bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid determination of natural steroidal hormones in saliva for the clinical diagnoses
Authors: Oh Jin-Aa , Shin Ho-Sang
Published: March 2012

Background

Saliva samples are easily collectable and non-invasive, and the monitoring of natural steroidal hormones, such as estrone (E1), 17β-estradiol (E2), estriol (E3), progesterone (P), and testosterone (T), in saliva has attracted much attention due to its numerous potential clinical and health-related applications. Because E1, E2, E3, P and T are useful indicators in numerous clinical and health-related diagnoses, there is a need for simultaneous determination.

Results

A gas chromatography-mass spectrometric assay was developed for rapid simultaneous determination of E1, E2, E3, P and T in saliva for clinical diagnoses. Extraction was achieved with a liquid extraction using 3.0 mL of pentane. The extract was dried and silylated with N-methyl-N-(trimethylsilyl) trifluoroacetamide/NH4I (100:2) under a catalysis of 1.5% dithioerythritol for 10 min at 90°C. The accuracy of the analytes was in the range of 96% to 112% at concentrations of 0.05 and 0.10 μg/L (5.0 and 10.0 μg/L for E3), respectively, with relative standard deviations of less than 11%. The lowest quantification limits were from 0.002 to 0.6 μg/L for 1.0 mL of saliva.

Conclusion

Natural steroidal hormones were detected in the concentration ranges of nd to 0.2 μg/L in human saliva. The salivary testosterone values in the patients with prostatic carcinoma were significantly lower than in normal males. The method may useful in numerous clinical and health-related diagnoses.
Efficient and robust RNA-seq process for cultured bacteria and complex community transcriptomes
Authors: Giannoukos Georgia , Ciulla Dawn M , Huang Katherine , Haas Brian J , Izard Jacques , Levin Joshua Z , Livny Jonathan , Earl Ashlee M , Gevers Dirk , Ward Doyle V , Nusbaum Chad , Birren Bruce W , Gnirke Andreas
Published: March 2012

We have developed a process for transcriptome analysis of bacterial communities that accommodates both intact and fragmented starting RNA and combines efficient rRNA removal with strand-specific RNA-seq. We applied this approach to an RNA mixture derived from three diverse cultured bacterial species and to RNA isolated from clinical stool samples. The resulting expression profiles were highly reproducible, enriched up to 40-fold for non-rRNA transcripts, and correlated well with profiles representing undepleted total RNA.
Visualization of mucosal homeostasis via single- and multiphoton intravital fluorescence microscopy
Authors: Xu Cassie , Shen Yuelei , Littman Dan R , Dustin Michael L , Velázquez Peter
Published: March 2012

Intact vascular perfusion done while intravitally visualizing the intestine: mucosal DCs and T cells display activity similar to that found in secondary lymphoid organs.

FIVM has provided many insights into the regulation of immunity. We report the validation of an approach for visualizing murine small bowel via single- and multiphoton FIVM. Tissue damage is limited to ∼200 μm, immediately adjacent to the incision, as confirmed by intravital PI staining. Treatment with 10 KDa dextran-FITC and 70 KDa dextran-TR confirms that perfusion is intact. Selective filtration of 10 KDa but not 70 KDa dextran from the blood indicated that kidney function is also intact. Interestingly, lamina propria vasculature is semipermeable to 10 KDa dextran. Next, reporter mice expressing egfp from the CX3CR1 locus, egfp from the FoxP3 locus, or RFP from the IL-17F locus were used to track DC subsets, FoxP3+ Tregs, or Th17f cells, respectively. Resident cx3cr1+/egfp cells were sessile but actively probed the surrounding microenvironment. Both T cell populations patrol the lamina propria, but the Th17f cells migrate more rapidly than Tregs. Together, these data demonstrate intact vascular perfusion, while intravitally visualizing the mucosal surface of the small bowel. Lastly, the cx3cr1+ DCs and T cells display activity similar to that found in steady-state, secondary lymphoid organs.
HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis
Authors: Higashiyama Masaaki , Hokari Ryota , Hozumi Hideaki , Kurihara Chie , Ueda Toshihide , Watanabe Chikako , Tomita Kengo , Nakamura Mitsuyasu , Komoto Shunsuke , Okada Yoshikiyo , Kawaguchi Atsushi , Nagao Shigeaki , Suematsu Makoto , Goda Nobuhito , Miura Soichiro
Published: March 2012

HIF-1 is active in hypoxia, such as inflamed mucosa, and HIF-1 in epithelium has been reported to control inflamed mucosa in IBD models. Although T cells play an important role for pathogenesis of IBD, the function of HIF-1 in T cells remains to be elucidated. We aimed to clarify the function of HIF-1 in T cells in IBD with focus on the balance between Treg and Teff. Double immunohistochemistry of colonic mucosa in IBD patients showed that HIF-1 was expressed in T cells infiltrating the inflamed mucosa, suggesting that HIF-1 in T cells is involved in the pathogenesis. DSS administration to T cell-specific HIF-1α KO mice showed more severe colonic inflammation than control mice with the up-regulation of Th1 and Th17. Hypoxic stimulation in vitro increased Treg activation in WT T cells but not in HIF-1-deleted T cells. In contrast, hypoxic stimulation increased Th17 activation, and the degree was higher in HIF-1-deleted cells than in control cells. These results show that hypoxia controls intestinal inflammation by regulating cytokine balance in a HIF-1-dependent manner, suggesting that strengthening HIF-1 induction in T cells at the sites of inflammation might be a therapeutic strategy for IBD regulation.
Thyroid Regeneration: Characterization of Clear Cells After Partial Thyroidectomy
Authors: Ozaki Takashi , Matsubara Tsutomu , Seo Daekwan , Okamoto Minoru , Nagashima Kunio , Sasaki Yoshihito , Hayase Suguru , Murata Tsubasa , Liao Xiao-Hui , Hanson Jeffrey , Rodriguez-Canales Jaime , Thorgeirsson Snorri S. , Kakudo Kennichi , Refetoff Samuel , Kimura Shioko
Published: March 2012

Although having the capacity to grow in response to a stimulus that perturbs the pituitary-thyroid axis, the thyroid gland is considered not a regenerative organ. In this study, partial thyroidectomy (PTx) was used to produce a condition for thyroid regeneration. In the intact thyroid gland, the central areas of both lobes served as the proliferative centers where microfollicles, and bromodeoxyuridine (BrdU)-positive and/or C cells, were localized. Two weeks after PTx, the number of BrdU-positive cells and cells with clear or faintly eosinophilic cytoplasm were markedly increased in the central area and continuous to the cut edge. Clear cells were scant in the cytoplasm, as determined by electron microscopy; some retained the characteristics of calcitonin-producing C cells by having neuroendocrine granules, whereas others retained follicular cell-specific features, such as the juxtaposition to a lumen with microvilli. Some cells were BrdU-positive and expressed Foxa2, the definitive endoderm lineage marker. Serum TSH levels drastically changed due to the thyroidectomy-induced acute reduction in T4-generating tissue, resulting in a goitrogenesis setting. Microarray followed by pathway analysis revealed that the expression of genes involved in embryonic development and cancer was affected by PTx. The results suggest that both C cells and follicular cells may be altered by PTx to become immature cells or immature cells that might be derived from stem/progenitor cells on their way to differentiation into C cells or follicular cells. These immature clear cells may participate in the repair and/or regeneration of the thyroid gland.
Evolutionary Origin of the Structure and Function of Gonadotropin-Inhibitory Hormone: Insights from Lampreys
Authors: Osugi Tomohiro , Daukss Dana , Gazda Kristen , Ubuka Takayoshi , Kosugi Takayoshi , Nozaki Masumi , Sower Stacia A. , Tsutsui Kazuyoshi
Published: March 2012

Gonadotropin (GTH)-inhibitory hormone (GnIH) is a novel hypothalamic neuropeptide that inhibits GTH secretion in mammals and birds by acting on gonadotropes and GnRH neurons within the hypothalamic-pituitary-gonadal axis. GnIH and its orthologs that have an LPXRFamide (X = L or Q) motif at the C terminus (LPXRFamide peptides) have been identified in representative species of gnathostomes. However, the identity of an LPXRFamide peptide had yet to be identified in agnathans, the most ancient lineage of vertebrates, leaving open the question of the evolutionary origin of GnIH and its ancestral function(s). In this study, we identified an LPXRFamide peptide gene encoding three peptides (LPXRFa-1a, LPXRFa-1b, and LPXRFa-2) from the brain of sea lamprey by synteny analysis and cDNA cloning, and the mature peptides by immunoaffinity purification and mass spectrometry. The expression of lamprey LPXRFamide peptide precursor mRNA was localized in the brain and gonad by RT-PCR and in the hypothalamus by in situ hybridization. Immunohistochemistry showed appositions of lamprey LPXRFamide peptide immunoreactive fibers in close proximity to GnRH-III neurons, suggesting that lamprey LPXRFamide peptides act on GnRH-III neurons. In addition, lamprey LPXRFa-2 stimulated the expression of lamprey GnRH-III protein in the hypothalamus and GTHβ mRNA expression in the pituitary. Synteny and phylogenetic analyses suggest that the LPXRFamide peptide gene diverged from a common ancestral gene likely through gene duplication in the basal vertebrates. These results suggest that one ancestral function of LPXRFamide peptides may be stimulatory compared with the inhibitory function seen in later-evolved vertebrates (birds and mammals).
Habenular Kiss1 Neurons Modulate the Serotonergic System in the Brain of Zebrafish
Authors: Ogawa Satoshi , Ng Kai We , Ramadasan Priveena Nair , Nathan Fatima Megala , Parhar Ishwar S.
Published: March 2012

The Kiss1/KISS1 gene has recently been implicated as a potent hypothalamic regulator of reproductive functions, in particular, the onset of puberty in mammals. In zebrafish (Danio rerio), there are two kiss1 homologues (kiss1 and kiss2) expressed in the brain: Kiss2-expressing neurons in the hypothalamic nuclei are considered potent regulators of reproduction, whereas the role of Kiss1-expressing neurons in the habenula remains unknown. We first analyzed the expression of kiss1 mRNA in a transgenic zebrafish, in which the habenula-interpeduncular nucleus (IPN) pathway is labelled with green fluorescent protein, and our application of a biocytin neural tracer into the habenula showed the presence of neuronal projections of Kiss1 neurons to the ventral IPN. Therefore, we speculated that kiss1 neurons might regulate the serotonergic system in the raphe. However, laser microdissection followed by real-time PCR revealed the expression of Kiss1 receptor (kissr1) mRNA in the habenula and the ventral IPN but not in the dorsal IPN or the serotonergic neurons in the raphe nuclei. Dual-fluorescent in situ hybridization revealed the coexpression of kiss1 and kissr1 mRNA in the habenula. Administration of Kiss1 significantly decreased the level of kiss1 mRNA (0.3- to 0.5-fold, P < 0.001), but the level of c-fos mRNA was increased (∼3-fold, P < 0.05) in the ventral habenula, suggesting that there is autocrine regulation of the kiss1 gene. Kiss1 administration significantly increased the c-fos mRNA levels in the raphe nuclei (2.5-fold, P < 0.001) and genes involved in the regulation of serotonin levels (pet1 and slc6a4a; 3.3- and 2.2-fold, P < 0.01). These findings suggest that the autocrine-regulated habenular Kiss1 neurons indirectly regulate the serotonergic system in the raphe nuclei through the IPN in the zebrafish.
Differential MicroRNA Expression in Peripheral Blood Mononuclear Cells from Graves' Disease Patients
Authors: Liu Rongjiao , Ma Xinran , Xu Lingyan , Wang Dao , Jiang Xiaohua , Zhu Wei , Cui Bin , Ning Guang , Lin Dongping , Wang Shu
Published: March 2012

Context:

Graves' disease (GD) is a common autoimmune disease that affects the thyroid gland. As a new class of modulators of gene expression, microRNA (miRNA) have been reported to play a vital role in immune functions and in the development of autoimmunity and autoimmune disease.

Objective:

This study sought to characterize the different miRNA expression in peripheral blood mononuclear cells (PBMC) from GD patients and healthy individuals and examine their direct responses to T3 treatment.

Methods:

Forty-one patients who met criteria for initial GD, 13 GD patients in remission, and 35 healthy controls were recruited. Microarray was used to analyze the expression patterns of miRNA in PBMC obtained from initial GD patients and healthy controls. Three top-ranked miRNA were selected and validated by TaqMan-based real-time PCR in healthy controls, initial GD patients, and GD patients in remission. Furthermore, we cultured PBMC from healthy donors with or without T3 treatment to examine direct effects of T3 on selective miRNA.

Results:

There were sixteen miRNA expressed differently in PBMC from initial GD patients compared with normal subjects. Further analysis consistently showed that the expression of miR-154*, miR-376b, and miR-431* were suppressed in PBMC from initial GD patients. In addition, their expression levels were recovered in GD patients in remission. Meanwhile, T3 treatment could directly inhibit the expression of these miRNA in cultured PBMC from healthy subjects.

Conclusions:

The present work revealed that differentially expressed miRNA were associated with GD and T3 exposure, which might serve as novel biomarkers of GD and potential targets for GD treatment.
The translational repressor Cup is required for germ cell development inDrosophila
Authors: Cristina Ottone , Silvia Gigliotti , Angela Giangrande , Franco Graziani , di Pianella Arturo Verrotti
Published: March 2012

In Drosophila, germ cell formation depends on inherited maternal factors localized in the posterior pole region of oocytes and early embryos, known as germ plasm. Here, we report that heterozygous cup mutant ovaries and embryos have reduced levels of Staufen (Stau), Oskar (Osk), and Vasa (Vas) proteins at the posterior pole. Moreover, we demonstrate that Cup interacts with Osk and Vas to assure anchoring and/or maintenance of germ plasm particles at the posterior pole of oocytes and early embryos. Homozygous cup mutant embryos display a reduced number of germ cells, compared to heterozygous cup mutants, which, in turn, have fewer germ cells than wild type embryos. In addition, we show that cup and osk interact genetically, since reducing cup copy number further decreases the total number of germ cells observed in heterozygous osk mutant embryos. Finally, we detected cup mRNA and protein within both early and late embryonic germ cells, thus suggesting a novel role of Cup during germ cell development in Drosophila.
A role for protein phosphatase PP1γ in SMN complex formation and subnuclear localization to Cajal bodies
Authors: Renvoisé Benoît , Quérol Gwendoline , Verrier Eloi Rémi , Burlet Philippe , Lefebvre Suzie
Published: March 2012

The spinal muscular atrophy (SMA) gene product SMN forms with Gemin2 to 8 and unrip the ubiquitous SMN complex that is required for the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), their nuclear import and localization to subnuclear domain Cajal bodies (CBs). The concentration of the SMN complex and snRNPs in CBs are reduced upon SMN deficiency in SMA cells. Subcellular localization of the SMN complex is regulated in a phosphorylation-dependent manner and the precise mechanisms remain poorly understood. Using coimmunoprecipitation in HeLa cell extracts and in vitro protein binding assays, we show here that the SMN complex and its component Gemin8 interact directly with protein phosphatase PP1γ. Overexpression of Gemin8 in cells increases the number of CBs and results in targeting of PP1γ to CBs. Moreover, depletion of PP1γ by RNA interference enhances the localization of the SMN complex and snRNPs to CBs. Consequently, the interaction between SMN and Gemin8 increases in cytoplasmic and nuclear extracts of PP1γ-depleted cells. Two-dimensional protein gel electrophoresis reveals that SMN is hyperphosphorylated in nuclear extracts of PP1γ-depleted cells and expression of PP1γ restores these isoforms. Notably, SMN deficiency in SMA leads to the aberrant subcellular localization of Gemin8 and PP1γ in the atrophic skeletal muscles, suggesting that the function of PP1γ is likely to be affected in disease. Our findings reveal a role of PP1γ in the formation of the SMN complex and the maintenance of CB integrity. Finally, we propose Gemin8 interaction with PP1γ as a target for therapeutic intervention in SMA.
A cis-acting five-amino acid motif controls targeting of ABCC2 to the apical plasma membrane domain
Authors: Emi Yoshikazu , Yasuda Yuki , Sakaguchi Masao
Published: March 2012

ATP-binding cassette transporter isoform C2 (ABCC2) is exclusively targeted to the apical plasma membrane of polarized cells. Although apical localization of ABCC2 in hepatocytes is crucial for the biliary excretion of a variety of metabolites, the mechanism regulating its apical targeting is poorly understood. In the present study, an apical targeting signal was identified in the first cytoplasmic loop domain (CLD1) of ABCC2 in HepG2 cells. Overexpression of CLD1 significantly disturbed the apical targeting of FLAG-ABCC2 in a competitive manner, suggesting the presence of a saturable sorting machinery in HepG2 cells. Next, deletion analysis identified a potential targeting sequence within a 20-amino acid long peptide (aa 272-291) of CLD1. Alanine scanning mutagenesis of this region in full-length ABCC2 further narrowed down the apical targeting determinant to five amino acids, S283QDAL287. Of these, S283 and L287 were conserved among vertebrate ABCC2 orthologs. Site-directed mutagenesis showed that both S283 and L287 were critical for the targeting specificity of ABCC2. Introducing this apical targeting sequence into the corresponding region of ABCC1, an exclusively basolateral protein, caused the hybrid ABCC1 to partially localize in the apical membrane. Thus, the CLD1 of ABCC2 contains a novel apical sorting determinant, and a saturable sorting machinery is present in polarized HepG2 cells.
c-Fos plays an essential role in the up-regulation of RANK expression in osteoclast precursors within the bone microenvironment
Authors: Arai Atsushi , Mizoguchi Toshihide , Harada Suguru , Kobayashi Yasuhiro , Nakamichi Yuko , Yasuda Hisataka , Penninger Josef M. , Yamada Kazuhiro , Udagawa Nobuyuki , Takahashi Naoyuki
Published: March 2012

c-Fos plays essential roles in the osteoclastic differentiation of precursors generated by colony-stimulating factor 1 (CSF-1) and receptor activator of NF-κB ligand (RANKL). RANKL-deficient (RANKL−/−) mice and c-Fos−/− mice exhibit osteopetrosis due to an osteoclast deficiency. We previously reported that RANK-positive osteoclast precursors existed in bone in RANKL−/− mice but not c-Fos−/− mice. Here we examined the role of c-Fos in RANK expression in osteoclast precursors. Medullary thymic epithelial cells and intestinal antigen-sampling microfold cells have been shown to express RANK. High expression of RANK was observed in some epithelial cells in the thymic medulla and intestine but not in osteoclast precursors in c-Fos−/− mice. RANK mRNA and protein levels in bone were lower in c-Fos−/− mice than RANKL−/− mice, suggesting that c-Fos-regulated RANK expression is tissue specific. When wild-type bone marrow cells were inoculated into c-Fos−/− mice, RANK-positive cells appeared along bones. RANK expression in wild-type macrophages was up-regulated by coculturing with RANKL−/− osteoblasts as well as wild-type osteoblasts, suggesting that cytokines other than RANKL expressed by osteoblasts up-regulate RANK expression in osteoclast precursors. CSF-1 receptor-positive cells were detected near CSF-1-expressing osteoblastic cells in bone in c-Fos−/− mice. CSF-1 up-regulated RANK expression in wild-type macrophages but not c-Fos−/− macrophages. Overexpression of c-Fos in c-Fos−/− macrophages resulted in the up-regulation of RANK expression. Overexpression of RANK in c-Fos−/− macrophages caused RANKL-induced signals, but failed to recover the RANKL-induced osteoclastogenesis. These results suggest that c-Fos plays essential roles in the up-regulation of RANK expression in osteoclast precursors within the bone environment.
The ubiquitin-like (UBX)-domain-containing protein Ubx2/ Ubxd8 regulates lipid droplet homeostasis
Authors: Wang Chao-Wen , Lee Shu-Chuan
Published: March 2012

Lipid droplets (LDs) are central organelles for maintaining lipid homeostasis. However, how cells control the size and number of LDs remains largely unknown. Herein, we report that Ubx2, a UBX-domain-containing protein involved in endoplasmic reticulum (ER)-associated degradation (ERAD), is crucial for LD maintenance. Ubx2 redistributes from ER to LDs when LDs start to form and enlarge during diauxic shift and in the stationary phase. ubx2Δ cells contain abnormal number and reduced size of LDs and their triacylglycerol (TAG) is reduced to 50% of the normal level. Deletion of either UBX or UBA domain in Ubx2 has no effect, but deletion of both causes LD phenotypes similar to that in ubx2Δ. The reduced TAG in ubx2Δ is likely due to mislocalization of Lro1, one of the two TAG-synthesizing enzymes in yeast, which moves along the ER and distributes dynamically to the putative LD assembly sites abutting LDs. Thus, Ubx2 is important for the maintenance of cellular TAG homeostasis likely through Lro1. The mammalian Ubxd8 expressed in yeast complements the defect of ubx2Δ, implying a functional conservation for these UBX-domain-containing proteins in lipid homeostasis.
A novel regulatory mechanism links PLCγ1 to PDK1
Authors: Raimondi Claudio , Chikh Anissa , Maffucci Tania , Falasca Marco
Published: March 2012

3-Phosphoinositide dependent protein kinase-1 (PDK1) and phospholipase C (PLC)γ1 are two key enzymes in signal transduction that control several intracellular processes. Despite the fact that PLCγ1 has been investigated for several years, the mechanisms of activation of this enzyme are still not completely clear. Similarly, although PDK1 has been mostly investigated for its role in activation of Akt, a crucial enzyme in regulation of several cellular processes, it has become recently evident that the role of PDK1 in physiological and pathological conditions is not limited to Akt activation.

Here we demonstrate that PDK1 regulates PLCγ1 activation in a mechanism involving association of the two enzymes and modulation of PLCγ1 tyrosine phosphorylation. We further show that this novel PDK1-PLCγ1 pathway is important for cancer cell invasion. The identification of a PDK1-PLCγ1 pathway reveals the existence of a previously undetected link between two of the most important enzymes in signal transduction. This is likely to have profound consequences in our understanding of several cellular functions dependent on phosphoinositides and controlled by PDK1 and PLCγ1.
Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3
Authors: Ryan Katie R. , Lock Frances E. , Heath John K. , Hotchin Neil A.
Published: March 2012

The human epidermis is a self-renewing, stratified epithelial tissue that provides the protective function of the skin. The principal cell type within the epidermis is the keratinocyte and normal function of the epidermis requires that keratinocyte proliferation, differentiation and cell death be carefully controlled. There is clear evidence that signalling through adhesion receptors such as integrins and cadherins plays a key role in regulating epidermal function. Previous work has shown that Rho family GTPases regulate cadherin- and integrin-based adhesion structures and hence epidermal function. In this study we show that a member of this family - Rnd3 - regulates desmosomal cell-cell adhesion in that loss of Rnd3 expression leads to an increase in desmosomes at sites of cell-cell adhesion and altered colony morphology. Loss of Rnd3 expression is also associated with resistance to cisplatin-mediated apoptosis in keratinocytes and this resistance is mediated via the desmosomal protein plakoglobin. We propose a novel plakoglobin-dependent role for Rnd3 in the regulation of keratinocyte cell death.
Getting Up to Speed on the Financial Crisis: A One-Weekend-Reader's Guide
Authors: Gorton Gary , Metrick Andrew
Published: March 2012

All economists should be conversant with “what happened?” during the financial crisis of 2007–09. We select and summarize sixteen documents, including academic papers and reports from regulatory and international agencies. This reading list covers the key facts and mechanisms in the build-up of risk, the panics in short-term-debt markets, the policy reactions, and the real effects of the financial crisis. (JEL E32, E44, E52, G01, G21, G28)
Economic Perspectives on Corporate Social Responsibility
Authors: Kitzmueller Markus , Shimshack Jay
Published: March 2012

This paper synthesizes the expanding corporate social responsibility (CSR) literature. We define CSR from an economic perspective and develop a CSR taxonomy that connects disparate approaches to the subject. We explore whether CSR should exist and investigate conditions when CSR may produce higher welfare than other public good provision channels. We also explore why CSR does exist. Here, we integrate theoretical predictions with empirical findings from economic and noneconomic sources. We find limited systematic empirical evidence in favor of CSR mechanisms related to induced innovation, moral hazard, shareholder preferences, or labor markets. In contrast, we uncover consistent empirical evidence in favor of CSR mechanisms related to consumer markets, private politics, and public politics. (JEL D21, L21, M14)
Exposure of alveolar macrophages to polybrominated diphenyl ethers suppresses the release of pro-inflammatory products in vitro
Authors: Hennigar Stephen R , Myers Jay L , Tagliaferro Anthony R
Published: March 2012

Inhalation of chemical pollutants has been associated with a reduced immune response in humans. Inhalation of dust is a major route of exposure for one endocrine-disrupting chemical and suspected xenoestrogen, polybrominated diphenyl ethers (PBDEs); however, the impact of PBDEs on immune function is unclear. The objective of this study was to investigate the action of PBDEs on cytokine and eicosanoid release by alveolar macrophages and determine whether the effects are mediated via the estrogen receptor. The production of tumor necrosis factor (TNF)- α, interleukin (IL)-6, IL-1 β, IL-10 and prostaglandin E2 (PGE2) by porcine alveolar macrophages exposed to different concentrations of the pentabrominated diphenyl ether mixture, DE-71, were measured; cells were also exposed to varying concentrations of 17 β-estradiol and the selective estrogen receptor-modulating agent, tamoxifen. Cells exposed to PBDEs released significantly less pro-inflammatory cytokines (TNF- α and IL-6) and PGE2 compared with controls; IL-1 β and IL-10 were not detected in the culture medium. Cells exposed to 17 β-estradiol released significantly less TNF- α compared with controls, an effect that was reversed by the addition of tamoxifen; tamoxifen had no effect on the inhibition of TNF- α release by PBDEs. Although the suppression of TNF- α with DE-71 was similar to that of estrogen, the inhibitory effects of DE-71 were not found to be dependent on the estrogen receptor. Findings of this study suggest that chronic exposure to PBDEs suppressed innate immunity in vitro. Whether the immunosuppressant effects of PBDEs occur in vivo, remains to be determined.
Diagnostic tests and strategies in venous thromboembolism
Authors: Tenna A M S , Kappadath S , Stansby G
Published: March 2012

Venous thromboembolism (VTE) is a term including deep vein thrombosis (DVT) and pulmonary embolism (PE). Timely and accurate diagnosis of both is essential as delayed or missed diagnoses can result in death or longer term complications. Patients with suspected DVT should initially undergo a pretest probability Wells score. Depending on pretest probability Wells score they should then either proceed to two-point ultrasound scanning or D-dimer testing. Likewise, patients suspected of PE should undergo a two-level PE Wells score, and, if scored likely, a computed tomography pulmonary angiogram (CTPA), or, if there is a low pretest probability score, D-dimer testing. If positive, patients should undergo CTPA. Ventilation perfusion scanning (V/Q scan) or V/Q SPECT should be considered in place of CTPA if there is allergy to contrast media or renal impairment.
Troponin-positive chest pain with unobstructed coronary arteries: definitive differential diagnosis using cardiac MRI
Authors: Mahmoudi M , Harden S , Abid N , Peebles C , Nicholas Z , Jones T , Mckenzie D , Curzen N
Published: March 2012

Objective: The purpose of this study was to assess the outcome of cardiac MRI (CMRI) with late gadolinium enhancement (LGE) at outpatient follow-up in a consecutive series of patients with troponin-positive chest pain but unobstructed coronary arteries at the index admission.

Methods: The study group comprised 91 consecutive patients who presented to our institution with cardiac chest pain, elevated troponin I and unobstructed coronary arteries on coronary angiography. All patients underwent an outpatient CMRI with LGE imaging in order to establish a definitive diagnosis.

Results: The average time from coronary angiography to LGE-CMRI was 2 months. 73% of patients had no abnormality on their LGE-CMRI, 16% of patients had patchy late enhancement consistent with myocarditis and 11% had focal subendocardial or full thickness late enhancement consistent with myocardial infarction. There were no deaths in this cohort during a mean follow-up of 21 months.

Conclusion: LGE-CMRI is a useful tool for establishing whether such patients have definitive evidence of non-ST-segment elevation myocardial infarction (NSTEMI), and can make an important contribution to the long-term management strategy of these patients as an inappropriate diagnosis of NSTEMI carries important medical, social and financial implications.
The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B
Authors: Anderson Erik S. , Lin Chia-Ho , Xiao Xinshu , Stoilov Peter , Burge Christopher B. , Black Douglas L.
Published: March 2012

Modulation of alternative pre-mRNA splicing is a potential approach to therapeutic targeting for a variety of human diseases. We investigated the mechanism by which digitoxin, a member of the cardiotonic steroid class of drugs, regulates alternative splicing. Transcriptome-wide analysis identified a large set of alternative splicing events that change after digitoxin treatment. Within and adjacent to these regulated exons, we identified enrichment of potential binding sites for the splicing factors SRp20 (SRSF3/SFRS3) and Tra2-β (SFRS10/TRA2B). We further find that both of these proteins are depleted from cells by digitoxin treatment. Characterization of SRp20 and Tra2-β splicing targets revealed that many, but not all, digitoxin-induced splicing changes can be attributed to the depletion of one or both of these factors. Re-expression of SRp20 or Tra2-β after digitoxin treatment restores normal splicing of their targets, indicating that the digitoxin effect is directly due to these factors. These results demonstrate that cardiotonic steroids, long prescribed in the clinical treatment of heart failure, have broad effects on the cellular transcriptome through these and likely other RNA binding proteins. The approach described here can be used to identify targets of other potential therapeutics that act as alternative splicing modulators.
Supply Chain Dynamics and Channel Efficiency in Durable Product Pricing and Distribution
Authors: Chiang Wei-yu Kevin
Published: March 2012

This study extends the single-period vertical price interaction in a manufacturer–retailer dyad to a multiperiod setting. A manufacturer distributes a durable product through an exclusive retailer to an exhaustible population of consumers with heterogeneous reservation prices. In each period, the manufacturer and retailer in turn set wholesale and retail prices, respectively, and customers with valuation above the retail price adopt the product at a constant (hazard) rate. We derive the open-loop, feedback, and myopic equilibria for this dynamic pricing game and compare it to the centralized solution. Although in an integrated supply chain a forward-looking dynamic pricing strategy is always desirable, we show that this is not the case in a decentralized setting, because of vertical competition. Our main result is that both supply chain entities are better off in the long run when they ignore the impact of current prices on future demand and focus on immediate-term profits. A numerical study confirms that this insight is robust under various supply- and demand-side effects. We use the channel efficiency corresponding to various pricing rules to further derive insights into decisions on decentralization and disintermediation.
The Pro-Competitive Effect of Coffee Cooperatives in Chiapas, Mexico
Authors: Milford Anna B.
Published: March 2012

Imperfect competition among purchasers of coffee is a common problem for small scale producers. Producer-owned marketing cooperatives can reduce the market power of private purchasers and restore competition. Non-members as well as members of the cooperatives will then receive higher prices. In the present paper I carry out a theoretical and an empirical investigation into the effect of Fairtrade and organically certified cooperatives on local competition and coffee prices in Chiapas, Mexico. A theoretical model is presented which explains how the competitive effect may work in this particular setting, where cooperative membership implies certain costs that are perceived differently by different producers. Also, using both qualitative and quantitative methods, I present evidence that is consistent with the hypothesis of a pro-competitive effect of cooperatives.
Introduction: Economics and Occupy Wall Street
Authors: Naidu Suresh
Published: March 2012

This issue of the The Economists’ Voice is showcasing views around the issues Occupy Wall Street has raised.
Extent of Bilateral Neuronal Network Reorganization and Functional Recovery in Relation to Stroke Severity
Authors: van Meer Maurits P.A. , Otte Willem M. , van der Marel Kajo , Nijboer Cora H. , Kavelaars Annemieke , van der Sprenkel Jan Willem Berkelbach , Viergever Max A. , Dijkhuizen Rick M.
Published: March 2012

Remodeling of neuronal structures and networks is believed to significantly contribute to (partial) restoration of functions after stroke. However, it has been unclear to what extent the brain reorganizes and how this correlates with functional recovery in relation to stroke severity. We applied serial resting-state functional MRI and diffusion tensor imaging together with behavioral testing to relate longitudinal modifications in functional and structural connectivity of the sensorimotor neuronal network to changes in sensorimotor function after unilateral stroke in rats. We found that gradual improvement of functions is associated with wide-ranging changes in functional and structural connectivity within bilateral neuronal networks, particularly after large stroke. Both after medium and large stroke, brain reorganization eventually leads to (partial) normalization of neuronal signal synchronization within the affected sensorimotor cortical network (intraregional signal coherence), as well as between the affected and unaffected sensorimotor cortices (interhemispheric functional connectivity). Furthermore, the bilateral network configuration shifts from subacutely increased “small-worldness,” possibly reflective of initial excessive neuronal clustering and wiring, toward a baseline small-world topology, optimal for global information transfer and local processing, at chronic stages. Cortical network remodeling was accompanied by recovery of initially disrupted structural integrity in corticospinal tract regions, which correlated positively with retrieval of sensorimotor functions. Our study demonstrates that the degree of functional recovery after stroke is associated with the extent of preservation or restoration of ipsilesional corticospinal tracts in combination with reinstatement of interhemispheric neuronal signal synchronization and normalization of small-world cortical network organization.
Understanding How the Brain Changes Its Mind: Microstimulation in the Macaque Frontal Eye Field Reveals How Saccade Plans Are Changed
Authors: Ramakrishnan Arjun , Sureshbabu Ramakrishnan , Murthy Aditya
Published: March 2012

Accumulator models that integrate incoming sensory information into motor plans provide a robust framework to understand decision making. However, their applicability to situations that demand a change of plan raises an interesting problem for the brain. This is because interruption of the current motor plan must occur by a competing motor plan, which is necessarily weaker in strength. To understand how changes of mind get expressed in behavior, we used a version of the double-step task called the redirect task, in which monkeys were trained to modify a saccade plan. We microstimulated the frontal eye fields during redirect behavior and systematically measured the deviation of the evoked saccade from the response field to causally track the changing saccade plan. Further, to identify the underlying mechanisms, eight different computational models of redirect behavior were assessed. It was observed that the model that included an independent, spatially specific inhibitory process, in addition to the two accumulators representing the preparatory processes of initial and final motor plans, best predicted the performance and the pattern of saccade deviation profile in the task. Such an inhibitory process suppressed the preparation of the initial motor plan, allowing the final motor plan to proceed unhindered. Thus, changes of mind are consistent with the notion of a spatially specific, inhibitory process that inhibits the current inappropriate plan, allowing expression of the new plan.
δ-Opioid Receptor Function in the Dorsal Striatum Plays a Role in High Levels of Ethanol Consumption in Rats
Authors: Nielsen Carsten K. , Simms Jeffrey A. , Li Rui , Mill Douglas , Yi Henry , Feduccia Allison A. , Santos Nathan , Bartlett Selena E.
Published: March 2012

Binge-like patterns of excessive drinking during young adulthood increase the propensity for alcohol use disorders (AUDs) later in adult life; however, the mechanisms that drive this are not completely understood. Previous studies showed that the δ-opioid peptide receptor (DOP-R) is dynamically regulated by exposure to ethanol and that the DOP-R plays a role in ethanol-mediated behaviors. The aim of this study was to determine the role of the DOP-R in high ethanol consumption from young adulthood through to late adulthood by measuring DOP-R-mediated [35S]GTPγS binding in brain membranes and DOP-R-mediated analgesia using a rat model of high ethanol consumption in Long Evans rats. We show that DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia changes during development, being highest during early adulthood and reduced in late adulthood. Intermittent access to ethanol but not continuous ethanol or water from young adulthood leads to an increase in DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia into late adulthood. Multiple microinfusions of naltrindole into the dorsal striatum or multiple systemic administration of naltrindole reduces ethanol consumption, and following termination of treatment, DOP-R activity in the dorsal striatum is attenuated. These findings suggest that DOP-R activity in the dorsal striatum plays a role in high levels of ethanol consumption and suggest that targeting the DOP-R is an alternative strategy for the treatment of AUDs.
Cortical Dynamics of Sensorimotor Integration during Grasp Planning
Authors: Verhagen Lennart , Dijkerman H. Chris , Medendorp W. Pieter , Toni Ivan
Published: March 2012

Our sensorimotor interactions with objects are guided by their current spatial and perceptual features, as well as by learned object knowledge. A fresh red tomato is grasped differently than a soft overripe tomato, even when those objects possess the same spatial metrics of size and shape. Objects' spatial and perceptual features need to be integrated during grasping, but those features are analyzed in two anatomically distinct neural pathways. The anterior intraparietal sulcus (aIPS) might support the integration of those features. We combine transcranial magnetic stimulation (TMS) interference, EEG recordings, and psychophysical methods to test aIPS causal contributions to sensorimotor integration, characterizing the dynamics of those contributions during motor planning. Human subjects performing grasping movements were provided with visual information about a target object, namely spatial and pictorial cues, whose availability and information value were independently modulated on each trial. Maximally informative visual cues, irrespective of their spatial or perceptual nature, led to enhanced motor preparatory activity early during movement planning, and to stronger spatial congruency between finger trajectories and target object. Disturbing aIPS activity with single-pulse TMS within 200 ms after object presentation reduced those electrophysiological and behavioral indices of enhanced motor planning. TMS interference with aIPS also disturbed subjects' ability to use learned object knowledge during motor planning. These results indicate that aIPS is necessary for the fast generation of a new motor plan on the basis of both spatial and pictorial cues. Furthermore, as learned object knowledge becomes available, aIPS comes to strongly depend on this prior information for structuring the motor plan.
TheLhx2Transcription Factor Controls Thalamocortical Axonal Guidance by Specific Regulation of Robo1 and Robo2 Receptors
Authors: Marcos-Mondéjar Paula , Peregrín Sandra , Li James Y. , Carlsson Leif , Tole Shubha , López-Bendito Guillermina
Published: March 2012

The assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Actions of transcription factors in neural progenitors and postmitotic cells are key regulators in this process. LIM-homeodomain transcription factors control crucial aspects of neuronal differentiation, including subtype identity and axon guidance. Nonetheless, their regulation during development is poorly understood and the identity of the downstream molecular effectors of their activity remains largely unknown. Here, we demonstrate that theLhx2transcription factor is dynamically regulated in distinct pools of thalamic neurons during the development of thalamocortical connectivity in mice. Indeed, overexpression ofLhx2provokes defective thalamocortical axon guidancein vivo, while specific conditional deletion ofLhx2in the thalamus produces topographic defects that alter projections from the medial geniculate nucleus and from the caudal ventrobasal nucleus in particular. Moreover, we demonstrate thatLhx2influences axon guidance and the topographical sorting of axons by regulating the expression of Robo1 and Robo2 guidance receptors, which are essential for these axons to establish correct connections in the cerebral cortex. Finally, augmenting Robo1 function restores normal axon guidance in Lhx2-overexpressing neurons. By regulating axon guidance receptors, such as Robo1 and Robo2, Lhx2 differentially regulates the axon guidance program of distinct populations of thalamic neurons, thus enabling the establishment of specific neural connections.
Interaction of BDNF and COMT Polymorphisms on Paired-Associative Stimulation-Induced Cortical Plasticity
Authors: Witte A. Veronica , Kürten Julia , Jansen Stefanie , Schirmacher Anja , Brand Eva , Sommer Jens , Flöel Agnes
Published: March 2012

The common single-nucleotide polymorphism (SNP) brain-derived neurotrophic factor (BDNF) valine-to-methionine substitution at codon 66 (Val66Met) has been associated with differences in memory functions and cortical plasticity following brain stimulation. Other studies could not confirm these results, though, and potential interactions of BDNF carrier status with other learning-relevant SNPs are largely unknown. The present study aimed to evaluate the effects of BDNF Val66Met genotype on paired associative stimulation (PAS)-induced motor cortex plasticity, while additionally taking catechol-O-methyltransferase (COMT) Val158Met and kidney and brain (KIBRA) rs17070145 carrier status into account. Therefore, a cohort of 2 × 16 age- and education-matched healthy young females underwent transcranial magnetic stimulation using an excitatory PAS25protocol to induce cortical plasticity. Cognitive performance was assessed using implicit grammar- and motor-learning tasks and a detailed neuropsychological test battery. While BDNF carrier status alone did not significantly influence PAS-induced cortical plasticity, we found a significant BDNF × COMT interaction, showing higher plasticity immediately following the PAS25protocol for the BDNF Val/Val vs Met genotype in COMT Met homozygotes only (ANOVA,p= 0.027). A similar advantage for this group was noted for implicit grammar learning (ANOVA,p= 0.021). Accounting for KIBRA rs17070145 did not explain significant variance. Our findings for the first time demonstrate an interaction of BDNF by COMT on human cortical plasticity. Moreover, they show that genotype-related differences in neurophysiology translate into behavioral differences. These findings might contribute to a better understanding of the mechanisms of interindividual differences in cognition.
ADrosophilaDEG/ENaC Subunit Functions Specifically in Gustatory Neurons Required for Male Courtship Behavior
Authors: Starostina Elena , Liu Tong , Vijayan Vinoy , Zheng Zheng , Siwicki Kathleen K. , Pikielny Claudio W.
Published: March 2012

Detection of specific female pheromones stimulates courtship behavior inDrosophila melanogastermales, but the chemosensory molecules, cells, and mechanisms involved remain poorly understood. Here we show thatppk25, a DEG/ENaC ion channel subunit required for normal male response to females, is expressed at highest levels in a single sexually dimorphic gustatory neuron of most taste hairs on legs and wings, but not in neurons that detect courtship-inhibiting pheromones or food. Synaptic inactivation ofppk25-expressing neurons, or knockdown ofppk25expression in all gustatory neurons, significantly impairs male response to females, whereas gustatory expression ofppk25rescues the courtship behavior ofppk25mutant males. Remarkably, the only other detectable albeit significantly weaker expression ofppk25occurs in olfactory neurons implicated in modulation of courtship behavior. However, expression ofppk25in olfactory neurons is not required for male courtship under our experimental conditions. These data show thatppk25functions specifically in peripheral taste neurons involved in activation of courtship behavior, an unexpected function for this type of channel. Furthermore, our work identifies a small subset of gustatory neurons with an essential role in activation of male courtship behavior, most likely in response to female pheromones.