bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete plastid genomes from Ophioglossum californicum, Psilotum nudum, and Equisetum hyemale reveal an ancestral land plant genome structure and resolve the position of Equisetales among monilophytes
Authors: Grewe Felix , Guo Wenhu , Gubbels Emily A , Hansen A Katie , Mower Jeffrey P
Published: January 2013

Background

Plastid genome structure and content is remarkably conserved in land plants. This widespread conservation has facilitated taxon-rich phylogenetic analyses that have resolved organismal relationships among many land plant groups. However, the relationships among major fern lineages, especially the placement of Equisetales, remain enigmatic.

Results

In order to understand the evolution of plastid genomes and to establish phylogenetic relationships among ferns, we sequenced the plastid genomes from three early diverging species: Equisetum hyemale (Equisetales), Ophioglossum californicum (Ophioglossales), and Psilotum nudum (Psilotales). A comparison of fern plastid genomes showed that some lineages have retained inverted repeat (IR) boundaries originating from the common ancestor of land plants, while other lineages have experienced multiple IR changes including expansions and inversions. Genome content has remained stable throughout ferns, except for a few lineage-specific losses of genes and introns. Notably, the losses of the rps16 gene and the rps12i346 intron are shared among Psilotales, Ophioglossales, and Equisetales, while the gain of a mitochondrial atp1 intron is shared between Marattiales and Polypodiopsida. These genomic structural changes support the placement of Equisetales as sister to Ophioglossales + Psilotales and Marattiales as sister to Polypodiopsida. This result is augmented by some molecular phylogenetic analyses that recover the same relationships, whereas others suggest a relationship between Equisetales and Polypodiopsida.

Conclusions

Although molecular analyses were inconsistent with respect to the position of Marattiales and Equisetales, several genomic structural changes have for the first time provided a clear placement of these lineages within the ferns. These results further demonstrate the power of using rare genomic structural changes in cases where molecular data fail to provide strong phylogenetic resolution.
An analysis of online messages about probiotics
Authors: Brinich Margaret A , Mercer Mary Beth , Sharp Richard R
Published: January 2013

Internet websites are a resource for patients seeking information about probiotics. We examined a sample of 71 websites presenting probiotic information. We found that descriptions of benefits far outnumbered descriptions of risks and commercial websites presented significantly fewer risks than noncommercial websites. The bias towards the presentation of therapeutic benefits in online content suggests that patients are likely interested in using probiotics and may have unrealistic expectations for therapeutic benefit. Gastroenterologists may find it useful to initiate conversations about probiotics within the context of a comprehensive health management plan and should seek to establish realistic therapeutic expectations with their patients.
Utility of cardiac magnetic resonance in assessing right-sided heart failure in sarcoidosis
Authors: Lønborg Jacob , Ward Michael , Gill Anthony , Grieve Stuart M , Figtree Gemma A
Published: January 2013

Background

Cardiac involvement in sarcoidosis is associated with a poor prognosis. In patients with right sided heart failure, differentiating between cor-pulmonale, or cardiac sarcoidosis has important implications to management.

Case presentation

We present the case of a patient with severe but stable pulmonary sarcoidosis and new onset right sided heart failure despite only mild elevations of pulmonary artery pressure. CMR demonstration of extensive right ventricular fibrosis with associated dilatation and hypokinesis was a key finding for prognosis and management of the patient.

Conclusion

Cardiac magnetic resonance (CMR) is the preferred investigation in the diagnosis of cardiac sarcoidosis, allowing assessment of myocardial inflammation and fibrosis, as well as function, in a manner not matched by other technologies.
Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study
Authors: Fesinmeyer Megan D , North Kari E , Lim Unhee , Bůžková Petra , Crawford Dana C , Haessler Jeffrey , Gross Myron D , Fowke Jay H , Goodloe Robert , Love Shelley-Ann , Graff Misa , Carlson Christopher S , Kuller Lewis H , Matise Tara C , Hong Ching-Ping , Henderson Brian E , Allen Melissa , Rohde Rebecca R , Mayo Ping , Schnetz-Boutaud Nathalie , Monroe Kristine R , Ritchie Marylyn D , Prentice Ross L , Kolonel Lawrence N , Manson JoAnn E , Pankow James , Hindorff Lucia A , Franceschini Nora , Wilkens Lynne R , Haiman Christopher A , Le Marchand Loic , Peters Ulrike
Published: January 2013

Background

Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.

Methods

As part of the ‘Population Architecture using Genomics and Epidemiology (PAGE)’ Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.

Results

We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, pinteraction = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5x10-5), vs. former/never smokers (β = 0.006, p = 0.05, pinteraction = 0.08).

Conclusions

These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.

Clinical Trial Registration

NCT00000611
Identification of novel mutation in cathepsin C gene causing Papillon-Lefèvre Syndrome in Mexican patients
Authors: Romero-Quintana José G , Frías-Castro Luis O , Arámbula-Meraz Eliakym , Aguilar-Medina Maribel , Dueñas-Arias Jesús E , Melchor-Soto Jesús D , Romero-Navarro José G , Ramos-Payán Rosalío
Published: January 2013

Background

Papillon-Lefèvre Syndrome (PLS) is a type IV genodermatosis caused by mutations in cathepsin C (CTSC), with a worldwide prevalence of 1–4 cases per million in the general population. In México, the prevalence of this syndrome is unknown, and there are few case reports. The diagnosis of twenty patients in the state of Sinaloa highlights the need to characterize this syndrome in Mexicans.

Methods

To understand the basis of PLS in Mexicans, the gene expression, enzymatic activity and mutational analysis of CTSC were assayed in nine PLS patients and their relatives. Frequencies ofCTSCgene polymorphisms and HLA alleles were determined in these patients, their relatives, and the population.

Results

Patients showed normalCTSCgene expression, but a deep reduction (up to 85%) in enzymatic activity in comparison to unrelated healthy individuals. A novel loss-of-function mutation, c.203 T >; G (p.Leu68Arg), was found in all patients, and some carried the polymorphism c.458C >; T (p.Thr153Ile). Allelic frequencies in patients, relatives and controls were 88.89%, 38.24% and 0.25% for G (c.203 T >; G); and 11.11%, 8.82% and 9.00% for T (c.458C >; T). HLA-DRB1*11 was found significantly more frequent (P = 0.0071) in patients than controls (33.33%vs.7.32%), with an estimated relative risk of 6.33.

Conclusions

The novel loss-of function mutation ofCTSCgene (c.203 T >; G) found in patients correlated with their diminished enzymatic activity, and HLA-DRB1*11 was found to be associated with PLS. The study of more PLS patients may give more insights into the etiology of the disease as well as its prevalence in México.
Platelet-derived growth factor-induced Akt phosphorylation requires mTOR/Rictor and phospholipase C-γ1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D
Authors: Razmara Masoud , Heldin Carl-Henrik , Lennartsson Johan
Published: January 2013

Mammalian target of rapamycin (mTOR) can be found in two multi-protein complexes, i.e. mTORC1 (containing Raptor) and mTORC2 (containing Rictor). Here, we investigated the mechanisms by which mTORC1 and mTORC2 are activated and their downstream targets in response to platelet-derived growth factor (PDGF)-BB treatment. Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2. We found that in Rictor-null mouse embryonic fibroblasts, or after prolonged rapamycin treatment of NIH3T3 cells, PDGF-BB was not able to promote phosphorylation of Ser473 in the serine/threonine kinase Akt, whereas Thr308 phosphorylation was less affected, suggesting that Ser473 in Akt is phosphorylated in an mTORC2-dependent manner. This reduction in Akt phosphorylation did not influence the phosphorylation of the S6 protein, a well established protein downstream of mTORC1. Consistently, triciribine, an inhibitor of the Akt pathway, suppressed PDGF-BB-induced Akt phosphorylation without having any effect on S6 phosphorylation. Thus, mTORC2 does not appear to be upstream of mTORC1. We could also demonstrate that in Rictor-null cells the phosphorylation of phospholipase Cγ1 (PLCγ1) and protein kinase C (PKC) was impaired, and the PKCα protein levels strongly reduced. Furthermore, interfering with the PLCγ/Ca2+/PKC pathway inhibited PDGF-BB-induced Akt phosphorylation. In addition, PDGF-BB-induced activation of mTORC1, as measured by phosphorylation of the downstream S6 protein, was dependent on phospholipase D (PLD). It has been shown that Erk1/2 MAP-kinase directly phosphorylates and activates mTORC1; in partial agreement with this finding, we found that a Mek1/2 inhibitor delayed S6 phosphorylation in response to PDGF-BB, but it did not block it. Thus, whereas both mTORC1 and mTORC2 are activated in a PI3K-dependent manner, different additional signaling pathways are needed. mTORC1 is activated in a PLD-dependent manner and promotes phosphorylation of the S6 protein, whereas mTORC2, in concert with PLCγ signaling, promotes Akt phosphorylation.
Exogenous endothelial cells as accelerators of hematopoietic reconstitution
Authors: Mizer J Christopher , Ichim Thomas E , Alexandrescu Doru T , Dasanu Constantin A , Ramos Famela , Turner Andrew , Woods Erik J , Bogin Vladimir , Murphy Michael P , Koos David , Patel Amit N
Published: January 2013

Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a) ability to regulate secretion of cytokines based on biological need; b) long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c) potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC) in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery.
Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy
Authors: Castañon Eduardo , Bosch-Barrera Joaquim , López Inés , Collado Víctor , Moreno Marta , López-Picazo José María , Arbea Leire , Lozano María Dolores , Calvo Alfonso , Gil-Bazo Ignacio
Published: January 2013

Background

Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy).

Methods

We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy.

Results

Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed.

Conclusions

A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.
A mathematical model with time-varying delays in the combined treatment of chronic myeloid leukemia
Authors: Berezansky Leonid , Bunimovich-Mendrazitsky Svetlana , Domoshnitsky Alexander
Published: January 2013

In this paper, we propose and analyze a mathematical model for the treatment of chronic myelogenous (myeloid) leukemia (CML), a cancer of the blood. Our main focus is on the combined treatment of CML based on imatinib therapy and immunotherapy. Treatment with imatinib is a molecular targeted therapy that inhibits the cells involved in the chronic CML pathogenesis. Immunotherapy based on interferon alfa-2a (IFN-α) increases cancer cell mortality and leads to improvement of outcomes of the combined therapy. Interaction between CML cancer cells and effector cells of the immune system is modeled by a system of non-linear differential equations, where we introduced biologically motivated time-varying delays in the treatment terms. The analysis of the described system shows the existence of a unique global positive solution and a unique non-trivial equilibrium. We also derive explicit local and global stability conditions for the non-trivial equilibrium.
Lack of transient receptor potential vanilloid 1 channel modulates the development of neurogenic bladder dysfunction induced by cross-sensitization in afferent pathways
Authors: Lei Qi , Pan Xiao-Qing , Villamor Antonio N , Asfaw Tirsit S , Chang Shaohua , Zderic Steven A , Malykhina Anna P
Published: January 2013

Background

Bladder pain of unknown etiology has been associated with co-morbid conditions and functional abnormalities in neighboring pelvic organs. Mechanisms underlying pain co-morbidities include cross-sensitization, which occurs predominantly via convergent neural pathways connecting distinct pelvic organs. Our previous results showed that colonic inflammation caused detrusor instability via activation of transient receptor potential vanilloid 1 (TRPV1) signaling pathways, therefore, we aimed to determine whether neurogenic bladder dysfunction can develop in the absence of TRPV1 receptors.

Methods

Adult male C57BL/6 wild-type (WT) and TRPV1−/− (knockout) mice were used in this study. Colonic inflammation was induced by intracolonic trinitrobenzene sulfonic acid (TNBS). The effects of transient colitis on abdominal sensitivity and function of the urinary bladder were evaluated by cystometry, contractility and relaxation of detrusor smooth muscle (DSM) in vitro to various stimuli, gene and protein expression of voltage-gated sodium channels in bladder sensory neurons, and pelvic responses to mechanical stimulation.

Results

Knockout of TRPV1 gene did not eliminate the development of cross-sensitization between the colon and urinary bladder. However, TRPV1−/− mice had prolonged intermicturition interval and increased number of non-voiding contractions at baseline followed by reduced urodynamic responses during active colitis. Contractility of DSM was up-regulated in response to KCl in TRPV1−/− mice with inflamed colon. Application of Rho-kinase inhibitor caused relaxation of DSM in WT but not in TRPV1−/− mice during colonic inflammation. TRPV1−/− mice demonstrated blunted effects of TNBS-induced colitis on expression and function of voltage-gated sodium channels in bladder sensory neurons, and delayed development of abdominal hypersensitivity upon colon-bladder cross-talk in genetically modified animals.

Conclusions

The lack of TRPV1 receptors does not eliminate the development of cross-sensitization in the pelvis. However, the function of the urinary bladder significantly differs between WT and TRPV−/− mice especially upon development of colon-bladder cross-sensitization induced by transient colitis. Our results suggest that TRPV1 pathways may participate in the development of chronic pelvic pain co-morbidities in humans.
Molecular cloning and expression analysis of peptidase genes in the fish-pathogenic scuticociliate Miamiensis avidus
Authors: Seo Jung Soo , Jeon Eun Ji , Jung Sung Hee , Park Myoung Ae , Kim Jin Woo , Kim Ki Hong , Woo Sung Ho , Lee Eun Hye
Published: January 2013

Background

Parasite peptidases have been actively studied as vaccine candidates or drug targets for prevention or treatment of parasitic diseases because of their important roles for survival and/or invasion in the host. Like other parasites, the facultative histophagous ciliate Miamiensis avidus would possess peptidases that are closely associated with the invasion into the host tissue and survival in the host.

Results

The 17 genes encoding peptidases, including seven cathepsin-like cysteine peptidases, four serine carboxypeptidases, a eukaryotic aspartyl protease family protein, an ATP-dependent metalloprotease FtsH family protein, three leishmanolysin family proteins and a peptidase family M49 protein were identified from a Miamiensis avidus cDNA library by BLAST X search. Expression of genes encoding two cysteine peptidases, three leishmanolysin-like peptidases and a peptidase family M49 protein was up-regulated in the cell-fed ciliates compared to the starved ciliates. Especially, one cysteine peptidase (MaPro 4) and one leishmanolysin-like peptidase (MaPro 14) were transcribed more than 100-folds in the cell-fed ciliates.

Conclusions

The genetic information and transcriptional characteristics of the peptidases in the present results would be helpful to elucidate the role of peptidases in the invasion of scuticociliates into their hosts.
Effect of engineered TiO2and ZnO nanoparticles on erythrocytes, platelet-rich plasma and giant unilamelar phospholipid vesicles
Authors: Šimundić Metka , Drašler Barbara , Šuštar Vid , Zupanc Jernej , Štukelj Roman , Makovec Darko , Erdogmus Deniz , Hägerstrand Henry , Drobne Damjana , Kralj-Iglič Veronika
Published: January 2013

Background

Massive industrial production of engineered nanoparticles poses questions about health risks to living beings. In order to understand the underlying mechanisms, we studied the effects of TiO2 and ZnO agglomerated engineered nanoparticles (EPs) on erythrocytes, platelet-rich plasma and on suspensions of giant unilamelar phospholipid vesicles.

Results

Washed erythrocytes, platelet-rich plasma and suspensions of giant unilamelar phospholipid vesicles were incubated with samples of EPs. These samples were observed by different microscopic techniques. We found that TiO2 and ZnO EPs adhered to the membrane of washed human and canine erythrocytes. TiO2 and ZnO EPs induced coalescence of human erythrocytes. Addition of TiO2 and ZnO EPs to platelet-rich plasma caused activation of human platelets after 24 hours and 3 hours, respectively, while in canine erythrocytes, activation of platelets due to ZnO EPs occurred already after 1 hour. To assess the effect of EPs on a representative sample of giant unilamelar phospholipid vesicles, analysis of the recorded populations was improved by applying the principles of statistical physics. TiO2 EPs did not induce any notable effect on giant unilamelar phospholipid vesicles within 50 minutes of incubation, while ZnO EPs induced a decrease in the number of giant unilamelar phospholipid vesicles that was statistically significant (p < 0,001) already after 20 minutes of incubation.

Conclusions

These results indicate that TiO2 and ZnO EPs cause erythrocyte aggregation and could be potentially prothrombogenic, while ZnO could also cause membrane rupture.
MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma
Authors: Sarver Aaron L , Thayanithy Venugopal , Scott Milcah C , Cleton-Jansen Anne-Marie , Hogendoorn Pancras CW , Modiano Jaime F , Subramanian Subbaya
Published: January 2013

Background

Deregulation of microRNA (miRNA) transcript levels has been observed in many types of tumors including osteosarcoma. Molecular pathways regulated by differentially expressed miRNAs may contribute to the heterogeneous tumor behaviors observed in naturally occurring cancers. Thus, tumor-associated miRNA expression may provide informative biomarkers for disease outcome and metastatic potential in osteosarcoma patients. We showed previously that clusters of miRNAs at the 14q32 locus are downregulated in human osteosarcoma.

Methods

Human and canine osteosarcoma patient’s samples with clinical follow-up data were used in this study. We used bioinformatics and comparative genomics approaches to identify miRNA based prognostic biomarkers in osteosarcoma. Kaplan-Meier survival curves and Whitney Mann U tests were conducted for validating the statistical significance.

Results

Here we show that an inverse correlation exists between aggressive tumor behavior (increased metastatic potential and accelerated time to death) and the residual expression of 14q32 miRNAs (using miR-382 as a representative of 14q32 miRNAs) in a series of clinically annotated samples from human osteosarcoma patients. We also show a comparable decrease in expression of orthologous 14q32 miRNAs in canine osteosarcoma samples, with conservation of the inverse correlation between aggressive behavior and expression of orthologous miRNA miR-134 and miR-544.

Conclusions

We conclude that downregulation of 14q32 miRNA expression is an evolutionarily conserved mechanism that contributes to the biological behavior of osteosarcoma, and that quantification of representative transcripts from this family, such as miR-382, miR-134, and miR-544, provide prognostic and predictive markers that can assist in the management of patients with this disease.
Discontinuation of alendronate and administration of bone-forming agents after surgical nailing may promote union of atypical femoral fractures in patients on long-term alendronate therapy
Authors: Lin Tsung-Li , Wang Shyu-Jye , Fong Yi-Chin , Hsu Chin-Jung , Hsu Horng-Chaung , Tsai Chun-Hao
Published: January 2013

Background

Long-term alendronate therapy may lead to atypical femoral fractures in a very few patients. However, the management protocol to optimize fracture healing remains undetermined. The purpose of this study was to describe the time to union of atypical femoral fractures after surgical nailing in patients on long-term alendronate therapy, with continuation of alendronate or discontinuation of alendronate, and administration of bone-forming agents.

Findings

From January 2004 to December 2011, the records of patients at our institution on long-term alendronate therapy for more than 36 months and sustaining atypical femoral fractures that had undergone surgical nailing, with continuation of alendronate or discontinuation of alendronate and administration of bone-forming agents were reviewed.

During the 8-year study period, we treated 10 atypical femoral fractures with surgical nailing in 7 consecutive osteopenic or osteoporotic patients on long-term alendronate therapy for more than 36 months. There were no post-operative complications or needs for revision surgery. All fractures achieved union during follow-up. Mean union time was 23.5 months (range, 18–31 months) for 6 fractures with continuation of alendronate after surgery, and 4.5 months (range, 4–5 months) for 4 fractures with discontinuation of alendronate and administration of bone-forming agents after surgery.

Conclusions

Discontinuation of alendronate and administration of bone-forming agents after surgical nailing may promote union of atypical femoral fractures in patients on long-term alendronate therapy.
Statin use and ocular inflammatory disease risk
Authors: Yunker Jacob J , McGwin Gerald , Read Russell W
Published: January 2013

Background

This study aims to evaluate the effect of oral statin medication use on the subsequent development of ocular inflammatory disease (OID). A retrospective nested case–control study was carried out on patient records from the Birmingham Veterans Affairs Medical Center. All male patients with a new diagnosis of OID over a 5-year period were included. Ten control subjects (without OID) were age-matched to each OID case. Prescription files of all subjects were queried for statin use. Information on selected comorbid medical conditions was also obtained. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of OID development in the context of statin use, controlling for comorbid conditions.

Results

Ninety-two incident cases of OID were identified. A trend toward a reduction in the risk of new OID development was found in patients that used statins compared to those that did not (OR 0.50, 95% CI 0.20 to 1.23, p = 0.13). The longer the duration of statin use, the greater is the effect.

Conclusions

Use of oral statins may be associated with a reduced risk for the development of OID. This reduced risk increases with increasing duration of use. Larger clinical studies would be required to definitively establish the effectiveness of statins in lowering the incidence of OID.
PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease
Authors: Qu Zhaoxia , Fu Jing , Ma Huihui , Zhou Jingjiao , Jin Meihua , Mapara Markus Y , Grusby Michael J , Xiao Gutian
Published: January 2013

Background

PDLIM2 is essential for the termination of the inflammatory transcription factors NF-κB and STAT but is dispensable for the development of immune cells and immune tissues/organs. Currently, it remains unknown whether and how PDLIM2 is involved in physiologic and pathogenic processes.

Results

Here we report that naive PDLIM2 deficient CD4+ T cells were prone to differentiate into Th1 and Th17 cells. PDLIM2 deficiency, however, had no obvious effect on lineage commitment towards Th2 or Treg cells. Notably, PDLIM2 deficient mice exhibited increased susceptibility to experimental autoimmune encephalitis (EAE), a Th1 and/or Th17 cell-mediated inflammatory disease model of multiple sclerosis (MS). Mechanistic studies further indicate that PDLIM2 was required for restricting expression of Th1 and Th17 cytokines, which was in accordance with the role of PDLIM2 in the termination of NF-κB and STAT activation.

Conclusion

These findings suggest that PDLIM2 is a key modulator of T-cell-mediated immune responses that may be targeted for the therapy of human autoimmune diseases.
Glibenclamide inhibits cell growth by inducing G0/G1 arrest in the human breast cancer cell line MDA-MB-231
Authors: Núñez Mariel , Medina Vanina , Cricco Graciela , Croci Máximo , Cocca Claudia , Rivera Elena , Bergoc Rosa , Martín Gabriela
Published: January 2013

Background

Glibenclamide (Gli) binds to the sulphonylurea receptor (SUR) that is a regulatory subunit of ATP-sensitive potassium channels (KATP channels). Binding of Gli to SUR produces the closure of KATP channels and the inhibition of their activity. This drug is widely used for treatment of type 2-diabetes and it has been signaled as antiproliferative in several tumor cell lines. In previous experiments we demonstrated the antitumoral effect of Gli in mammary tumors induced in rats. The aim of the present work was to investigate the effect of Gli on MDA-MB-231 breast cancer cell proliferation and to examine the possible pathways involved in this action.

Results

The mRNA expression of the different subunits that compose the KATP channels was evaluated in MDA-MB-231 cells by reverse transcriptase-polymerase chain reaction. Results showed the expression of mRNA for both pore-forming isoforms Kir6.1 and Kir6.2 and for the regulatory isoform SUR2B in this cell line. Gli inhibited cell proliferation assessed by a clonogenic method in a dose dependent manner, with an increment in the population doubling time. The KATP channel opener minoxidil increased clonogenic proliferation, effect that was counteracted by Gli. When cell cycle analysis was performed by flow cytometry, Gli induced a significant cell-cycle arrest in G0/G1 phase, together with an up-regulation of p27 levels and a diminution in cyclin E expression, both evaluated by immunoblot. However, neither differentiation evaluated by neutral lipid accumulation nor apoptosis assessed by different methodologies were detected. The cytostatic, non toxic effect on cell proliferation was confirmed by removal of the drug.

Combination treatment of Gli with tamoxifen or doxorubicin showed an increment in the antiproliferative effect only for doxorubicin.

Conclusions

Our data clearly demonstrated a cytostatic effect of Gli in MDA-MB-231 cells that may be mediated through KATP channels, associated to the inhibition of the G1-S phase progression. In addition, an interesting observation about the effect of the combination of Gli with doxorubicin leads to future research for a potential novel role for Gli as an adjuvant in breast cancer treatment
Mitigation of salt stress in wheat seedlings by halotolerant bacteria isolated from saline habitats
Authors: Ramadoss Dhanushkodi , Lakkineni Vithal K , Bose Pranita , Ali Sajad , Annapurna Kannepalli
Published: January 2013

Eighty four halotolerant bacterial strains were isolated from the saline habitats and screened for growth at different NaCl concentrations. All grew well at 5% NaCl, but only 25% isolates showed growth at 20% NaCl concentration. Five strains SL3, SL32, SL35, J8W and PU62 growing well in 20% NaCl concentrations were further characterized for multiple plant growth promoting traits such as indole −3- acetic acid (IAA) production, HCN and siderophore production, ACC deaminase activity and P-solubilization. None were positive for HCN production and PCR amplification of acd S, the structural gene for ACC deaminase enzyme was found negative. 16S rRNA gene sequencing analysis of the five strains showed them to belong to two genera Bacillus and Hallobacillus. In vitro experiments showed that salt concentrations had significant inhibitory effects on development of seedlings but not on the growth of the bacterial strains. Inoculation of the 5 halotolerant bacterial strains to ameliorate salt stress (80 mM, 160 mM and 320 mM) in wheat seedlings produced an increase in root length of 71.7% in comparison with uninoculated positive controls. In particular, Hallobacillus sp. SL3 and Bacillus halodenitrificans PU62 showed more than 90% increase in root elongation and 17.4% increase in dry weight when compared to uninoculated wheat seedlings at 320 mM NaCl stress indicating a significant reduction of the deleterious effects of NaCl. These results indicate that halotolerant bacteria isolated from saline environments have potential to enhance plant growth under saline stress through direct or indirect mechanisms and would be most appropriate as bioinoculants under such conditions.
Identification and bioactive potential of endophytic fungi isolated from selected plants of the Western Himalayas
Authors: Qadri Masroor , Johri Sarojini , Shah Bhahwal A , Khajuria Anamika , Sidiq Tabasum , Lattoo Surrinder K , Abdin Malik Z , Riyaz-Ul-Hassan Syed
Published: January 2013

This study was conducted to characterize and explore the endophytic fungi of selected plants from the Western Himalayas for their bioactive potential. A total of 72 strains of endophytic fungi were isolated and characterized morphologically as well as on the basis of ITS1-5.8S-ITS2 ribosomal gene sequence acquisition and analyses. The fungi represented 27 genera of which two belonged to Basidiomycota, each representing a single isolate, while the rest of the isolates comprised of Ascomycetous fungi. Among the isolated strains, ten isolates could not be assigned to a genus as they displayed a maximum sequence similarity of 95% or less with taxonomically characterized organisms. Among the host plants, the conifers, Cedrus deodara, Pinus roxburgii and Abies pindrow harbored the most diverse fungi, belonging to 13 different genera, which represented almost half of the total genera isolated. Several extracts prepared from the fermented broth of these fungi demonstrated strong bioactivity against E. coli and S. aureus with the lowest IC50 of 18 μg/ml obtained with the extract of Trichophaea abundans inhabiting Pinus sp. In comparison, extracts from only three endophytes were significantly inhibitory to Candida albicans, an important fungal pathogen. Further, 24 endophytes inhibited three or more phytopathogens by at least 50% in co-culture, among a panel of seven test organisms. Extracts from 17 fungi possessed immuno-modulatory activities with five of them showing significant immune suppression as demonstrated by the in vitro lymphocyte proliferation assay. This study is an important step towards tapping the endophytic fungal diversity from the Western Himalayas and assessing their bioactive potential. Further studies on the selected endophytes may lead to the isolation of novel natural products for use in medicine, industry and agriculture.
A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal
Authors: Kerebel Delphine , Joly Luc-Marie , Honnart Didier , Schmidt Jeannot , Galanaud Damien , Negrier Claude , Kursten Friedrich , Coriat Pierre ,   Lex206 Investigator Group
Published: January 2013

Introduction

Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.

Methods

We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).

Results

A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.

Conclusions

Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.

Trial registration

Eudra CT number 2007-000602-73.
Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1
Authors: Nies Anne T , Niemi Mikko , Burk Oliver , Winter Stefan , Zanger Ulrich M , Stieger Bruno , Schwab Matthias , Schaeffeler Elke
Published: January 2013

Background

Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates.

Methods

Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin (n = 82).

Results

Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing (P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression.

Conclusions

Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.
Calorie-Restricted Weight Loss Reverses High-Fat Diet-Induced Ghrelin Resistance, Which Contributes to Rebound Weight Gain in a Ghrelin-Dependent Manner
Authors: Briggs Dana I. , Lockie Sarah H. , Wu Qunli , Lemus Moyra B. , Stark Romana , Andrews Zane B.
Published: January 2013

Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat–fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.
Development of the γ-amino butyric acid (GABA)-ergic signaling system and its role in larval swimming in sea urchin
Authors: Katow Hideki , Abe Kouki , Katow Tomoko , Zamani Alemeh , Abe Hirokazu
Published: January 2013

The present study aimed to elucidate the development and γ-amino butyric acid (GABA)-ergic regulation of larval swimming in the sea urchin Hemicentrotus pulcherrimus by cloning, namely, glutamate decarboxylase (Hp-gad), the GABAA receptor (Hp-gabrA), and GABAA receptor-associated protein (Hp-gabarap), and by performing immunohistochemistry. The regulation of larval swimming was increasingly dependent on the GABAergic system, which was active from the 2-day-post-fertilization (dpf) pluteus stage onwards. GABA-immunoreactive cells were detected as a subpopulation of secondary mesenchyme cells during gastrulation and eventually constituted the ciliary band and a subpopulation of blastocoelar cells during the pluteus stage. Hp-gad transcription was detected by reverse transcription-polymerase chain reaction during the period when Hp-Gad-positive cells were seen as a subpopulation of blastocoelar cells and on the apical side of the ciliary band from the 2-dpf pluteus stage. Consistent with these observations, inhibition of GAD with 3-mercaptopropioninc acid inhibited GABA-immunoreactivity and larval swimming dose dependently. Hp-gabrA amplimers were detected weakly in unfertilized eggs and 4-dpf plutei, but strongly from fertilized eggs to 2-dpf plutei, and Hp-GabrA, together with GABA, was localized at the ciliary band in association with dopamine receptor D1 from the 2-arm pluteus stage. Hp-gabarap transcription and protein expression were detected from the swimming blastula stage. GABAA receptor inhibition by bicuculline inhibited larval swimming dose dependently. Inhibition of larval swimming by either 3-mercaptopropionic acid or bicuculline was more severe in older larvae (17-dpf and 34-dpf plutei) than in younger ones (1-dpf prism larvae).
The invisible cues that guide king penguin chicks home. The use of magnetic and acoustic cues during orientation and short-range navigation
Authors: Nesterova Anna P. , Chiffard Jules , Couchoux Charline , Bonadonna Francesco
Published: January 2013

King penguins (Aptenodytes patagonicus) live in large and densely populated colonies, where navigation can be challenging due to the presence of many conspecifics that could obstruct locally available cues. Our previous experiments demonstrated that visual cues were important but not essential for king penguin chicks' homing. The main objective of this study was to investigate the importance of non-visual cues, such as magnetic and acoustic cues, for chicks' orientation and short-range navigation. In a series of experiments, the chicks were individually displaced from the colony to an experimental arena where they were released under different conditions. In the magnetic experiments, a strong magnet was attached to the chicks' heads. Trials were conducted in daylight and at night to test the relative importance of visual and magnetic cues. Our results showed that when the geomagnetic field around chicks was modified, their orientation in the arena and the overall ability to home was not affected. In the low sound experiment we limited the acoustic cues available to the chicks by putting ear pads over their ears, and in the loud sound experiment we provided additional acoustic cues by broadcasting colony sounds on the opposite side of the arena to the real colony. In the low sound experiment, the behavior of the chicks was not affected by the limited sound input. In the loud sound experiment, the chicks reacted strongly to the colony sound. These results suggest that king penguin chicks may use the sound of the colony while orienting towards their home.
Negative gravitactic behavior ofCaenorhabditis japonicadauer larvae
Authors: Okumura Etsuko , Tanaka Ryusei , Yoshiga Toyoshi
Published: January 2013

Gravity on Earth is a constant stimulus and many organisms are able to perceive and respond to it. However, there is no clear evidence that nematodes respond to gravity. In this study, we demonstrated negative gravitaxis in a nematode using dauer larvae (DL) of Caenorhabditis japonica and form an association with their carrier insect. C. japonica DL demonstrating nictation, a typical host-finding behavior, had a negative gravitactic behavior, whereas non-nictating C. japonica and C. elegans DL did not. The negative gravitactic index of nictating DL collected from younger nematode cultures was higher than that from older cultures. A 24-h incubation of nictating DL in M9 buffer did not alter their negative gravitactic behavior but a longer incubation resulted in less pronounced negative gravitaxis. These results are indicative of negative gravitaxis in nictating C. japonica DL, which is maintained once initiated, seems to be affected by the age of DL, and does not appear to be a simple passive mechanism.
Rapid mitochondrial adjustments in response to short-term hypoxia and re-oxygenation in the Pacific oysterCrassostrea gigas
Authors: Sussarellu Rossana , Dudognon Tony , Fabioux Caroline , Soudant Philippe , Moraga Dario , Kraffe Edouard
Published: January 2013

As oxygen concentrations in marine coastal habitats can fluctuate rapidly and drastically, sessile marine organisms like the oyster Crassostrea gigas can experience marked and rapid oxygen variations. In this study, we investigated the responses of oyster gill mitochondria to short-term hypoxia (3 h and 12 h, at 1.7 mg O2 L-1) and subsequent re-oxygenation. Mitochondrial respiratory rates (state 3 and 4 stimulated by glutamate), phosphorylation efficiency (RCR ratio and ADP/O) were measured. Cytochrome c oxidase activity (CCO) and cytochrome concentrations (a, b, c1, c) were measured to investigate the rearrangements of respiratory chain subunits. The potential implication of an alternative oxidase (AOX) was investigated using an inhibitor of the respiratory chain (antimycin A) and through gene expression analysis in gills and digestive gland. Results indicate a down regulation of mitochondrial capacity, with 60% inhibition of respiratory rates after 12 h of hypoxia. RCR ratio remained stable, while ADP/O increased after 12 h of hypoxia and 1 h of re-oxygenation, suggesting increased phosphorylation efficiency. CCO showed a fast and remarkable increase of its catalytic activity only after 3 h of hypoxia. AOX mRNA levels showed similar patterns in gill and digestive gland, and were up regulated after 12 and 24 h of hypoxia and during re-oxygenation. Results suggest a set of controls in regulating mitochondrial functions in response to oxygen fluctuations and demonstrate the fast and extreme plasticity of oyster mitochondria in response to oxygen variations.
Konstanz und Dynamik
Authors: Klauser Hella
Published: January 2013

Vom 12.–15. September 2012 fand in Konstanz der Schweizer Bibliothekskongress BIS (Bibliothek Information Schweiz) 2012 statt. ‚Konstanz und Dynamik – Konstanz versus Dynamik?‘ lautete das Thema, und Bibliotheken und Politik, Informationskompetenz, Vernetzung und Elending wurden in diesem Spannungsfeld diskutiert. Auch um die Zukunft der Bibliotheken ging es. Die Notwendigkeit einer nationalen Gesamtstrategie für die Bibliotheken in der Schweiz wurde bestätigt, verschiedene Sprachräume und die Autonomie der 26 Kantone und Gemeinden bieten keine einfachen Voraussetzungen dazu.