bluuebunny/crossref_metadata_2025 huggingface dataset:
Coexpression analysis of large cancer datasets provides insight into the cellular phenotypes of the tumour microenvironment
Authors: Doig Tamasin N , Hume David A , Theocharidis Thanasis , Goodlad John R , Gregory Christopher D , Freeman Tom C
Published: July 2013

Background

Biopsies taken from individual tumours exhibit extensive differences in their cellular composition due to the inherent heterogeneity of cancers and vagaries of sample collection. As a result genes expressed in specific cell types, or associated with certain biological processes are detected at widely variable levels across samples in transcriptomic analyses. This heterogeneity also means that the level of expression of genes expressed specifically in a given cell type or process, will vary in line with the number of those cells within samples or activity of the pathway, and will therefore be correlated in their expression.

Results

Using a novel 3D network-based approach we have analysed six large human cancer microarray datasets derived from more than 1,000 individuals. Based upon this analysis, and without needing to isolate the individual cells, we have defined a broad spectrum of cell-type and pathway-specific gene signatures present in cancer expression data which were also found to be largely conserved in a number of independent datasets.

Conclusions

The conserved signature of the tumour-associated macrophage is shown to be largely-independent of tumour cell type. All stromal cell signatures have some degree of correlation with each other, since they must all be inversely correlated with the tumour component. However, viewed in the context of established tumours, the interactions between stromal components appear to be multifactorial given the level of one component e.g. vasculature, does not correlate tightly with another, such as the macrophage.
Analysis and annotation of the hexaploid oat seed transcriptome
Authors: Gutierrez-Gonzalez Juan J , Tu Zheng Jin , Garvin David F
Published: July 2013

Background

Next generation sequencing provides new opportunities to explore transcriptomes. However, challenges remain for accurate differentiation of homoeoalleles and paralogs, particularly in polyploid organisms with no supporting genome sequence. In this study, RNA-Seq was employed to generate and characterize the first gene expression atlas for hexaploid oat.

Results

The software packages Trinity and Oases were used to produce a transcript assembly from nearly 134 million 100-bp paired-end reads from developing oat seeds. Based on the quality-parameters employed, Oases assemblies were superior. The Oases67-kmer assembly, denoteddnOST (de novoOat Seed Transcriptome), is over 55 million nucleotides in length and the average transcript length is 1,043 nucleotides. The 74.8× sequencing depth was adequate to differentiate a large proportion of putative homoeoalleles and paralogs. To assess the robustness ofdnOST, we successfully identified gene transcripts associated with the biosynthetic pathways of three compounds with health-promoting properties (avenanthramides, tocols, β-glucans), and quantified their expression.

Conclusions

To our knowledge, this study provides the first direct performance comparison between two major assemblers in a polyploid organism. The workflow we developed provides a useful guide for comparable analyses in other organisms. The transcript assembly developed here is a major advance. It expands the number of oat ESTs 3-fold, and constitutes the first comprehensive transcriptome study in oat. This resource will be a useful new tool both for analysis of genes relevant to nutritional enhancement of oat, and for improvement of this crop in general.
Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease
Authors: Cheng Jing , Kalliomäki Marko , Heilig Hans GHJ , Palva Airi , Lähteenoja Hannu , de Vos Willem M , Salojärvi Jarkko , Satokari Reetta
Published: July 2013

Background

Celiac disease (CD) is an autoimmune disorder of the small intestine which is triggered by dietary gluten in genetically predisposed (HLA-DQ2/DQ8 positive) individuals. Only a fraction of HLA-DQ2/DQ8 positive individuals develop CD indicating that other factors have a role in the disorder. Several studies have addressed intestinal microbiota aberrancies in pediatric CD, but the results are inconsistent. Previously, we demonstrated that pediatric CD patients have lower duodenal expression of TLR2 and higher expression of TLR9 as compared to healthy controls (HC) indicating that microbiota may have a role in CD.

Methods

We used bacterial phylogenetic microarray to comprehensively profile the microbiota in duodenal biopsies of CD (n = 10) and HC (n = 9) children. The expression of selected mucosa-associated genes was assessed by qRT-PCR in CD and HC children and in treated CD adults (T-CD, n = 6) on gluten free diet.

Results

The overall composition, diversity and the estimated microbe associated molecular pattern (MAMP) content of microbiota were comparable between CD and HC, but a sub-population profile comprising eight genus-like bacterial groups was found to differ significantly between HC and CD. In HC, increased TLR2 expression was positively correlated with the expression of tight junction protein ZO-1. In CD and T-CD, the expression of IL-10, IFN-g and CXCR6 were higher as co5mpared to HC.

Conclusions

The results suggest that microbiota and altered expression of mucosal receptors have a role in CD. In CD subjects, the increased expression of IL-10 and IFN-g may have partly resulted from the increased TLR9 expression and signaling.
Comparison between bacteremia caused by carbapenem resistant Acinetobacter baumannii and Acinetobacter nosocomialis
Authors: Yang Ya-Sung , Lee Yi-Tzu , Tsai Wen-Chiuan , Kuo Shu-Chen , Sun Jun-Ren , Yang Chin-Hsuan , Chen Te-Li , Lin Jung-Chung , Fung Chang-Phone , Chang Feng-Yee
Published: July 2013

Background

It is unknown whether there are differences between bacteremia caused by carbapenem resistant Acinetobacter baumannii (CRAB) and carbapenem resistant Acinetobacter nosocomialis (CRAN). This study aims to investigate the differences, especially in clinical outcomes, between patients with bacteremia caused by CRAB or CRAN.

Methods

This is a 9-year retrospective study comparing the clinical manifestations, antimicrobial susceptibilities, and clinical outcomes of 71 patients with CRAB bacteremia and 64 patients with CRAN bacteremia.

Results

Patients with CRAB were more likely to have hematologic malignancies and presented with more shock episodes than those with CRAN. CRAB isolates were more resistant to various classes of antimicrobials except colistin, and therefore the patients with CRAB bacteremia were more likely to receive inappropriate antimicrobial therapies. The 14-day mortality was significantly higher in patients with CRAB (40.8% vs. 14.1%; p = 0.001), and in this study, acquisition of CRAB was identified as an independent risk factor for mortality (odds ratio = 4.003; 95% confidence interval = 1.566-10.231; p = 0.004).

Conclusions

CRAB and CRAN bacteremia are different in clinical characteristics, antimicrobial susceptibilities, and mortality rates. Genomic species identification should be performed in the study of carbapenem resistant Acinetobacters to better delineate the role of different species.
Adverse events during the titration phase of interferon-beta in remitting-relapsing multiple sclerosis are not predicted by body mass index nor by pharmacodynamic biomarkers
Authors: Muñoz Delicias , Escartín Antonio , Dapena Dolores , Coret Francisco , Fernández-Uría Dionisio , Pérez Domingo , Casanova Bonaventura , Guijarro-Castro Cristina , Munteis Elvira , del-Campo Amigo María , Pego Robustiano , Calles Carmen , García-Rey César , Monsalve Nuria , Sánchez-Matienzo David
Published: July 2013

Background

This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN β-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naïve to IFN β.

Methods

Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese.

Results

Biomarkers steadily increased during all study period by 45.3% for β2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration.

Conclusions

BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either.
Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies – results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers
Authors: Wan Shaogui , Lai Yinzhi , Myers Ronald E , Li Bingshan , Palazzo Juan P , Burkart Ashlie L , Chen Guokai , Xing Jinliang , Yang Hushan
Published: July 2013

Background

Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.

Methods

We identified 6675 patients with a diagnosis of primary lung, breast, colorectal, or liver cancer who visited the Kimmel Cancer Center at the Thomas Jefferson University from 1998 to 2011. All patients had at least two Hb measurements within the first six months after diagnosis. We analyzed the main, dose-dependent, and time-dependent effects of Hb changes on patient survival.

Results

Compared to patients with a low Hb change (|∆Hb|≤2.6), those having a |∆Hb|>2.6 exhibited a significantly shorter survival (hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5 × 10-22, P
log rank=1.6 × 10-39). This association remained significant across the four cancer types. Bootstrap resampling validated these findings 100% of the time with P<0.01 in all patients and in patients of individual cancers. The association exhibited an apparent U-shape dose-dependent pattern. Time-dependent modeling demonstrated that the effect of Hb change on the survival of the overall patient population persisted for approximately 4.5 years after diagnosis.

Conclusion

Post-diagnosis Hb change associates with the survival of multiple cancers and may have clinical values in tailoring anti-anemia treatments. Because Hb level is frequently measured during cancer treatment, Hb changes may be a potentially important variable in building cancer prognosis models.
Altered cardiac autonomic nervous function in depression
Authors: Wang Yiming , Zhao Xun , O'Neil Adrienne , Turner Alyna , Liu Xingde , Berk Michael
Published: July 2013

Background

Depression is an independent risk factor for coronary artery disease. Autonomic instability may play a mediating or moderating role in this relationship; however this is not well understood. The objective of this study was to explore cardiac autonomic function and cardiac arrhythmia in depression, the correlation between depression severity and Heart Rate Variability (HRV) related indices, and the prevalence of arrhythmia.

Methods

Individuals (n = 53) with major depression as assessed by the Diagnostic and Statistical Manual of Mental Disorders, who had a Hamilton Rating Scale for Depression (HAMD) score ≥20 and a Zung Self-Rating Depression Scale score > 53 were compared to 53 healthy individuals, matched for age and gender. Multichannel Electrocardiograph ECG-92C data were collected over 24 hours. Long-term changes in HRV were used to assess the following vagally mediated changes in autonomic tone, expressed as time domain indices: Standard deviation of the NN intervals (SDNN), standard deviation of 5 min averaged NN intervals (SDANN), Root Mean Square of the Successive Differences (RMSSD) and percentage of NN intervals > 50 ms different from preceding interval (pNN50). Pearson’s correlations were conducted to explore the strength of the association between depression severity (using the SDS and HRV related indices, specifically SDNN and low frequency domain / high frequency domain (LF/HF)).

Results

The values of SDNN, SDANN, RMSSD, PNN50 and HF were lower in the depression group compared to the control group (P<.05). The mean value of the LF in the depression group was higher than the in control group (P<.05). Furthermore the ratio of LF/HF was higher among the depression group than the control group (P<.05). A linear relationship was shown to exist between the severity of the depression and HRV indices. In the depression group, the prevalence of arrhythmia was significantly higher than in the control group (P<.05), particularly supraventricular arrhythmias.

Conclusions

Our findings suggest that depression is accompanied by dysfunction of the cardiac autonomic nervous system, and further, that depression severity is linked to severity of this dysfunction. Individuals with depression appear to be susceptible to premature atrial and/or ventricular disease.
Towards the eradication of HPV infection through universal specific vaccination
Authors: Crosignani Piergiorgio , De Stefani Antonella , Fara Gaetano Maria , Isidori Andrea M , Lenzi Andrea , Liverani Carlo Antonio , Lombardi Alberto , Mennini Francesco Saverio , Palu’ Giorgio , Pecorelli Sergio , Peracino Andrea P , Signorelli Carlo , Zuccotti Gian Vincenzo
Published: July 2013

Background

The Human Papillomavirus (HPV) is generally recognized to be the direct cause of cervical cancer. The development of effective anti-HPV vaccines, included in the portfolio of recommended vaccinations for any given community, led to the consolidation in many countries of immunization programs to prevent HPV-related cervical cancers. In recent years, increasing evidence in epidemiology and molecular biology have supported the oncogenic role of HPV in the development of other neoplasm including condylomas and penile, anal, vulvar, vaginal, and oro-pharyngeal cancers. Men play a key role in the paradigm of HPV infection: both as patients and as part of the mechanisms of transmission. Data show they are affected almost as often as women. Moreover, no screening procedures for HPV-related disease prevention are applied in men, who fail to undergo routine medical testing by any medical specialist at all. They also do not benefit from government prevention strategies.

Discussion

A panel of experts convened to focus on scientific, medical, and economic studies, and on the achievements from health organizations’ intervention programs on the matter. One of the goals was to discuss on the critical issues emerging from the ongoing global implementation of HPV vaccination. A second goal was to identify contributions which could overcome the barriers that impede or delay effective vaccination programs whose purpose is to eradicate the HPV infection both in women and men.

The reviewed studies on the natural history of HPV infection and related diseases in women and men, the increasing experience of HPV vaccination in women, the analysis of clinical effectiveness vs economic efficacy of HPV vaccination, are even more supportive of the economic sustainability of vaccination programs both in women and men. Those achievements address increasing and needed attention to the issue of social equity in healthcare for both genders.
Identification of Enolase 1 and Thrombospondin-1 as serum biomarkers in HBV hepatic fibrosis by proteomics
Authors: Zhang Bin , Wang Zi , Deng Bin , Wu Xiaoqiong , Liu Jing , Feng Xueping
Published: July 2013

Hepatic fibrosis is an inevitable process in the progression of chronic HBV infection to hepatic cirrhosis, but its detailed mechanism is still unknown. Clinic serum biomarkers of HBV hepatic cirrhosis were scanned by proteomic methods. We used two-dimensional electrophoresis (2-DE) and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) to separate and identify the proteins which were differentially expressed in the serum of patients with hepatic fibrosis compared to HBV carriers. We identified 27 differentially expressed proteins, of which 19 proteins were up-regulated and 8 proteins were down-regulated in the serum of patients with hepatic fibrosis compared to HBV carriers. The expression level of enolase-1 (α-enolase) was decreased while the level of thrombospondin-1 (TSP-1) increased in the serum of patients with hepatic fibrosis by western blot. Enolase-1 and TSP-1 may be useful as biomarkers for the clinic diagnosis of hepatic fibrosis, but further study is necessary.
DAP12 and CD11b contribute to the microglial-induced death of dopaminergic neurons in vitro but not in vivo in the MPTP mouse model of Parkinson’s disease
Authors: Kinugawa Kiyoka , Monnet Yann , Béchade Catherine , Alvarez-Fischer Daniel , Hirsch Etienne C , Bessis Alain , Hunot Stéphane
Published: July 2013

Background

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons (DN) in the substantia nigra (SN). Several lines of evidence suggest that apoptotic cell death of DN is driven in part by non-cell autonomous mechanisms orchestrated by microglial cell-mediated inflammatory processes. Although the mechanisms and molecular network underlying this deleterious cross-talk between DN and microglial cells remain largely unknown, previous work indicates that, upon DN injury, activation of the β2 integrin subunit CD11b is required for microglia-mediated DN cell death. Interestingly, during brain development, the CD11b integrin is also involved in microglial induction of neuronal apoptosis and has been shown to act in concert with the DAP12 immunoreceptor. Whether such a developmental CD11b/DAP12 pathway could be reactivated in a pathological context such as PD and play a role in microglia-induced DN cell death is a tantalizing hypothesis that we wished to test in this study.

Methods

To test the possibility that DAP12 could be involved in microglia-associated DN injury, we used both in vitro and in vivo toxin-based experimental models of PD recapitulating microglial-mediated non-cell autonomous mechanisms of DN cell death. In vitro, enriched mesencephalic neuronal/microglial co-cultures were exposed to the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) whereas in vivo, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) according to acute or subchronic mode. Mice deficient for DAP12 or CD11b were used to determine the pathological function of the CD11b/DAP12 pathway in our disease models.

Results

Our results show that DAP12 and CD11b partially contribute to microglia-induced DN cell death in vitro. Yet, in vivo, mice deficient for either of these factors develop similar neuropathological alterations as their wild-type counterparts in two different MPTP mouse models of PD.

Conclusion

Overall, our data suggest that DAP12 and CD11b contribute to microglial-induced DN cell death in vitro but not in vivo in the MPTP mouse model of PD. Therefore, the CD11b/DAP12 pathway may not be considered as a promising therapeutic target for PD.
Enhancement of mitochondrial biogenesis with polyphenols: combined effects of resveratrol and equol in human endothelial cells
Authors: Davinelli Sergio , Sapere Nadia , Visentin Manuela , Zella Davide , Scapagnini Giovanni
Published: July 2013

Emerging evidence suggests that combinatorial action of numerous biologically active compounds may be a valuable source in a variety of therapeutic applications. Several nutraceuticals have demonstrated to augment the efficacy of pharmacological approaches or provide physiological benefit to improve age-related decline. Recently, the possibilities of anti-ageing interventions have multiplied also to ameliorate the mitochondrial alterations in ageing-associated diseases. In this report, we approached a novel treatment strategy by combining two bioactive dietary constituents (resveratrol and equol) to determine their effect on mitochondrial function. Taking into account that the biological activities of resveratrol and equol has been observed in a wide range of biological processes, they were selected to examine whether combining them would be more effective to modulate mitochondrial function. In HUVEC cells our results demonstrate that the co-administration of these natural products increased mitochondrial mass and mitochondrial DNA content. Additionally, combined use of both compounds increased SIRT1 enzymatic activity and induced mitochondrial biogenesis factors such as PGC1-α, TFAM and NRF-1. Therefore, identification of this novel synergism may provide a new perspective for future treatments aiming to modulate the mitochondrial activity with implications in maintaining endothelial function which is crucial in the regulation of immune response. Further studies to discover the molecular details of this crosstalk and to identify new combinations of active compounds affecting the mitochondrial function will be extremely beneficial to prevent mitochondrial decline.
How protein targeting to primary plastids via the endomembrane system could have evolved? A new hypothesis based on phylogenetic studies
Authors: Gagat Przemysław , Bodył Andrzej , Mackiewicz Paweł
Published: July 2013

Background

It is commonly assumed that a heterotrophic ancestor of the supergroup Archaeplastida/Plantae engulfed a cyanobacterium that was transformed into a primary plastid; however, it is still unclear how nuclear-encoded proteins initially were imported into the new organelle. Most proteins targeted to primary plastids carry a transit peptide and are transported post-translationally using Toc and Tic translocons. There are, however, several proteins with N-terminal signal peptides that are directed to higher plant plastids in vesicles derived from the endomembrane system (ES). The existence of these proteins inspired a hypothesis that all nuclear-encoded, plastid-targeted proteins initially carried signal peptides and were targeted to the ancestral primary plastid via the host ES.

Results

We present the first phylogenetic analyses ofArabidopsis thalianaα-carbonic anhydrase (CAH1),Oryza sativanucleotide pyrophosphatase/phosphodiesterase (NPP1), and twoO. sativaα-amylases (αAmy3, αAmy7), proteins that are directed to higher plant primary plastids via the ES. We also investigated protein disulfide isomerase (RB60) from the green algaChlamydomonas reinhardtiibecause of its peculiar dual post- and co-translational targeting to both the plastid and ES. Our analyses show that these proteins all are of eukaryotic rather than cyanobacterial origin, and that their non-plastid homologs are equipped with signal peptides responsible for co-translational import into the host ES. Our results indicate that vesicular trafficking of proteins to primary plastids evolved long after the cyanobacterial endosymbiosis (possibly only in higher plants) to permit their glycosylation and/or transport to more than one cellular compartment.

Conclusions

The proteins we analyzed are not relics of ES-mediated protein targeting to the ancestral primary plastid. Available data indicate that Toc- and Tic-based translocation dominated protein import into primary plastids from the beginning. Only a handful of host proteins, which already were targeted through the ES, later were adapted to reach the plastid via the vesicular trafficking. They represent a derived class of higher plant plastid-targeted proteins with an unusual evolutionary history.

Reviewers

This article was reviewed by Prof. William Martin, Dr. Philippe Deschamps (nominated by Dr. Purificacion Lopez-Garcia) and Dr Simonetta Gribaldo.
Fecal shedding of Brachyspira spp. on a farrow-to-finish swine farm with a clinical history of “Brachyspira hampsonii”-associated colitis
Authors: Patterson Amy H , Rubin Joseph E , Fernando Champika , Costa Matheus O , Harding John CS , Hill Janet E
Published: July 2013

Background

Brachyspira associated diarrhea is a re-emerging concern for Canadian swine producers. To identify critical control points for reducing the impact of Brachyspira on production, improved diagnostic tools and a better understanding of the on-farm epidemiology of these pathogens are required. A cross-sectional study was conducted for the detection of Brachyspira on a commercial, two-site, farrow-to-finish pork production unit in Saskatchewan, Canada with a clinical history of mucohaemorrhagic colitis associated with “B. hampsonii”.

Results

Rectal swabs from pigs at all production stages were collected over 13 weeks (n = 866). Two swabs were collected per pig for culture and Gram stain, and for PCR. Ninety-one culture positive samples were detected, with the highest prevalence of Brachyspira shedding in grower pigs (21%). No Brachyspira were detected in pre-weaned piglets. PCR and Gram stain of rectal swabs detected fewer positive samples than culture. The most prevalent species detected was B. murdochii; other species detected included B. pilosicoli, B. innocens, and “Brachyspira hampsonii”. Phylogenetic analysis revealed that several of the isolates, including some strongly beta-haemolytic isolates, might represent novel taxa.

Conclusions

Our results indicate that apparently healthy pigs can be colonized with diverse Brachyspira species, including some potential pathogens, and that frequency of shedding peaks in the grower stage. Difference in the detection rates of Brachyspira amongst culture, Gram stain or PCR on rectal swabs have implications for choice of detection methods and surveillance approaches that may be most effective in Brachyspira control strategies.
Five markers useful for the distinction of canine mammary malignancy
Authors: Pawłowski Karol M , Maciejewski Henryk , Majchrzak Kinga , Dolka Izabella , Mol Jan A , Motyl Tomasz , Król Magdalena
Published: July 2013

Background

Spontaneous canine mammary tumors constitute a serious clinical problem. There are significant differences in survival between cases with different tumor grades. Unfortunately, the distinction between various grades is not clear. A major problem in evaluating canine mammary cancer is identifying those, that are “truly” malignant. That is why the aim of our study was to find the new markers of canine malignancy, which could help to diagnose the most malignant tumors.

Results

Analysis of gene expression profiles of canine mammary carcinoma of various grade of malignancy followed by the boosted tree analysis distinguished a `gene set`. The expression of this gene set (sehrl, zfp37, mipep, relaxin, and magi3) differs significantly in the most malignant tumors at mRNA level as well as at protein level. Despite this `gene set` is very interesting as an additional tool to estimate canine mammary malignancy, it should be validated using higher number of samples.

Conclusions

The proposed gene set can constitute a `malignancy marker` that could help to distinguish the most malignant canine mammary carcinomas. These genes are also interesting as targets for further investigations and therapy. So far, only two of them were linked with the cancer development.
A retrospective study of clinical signs and epidemiology of chronic valve disease in a group of 207 Dachshunds in Poland
Authors: Garncarz Magdalena , Parzeniecka-Jaworska Marta , Jank Michał , Łój Magdalena
Published: July 2013

Background

Chronic mitral valve disease is frequently seen in the Dachshund. Dachshunds (n=207) made up 11.73% of the dogs admitted to the Cardiology Service at the Small Animal Clinic, Warsaw University of Life Sciences, Poland (first visits only).

Results

Of these, 35 dogs had no clinically detectable heart disease while 172 had chronic valve disease with the mitral valve affected most often (130 dogs), both mitral and tricuspid valves infrequently (39 dogs) and rarely the tricuspid valve (3 dogs). Males were affected more frequently than females and the average age of dogs with chronic valve disease was 11.9 years for females and 11.3 years for males. A majority of the diseased Dachshunds were classified as ISACHC 2 (79), followed by ISACHC 1 (60). Most frequent clinical signs noted by owners included coughing, exercise intolerance, dyspnea and tachypnea. Heart murmurs were generally louder with increased disease severity; however there were 20 dogs in the ISACHC 1 group with no audible heart murmurs. The most frequent electrocardiographic abnormalities included an increased P wave and QRS complex duration, increased R wave amplitude and tachycardia. With increased disease severity, echocardiography revealed an increase in heart size. A higher ISACHC class was related to increased heart size (based on echocardiography) and increased percentage of patients exhibiting enlargement of both left atrium and left ventricle (based on radiography).

Conclusions

The Dachshund is often affected by chronic mitral valvular disease with a late onset of associated clinical signs and few cardiac complications.
Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2
Authors: Liu Shu , Hsieh David , Yang Yi-Lin , Xu Zhidong , Peto Csaba , Jablons David M , You Liang
Published: July 2013

Background

Casein kinase 2 (CK2) is involved in various cellular events such as proliferation, apoptosis, and the cell cycle. CK2 overexpression is associated with multiple human cancers and may therefore be a promising target for cancer therapy. To identity novel classes of inhibitors for CK2, we screened a natural product library obtained from National Cancer Institute.

Methods

The quantitative luminescent kinase assay ADP-Glo™ was used to screen CK2 inhibitors from the natural product library. The same assay was used to determine cell-free dose-dependent response of CK2 inhibitors and conduct a kinetic study. Docking was performed to predict the binding patterns of selected CK2 inhibitors. Western blot analysis was used to evaluate Akt phosphorylation specific to CK2 and apoptosis effect. The cell viability assay CellTiter-Glo® was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells.

Results

We identified coumestrol as a novel reversible ATP competitive CK2 inhibitor with an IC50 value of 228 nM. Coumestrol is a plant-derived compound that belongs to the class of phytoestrogens, natural compounds that mimic the biological activity of estrogens. In our study, coumestrol showed high selectivity among 13 kinases. The hydrogen bonds formed between coumestrol and the amino acids in the ATP binding site were first reviewed by a molecular docking study that suggested a possible interaction of coumestrol with the hinge region of ATP site of CK2. In addition, coumestrol inhibited cancer cell growth partially through down-regulation of CK2-specific Akt phosphorylation. Finally, coumestrol exerted strong inhibition effects on the growth of three cancer cell lines.

Conclusion

Our study shows that coumestrol, a novel ATP competitive and cell permeable CK2 inhibitor with submicromolar IC50, had inhibition effects on the growth of three cancer cell lines and may represent a promising class of CK2 inhibitors.
Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments
Authors: Levenga Josien , Krishnamurthy Pavan , Rajamohamedsait Hameetha , Wong Helen , Franke Thomas F , Cain Peter , Sigurdsson Einar M , Hoeffer Charles A
Published: July 2013

Background

Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs.

Results

We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice.

Conclusions

We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies.
High positive end-expiratory pressure: only a dam against oedema formation?
Authors: Protti Alessandro , Andreis Davide T , Iapichino Giacomo E , Monti Massimo , Comini Beatrice , Milesi Marta , Zani Loredana , Gatti Stefano , Lombardi Luciano , Gattinoni Luciano
Published: July 2013

Introduction

Healthy piglets ventilated with no positive end-expiratory pressure (PEEP) and with tidal volume (VT) close to inspiratory capacity (IC) develop fatal pulmonary oedema within 36 h. In contrast, those ventilated with high PEEP and low VT, resulting in the same volume of gas inflated (close to IC), do not. If the real threat to the blood-gas barrier is lung overinflation, then a similar damage will occur with the two settings. If PEEP only hydrostatically counteracts fluid filtration, then its removal will lead to oedema formation, thus revealing the deleterious effects of overinflation.

Methods

Following baseline lung computed tomography (CT), five healthy piglets were ventilated with high PEEP (volume of gas around 75% of IC) and low VT (25% of IC) for 36 h. PEEP was then suddenly zeroed and low VT was maintained for 18 h. Oedema was diagnosed if final lung weight (measured on a balance following autopsy) exceeded the initial one (CT).

Results

Animals were ventilated with PEEP 18 ± 1 cmH2O (volume of gas 875 ± 178 ml, 89 ± 7% of IC) and VT 213 ± 10 ml (22 ± 5% of IC) for the first 36 h, and with no PEEP and VT 213 ± 10 ml for the last 18 h. On average, final lung weight was not higher, and actually it was even lower, than the initial one (284 ± 62 vs. 347 ± 36 g; P = 0.01).

Conclusions

High PEEP (and low VT) do not merely impede fluid extravasation but rather preserve the integrity of the blood-gas barrier in healthy lungs.
Comparison of the predictive performance of the BIG, TRISS, and PS09 score in anadult trauma population derived from multiple international trauma registries
Authors: Brockamp Thomas , Maegele Marc , Gaarder Christine , Goslings J Carel , Cohen Mitchell J , Lefering Rolf , Joosse Pieter , Naess Paal A , Skaga Nils O , Groat Tahnee , Eaglestone Simon , Borgman Matthew A , Spinella Philip C , Schreiber Martin A , Brohi Karim
Published: July 2013

Background

The BIG score (Admission base deficit (B), International normalized ratio (I), andGlasgow Coma Scale (G)) has been shown to predict mortality on admission inpediatric trauma patients. The objective of this study was to assess itsperformance in predicting mortality in an adult trauma population, and to compareit with the existing Trauma and Injury Severity Score (TRISS) and probability ofsurvival (PS09) score.

Materials and methods

A retrospective analysis using data collected between 2005 and 2010 from seventrauma centers and registries in Europe and the United States of America wasperformed. We compared the BIG score with TRISS and PS09 scores in a population ofblunt and penetrating trauma patients. We then assessed the discrimination abilityof all scores via receiver operating characteristic (ROC) curves and compared theexpected mortality rate (precision) of all scores with the observed mortalityrate.

Results

In total, 12,206 datasets were retrieved to validate the BIG score. The mean ISSwas 15 ± 11, and the mean 30-day mortality rate was 4.8%. With an AUROC of0.892 (95% confidence interval (CI): 0.879 to 0.906), the BIG score performed wellin an adult population. TRISS had an area under ROC (AUROC) of 0.922 (0.913 to0.932) and the PS09 score of 0.825 (0.915 to 0.934). On a penetrating-traumapopulation, the BIG score had an AUROC result of 0.920 (0.898 to 0.942) comparedwith the PS09 score (AUROC of 0.921; 0.902 to 0.939) and TRISS (0.929; 0.912 to0.947).

Conclusions

The BIG score is a good predictor of mortality in the adult trauma population. Itperformed well compared with TRISS and the PS09 score, although it hassignificantly less discriminative ability. In a penetrating-trauma population, theBIG score performed better than in a population with blunt trauma. The BIG scorehas the advantage of being available shortly after admission and may be used topredict clinical prognosis or as a research tool to risk stratify trauma patientsinto clinical trials.
High-frequency oscillation and tracheal gas insufflation in patients with severe acute respiratory distress syndrome and traumatic brain injury: an interventional physiological study
Authors: Vrettou Charikleia S , Zakynthinos Spyros G , Malachias Sotirios , Mentzelopoulos Spyros D
Published: July 2013

Introduction

In acute respiratory distress syndrome (ARDS), combined high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) improves gas exchange compared with conventional mechanical ventilation (CMV). We evaluated the effect of HFO-TGI on PaO2/fractional inspired O2 (FiO2) and PaCO2, systemic hemodynamics, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) in patients with traumatic brain injury (TBI) and concurrent severe ARDS.

Methods

We studied 13 TBI/ARDS patients requiring anesthesia, hyperosmolar therapy, and ventilation with moderate-to-high CMV-tidal volumes for ICP control. Patients had PaO2/FiO2 <100 mm Hg at end-expiratory pressure ≥10 cm H2O. Patients received consecutive, daily, 12-hour rescue sessions of HFO-TGI interspersed with 12-hour periods of CMV. HFO-TGI was discontinued when the post-HFO-TGI PaO2/FiO2 exceeded 100 mm Hg for >12 hours. Arterial/central-venous blood gases, hemodynamics, and ICP were recorded before, during (every 4 hours), and after HFO-TGI, and were analyzed by using repeated measures analysis of variance. Respiratory mechanics were assessed before and after HFO-TGI.

Results

Each patient received three to four HFO-TGI sessions (total sessions, n = 43). Pre-HFO-TGI PaO2/FiO2 (mean ± standard deviation (SD): 83.2 ± 15.5 mm Hg) increased on average by approximately 130% to163% during HFO-TGI (P < 0.01) and remained improved by approximately 73% after HFO-TGI (P < 0.01). Pre-HFO-TGI CMV plateau pressure (30.4 ± 4.5 cm H2O) and respiratory compliance (37.8 ± 9.2 ml/cm H2O), respectively, improved on average by approximately 7.5% and 20% after HFO-TGI (P < 0.01 for both). During HFO-TGI, systemic hemodynamics remained unchanged. Transient improvements were observed after 4 hours of HFO-TGI versus pre-HFO-TGI CMV in PaCO2 (37.7 ± 9.9 versus 41.2 ± 10.8 mm Hg; P < 0.01), ICP (17.2 ± 5.4 versus 19.7 ± 5.9 mm Hg; P < 0.05), and CPP (77.2 ± 14.6 versus 71.9 ± 14.8 mm Hg; P < 0.05).

Conclusions

In TBI/ARDS patients, HFO-TGI may improve oxygenation and respiratory mechanics, without adversely affecting PaCO2, hemodynamics, or ICP. These findings support the use of HFO-TGI as a rescue ventilatory strategy in patients with severe TBI and imminent oxygenation failure due to severe ARDS.
REAPR: a universal tool for genome assembly evaluation
Authors: Hunt Martin , Kikuchi Taisei , Sanders Mandy , Newbold Chris , Berriman Matthew , Otto Thomas D
Published: July 2013

Methods to reliably assess the accuracy of genome sequence data are lacking. Currently completeness is only described qualitatively and mis-assemblies are overlooked. Here we present REAPR, a tool that precisely identifies errors in genome assemblies without the need for a reference sequence. We have validated REAPR on complete genomes or de novo assemblies from bacteria, malaria and Caenorhabditis elegans, and demonstrate that 86% and 82% of the human and mouse reference genomes are error-free, respectively. When applied to an ongoing genome project, REAPR provides corrected assembly statistics allowing the quantitative comparison of multiple assemblies. REAPR is available at http://www.sanger.ac.uk/resources/software/reapr/.
Variants in exons and in transcription factors affect gene expression in trans
Authors: Kreimer Anat , Pe'er Itsik
Published: July 2013

Background

In recent years many genetic variants (eSNPs) have been reported as associated with expression of transcripts in trans. However, the causal variants and regulatory mechanisms through which they act remain mostly unknown. In this paper we follow two kinds of usual suspects: SNPs that alter coding regions or transcription factors, identifiable by sequencing data with transcriptional profiles in the same cohort. We show these interpretable genomic regions are enriched for eSNP association signals, thereby naturally defining source-target gene pairs. We map these pairs onto a protein-protein interaction (PPI) network and study their topological properties.

Results

For exonic eSNP sources, we report source-target proximity and high target degree within the PPI network. These pairs are more likely to be co-expressed and the eSNPs tend to have a cis effect, modulating the expression of the source gene. In contrast, transcription factor source-target pairs are not observed to have such properties, but instead a transcription factor source tends to assemble into units of defined functional roles along with its gene targets, and to share with them the same functional cluster of the PPI network.

Conclusions

Our results suggest two modes of trans regulation: transcription factor variation frequently acts via a modular regulation mechanism, with multiple targets that share a function with the transcription factor source. Notwithstanding, exon variation often acts by a local cis effect, delineating shorter paths of interacting proteins across functional clusters of the PPI network.
Subcortical connectivity in dementia with Lewy bodies and Alzheimer's disease
Authors: Kenny Eva R. , O'Brien John T. , Firbank Michael J. , Blamire Andrew M.
Published: July 2013

Background

Resting-state functional magnetic resonance imaging (fMRI) can be used to measure correlations in spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) signal which represent functional connectivity between key brain areas.

Aims

To investigate functional connectivity with regions hypothesised to be differentially affected in dementia with Lewy bodies (DLB) compared with Alzheimer's disease and controls.

Method

Fifteen participants with probable DLB, 16 with probable Alzheimer's disease and 16 controls were scanned in the resting-state using a 3T scanner. The BOLD signal time-series of fluctuations in seed regions were correlated with all other voxels to measure functional connectivity.

Results

Participants with DLB and Alzheimer's disease showed greater caudate and thalamic connectivity compared with controls. Those with DLB showed greater putamen connectivity compared with those with Alzheimer's disease and the controls. No regions showed less connectivity in DLB or Alzheimer's disease v. controls, or in DLB v. Alzheimer's disease.

Conclusions

Altered connectivity in DLB and Alzheimer's disease provides new insights into the neurobiology of these disorders and may aid in earlier diagnosis.
Introduction: Homines Liberi
Authors: Murphy Timothy S.
Published: July 2013

In addition to providing brief summaries of the contributions to the issue, this essay draws a portrait of Antonio Negri as an example of the “free man” defined by Baruch Spinoza in part 4 of his Ethics.
Care and the Common
Authors: Del Re Alisa
Published: July 2013

This essay investigates the present reality of reproduction and the labor it requires. Labor of reproduction, encompassing not only childbearing and rearing but also more generally domestic labor and the care of dependent persons, is usually excluded from political and economic analysis as a result of the separation of private life from public life. In the recent past such labor was sometimes delegated to the state, but today it is increasingly delegated to the labor market. This produces the “wagification” of reproductive labor, which results in large-scale migrations of care workers throughout Europe. Migrant care workers and their nonmigratory families themselves require care, and to provide it “global care chains” are constructed across national boundaries. Such commodification cannot constitute the common of care, which calls instead for a revolutionary solution.
Materials for a Subversive Constitutionalism
Authors: Mattei Ugo
Published: July 2013

Recent judgments of the Italian Constitutional Court and the transformation of the joint-stock company Azienda Risorse Idriche Napoli (ARIN, Naples Water Resource Company) into the public concern Acqua Bene Comune Napoli (Naples Water Common Good) are important examples of how social and political movements of the common can be translated into positive law. The Constitutional Court's judgments establish the priority of the results of popular referenda over parliamentary legislation and the validity of certain forms of “constituent illegality,” such as collective occupation, as allowed forms of political struggle. The conversion of ARIN demonstrates that the privatization of common or public resources, a widespread neoliberal practice, can be reversed by the collective action of the multitude.
Alternative fates of newly formed PrPSc upon prion conversion on the plasma membrane
Authors: Goold R , McKinnon C , Rabbanian S , Collinge J , Schiavo G , Tabrizi SJ
Published: July 2013

Prion diseases are fatal neurodegenerative diseases characterised by the accumulation of misfolded prion protein (PrPSc) in the brain. They are caused by the templated misfolding of normal cellular protein, PrPC, by PrPSc. We have recently generated a unique cell system in which epitope-tagged PrPC competent to produce bona fide PrPSc is expressed in neuroblastoma cells. Using this system we demonstrated that PrPSc forms on the cell surface within minutes of prion exposure. Here, we describe the intracellular trafficking of newly formed PrPSc. After formation in GM1-enriched lipid microdomains at the plasma membrane, PrPSc is rapidly internalised to early endosomes containing transferrin and cholera toxin B subunit. Following endocytosis, PrPSc intracellular trafficking diverges: some is recycled to the plasma membrane via Rab11 labelled recycling endosomes; the remaining PrPSc is subject to retromer-mediated retrograde transport to the Golgi. This pathway leads to lysosomal degradation and we show that this is the dominant PrPSc degradative mechanism in the early stages of prion infection.