml concentration). Nine of the whole studied plants crude extracts were found as the most effective with IC50 values less than 500 μg/ml including; Rheum ribes, Sambucus ebulus, Pistachia lentiscus, Myrtus communis, Areca catechu, Citrus aurantifolia, Myristica fragrans, Cinnamomum zeylanicum and Nicotiana tabacum.

Conclusions

The most potent urease inhibitory was observed for Sambucus ebulus and Rheum ribes extracts with IC50 values of 57 and 92 μg/ml, respectively.
Levels of organophosphorus pesticides in medicinal plants commonly consumed in Iran
Authors: Sarkhail Parisa , Yunesian Masud , Ahmadkhaniha Reza , Sarkheil Pantea , Rastkari Noushin
Published: October 2012

The frequent occurrence of pesticide residues in herbal materials was indicated by previous studies. In this study, the concentration of some of the organophosphorus pesticides including parathion, malathion, diazinon and pirimiphos methyl in different kinds of medicinal plants were determined. The samples were collected randomly from ten local markets of different areas of Iran. At the detection limit of 0.5 ng g-1, parathion and pirimiphos methyl were not detected in any of the samples. Some amounts of malathion and diazinon were found in Zataria, Matricaria chamomile, Spearmint and Cumin Seed samples while, the concentrations of target organophosphorus pesticides in Borage samples were below the detection limits of the methods which could be a result of intensive transformation of organophosphorus pesticides by Borage. In addition the organophosphorus pesticides were detected in all of the samples below the maximum residue levels (MRLs) proposed by the international organizations.
Vldlr overexpression causes hyperactivity in rats
Authors: Iwata Keiko , Izumo Nobuo , Matsuzaki Hideo , Manabe Takayuki , Ishibashi Yukiko , Ichitani Yukio , Yamada Kazuo , Thanseem Ismail , Anitha Ayyappan , Vasu Mahesh Mundalil , Shimmura Chie , Wakuda Tomoyasu , Kameno Yosuke , Takahashi Taro , Iwata Yasuhide , Suzuki Katsuaki , Nakamura Kazuhiko , Mori Norio
Published: October 2012

Background

Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients.

Methods

We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.

Results

Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function.

Conclusions

Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities.
Aldosterone and the mineralocorticoid receptor in the cerebral circulation and stroke
Authors: Dinh Quynh N , Arumugam Thiruma V , Young Morag J , Drummond Grant R , Sobey Christopher G , Chrissobolis Sophocles
Published: October 2012

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Elevated plasma aldosterone levels are an independent cardiovascular risk factor and are thought to contribute to hypertension, a major risk factor for stroke. Evidence from both experimental and human studies supports a role for aldosterone and/or the mineralocorticoid receptor (MR) in contributing to detrimental effects in the cerebral vasculature and to the incidence and outcome of ischemic stroke. This article reviews the evidence, including the protective effects of MR antagonism. Specifically, the effects of aldosterone and/or MR activation on cerebral vascular structure and on immune cells will be reviewed. The existing evidence suggests that aldosterone and the MR contribute to cerebral vascular pathology and to the incidence and outcome of stroke. We suggest that further research into the signaling mechanisms underlying the effects of aldosterone and MR activation in the brain and its vasculature, especially with regard to cell-specific actions, will provide important insight into causes and potential treatments for cerebrovascular disease and stroke.
A revision of Artemia biodiversity in Macaronesia
Authors: Hontoria Francisco , Redón Stela , Maccari Marta , Varó Inmaculada , Navarro Juan Carlos , Ballell Lluis , Amat Francisco
Published: October 2012

In a biogeographical context, the term Macaronesia broadly embraces the North Atlantic archipelagos of the Azores, Madeira, Selvagens, the Canary Islands, and Cape Verde. The peculiar arid climatic conditions in some of these places have led to the development of marine salt exploitations, which can be counted among the hypersaline habitats of the brine shrimpArtemia(Branchiopoda, Anostraca). Parthenogenetic populations of this anostracan were described in the Canary Islands during the last decades of the 20th century, while the AmericanArtemia franciscanaspecies was recently found in the Cape Verde archipelago. Following an invasive pattern, this exotic species has recently reached the Canary Islands, too. This paper reports information dealing with biotope loss (solar saltworks) in this biogeographical region, together with possible consequences concerning the arrival of invasive species, two factors that frequently promote dramatic biodiversity losses. The discussion of this threat focuses mainly on the Canary Islands archipelago where native species ofArtemiastill exist.
Identification of an intestine-specific promoter and inducible expression of bacterial α-galactosidase in mammalian cells by a lac operon system
Authors: Zhai Yafeng , Shu Gang , Zhu Xiaotong , Zhang Zhiqi , Lin Xiajing , Wang Songbo , Wang Lina , Zhang Yongliang , Jiang Qingyan
Published: October 2012

Background

α-galactosidase has been widely used in animal husbandry to reduce anti-nutritional factors (such as α-galactoside) in feed. Intestine-specific and substrate inducible expression of α-galactosidase would be highly beneficial for transgenic animal production.

Methods

To achieve the intestine-specific and substrate inducible expression of α-galactosidase, we first identified intestine-specific promoters by comparing the transcriptional activity and tissue specificity of four intestine-specific promoters from human intestinal fatty acid binding protein, rat intestinal fatty acid binding protein, human mucin-2 and human lysozyme. We made two chimeric constructs combining the promoter and enhancer of human mucin-2, rat intestinal trefoil factor and human sucrase-isomaltase. Then a modified lac operon system was constructed to investigate the induction of α-galactosidase expression and enzyme activity by isopropyl β-D-1-thiogalactopyranoside (IPTG) and an α-galactosidase substrate, α-lactose.

We declared that the research carried out on human (Zhai Yafeng) was in compliance with the Helsinki Declaration, and experimental research on animals also followed internationally recognized guidelines.

Results

The activity of the human mucin-2 promoter was about 2 to 3 times higher than that of other intestine-specific promoters. In the lac operon system, the repressor significantly decreased (P < 0.05) luciferase activity by approximately 6.5-fold and reduced the percentage of cells expressing green fluorescent protein (GFP) by approximately 2-fold. In addition, the expression level of α-galactosidase mRNA was decreased by 6-fold and α-galactosidase activity was reduced by 8-fold. In line with our expectations, IPTG and α-lactose supplementation reversed (P < 0.05) the inhibition and produced a 5-fold increase of luciferase activity, an 11-fold enhancement in the percentage of cells with GFP expression and an increase in α-galactosidase mRNA abundance (by about 5-fold) and α-galactosidase activity (by about 7-fold).

Conclusions

We have successfully constructed a high specificity inducible lac operon system in an intestine-derived cell line, which could be of great value for gene therapy applications and transgenic animal production.
Understanding the hypoxic niche of multiple myeloma: therapeutic implications and contributions of mouse models
Authors: Hu Jinsong , Van Valckenborgh Els , Menu Eline , De Bruyne Elke , Vanderkerken Karin
Published: October 2012

Multiple myeloma (MM) is the second most common hematological malignancy and is characterized by the clonal expansion of plasma cells in the bone marrow. Recently, hypoxia has received increased interest in the context of MM, in both basic and translational research. In this review, we describe the discovery of the hypoxic niche in MM and how it can be targeted therapeutically. We also discuss mouse models that closely mimic human MM, highlighting those that allow preclinical research into new therapies that exploit the hypoxic niche in MM.
Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis
Authors: Kaplan Frederick S. , Chakkalakal Salin A. , Shore Eileen M.
Published: October 2012

Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of connective tissue metamorphosis. It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO) postnatally, which leads to the formation of a second skeleton of heterotopic bone. Individuals with these classic clinical features of FOP have the identical heterozygous activating mutation (c.617G>A; R206H) in the gene encoding ACVR1 (also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Disease activity caused by this ACVR1 mutation also depends on altered cell and tissue physiology that can be best understood in the context of a high-fidelity animal model. Recently, we developed such a knock-in mouse model for FOP (Acvr1R206H/+) that recapitulates the human disease, and provides a valuable new tool for testing and developing effective therapies. The FOP knock-in mouse and other models in Drosophila, zebrafish, chickens and mice provide an arsenal of tools for understanding BMP signaling and addressing outstanding questions of disease mechanisms that are relevant not only to FOP but also to a wide variety of disorders associated with regenerative medicine and tissue metamorphosis.
Finding NECA: zebrafish screen identifies key signalling pathway in β-cell regeneration
Authors: Seth Asha
Published: October 2012

Summary of and comment on a recent Cell Metabolism paper entitled ‘Adenosine signaling promotes regeneration of pancreatic β cells in vivo’ (Andersson et al., 2012).
Lactate-starved neurons in ALS
Authors: Martinez Bryan A.
Published: October 2012

Summary and comment on a recent Nature article entitled ‘Oligodendroglia metabolically support axons and contribute to neurodegeneration’ (Lee et al., 2012).
Cerebral venous outflow resistance and interpretation of cervical plethysmography data with respect to the diagnosis of chronic cerebrospinal venous insufficiency
Authors: Beggs C , Shepherd S , Zamboni P
Published: October 2012

Objective: While chronic cerebrospinal venous insufficiency (CCSVI) can be characterized using cervical plethysmography, much remains unknown about the haemodynamics associated with this procedure. The aim of the study was therefore to gain a deeper understanding of the observed haemodynamics.

Method: Forty healthy controls and 44 CCSVI patients underwent cervical plethysmography, which involved placing a strain-gauge collar around their necks and tipping them from the upright (90°) to supine position (0°) in a chair. Once stabilized, they were returned to the upright position, allowing blood to drain from the neck. A mathematical model was used to calculate the hydraulic resistance of the extracranial venous system for each subject in the study.

Results: The mean hydraulic resistance of the extracranial venous system was 10.28 (standard deviation [SD] 5.14) mmHg.s/mL in the healthy controls and 16.81 (SD 9.22) in the CCSVI patients ( P < 0.001).

Conclusions: The haemodynamics of the extracranial venous system are greatly altered in CCSVI patients.
Migrant labour, urban exclusion and social harmony in China
Authors: Ngok Kinglun
Published: October 2012

Focusing on peasant workers, or domestic migrant labour – this article aims to address the issue of social exclusion in urban China. The first section provides, an overview of migration from rural to urban areas in China. This is followed by a section on the social exclusion experienced by migrant workers in cities. The third section is about the recent efforts by the Chinese government to use social policy to increase social inclusion and achieve social harmony. It argues that it is imperative for the Chinese authorities to take concrete action to abolish the hukou system entirely and give full citizenship to migrant workers.
Social inequality and inclusive growth in China: the significance of social policy in a new era
Authors: Xiong Yuegen
Published: October 2012

This article aims to explore and interpret the growing social inequality in China, in particular between urban and rural areas, and between ordinary people and the elite classes. It also attempts to explain the impact of social policy on reducing inequality in China, as well as its institutional constraints as the government strives to integrate the fragmented social security system. Finally, the author discusses how inclusive growth as a core guideline for building a harmonious society will affect the future development trajectory of China in the context of globalisation.
The new Roche Vitamin D Total assay: fit for its purpose?
Authors: Emmen Judith M.A. , Wielders Jos P.M. , Boer Arjen-Kars , van den Ouweland Johannes M.W. , Vader Huib L.
Published: October 2012

Background: Measurement of serum 25-hydroxyvitamin D [25(OH)D] is used to assess vitamin D status. We evaluated the analytical performance of a new automated assay, Elecsys Vitamin D Total (Roche Diagnostics, Mannheim, Germany), based on competitive protein binding.

Methods: The Elecsys assay was tested for imprecision, linearity and functional sensitivity at three test-sites and compared to a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, a high-performance liquid chromatography (HPLC) method and the Liaison 25(OH) Vitamin D Total immunoassay (Diasorin).

Results: Imprecision testing with human serum specimens showed within-run CVs of ≤6% and between-run CVs of ≤8%. The assay was linear from 33 up to at least 111 nmol/L and showed equivalent 25(OH)D levels for matched serum and heparinized plasma samples. The assay correlated reasonable to well with LC-MS/MS (r=0.93; y=1.07x–5.04 nmol/L), HPLC (r=0.91, y=0.90x+3.03 nmol/L) and the Liaison assay (r=0.86, y=1.19x+2.80 nmol/L). Some of the samples showed large between-method differences.

Conclusions: The new Elecsys assay fulfilled present analytical performance requirements and showed close agreement to other well-established methods for 25(OH)D analysis, making it fit for routine assessment of vitamin D status.
25-Hydroxyvitamin D testing: challenging the performance of current automated immunoassays
Authors: Farrell Chris , Soldo Joshua , Williams Paul , Herrmann Markus
Published: October 2012

Background: Clinical laboratories require accurate and precise 25-hydroxyvitamin D (25-OHD) immunoassays to allow comparison of patient results with published decision limits. However, some variation in performance has been found with the previous generation of automated 25-OHD immunoassays. This study assessed the performance of four recently released automated 25-OHD immunoassays against a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.

Methods: A total of 983 samples from apparently healthy adults, plus 253 samples chosen to challenge the performance of the assays, were analyzed by the latest generation of immunoassays from Abbott, DiaSorin, Roche and Siemens. LC-MS/MS analysis was performed on a random subset of 264 samples. The precision of the immunoassays was assessed over 5 days with samples ranging between 3.0 and 370 nmol/L in concentration.

Results: Immunoassays showed significant differences in precision at 25-OHD concentrations of 3.0–86.5 nmol/L but all showed acceptable precision at higher concentrations. The DiaSorin assay agreed with LC-MS/MS across the measuring range of samples tested (7.7–425 nmol/L). The other assays showed generally good performance, but had some limitations when their performance was challenged with samples with low and high 25-OHD concentrations, heterophilic antibodies or high 25-OHD2 concentrations. The C3-epimer of 25-OHD was identified in 40.4% of healthy adults tested and was a source of analytical variance in immunoassays.

Conclusions: The latest generation of 25-OHD immunoassays has improved performance compared to previous assays. However, some immunoassays can still give discrepant results and this is most apparent when immunoassays are evaluated with a range of samples that challenge their analytical performance.
The completeness of Kant’s metaphysical exposition of space
Authors: Blomme Henny
Published: October 2012

In the first edition of his book on the completeness of Kant’s table of judgments, Klaus Reich shortly indicates that the B-version of the metaphysical exposition of space in the Critique of pure reason is structured following the inverse order of the table of categories. In this paper, I develop Reich’s claim and provide further evidence for it. My argumentation is as follows: Through analysis of our actually given representation of space as some kind of object (the formal intuition of space in general), the metaphysical exposition will show that this representation is secondary to space considered as an original, undetermined and as such unrepresentable intuitive manifold. Now, following Kant, the representation of any kind of object involves diversity, synthesis and unity. In the case of our representation of space as formal intuition, this involves, firstly, a manifold a priori, i.e. space as pure form, delivered by the transcendental Aesthetic, secondly, a figurative, productive synthesis of that manifold, and, thirdly, the unity provided by the categories. Analysing our given representation of space – the task of the metaphysical exposition – amounts to dismantling its unity and determine its characteristics with respect to the categories.
Difficulty Still Awaits: Kant, Spinoza, and the Threat of Theological Determinism
Authors: Brewer Kimberly , Watkins Eric
Published: October 2012

In a short and much-neglected passage in the second Critique, Kant discusses the threat posed to human freedom by theological determinism. In this paper we present an interpretation of Kant’s conception of and response to this threat. Regarding his conception, we argue that he addresses two versions of the threat: either God causes appearances (and hence our spatio-temporal actions) directly or he does so indirectly by causing things in themselves which in turn cause appearances. Kant’s response to the first version is that God cannot cause appearances directly because they depend essentially on the passive sensibility of finite beings. Kant’s response to the second version is that human beings are endowed with transcendental freedom, which blocks the causal transitivity that is presupposed by this version. We also contrast his position on this topic with Leibniz’s and Spinoza’s.
Logica naturalis, Healthy Understanding and the Reflecting Power of Judgment in Kant’s Philosophy
Authors: Rodríguez Manuel Sánchez
Published: October 2012

The aim of this article is to explore the origin of the difficulty of founding the reflecting power of judgment as Kant outlines it in the Preface of the third Critique. Although a foundation for this faculty was only established in 1790, we must interpret it as a critical solution to an old problem, which Kant had already recognized around 1770. Through his comprehension of the meaning of healthy understanding and native wit he already confirms the impossibility of determining the correctness of our judging activity from the use of rules. This approach of the problem must be understood in the context of the controversy about the concept ‘logica naturalis’ in the Leibniz-Wolffian aesthetics and logic. In close conjunction with this tradition, Kant already tries to offer an elucidation of the question of judging through the aesthetics.
Beauty, Disinterested Pleasure, and Universal Communicability: Kant’s Response to Burke
Authors: Vandenabeele Bart
Published: October 2012

Although Kant (wrongly) holds that the universal communicability of aesthetic judgments logically follows from the disinterested character of the pleasure upon which they are based, Kant’s emphasis on the a priori validity of judgments of beauty can be viewed as a rebuttal of the kind of empiricist arguments that Burke offers to justify the social nature of the experience of beauty. I argue that the requirement of universal communicability is not a mere addition to the requirement of universal validity and is far more relevant to an adequate characterisation of the beautiful than has customarily been assumed. I further argue that the ‘exemplary necessity’ of pure judgments of taste, if understood correctly, reveals beauty’s primordial social significance, enabling us to become alive to a profound universal solidarity among aesthetic subjects.
Remarque philologique sur le terme «Classe» dans le § 11 de la Critique de la raison pure
Authors: Bitran Maurice
Published: October 2012

§ 11 of the Critique of Pure Reason, intended to strengthen the explanation of the categories in the second edition, introduces in its two first remarks the important distinction between the mathematical and the dynamical that will occur also in other later works.

In these remarks Kant creates a two-fold grouping within the categories, which seems to be spoilt by a lexical weakness concerning the terms «Classe» and «Abtheilung».

As this textual anomaly does not rest on any philosophical foundation we propose a correction aiming at expressing the original Kantian thought.
Irrational Choice under Uncertainty Correlates with Lower Striatal D2/3Receptor Binding in Rats
Authors: Cocker Paul J. , Dinelle Katherine , Kornelson Rick , Sossi Vesna , Winstanley Catharine A.
Published: October 2012

Individual differences in dopamine (DA) signaling, including low striatal D2/3receptors, may increase vulnerability to substance abuse, although whether this phenotype confers susceptibility to nonchemical addictions is unclear. The degree to which people use “irrational” cognitive heuristics when choosing under uncertainty can determine whether they find gambling addictive. Given that dopaminergic projections to the striatum signal reward expectancy and modulate decision-making, individual differences in DA signaling could influence the extent of such biases. To test this hypothesis, we used a novel task to model biased, risk-averse decision-making in rats. Animals chose between a “safe” lever, which guaranteed delivery of the wager, or an “uncertain” lever, which delivered either double the wager or nothing with 50:50 odds. The bet size varied from one to three sugar pellets. Although the amount at stake did not alter the options' utility, a subgroup of “wager-sensitive” rats increased their preference for the safe lever as the bet size increased, akin to risk aversion. In contrast, wager-insensitive rats slightly preferred the uncertain option consistently. Amphetamine increased choice of the uncertain option in wager-sensitive, but not in wager-insensitive rats, whereas a D2/3receptor antagonist decreased uncertain lever choice in wager-insensitive rats alone. Micro-PET and autoradiography using [11C]raclopride confirmed a strong correlation between high wager sensitivity and low striatal D2/3receptor density. These data suggest that the propensity for biased decision-making under uncertainty is influenced by striatal D2/3receptor expression, and provide novel support for the hypothesis that susceptibility to chemical and behavioral addictions may share a common neurobiological basis.
Glutamate Receptor δ2 Associates with Metabotropic Glutamate Receptor 1 (mGluR1), Protein Kinase Cγ, and Canonical Transient Receptor Potential 3 and Regulates mGluR1-Mediated Synaptic Transmission in Cerebellar Purkinje Neurons
Authors: Kato Akihiko S. , Knierman Michael D. , Siuda Edward R. , Isaac John T. R. , Nisenbaum Eric S. , Bredt David S.
Published: October 2012

Cerebellar motor coordination and cerebellar Purkinje cell synaptic function require metabotropic glutamate receptor 1 (mGluR1, Grm1). We used an unbiased proteomic approach to identify protein partners for mGluR1 in cerebellum and discovered glutamate receptor δ2 (GluRδ2, Grid2, GluΔ2) and protein kinase Cγ (PKCγ) as major interactors. We also found canonical transient receptor potential 3 (TRPC3), which is also needed for mGluR1-dependent slow EPSCs and motor coordination and associates with mGluR1, GluRδ2, and PKCγ. Mutation of GluRδ2 changes subcellular fractionation of mGluR1 and TRPC3 to increase their surface expression. Fitting with this, mGluR1-evoked inward currents are increased in GluRδ2 mutant mice. Moreover, loss of GluRδ2 disrupts the time course of mGluR1-dependent synaptic transmission at parallel fiber–Purkinje cells synapses. Thus, GluRδ2 is part of the mGluR1 signaling complex needed for cerebellar synaptic function and motor coordination, explaining the shared cerebellar motor phenotype that manifests in mutants of the mGluR1 and GluRδ2 signaling pathways.
Neuroprotective Effects of Reactive Oxygen Species Mediated by BDNF-Independent Activation of TrkB
Authors: Huang Yang Zhong , McNamara James O.
Published: October 2012

Reactive oxygen species (ROS) have diverse biological consequences in the mammalian CNS, but the molecular targets mediating these pleiotropic effects are incompletely understood. Like ROS, the neurotrophin receptor, TrkB receptor tyrosine kinase, has diverse effects in the developing and mature mammalian brain. Our discovery that zinc can transactivate TrkB, together with the finding that ROS can trigger zinc release from cytosolic zinc binding proteins, led us to hypothesize that ROS can transactivate TrkB in CNS neurons by a zinc-dependent mechanism. We found that both exogenous H2O2and endogenous ROS activate TrkB signaling by a Src family kinase-dependent but brain-derived neurotrophic factor-independent mechanism in cultured rat cortical neurons. Exogenous H2O2enhances cytosolic zinc content in a metallothionein-3 (MT-3)-requiring manner. Both exogenous H2O2and endogenous ROS mediated transactivation of TrkB requires intracellular zinc and MT-3. The ROS-triggered transactivation of TrkB exerts neuroprotective effects, because inhibition of TrkB kinase activity or uncoupling Shc signaling from TrkB exacerbates neuronal cell death induced by H2O2. Thus, we propose a molecular signaling event whereby ROS induce release of zinc from cytosolic MT-3, the increased cytosolic zinc transactivates TrkB, and the enhanced Shc signaling downstream from TrkB promotes prosurvival effects. We suggest that such neuroprotective effects mediated by ROS are operative in diverse acute and chronic neurological disorders.